Combinatorial Synthesis of Structurally Diverse Triazole-Bridged Flavonoid Dimers and Trimers

Abstract

Flavonoids are a large family of compounds associated with a broad range of biologically useful properties. In recent years, synthetic compounds that contain two flavonoid units linked together have attracted attention in drug discovery and development projects. Numerous flavonoid dimer systems, incorporating a range of monomers attached via different linkers, have been reported to exhibit interesting bioactivities. From a medicinal chemistry perspective, the 1,2,3-triazole ring system has been identified as a particularly attractive linker moiety in dimeric derivatives (owing to several favourable attributes including proven biological relevance and metabolic stability) and triazole-bridged flavonoid dimers possessing anticancer and antimalarial activities have recently been reported. However, there are relatively few examples of libraries of triazole-bridged flavonoid dimers and the diversity of flavonoid subunits present within these is typically limited. Thus, this compound type arguably remains underexplored within drug discovery. Herein, we report a modular strategy for the synthesis of novel and biologically interesting triazole-bridged flavonoid heterodimers and also very rare heterotrimers from readily available starting materials. Application of this strategy has enabled step-efficient and systematic access to a library of structurally diverse compounds of this sort, with a variety of monomer units belonging to six different structural subclasses of flavonoid successfully incorporated.

1. Introduction

Flavonoids are a large family of polyphenolic compounds that represent dietary constituents of importance to good health as well as a potentially important new class of pharmaceutical lead substrates [1,2,3]. There are several subclasses of flavonoids, including aurones, chalcones, coumarins, flavones and isoflavones, which serve as the core structural units of numerous biologically active molecules [4,5,6,7]. In recent years, synthetic compounds that contain two such flavonoid units linked together (so-called flavonoid dimers) have garnered attention from the synthetic and medicinal chemistry communities [8,9,10,11,12,13,14,15,16,17]. The generation of species that integrate two pharmacophoric entities (both homo- and hetero-dimers) is a common strategy in drug discovery [18,19] and numerous flavonoid dimer systems, incorporating a range of monomers linked in a variety of ways, have been reported to exhibit biologically useful properties [8,9,10,11,12,13,14,15,16,17]. From a medicinal chemistry perspective, the 1,2,3-triazole ring system has been identified as a particularly attractive linker moiety owing to various favourable properties including ease of synthesis, proven biological relevance and metabolic stability [11,18,20]; indeed, triazole-bridged flavonoid dimers possessing anticancer [10,11] and antimalarial [11] activities have recently been reported (Figure 1). However, there are relatively few examples of libraries of triazole-bridged flavonoid dimers, and the diversity of flavonoid subunits present within these is typically limited. Thus, the triazole-bridged flavonoid dimer compound type arguably remains underexplored within drug discovery. We were interested in investigating the biological potential of triazole-bridged flavonoid dimers further and so sought access to a more structurally diverse collection of such compounds incorporating a wide range of flavonoid units. In addition, we were also interested in accessing triazole-bridged trimeric derivatives, which are also expected to have interesting biological properties. Though the synthesis of triazole-bridged flavonoid trimers has previously been reported [10], compounds of this sort are very rare and they have received relatively little attention from synthetic and medicinal chemists. Herein, we report the development of a modular strategy for the synthesis of novel triazole-bridged flavonoid heterodimers and heterotrimers. Application of this strategy has enabled concise and systematic access to a library of 46 structurally diverse compounds of this sort (41 dimers and five trimers) from readily available starting materials.

2. Results and Discussion

2.1. Outline of the Synthetic Strategy

Inspired by previous studies on the synthesis of triazole-linked flavonoid libraries [10,11] we envisaged a branching-type strategy to access triazole-bridged flavonoid dimers and trimers, based around the use of iterative copper-catalysed “click”-type alkyne-azide 1,3-dipolar cycloadditions (Scheme 1) [21]. It was anticipated that flavonoid monomer units bearing a terminal alkyne group (“alkyne-flavonoid” building blocks) could be reacted with a range of flavonoid monomer units bearing a terminal azide group (“azido-flavonoid” building blocks) to furnish diverse and novel triazole-bridged flavonoid homo- and hetero-dimers (of the general structure A, Scheme 1). The presence of a free hydroxyl functionality in either monomer unit would allow for post-cyclisation introduction of a terminal alkyne group in the dimers, thus providing the necessary synthetic handle for a further cycloaddition with varied alkyne-flavonoids to furnish structurally diverse triflavonoid derivatives of the general forms B and C (Scheme 1). The presence of additional synthetic handles in any given monomer unit should also allow for further elaboration of the dimers and trimers. Overall, it was anticipated that this modular strategy would enable step-efficient and facile access to a structurally diverse library of triazole-bridged flavonoid dimers and trimers through the use of a variety of different flavonoid building blocks belonging to different flavonoid structural subclasses.

2.2. Building Block Design and Synthesis

In order to facilitate the generation of structural diversity in the final compound collection, building blocks belonging to a variety of flavonoid structural subclasses (chalcone, coumarin, flavone, aurone, flavonol and isoflavone, see Scheme 1) and derivatives thereof were targeted. Structural diversity, including functional group diversity, within building blocks of some subclasses was also sought in order to further increase the overall structural diversity of the final library (as well as providing a means of introducing additional biomolecular-interacting elements into the library compounds, for example, additional bio-relevant heterocyclic motifs and hydrogen-bonding functionalities). Variation in the position of the key alkyne/azide ligation handles around the flavonoid structures was also envisaged as a strategy to further increase library structural diversity, since this would enable access to different structural isomers of any given dimers/trimers. On the basis of synthetic tractability, various alkyne-chalcones, flavones and isoflavones and azido-chalcone, flavonols and flavones were targeted. Hydroxyl-substituted building blocks were also required in order to allow access to trimeric species (as outlined in Scheme 1). Based on predicted synthetic accessibility, the syntheses of a hydroxyl-substituted alkyne-chalcone, alkyne-flavonol, azido-chalcone and azido-flavonol were targeted.

2.2.1. Synthesis of the Alkyne-Flavonoid Building-Blocks

Alkyne-Chalcones

Hydroxyl-substituted alkyne-chalcone 4 was accessed from phenol 1 via a two-step sequence: alkylation with propargyl bromide proceeded smoothly to yield aldehyde 2 and subsequent Claisen-Schmidt aldol reaction with acetophenone 3 yielded the target compound 4 (Scheme 2) [22].

Structurally diverse alkyne-chalcone building blocks 20–26, including chalconoid derivatives incorporating a range of heteroaromatic scaffolds and an unusual ferrocenyl motif, were generated from aldehydes 5–9 respectively by Claisen-Schmidt aldol condensation with various acetophenone derivatives followed by propargylation (Scheme 3).

Alkyne-Flavones

Propargylation of commercially available flavones 27–29 proceeded smoothly to furnish alkyne-flavones 30–32 with the alkyne synthetic handle appended at various positions on the flavone core unit (Scheme 4) [23,24].

Alkyne-Flavonol

The preparation of alkyne-flavonol 36 commenced with the synthesis of chalcone 35 via the Claisen-Schmidt reaction of the alkyne-substituted benzaldehyde 34 with acetophenone 10. Subsequent Algar-Flynn-Oyamada (AFO) oxidation [22] of the chalcone 35 proceeded smoothly to furnish 36 (Scheme 5).

Alkyne-Isoflavones

The preparation of the alkyne-isoflavone building blocks 45 and 46 commenced with the acylation of commercially available substituted phenols 37 and 38 with phenylacetic acids 39 and 40 to afford the deoxybenzoins 41 and 42 [25]. Subsequent cyclization of 41 and 42 in methanesulfonyl chloride afforded the corresponding isoflavones 43 and 44 which then underwent propargylation to yield the desired alkyne-isoflavones 45 and 46 (Scheme 6) [25].

Alkyne-Coumarin

Alkyne-coumarin 48 was synthesised by propargylation of hydroxycoumarin 47 in the presence of anhydrous potassium carbonate (Scheme 7) [11].

Alkyne-Aurone

Alkyne-aurone 56 was prepared from commercially available phloroglucinol 49 (Scheme 8). Condensation with chloroacetonitrile in the presence of ZnCl₂ furnished imine 50 [26]. Subsequent hydrolysis under acidic conditions afforded ketone 51 which was then treated with methanolic sodium methoxide to give hydroxybenzofuranone 52 [26]. Methyl protection of the free hydroxyl groups afforded benzofuranone 53 which was then condensed with 3-hydroxybenzaldehyde 54 under basic conditions to yield hydroxyaurone 55. Subsequent propargylation gave the desired alkyne-aurone 56 in an excellent yield (Scheme 8).

2.2.2. Synthesis of the Azido-Flavonoid Building Blocks

Azido-Coumarin

Azido-coumarin 58 was prepared from readily available hydroxycoumarin 47 by alkylation (to form 57) followed by reaction with sodium azide (Scheme 9) [27].

Azido-Chalcones

Hydroxyl-substituted azido-chalcone 61 was prepared by a three step sequence from phenolic aldehyde 33 (Scheme 10). Reaction with 1,2-dibromoethane generated aldehyde 59 and subsequent nucleophilic substitution with sodium azide produced azide 60 in an excellent yield. Claisen-Schmidt aldol condensation with ketone 10b then yielded the target compound 61 [22]. Alternatively, Claisen-Schmidt aldol condensation of aldehydes 64–66 and 7 with readily-prepared azido-ketone 63 furnished azido-chalcone building blocks 67–70 respectively (Scheme 11) [22].

Azido-Flavonols

Aldehydes 59 and 72 and 73, generated by alkylation of 33, 71 and 1 respectively with 1,2-dibromoethane, were reacted with sodium azide to form 60 and 74 and 75 respectively (Scheme 12). Subsequent aldol condensation with acetophenones 10 or 3 (see Scheme 12) furnished chalcones 61 and 76–78 and AFO proceeded smoothly in all cases to furnish azido-flavonols 79 and 80–82 in good yields [22].

Azido-Flavones

Azido-flavones 85 and 86 were readily accessed from commercially available hydroxyflavones 28 and 29 by reaction with 1,2-dibromoethane to forge 83 and 84 followed by nucleophilic substitution with sodium azide (Scheme 13) [10,28]. Azido-flavone 87 was prepared in an excellent yield from chalcone 76 by an iodine-mediated oxidative cyclization (Scheme 14).

Azido-Aurones

Mercury(II) acetate-mediated oxidative cyclization of chalcones 61 and 76 furnished azido-aurones 88 and 89 respectively in excellent yields (Scheme 15) [29].

2.2.3. Synthesis of Triazole-Bridged Flavonoid Dimers

With the alkyne- and azido-flavonoid building blocks in hand, we were ready to forge a series of dimeric combinations via triazole formation. Thus, various pairs of building blocks were subjected to standard copper-mediated “click” cycloaddition conditions to generate 41 distinct and diverse triazole-bridged flavonoid dimers (compounds 90–130, Scheme 16, Scheme 17, Scheme 18, Scheme 19 and Scheme 20). The reactions generally proceeded smoothly and with high levels of regioselectivity and isolated yields of the target compounds were typically moderate-to-good. Six different biologically-relevant flavonoid structural subclasses (chalcone, flavonol, aurone, flavone, coumarin and isoflavone) were successfully incorporated into the dimer library together with other biologically-relevant features, and variation within building blocks belonging to certain subclasses allowed for the generation of additional structural diversity in the library and the concomitant introduction of additional biomolecule-interacting elements (for example, the varied heterocyclic motifs exhibited by the chalcone-chalcone dimers 90–97). Several compounds also featured groups that could provide synthetic handles for further elaboration or diversification (for example, compounds 96 and 97 and 105 and 106 contain a hydroxyl group and the aryl-bromide group present in 107 and 108 could conceivably be exploited in various metal-catalysed cross-coupling processes).

2.2.4. Synthesis of Triazole-Bridged Flavonoid Trimers

Propargylation of the free phenolic hydroxyl groups of triazole-bridged flavonoid dimers 126, 122, 92 and 110 and 106 led to the formation of alkyne-capped derivatives 131–135 respectively. These were successfully coupled with three azido-flavonoid building blocks (86 for 131 and 132; 87 for 133; and 89 for 134 and 135) via copper-catalysed triazole formation to furnish five structurally diverse triazole-bridged flavonoid trimers 136–140 (Scheme 21).

2.3. Preliminary Biological Screening

A representative sample of 13 final triazole-bridged dimers (90–93, 112–114, 122, 123, 125, 126, 129 and 130) was screened for inhibitory activity against the aggregation of amyloid beta (1–42) (Aβ₄₂), a pathological hallmark of Alzheimer’s disease [30]. Aggregation of the monomeric form of the peptide into oligomeric and fibrillar species is associated with disease onset and progression. As such, the identification of compounds capable of inhibiting the aggregation process holds great potential for the development of therapeutic agents [31]. Flavonoid and chalcone derivatives have previously shown activity in perturbing the aggregation of Aβ, with compounds such as EGCG myricetin and morin displaying inhibitory activity in a variety of biophysical and in vivo tests [32,33,34,35]. It has also been shown that dimeric flavonoids can display enhanced inhibitory activity than their monomeric counterparts [36], suggesting that the libraries synthesised may be effective at targeting this peptide aggregation pathway. The ability of the triazole-linked dimers to inhibit the Aβ₄₂ aggregation was assessed using a thioflavin T (THT) assay (Figure 2). Three of the compounds screened were found to have moderate inhibitory activity, with 92 found to be the most potent and comparable to the inhibitor morin.

It is difficult to draw any firm conclusions at this time regarding structure-activity relationships in the triazole-bridged dimer compound class due to the relatively small sample size and some issues with the solubility and fluorescence behaviour of some compounds under the assay conditions. Nevertheless, this preliminary screen has identified structurally novel Aβ₄₂ aggregation inhibitors which could represent interesting scaffolds for further study in this regard.

3. Materials and Methods

3.1. Chemical Synthesis

3.1.1. General Information

All non-aqueous reactions were performed under a constant stream of dry nitrogen using oven-dried glassware. Standard practices were employed when handling moisture and air-sensitive materials. All reagents and solvents were purchased from commercial sources and used without further purification unless otherwise stated. Room temperature refers to ambient temperature. Temperatures of 0 °C were maintained using an ice-water bath. Petroleum ether was distilled before use. Ethyl acetate and methanol were distilled from calcium hydride. Melting points were measured using a Büchi B545 melting point apparatus and are uncorrected. Thin layer chromatography (TLC) was performed on pre-coated silica gel GF254 plates (Merck, Kenilworth, NJ, USA). Infrared (IR) spectra were recorded on a Spectrum One (FT-IR) spectrophotometer (Perkin-Elmer, Waltham, MA, USA) with internal referencing. Absorption maxima (ν_max) are reported in wavenumbers (cm⁻¹). Flash column chromatography was performed on silica gel (230–400 mesh). ¹H-NMR and ¹³C-NMR were recorded on an Avance 500 MHz instrument (Bruker, Billerica, MA, USA) in CDCl₃ or (CD₃)₂CO. Chemical shifts (δ) are quoted in ppm, to the nearest 0.01 ppm (¹H-NMR) or 0.1 ppm (¹³C-NMR) and are referenced to the residual non-deuterated solvent peak. ¹H-NMR and ¹³C-NMR data for all compounds can be found in Supplementary Materials. LCMS analysis was performed on an ACQUITY H-Class UPLC (Waters, Milford, MA, USA) with an ESCi Multi-Mode Ionisation Waters SQ Detector 2 spectrometer using MassLynx 4.1 software. LC system: solvent A: 2 mM NH₄OAc in H₂O/MeCN (95:5); solvent B: MeCN; solvent C: 2% aqueous formic acid; gradient: 5%–95% B with constant 5% C over 1 min at flow rate of 0.6 mL/min. High resolution mass spectrometry (HRMS) measurements were recorded on a Q-TOF mass spectrometer (Micromass, Cary, NC, USA) or a Waters LCT Premier Time of Flight mass spectrometer. Mass values are quoted within the error limits of ±5 ppm mass units. ESI+ refers to the mass ionisation technique.

3.1.2. General Synthetic Procedures

General Procedure A: Synthesis of Biflavonoid Triazole Hybrids (GP-A). To a stirred solution of alkyne flavonoid (1.0 equiv.) and azide flavonoid (1.0 equiv.) in t-BuOH/H₂O (1:1, 40 mL) were added CuSO₄·5H₂O (1.1 equiv.) and sodium ascorbate (2.5 equiv.). The reaction mixture was stirred at room temperature for 24 h or until TLC analysis indicated complete consumption of starting material. The resulting mixture was poured into H₂O (100 mL) and the aqueous solution was extracted with CHCl₃ (3 × 100 mL). The combined organic layer was washed with H₂O (2 × 100 mL), brine (2 × 100 mL), dried over anhydrous MgSO₄, filtered and the solvent removed under reduced pressure. The crude residue was purified by flash column chromatography over silica and recrystallized from MeOH to afford the corresponding biflavonoid triazole hybrids.

General Procedure B: Synthesis of Alkyne Biflavonoid Triazole Hybrids (GP-B). To a stirred solution of the corresponding biflavonoid triazole hybrid (1.0 equiv.) in dry acetone (50 mL) were added propargyl bromide (3.0 equiv.) and anhydrous K₂CO₃ (3.0 equiv.). The reaction mixture was heated at reflux with stirring for 24 h under a nitrogen atmosphere or until TLC analysis indicated complete consumption of starting material. The resulting mixture was allowed to cool to room temperature and the solvent removed in vacuo. The crude residue was re-suspended in CHCl₃ (50 mL) and the organic layer was washed with H₂O (2 × 100 mL), brine (2 × 100 mL), dried over anhydrous MgSO₄, filtered and evaporated to dryness. The crude residue was purified by flash column chromatography over silica to afford the corresponding propynyloxy biflavonoid triazole hybrid.

General Procedure C: Synthesis of Propynyloxy flavonoids or benzaldehydes (GP-C). To a stirred solution of the corresponding flavonoid or benzaldehyde (1.0 equiv.) in dry acetone (50 mL) were added anhydrous K₂CO₃ (3.0 equiv.) and propargyl bromide (3.0 equiv.). The reaction mixture was heated at reflux with stirring for 24 h under a nitrogen atmosphere or until TLC analysis indicated complete consumption of starting material. The resulting mixture was allowed to cool to room temperature and the solvent removed in vacuo. The crude residue was re-suspended in CHCl₃ (100 mL) and the organic layer was washed with H₂O (2 × 100 mL), brine (2 × 100 mL), dried over anhydrous MgSO₄, filtered and evaporated to dryness. The crude residue was purified by flash column chromatography over silica to afford the corresponding propynyloxy flavonoids or benzaldehydes.

General Procedure D: Synthesis of Chalcones (GP-D). To a stirred solution of KOH (12.0 equiv.) in absolute EtOH (100 mL) cooled to 0 °C in an ice-bath were added dropwise a solution of the corresponding acetophenone (1.0 equiv.) and aldehyde (1.0 equiv.) in EtOH (20 mL). The reaction mixture was stirred at 0 °C for 1 h and then at room temperature for 72 h under a nitrogen atmosphere or until TLC analysis indicated complete consumption of starting material. The resulting mixture was then poured into ice-water (100 mL) and acidified to pH 3–4 with 3 M HCl. The aqueous solution was extracted with CHCl₃ (3 × 100 mL) and the combined organic layer was washed with satd NaHCO₃ (2 × 100 mL), brine (2 × 100 mL), dried over anhydrous MgSO₄, filtered and the solvent removed under reduced pressure. The crude residue was purified by flash column chromatography over silica and/or recrystallized from MeOH or absolute EtOH to afford the corresponding chalcones.

General Procedure E: Synthesis of Indole or Pyrrole 2-hydroxychalcones (GP-E). To a stirred solution of indole or pyrrole aldehyde (1.0 equiv.) and the corresponding 2-hydroxyacetophenone (1.0 equiv.) in absolute EtOH (100 mL) was added piperidine (1.0 equiv.). The reaction mixture was heated at reflux for 24 h under a nitrogen atmosphere or until TLC analysis indicated complete consumption of starting material. The reaction mixture was allowed to cool to room temperature, poured into ice-water (100 mL) and then acidified to pH 3–4 with 3 M HCl. The resulting suspension was filtered and the precipitate washed with ice-water (2 × 100 mL), suction-dried and recrystallized from MeOH to afford the corresponding indole or pyrrole chalcones.

General Procedure F: Synthesis of Flavonols (GP-F). To a stirred solution of the corresponding chalcone (0.30 mmol) in MeOH (20 mL) were added 16% NaOH (aq) (0.60 mL) and 15% H₂O₂ (0.30 mL). The reaction mixture was stirred at room temperature for 24 h under a nitrogen atmosphere or until TLC analysis indicated complete consumption of starting material. The resulting mixture was then poured into ice-water (50 mL) and acidified to pH 3–4 with 3 M HCl. The aqueous solution was extracted with CHCl₃ (3 × 50 mL) and the combined organic layer was washed with satd NaHCO₃ (2 × 50 mL), brine (2 × 50 mL), dried over anhydrous MgSO₄, filtered and the solvent removed under reduced pressure. The crude residue was purified by flash column chromatography over silica to afford the corresponding flavonols.

General Procedure G: Synthesis of Phenylethanones (GP-G). To a stirred solution of substituted phenol (1.2 equiv.) in BF₃·OEt₂ (50 mL) was added the corresponding phenylacetic acid (1.0 equiv.) and the reaction mixture was heated at 80 °C for 8 h under a nitrogen atmosphere. The resulting dark solution was allowed to cool to room temperature and slowly poured into ice-water (100 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layer was washed with satd NaHCO₃ (2 × 100 mL), brine (2 × 100 mL), dried over anhydrous MgSO₄, filtered and evaporated to dryness. The crude residue was purified by flash column chromatography over silica to afford the corresponding phenylethanones.

General Procedure H: Synthesis of Isoflavones (GP-H). To a stirred solution of the corresponding phenylethanone (1.0 equiv.) in dry DMF (15 mL) was carefully added BF₃·OEt₂ (4.0 equiv.) over 10 min under a nitrogen atmosphere. To this mixture, methanesulfonyl chloride (3.0 equiv.) was added at 55 °C, stirred for 1 h and then heated at 80 °C for 24 h. The resulting dark solution was allowed to cool to room temperature and then poured with rapid stirring into ice-water (100 mL). The resulting precipitate was filtered, washed with H₂O (2 × 100 mL), suction-dried and re-dissolved in EtOAc (100 mL). The organic solution was washed with H₂O (2 × 100 mL), brine (2 × 100 mL), dried over anhydrous MgSO₄, filtered and evaporated to dryness. The crude residue was purified by flash column chromatography over silica to afford the corresponding isoflavones.

General Procedure I: Synthesis of Bromoalkylated flavonoids or benzaldehdyes (GP-I). To a stirred solution of the corresponding flavonoid or benzaldehyde (1.0 equiv.) in dry acetone (50 mL) or dry DMF (50 mL) were added anhydrous K₂CO₃ (3.0 equiv.) and 1,2-dibromoethane (3.0 equiv.). The reaction mixture was heated at reflux with stirring for 24 h under a nitrogen atmosphere or until TLC analysis indicated complete consumption of starting material. The resulting mixture was allowed to cool to room temperature and the solvent removed in vacuo. The crude residue was re-suspended in CHCl₃ (100 mL) and the organic layer was washed with H₂O (2 × 100 mL), brine (2 × 100 mL), dried over anhydrous MgSO₄, filtered and evaporated to dryness. The crude residue was purified by flash column chromatography over silica to afford the corresponding bromoalkylated flavonoids or benzaldehydes.

General Procedure J: Synthesis of Azido flavonoids or benzaldehydes (GP-J). To a stirred solution of the corresponding bromoalkylated flavonoids or benzaldehydes (1.0 equiv.) in dry DMF (30 mL) was added NaN₃ (3.0 equiv.). The reaction mixture was heated at 100 °C with stirring for 3 h under a nitrogen atmosphere. The resulting mixture was allowed to cool to room temperature and poured into H₂O (100 mL). The aqueous solution was extracted with CHCl₃ (3 × 100 mL) and the combined organic layer was washed with H₂O (2 × 100 mL), brine (2 × 100 mL), dried over anhydrous MgSO₄, filtered and evaporated to dryness to afford the corresponding azido flavonoids or benzaldehydes and were used without further purification.

General Procedure K: Synthesis of Aurones (GP-K). To a stirred solution of the corresponding chalcone (1.0 equiv.) in pyridine (10 mL) was added Hg(OAc)₂ (1.0 equiv.). The reaction mixture was heated at 110 °C with stirring for 1 h under a nitrogen atmosphere. The resulting mixture was then poured into ice-water (50 mL) and acidified to pH 3–4 with 3 M HCl. The aqueous solution was extracted with CHCl₃ (3 × 50 mL) and the combined organic layer was washed with H₂O (2 × 50 mL), brine (2 × 50 mL), dried over anhydrous MgSO₄, filtered and the solvent removed under reduced pressure. The crude residue was purified by flash column chromatography over silica to afford the corresponding aurones.

3.2. Synthetic Procedures

3.2.1. Building Block Synthesis

4-Methoxy-3-(prop-2-yn-1-yloxy)benzaldehyde (2). A mixture of isovanillin (1, 10.0 g, 65.7 mmol), propargyl bromide (8.78 mL, 98.6 mmol) and anhydrous K₂CO₃ (18.2 g, 131 mmol) in dry acetone (100 mL) was reacted according to GP-C. The crude residue was purified by flash column chromatography (SiO₂, CH₂Cl₂) to afford benzaldehyde 2 (9.23 g, 74%) as a white fluffy solid. m.p. 78–80 °C. TLC R_f = 0.21 (CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3229m (C≡C-H str), 3096w (C-H str), 2839w (C-H str), 2124w (C≡C str), 1671s (C=O str), 1599s (C=C str), 1586s (C=C str), 1508s (C=C str), 1436m, 1407m, 1387m, 1261s, 1229s, 1161s, 1129s, 1012s. ¹H-NMR (500 MHz, CDCl₃): δ 2.55 (1H, t, J = 2.4 Hz, -OCH₂C≡CH), 3.97 (3H, s, -OCH₃), 4.83 (2H, d, J = 2.4 Hz, -OCH₂C≡CH), 7.01 (1H, d, J = 8.0 Hz, ArH), 7.53 (1H, dd, J = 8.0, 1.6 H z, ArH), 7.55 (1H, d, J = 1.6 Hz, ArH), 9.87 (1H, s, CHO). ¹³C-NMR (500 MHz, CDCl₃): δ 56.2, 56.6, 76.4, 77.7, 110.9, 112.0, 127.3, 129.9, 147.3, 154.9, 190.7. LCMS (ES+) m/z = 191.2 ([M + H]⁺, t_R = 3.09 min). These characterisation data are in accordance with that previously reported in the literature [37].

(E)-1-(2-Hydroxy-4-methoxyphenyl)-3-(4-methoxy-3-(prop-2-yn-1-yloxy)phenyl)prop-2-en-1-one (4). A mixture of benzaldehyde 2 (2.05 g, 10.8 mmol), acetophenone 3 (1.80 g, 10.8 mmol) and KOH (3.02 g, 53.8 mmol) in absolute EtOH (100 mL) was reacted according to GP-D. The crude residue was purified by flash column chromatography (SiO₂, PE/EtOAc; 5:1) and recrystallized from MeOH to afford chalcone 4 (1.42 g, 39%) as a bright yellow-orange fluffy solid. m.p. 144–146 °C. TLC R_f = 0.37 (PE/EtOAc; 2:1). IR ν_max (neat)/cm⁻¹: 3506w (br) (O-H str), 3229m (C≡C-H str), 3081w (C-H str), 2973w (C-H str), 2111w (C≡C str), 1633m (C=O str), 1572m (C=C str), 1556s (C=C str), 1507s (C=C str), 1466m, 1440s, 1361s, 1339s, 1260s, 1206s, 1170m, 1126s, 1018s. ¹H-NMR (500 MHz, CDCl₃): δ 2.58 (1H, t, J = 2.0 Hz, -OCH₂C≡CH), 3.87 (3H, s, -OCH₃), 3.94 (3H, s, -OCH₃), 4.85 (2H, d, J = 2.4 Hz, -OCH₂C≡CH), 6.49–6.52 (2H, m, ArH), 6.94 (1H, d, J = 8.4 Hz, ArH), 7.32 (1H, dd, J = 8.4, 2.0 Hz, ArH), 7.35 (1H, d, J = 1.2 Hz, ArH), 7.45 (1H, d, J = 15.2 Hz, -CH=CHCO-), 7.83 (1H, d, J = 8.4 Hz, ArH), 7.85 (1H, d, J = 15.6 Hz, -CH=CHCO-), 13.53 (1H, s, OH). ¹³C-NMR (500 MHz, CDCl₃): δ 55.6, 56.0, 56.9, 76.3, 78.1, 101.0, 107.7, 111.7, 113.8, 114.1, 118.3, 124.3, 127.7, 131.1, 144.3, 146.9, 152.2, 166.1, 166.6, 191.7. LCMS (ES+) m/z = 339.2 ([M + H]⁺, t_R = 1.70 min). HRMS (ESI+) m/z = 339.1224 [M + H]⁺ found, C₂₀H₁₉O₅⁺ required 339.1227.

(E)-1-(4-Hydroxy-3-methoxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (13). A mixture of aldehyde 5 (7.40 mL, 60.8 mmol), acetophenone 11 (10.0 g, 60.3 mmol) and KOH (16.9 g, 302 mmol) in absolute EtOH (100 mL) was reacted according to GP-D. The crude residue was purified by flash column chromatography (SiO₂, PE/EtOAc; 5:1) to afford chalcone 13 (10.7 g, 63%) as a bright yellow-orange powdery solid. m.p. 148–150 °C. TLC R_f = 0.40 (PE/EtOAc; 1:1). IR ν_max (neat)/cm⁻¹: 3180m (br) (O-H str), 2991w (C-H str), 2836w (C-H str), 1643m (C=O str), 1602m (C=C str), 1560s (C=C str), 1508s (C=C str), 1461w, 1424s, 1338m, 1296s, 1278s, 1248s, 1166s, 1048m, 1026s. ¹H-NMR (500 MHz, CDCl₃): δ 3.86 (3H, s, -OCH₃), 3.98 (3H, s, -OCH₃), 6.23 (1H, s, OH), 6.94 (2H, d, J = 9.0 Hz, ArH), 7.00 (1H, d, J = 8.0 Hz, ArH), 7.45 (1H, d, J = 15.5 Hz, -CH=CHCO-), 7.61 (2H, d, J = 8.5 Hz, ArH), 7.64–7.66 (2H, m, ArH), 7.79 (1H, d, J = 16.0 Hz, -CH=CHCO-). ¹³C-NMR (500 MHz, CDCl₃): δ 55.4, 56.1, 110.5, 113.7, 114.3, 119.3, 123.5, 127.8, 130.1, 131.2, 143.8, 146.8, 150.2, 161.5, 188.6. LCMS (ES+) m/z = 285.2 ([M + H]⁺, t_R = 1.75 min). These characterisation data are in accordance with that previously reported in the literature [38].

(E)-1-(5-Bromo-2-hydroxyphenyl)-3-(1-methyl-1H-indol-3-yl)prop-2-en-1-one (14). A mixture of indole aldehyde 6 (1.03 g, 6.47 mmol), acetophenone 12 (1.38 g, 6.42 mmol) and piperidine (0.62 mL, 6.28 mmol) in absolute EtOH (100 mL) was reacted according to GP-E. The crude residue was purified by recrystallization from MeOH to afford chalcone 14 (2.15 g, 94%) as a bright orange fluffy solid. m.p. 250–252 °C. TLC R_f = 0.45 (PE/EtOAc 2:1). IR ν_max (neat)/cm⁻¹: 3101w (C-H str), 2885w (C-H str), 1626s (C=O str), 1541m (C=C str), 1513s (C=C str), 1462m, 1387m, 1375m, 1344m, 1295m, 1252s, 1177s, 1126s, 1074s, 1028s, 1014m. ¹H-NMR (500 MHz, CDCl₃): δ 3.88 (3H, s, -NCH₃), 6.93 (1H, d, J = 8.8 Hz, ArH), 7.38–7.40 (3H, m, ArH), 7.49–7.56 (2H, m, ArH), 7.55 (1H, d, J = 15.6 Hz, -CH=CHCO-), 8.00–8.03 (2H, m, ArH), 8.23 (1H, d, J = 15.2 Hz, -CH=CHCO-), 13.25 (1H, br s, OH). ¹³C-NMR (500 MHz, CDCl₃): δ 33.5, 110.2, 110.3, 113.1, 113.6, 120.5, 120.8, 121.7, 122.1, 123.6, 126.1, 131.5, 135.6, 138.1, 138.4, 140.4, 162.4, 192.5. LCMS (ES+) m/z = 358.0 ([M + H]⁺, t_R = 4.96 min). HRMS (ESI+) m/z = 356.0279 [M + H]⁺ found, C₁₈H₁₅O₂NBr⁺ required 356.0281.

(E)-1-(2-Hydroxyphenyl)-3-(1-methyl-1H-pyrrol-2-yl)prop-2-en-1-one (15). A mixture of pyrrole aldehyde 7 (4.00 mL, 37.2 mmol), acetophenone 10 (4.50 mL, 37.4 mmol) and piperidine (3.80 mL, 38.5 mmol) in absolute EtOH (100 mL) was reacted according to GP-E. The crude residue was purified by recrystallization from MeOH to afford chalcone 15 (2.28 g, 27%) as a bright yellow-orange powdery solid. m.p. 98–100 °C. TLC R_f = 0.45 (PE/EtOAc; 3:1). IR ν_max (neat)/cm⁻¹: 3112w (C-H str), 2937w (C-H str), 1627s (C=O str), 1579w (C=C str), 1549s (C=C str), 1479s, 1440m, 1412m, 1384m, 1356w, 1338m, 1290m, 1260s, 1249s, 1203s, 1182w, 1155s, 1092w, 1061s, 1025s. ¹H-NMR (500 MHz, CDCl₃): δ 3.81 (3H, s, -NCH₃), 6.26–6.27 (1H, m, ArH), 6.87 (1H, t, J = 2.0 Hz, ArH), 6.91–6.96 (2H, m, ArH), 7.02 (1H, dd, J = 8.4, 0.8 Hz, ArH), 7.40 (1H, d, J = 14.8 Hz, -CH=CHCO-), 7.48 (1H, t, J = 8.4 Hz, ArH), 7.89 (1H, dd, J = 8.0, 2.0 Hz, ArH), 7.92 (1H, d, J = 14.8 Hz, -CH=CHCO-), 13.14 (1H, s, OH). ¹³C-NMR (500 MHz, CDCl₃): δ 34.4, 110.2, 113.3, 114.5, 118.5, 118.7, 120.2, 128.6, 129.2, 130.2, 132.8, 135.8, 163.4, 193.1. LCMS (ES+) m/z = 228.1 ([M + H]⁺, t_R = 1.68 min). HRMS (ESI+) m/z = 228.1020 [M + H]⁺ found, C₁₄H₁₄O₂N⁺ required 228.1019.

(E)-1-(4-Hydroxy-3-methoxyphenyl)-3-(1-methyl-1H-pyrrol-2-yl)prop-2-en-1-one (16). A mixture of pyrrole aldehyde 7 (3.30 mL, 30.7 mmol), acetophenone 11 (5.02 g, 30.2 mmol) and KOH (10.2 g, 182 mmol) in absolute EtOH (100 mL) was reacted according to GP-D. The crude residue was purified by flash column chromatography (SiO₂, PE/EtOAc; 5:1) and recrystallized from absolute EtOH to afford chalcone 16 (4.28 g, 55%) as a dark red-brown powdery solid. m.p. 150–152 °C. TLC R_f = 0.31 (PE/EtOAc; 1:1). IR ν_max (neat)/cm⁻¹: 3177m(br) (O-H str), 2958w (C-H str), 2930w (C-H str), 1630m (C=O str), 1600m (C=C str), 1587m (C=C str), 1543s (C=C str), 1508s (C=C str), 1478m, 1380w, 1333m, 1270s, 1218m, 1196s, 1169s, 1052s, 1031s. ¹H-NMR (500 MHz, CDCl₃): δ 3.77 (3H, s, -NCH₃), 3.99 (3H, s, -OCH₃), 6.18 (1H, s, OH), 6.23 (1H, t, J = 3.2 Hz, ArH), 6.81 (1H, t, J = 2.0 Hz, ArH), 6.84 (1H, dd, J = 4.0, 1.6 Hz, ArH), 6.99 (1H, d, J = 8.8 Hz, ArH), 7.32 (1H, d, J = 15.2 Hz, -CH=CHCO-), 7.62–7.64 (2H, m, ArH), 7.81 (1H, d, J = 14.8 Hz, -CH=CHCO-). ¹³C-NMR (500 MHz, CDCl₃): δ 34.3, 56.1, 109.6, 110.4, 112.0, 113.7, 116.4, 123.1, 127.5, 130.3, 131.5, 131.5, 146.8, 150.0, 188.1. LCMS (ES+) m/z = 258.1 ([M + H]⁺, t_R = 1.40 min). HRMS (ESI+) m/z =280.0935 [M + Na]⁺ found, C₁₅H₁₅O₃NNa⁺ required 280.0944.

(E)-1-(5-Bromo-2-hydroxyphenyl)-3-(furan-2-yl)prop-2-en-1-one (17). A mixture of furan aldehyde 8 (1.20 mL, 14.5 mmol), acetophenone 12 (3.06 g, 14.2 mmol) and KOH (4.70 g, 83.8 mmol) in absolute EtOH (100 mL) was reacted according to GP-D. The crude residue was purified by recrystallization from MeOH to afford chalcone 17 (1.97 g, 47%) as a bright yellow-orange fluffy solid. m.p. 80–82 °C. TLC R_f = 0.50 (PE/EtOAc; 3:1). IR ν_max (neat)/cm⁻¹: 3128w (C-H str), 3046w (C-H str), 2868w (C-H str), 1638m (C=O str), 1567s (C=C str), 1548s (C=C str), 1467s, 1364m, 1335s, 1296m, 1258s, 1202s, 1177s, 1077w, 1013s. ¹H-NMR (500 MHz, CDCl₃): δ 6.56–6.57 (1H, m, ArH), 6.82 (1H, d, J = 3.6 Hz, ArH), 6.93 (1H, d, J = 8.8 Hz, ArH), 7.45 (1H, d, J = 15.2 Hz, -CH=CHCO-), 7.56 (1H, dd, J = 9.2, 2.4 Hz, ArH), 7.60 (1H, d, J = 0.8 Hz, ArH), 7.70 (1H, d, J = 15.2 Hz, -CH=CHCO-), 8.00 (1H, d, J = 2.4 Hz, ArH), 12.83 (1H, s, OH). ¹³C-NMR (500 MHz, CDCl₃): δ 110.4, 113.0, 116.8, 117.8, 120.5, 121.2, 131.8, 131.9, 138.8, 145.8, 151.3, 162.4, 192.3. LCMS (ES+) m/z = 293.1 ([M + H]⁺, t_R = 1.85 min). These characterisation data are in accordance with that previously reported in the literature [39].

(E)-3-(Ferrocenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one (18). A mixture of ferrocene aldehyde 9 (4.77 g, 22.3 mmol), acetophenone 10 (2.70 mL, 22.4 mmol) and KOH (7.63 g, 136 mmol) in absolute EtOH (100 mL) was reacted according to GP-D. The crude residue was purified by recrystallization from MeOH to afford chalcone 18 (4.99 g, 67%) as a dark purple microcrystalline solid. m.p. 162–164 °C. TLC R_f = 0.43 (PE/EtOAc; 7:1). IR ν_max (neat)/cm⁻¹: 3315w(br) (O-H str), 3088w (C-H str), 1742w (C=O str), 1627m, 1554s (C=C str), 1489s, 1440m, 1383w, 1347m, 1302s, 1271m, 1246m, 1206s, 1158m, 1104m, 1048w, 1023m, 1002w. ¹H-NMR (500 MHz, CDCl₃): δ 4.21 (5H, s, -C₅H₅), 4.55 (2H, t, J = 2.0 Hz, -C₅H₄), 4.65 (2H, t, J = 2.0 Hz, -C₅H₄), 6.94 (1H, t, J = 8.0 Hz, ArH), 7.03 (1H, dd, J = 8.5, 1.0 Hz, ArH), 7.26 (1H, d, J = 15.0 Hz, -CH=CHCO-, overlain by CDCl₃), 7.49 (1H, t, J = 8.5 Hz, ArH), 7.87 (1H, dd, J = 8.0, 1.0 Hz, ArH), 7.91 (1H, d, J = 15.0 Hz, -CH=CHCO-), 13.07 (1H, s, OH). ¹³C-NMR (500 MHz, CDCl₃): δ 69.3, 69.9, 71.8, 78.8, 116.7, 118.6, 118.6, 120.0, 129.3, 135.9, 147.9, 163.6, 192.7. LCMS (ES+) m/z = 333.1 ([M + H]⁺, t_R = 1.87 min). These characterisation data are in accordance with that previously reported in the literature [40].

(E)-3-(Ferrocenyl)-1-(4-hydroxy-3-methoxyphenyl)prop-2-en-1-one (19). A mixture of ferrocene aldehyde 9 (3.86 g, 18.0 mmol), acetophenone 11 (3.05 g, 18.4 mmol) and KOH (6.10 g, 109 mmol) in absolute EtOH (100 mL) was reacted according to GP-D. The crude residue was purified by flash column chromatography (SiO₂, PE/EtOAc; 5:1) to afford chalcone 19 (5.61 g, 86%) as a dark purple microcrystalline solid. m.p. 78–80 °C. TLC R_f = 0.29 (PE/EtOAc; 2:1). IR ν_max (neat)/cm⁻¹: 3098w(C-H str), 2835w (C-H str), 1743w, 1642m, (C=O str) 1588s (C=C str), 1563s (C=C str), 1511s (C=C str), 1462m, 1424s, 1359m, 1347m, 1281s, 1264s, 1189s, 1162s, 1026s, 1001w. ¹H-NMR (500 MHz, CDCl₃): δ. 3.95 (3H, s, -OCH₃), 4.17 (5H, s, -C₅H₅), 4.47 (2H, t, J = 2.0 Hz, -C₅H₄), 4.59 (2H, t, J = 2.0 Hz, -C₅H₄), 6.54 (1H, br s, OH), 7.00 (1H, d, J = 8.0 Hz, ArH), 7.16 (1H, d, J = 15.0 Hz, -CH=CHCO-), 7.60 (1H, dd, J = 8.5, 1.5 Hz, ArH), 7.63 (1H, d, J = 1.5 Hz, ArH), 7.76 (1H, d, J = 15.5 Hz, -CH=CHCO-). ¹³C-NMR (500 MHz, CDCl₃): δ 56.0, 68.8, 69.7, 71.2, 79.3, 110.5, 113.8, 118.5, 123.2, 131.1, 145.8, 146.8, 150.1, 187.9. LCMS (ES+) m/z = 363.1 ([M + H]⁺, t_R = 1.66 min). HRMS (ESI+) m/z = 363.0595 [M + H]⁺ found, C₂₀H₁₉O₃Fe⁺ required 363.0600.

(E)-1-(3-Methoxy-4-(prop-2-yn-1-yloxy)phenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (20). A mixture of chalcone 13 (1.02 g, 3.57 mmol), propargyl bromide (0.63 mL, 7.07 mmol) and anhydrous K₂CO₃ (1.49 g, 10.8 mmol) in dry acetone (50 mL) was reacted according to GP-C. The crude residue was purified by flash column chromatography (SiO₂, CH₂Cl₂) to afford chalcone 20 (1.07 g, 93%) as a pale yellow powdery solid. m.p. 168–170 °C. TLC R_f = 0.41 (CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3251w (C≡C-H str), 2990w (C-H str), 2835w (C-H str), 2116w (C≡C str), 1651s (C=O str), 1598s (C=C str), 1577s (C=C str), 1508s (C=C str), 1466m, 1421s, 1382w, 1323m, 1257s, 1229s, 1165s, 1145s, 1056w, 1015s. ¹H-NMR (500 MHz, CDCl₃): δ 2.57 (1H, t, J = 2.4 Hz, -OCH₂C≡CH), 3.87 (3H, s, -OCH₃), 3.98 (3H, s, -OCH₃), 4.87 (2H, d, J = 2.4 Hz, -OCH₂C≡CH), 6.95 (2H, d, J = 8.8 Hz, ArH), 7.11 (2H, d, J = 8.4 Hz, ArH), 7.44 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.62 (2H, d, J = 8.8 Hz, ArH), 7.65 (1H, d, J = 2.0 Hz, ArH), 7.68 (1H, dd, J = 8.4, 2.0 Hz, ArH), 7.80 (1H, d, J = 15.6 Hz, -CH=CHCO-). ¹³C-NMR (500 MHz, CDCl₃): δ 55.4, 56.1, 56.6, 76.4, 77.8, 111.3, 112.3, 114.4, 119.3, 122.3, 127.7, 130.1, 132.6, 144.0, 149.7, 150.7, 161.6, 188.7. LCMS (ES+) m/z = 323.2 ([M + H]⁺, t_R = 1.56 min). HRMS (ESI+) m/z = 323.1265 [M + H]⁺ found, C₂₀H₁₉O₄⁺ required 323.1278.

(E)-1-(5-Bromo-2-(prop-2-yn-1-yloxy)phenyl)-3-(1-methyl-1H-indol-3-yl)prop-2-en-1-one (21). A mixture of indole chalcone 14 (2.07 g, 5.81 mmol), propargyl bromide (1.50 mL, 16.8 mmol) and anhydrous K₂CO₃ (2.52 g, 18.2 mmol) in dry acetone (100 mL) was reacted according to GP-C. The crude residue was purified by flash column chromatography (SiO₂, CH₂Cl₂) to afford chalcone 21 (2.20 g, 96%) as a bright yellow powdery solid. m.p. 126–128 °C. TLC R_f = 0.20 (CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3257w (C≡C-H str), 3070w (C-H str), 2942w (C-H str), 2114w (C≡C str), 1638s (C=O str), 1587m (C=C str), 1544s (C=C str), 1524s (C=C str), 1473m, 1373s, 1269s, 1213m, 1176s, 1133m, 1073m, 1006s. ¹H-NMR (500 MHz, CDCl₃): δ 2.55 (1H, t, J = 2.4 Hz, -OCH₂C≡CH), 3.82 (3H, s, -NCH₃), 4.79 (2H, d, J = 2.4 Hz, -OCH₂C≡CH), 7.03 (1H, d, J = 9.2 Hz, ArH), 7.26–7.38 (3H, m, ArH), 7.38 (1H, d, J = 16.0 Hz, -CH=CHCO-), 7.41 (1H, s, ArH), 7.55 (1H, dd, J = 8.8, 2.4 Hz, ArH), 7.77 (1H, d, J = 2.4 Hz, ArH), 7.88 (1H, d, J = 15.6 Hz, -CH=CHCO-), 8.01 (1H, d, J = 8.0 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 33.3, 56.6, 76.4, 77.8, 110.0, 112.9, 114.3, 115.3, 121.0, 121.5, 121.6, 123.2, 126.0, 132.6, 132.9, 134.3, 134.8, 138.2, 138.6, 154.6, 191.0. LCMS (ES+) m/z = 396.1 ([M + H]⁺, t_R = 1.98 min). HRMS (ESI+) m/z = 394.0425 [M + H]⁺ found, C₂₁H₁₇NO₂Br⁺ required 394.0443.

(E)-1-(3-Methoxy-4-(prop-2-yn-1-yloxy)phenyl)-3-(1-methyl-1H-pyrrol-2-yl)prop-2-en-1-one (22). A mixture of pyrrole chalcone 16 (1.00 g, 3.89 mmol), propargyl bromide (0.70 mL, 7.86 mmol) and anhydrous K₂CO₃ (1.61 g, 1.17 mmol) in dry acetone (50 mL) was reacted according to GP-C. The crude residue was purified by flash column chromatography (SiO₂, PE/EtOAc; 3:1) to afford chalcone 22 (1.06 g, 92%) as a bright yellow powdery solid. m.p. 164–166 °C. TLC R_f = 0.41 (PE/EtOAc; 1:1). IR ν_max (neat)/cm⁻¹: 3234m (C≡C-H str), 2995w (C-H str), 2866w (C-H str), 1739m (C=O str), 1645m, 1598s, (C=C str), 1561s (C=C str), 1515m (C=C str), 1483m, 1416w, 1374m, 1346s, 1272s, 1179m, 1129s, 1087w, 1042m, 1012m. ¹H-NMR (500 MHz, CDCl₃): δ 2.56 (1H, t, J = 2.5 Hz, -OCH₂C≡CH), 3.78 (3H, s, -NCH₃), 3.98 (3H, s, -OCH₃), 4.86 (1H, d, J = 2.5 Hz, -OCH₂C≡CH), 6.23–6.24 (1H, m, ArH), 6.82 (1H, t, J = 2.0 Hz, ArH), 6.85 (1H, dd, J = 4.0, 1.0 Hz, ArH), 7.10 (1H, d, J = 8.0 Hz, ArH), 7.32 (1H, d, J = 15.0 Hz, -CH=CHCO-), 7.64–7.67 (2H, m, ArH), 7.82 (1H, d, J = 15.0 Hz, -CH=CHCO-). ¹³C-NMR (500 MHz, CDCl₃): δ 34.4, 56.1, 56.6, 76.4, 77.8, 109.7, 111.2, 112.1, 112.4, 116.4, 122.0, 127.6, 130.3, 131.7, 132.9, 149.6, 150.5, 188.1. LCMS (ES+) m/z = 296.2 ([M + H]⁺, t_R = 1.57 min). HRMS (ESI+) m/z = 294.1119 [M − H]⁺ found, C₁₈H₁₆O₃N⁺ required 294.1125.

(E)-3-(1-Methyl-1H-pyrrol-2-yl)-1-(2-(prop-2-yn-1-yloxy)phenyl)prop-2-en-1-one (23). A mixture of pyrrole chalcone 15 (308 mg, 1.32 mmol), propargyl bromide (0.25 mL, 2.81 mmol) and anhydrous K₂CO₃ (568 mg, 4.11 mmol) in dry acetone (20 mL) was reacted according to GP-C. The crude residue was purified by flash column chromatography (SiO₂, PE/EtOAc; 3:1) to afford chalcone 23 (352 mg, 98%) as a bright yellow viscous oil. TLC R_f = 0.34 (PE/EtOAc; 2:1). IR ν_max (neat)/cm⁻¹: 3283w (C≡C-H str), 3072w (C-H str), 2923w (C-H str), 2120w (C≡C str), 1698w (C=O str), 1647m, 1598s (C=C str), 1580s (C=C str), 1564s (C=C str), 1480s, 1450m, 1330m, 1287s, 1217s, 1113w, 1057m, 1018s. ¹H-NMR (500 MHz, CDCl₃): δ 2.54 (1H, t, J = 2.4 Hz, -OCH₂C≡CH), 3.74 (3H, s, -NCH₃), 4.79 (2H, d, J = 2.4 Hz, -OCH₂C≡CH), 6.20–6.21 (1H, m, ArH), 6.78–6.80 (2H, m, ArH), 7.08–7.12 (2H, m, ArH), 7.19 (1H, d, J = 15.2 Hz, -CH=CHCO-), 7.47 (1H, t, J = 8.8 Hz, ArH), 7.65 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.66 (1H, dd, J = 7.6, 2.0 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 34.5, 56.4, 75.9, 78.2, 109.6, 112.8, 113.3, 121.8, 121.9, 127.7, 130.2, 130.5, 130.5, 131.1, 132.2, 155.7, 191.9. LCMS (ES+) m/z = 266.1 ([M + H]⁺, t_R = 1.57 min). HRMS (ESI+) m/z = 266.1183 [M + H]⁺ found, C₁₇H₁₆NO₂⁺ required 266.1181.

(E)-1-(5-Bromo-2-(prop-2-yn-1-yloxy)phenyl)-3-(furan-2-yl)prop-2-en-1-one (24). A mixture of furan chalcone 17 (2.02 g, 6.89 mmol), propargyl bromide (1.30 mL, 14.6 mmol) and anhydrous K₂CO₃ (2.90 g, 21.0 mmol) in dry acetone (100 mL) was reacted according to GP-C. The crude residue was purified by flash column chromatography (SiO₂, CH₂Cl₂) to afford chalcone 24 (2.14 g, 94%) as a pale yellow-brown powdery solid. m.p. 82–84 °C. TLC R_f = 0.21 (PE/CH₂Cl₂; 1:1). IR ν_max (neat)/cm⁻¹: 3224m (C≡C-H str), 3118w (C-H str), 2118w (C≡C str), 1660m (C=O str), 1600s (C=C str), 1586m (C=C str), 1554m (C=C str), 1476m, 1394m, 1313w, 1276m, 1211s, 1180m, 1131m, 1079w, 1048m, 1012s. ¹H-NMR (500 MHz, CDCl₃): δ 2.54 (1H, t, J = 2.4 Hz, -OCH₂C≡CH), 4.78 (2H, d, J = 2.4 Hz, -OCH₂C≡CH), 6.50–6.51 (1H, m, ArH), 6.70 (1H, d, J = 3.6 Hz, ArH), 7.03 (1H, d, J = 8.8 Hz, ArH), 7.21 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.40 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.52 (1H, d, J = 1.2 Hz, ArH), 7.56 (1H, dd, J = 8.8, 2.4 Hz, ArH), 7.73 (1H, d, J = 2.4 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 56.6, 76.5, 77.6, 112.6, 114.3, 115.4, 116.2, 123.8, 130.4, 131.6, 133.0, 135.0, 145.1, 151.5, 154.8, 190.5. LCMS (ES+) m/z = 333.0 ([M + H]⁺, t_R = 1.89 min). HRMS (ESI+) m/z = 330.9973 [M + H]⁺ found, C₁₆H₁₂O₃Br⁺ required 330.9970.

(E)-3-(Ferrocenyl)-1-(3-methoxy-4-(prop-2-yn-1-yloxy)phenyl)prop-2-en-1-one (25). A mixture of ferrocene chalcone 19 (1.01 g, 2.79 mmol), propargyl bromide (0.50 mL, 5.61 mmol) and anhydrous K₂CO₃ (1.18 g, 8.56 mmol) in dry acetone (50 mL) was reacted according to GP-C. The crude residue was purified by flash column chromatography (SiO₂, CH₂Cl₂) to afford chalcone 25 (1.01 g, 91%) as a dark red-purple microcrystalline solid. m.p. 128–130 °C. TLC R_f = 0.47 (0.5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3225m (C≡C-H str), 3008w (C-H str), 2939w (C-H str), 2114w (C≡C str), 1646s (C=O str), 1595m (C=C str), 1567s (C=C str), 1506m (C=C str), 1456m, 1413s, 1345w, 1295s, 1259s, 1194m, 1159s, 1136s, 1107m, 1060w, 1044m, 1020s. ¹H-NMR (500 MHz, CDCl₃): δ 2.56 (1H, t, J = 2.5 Hz, -OCH₂C≡CH), 3.96 (3H, s, -OCH₃), 4.18 (5H, s, -C₅H₅), 4.48 (2H, t, J = 2.0 Hz, -C₅H₄), 4.60 (2H, t, J = 2.0 Hz, -C₅H₄), 4.85 (2H, d, J = 2.0 Hz, -OCH₂C≡CH), 7.09 (1H, d, J = 8.5 Hz, ArH), 7.15 (1H, d, J = 15.5 Hz, -CH=CHCO-), 7.61–7.63 (2H, m, ArH), 7.75 (1H, d, J = 15.0 Hz, -CH=CHCO-). ¹³C-NMR (500 MHz, CDCl₃): δ 56.0, 56.5, 68.9, 69.7, 71.2, 76.3, 77.8, 79.3, 111.2, 112.3, 118.5, 122.1, 132.6, 146.0, 149.5, 150.4, 187.9. LCMS (ES+) m/z = 401.1 ([M + H]⁺, t_R = 1.81 min). HRMS (ESI+) m/z = 401.0823 [M + H]⁺ found, C₂₃H₂₁O₃Fe⁺ required 401.0840.

(E)-3-(Ferrocenyl)-1-(2-(prop-2-yn-1-yloxy)phenyl)prop-2-en-1-one (26). A mixture of chalcone 18 (1.02 g, 3.07 mmol), propargyl bromide (0.54 mL, 6.02 mmol) and anhydrous K₂CO₃ (1.20 g, 8.68 mmol) in dry acetone (50 mL) was reacted according to GP-C. The crude residue was purified by flash column chromatography (SiO₂, PE/CH₂Cl₂; 1:1) to afford chalcone 26 (919 mg, 81%) as a bright red powdery solid. m.p. 90–92 °C. TLC R_f = 0.38 (CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3257m (C≡C-H str), 2924w (C-H str), 2850w (C-H str), 2117w (C≡C str), 1654s (C=O str), 1587s (C=C str), 1480m, 1448m, 1356w, 1345w, 1289m, 1211s, 1159w, 1104m, 1058m, 1016s, 1001s. ¹H-NMR (500 MHz, CDCl₃): δ 2.56 (1H, t, J = 2.5 Hz, -OCH₂C≡CH), 4.19 (5H, s, -C₅H₅), 4.46 (2H, t, J = 2.0 Hz, -C₅H₄), 4.56 (2H, t, J = 2.0 Hz, -C₅H₄), 4.79 (2H, d, J = 2.5 Hz, -OCH₂C≡CH), 6.95 (1H, d, J = 16.0 Hz, -CH=CHCO-), 7.09–7.13 (2H, m, ArH), 7.47 (1H, t, J = 9.0 Hz, ArH), 7.50 (1H, d, J = 15.5 Hz, -CH=CHCO-), 7.58 (1H, dd, J = 7.5, 1.5 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 56.3, 69.0, 69.8, 71.2, 76.0, 78.2, 79.0, 113.3, 121.7, 124.6, 130.1, 130.5, 131.9, 146.2, 155.4, 192.5. LCMS (ES+) m/z = 371.1 ([M + H]⁺, t_R = 1.96 min). HRMS (ESI+) m/z = 370.0639 [M]⁺ found, C₂₂H₁₈O₂Fe⁺ required 370.0651.

3-(Prop-2-yn-1-yloxy)flavone (30). A mixture of 3-hydroxyflavone 27 (2.06 g, 8.65 mmol), propargyl bromide (1.50 mL, 16.8 mmol) and anhydrous K₂CO₃ (3.48 g, 25.2 mmol) in dry acetone (100 mL) was reacted according to GP-C. The crude residue was purified by flash column chromatography (SiO₂, CH₂Cl₂) to afford flavone 30 (2.38 g, 99%) as a pale yellow-white powdery solid. m.p. 104–106 °C. TLC R_f = 0.24 (CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3254m (C≡C-H str), 2946w (C-H str), 2114w (C≡C str), 1612s (C=O str), 1600s, 1557s (C=C str), 1468s, 1445m, 1399s, 1354m, 1345m, 1279w, 1234w, 1195s, 1185s, 1148s, 1110m, 1079w, 1036m. ¹H-NMR (500 MHz, CDCl₃): δ 2.33 (1H, t, J = 2.4 Hz, -OCH₂C≡CH), 5.00 (2H, d, J = 2.4 Hz, -OCH₂C≡CH), 7.42 (1H, t, J = 8.0 Hz, ArH), 7.50–7.54 (3H, m, ArH), 7.56 (1H, d, J = 8.4 Hz, ArH), 7.70 (1H, t, J = 8.4 Hz, ArH), 8.14–8.16 (2H, m, ArH), 8.27 (1H, dd, J = 8.0, 1.6 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 59.1, 76.1, 78.5, 118.0, 123.9, 124.7, 125.7, 128.3, 128.9, 130.7, 130.9, 133.5, 138.5, 155.2, 156.7, 174.8. LCMS (ES+) m/z = 277.5 ([M + H]⁺, t_R = 4.47 min). These characterisation data are in accordance with that previously reported in the literature [23].

6-(Prop-2-yn-1-yloxy)flavone (31). A mixture of 6-hydroxyflavone 28 (2.00 g, 8.39 mmol), propargyl bromide (1.50 mL, 16.8 mmol) and anhydrous K₂CO₃ (3.50 g, 25.3 mmol) in dry acetone (100 mL) was reacted according to GP-C. The crude residue was purified by flash column chromatography (SiO₂, 1% MeOH/CH₂Cl₂) to afford flavone 31 (2.03 g, 87%) as a white crystalline solid. m.p. 170–172 °C. TLC R_f = 0.44 (1% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3266m (C≡C-H str), 3059w (C-H str), 2116w (C≡C str), 1623s (C=O str), 1606s, 1582s (C=C str), 1568s (C=C str), 1497m, 1482m, 1455s, 1365s, 1283m, 1259m, 1234m, 1186s, 1144s, 1075m, 1048m, 1007s. ¹H-NMR (500 MHz, CDCl₃): δ 2.57 (1H, t, J = 2.4 Hz, -OCH₂C≡CH), 4.76 (2H, d, J = 2.4 Hz, -OCH₂C≡CH), 6.77 (1H, s, -C=CH), 7.31 (1H, dd, J = 9.2, 3.2 Hz, ArH), 7.46–7.51 (4H, m, ArH), 7.65 (1H, d, J = 3.2 Hz, ArH), 7.86–7.88 (2H, m, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 56.3, 76.0, 77.7, 106.4, 106.7, 119.6, 123.9, 124.4, 126.1, 128.9, 131.4, 131.6, 151.3, 154.7, 163.0, 177.9. LCMS (ES+) m/z = 277.0 ([M + H]⁺, t_R = 1.56 min). These characterisation data are in accordance with that previously reported in the literature [24].

7-(Prop-2-yn-1-yloxy)flavone (32). A mixture of 7-hydroxyflavone 29 (990 mg, 4.16 mmol), propargyl bromide (0.748 mL, 8.39 mmol) and anhydrous K₂CO₃ (1.75 g, 12.7 mmol) and in dry acetone (100 mL) was reacted according to GP-C. The crude residue was purified by flash column chromatography (SiO₂, 1% MeOH/CH₂Cl₂) to afford flavone 32 (1.10 g, 95%) as an off-white powdery solid. m.p. 216–218 °C. TLC R_f = 0.44 (2% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3194w (C≡C-H str), 2921w (C-H str), 2115w (C≡C str), 1619s (C=O str), 1591s (C=C str), 1568s (C=C str), 1496m, 1451s, 1435s, 1378s, 1350m, 1268m, 1229m, 1168s, 1135s, 1091s, 1017s. ¹H-NMR (500 MHz, CDCl₃): δ 2.62 (1H, t, J = 2.4 Hz, -OCH₂C≡CH), 4.83 (2H, d, J = 2.4 Hz, -OCH₂C≡CH), 6.77 (1H, s, -C=CH), 7.05 (1H, dd, J = 8.8, 2.4 Hz, ArH), 7.09 (1H, d, J = 2.4 Hz, ArH), 7.51–7.55 (3H, m, ArH), 7.90–7.93 (2H, m, ArH), 8.17 (1H, d, J = 8.8 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 56.2, 76.6, 77.3, 101.8, 107.6, 114.7, 118.4, 126.2, 127.2, 129.0, 131.5, 131.8, 157.7, 161.9, 163.1, 177.7. LCMS (ES+) m/z = 277.0 ([M + H]⁺, t_R = 1.54 min). These characterisation data are in accordance with that previously reported in the literature [24].

4-(Prop-2-yn-1-yloxy)benzaldehyde (34). A mixture of benzaldehyde 33 (10.2 g, 83.7 mmol), propargyl bromide (14.6 mL, 164 mmol) and anhydrous K₂CO₃ (22.7 g, 165 mmol) in dry acetone (200 mL) was reacted according to GP-C. The crude residue was purified by flash column chromatography (SiO₂, CH₂Cl₂) to afford benzaldehyde 34 (12.2 g, 91%) as a white crystalline solid. m.p. 88–90 °C. TLC R_f = 0.49 (CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3205m (C≡C-H str), 2971w (C-H str), 2837w (C-H str), 2123w (C≡C str), 1739s (C=O str), 1679s, 1601s, 1576s (C=C str), 1508m (C=C str), 1428w, 1384s, 1245s, 1217s, 1170s, 1009s. ¹H-NMR (500 MHz, CDCl₃): δ 2.58 (1H, t, J = 2.4 Hz, -OCH₂C≡CH), 4.77 (2H, d, J = 2.4 Hz, -OCH₂C≡CH), 7.08 (2H, d, J = 8.8 Hz, ArH), 7.85 (2H, d, J = 8.8 Hz, ArH), 9.89 (1H, s, CHO). ¹³C-NMR (500 MHz, CDCl₃): δ 55.9, 76.3, 77.5, 115.1, 130.5, 131.8, 162.3, 190.7. LCMS (ES+) m/z = 161.1 ([M + H]⁺, t_R = 1.65 min). These characterisation data are in accordance with that previously reported in the literature [41].

(E)-1-(2-Hydroxyphenyl)-3-(4-(prop-2-yn-1-yloxy)phenyl)prop-2-en-1-one (35). A mixture of benzaldehyde 34 (5.04 g, 31.5 mmol), acetophenone 10 (3.76 mL, 31.2 mmol), and KOH (10.6 g, 189 mmol) in absolute EtOH (100 mL) was reacted according to GP-D. The crude residue was purified by recrystallization from MeOH to afford chalcone 35 (6.67 g, 77%) as a bright yellow powdery solid. m.p. 144–146 °C. TLC R_f = 0.45 (PE/EtOAc; 3:1). IR ν_max (neat)/cm⁻¹: 3487w (O-H str), 3240m (C≡C-H str), 2923w (C-H str), 2124w (C≡C str), 1634s (C=O str), 1604m, 1559s (C=C str), 1509s (C=C str), 1488s, 1442m, 1368m, 1299s, 1270m, 1203m, 1177s, 1159s, 1027s. ¹H-NMR (500 MHz, CDCl₃): δ 2.58 (1H, t, J = 2.4 Hz, -OCH₂C≡CH), 4.75 (2H, d, J = 2.4 Hz, -OCH₂C≡CH), 6.94 (1H, t, J = 7.6 Hz, ArH), 7.03 (3H, d, J = 8.4 Hz, ArH), 7.49 (1H, t, J = 8.4 Hz, ArH), 7.54 (1H, d, J = 15.2 Hz, -CH=CHCO-), 7.63 (2H, d, J = 8.8 Hz, ArH), 7.89 (1H, d, J = 15.2 Hz, -CH=CHCO-), 7.90–7.92 (1H, m, ArH), 12.93 (1H, s, OH). ¹³C-NMR (500 MHz, CDCl₃): δ 55.8, 76.1, 77.9, 115.3, 118.0, 118.5, 118.7, 120.0, 128.0, 129.5, 130.4, 136.1, 145.0, 159.7, 163.5, 193.5. LCMS (ES+) m/z = 279.1 ([M + H]⁺, t_R = 1.75 min). HRMS (ESI+) m/z = 279.1005 [M + H]⁺ found, C₁₈H₁₅O₃⁺ required 279.1016.

3-Hydroxy-4′-(prop-2-yn-1-yloxy)flavone (36). A mixture of chalcone 35 (2.02 g, 7.26 mmol), 16% NaOH (14.4 mL) and 15% H₂O₂ (7.19 mL) in MeOH (50 mL) was reacted according to GP-F. The crude residue was purified by flash column chromatography (SiO₂, 1% MeOH/CH₂Cl₂) to afford flavonol 36 (1.56 g, 73%) as a pale yellow-white powdery solid. m.p. 194–196 °C. TLC R_f = 0.44 (0.5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3271s (C≡C-H str), 3260w (O-H str), 2979w (C-H str), 2119w (C≡C str), 1599s (C=O str), 1562s (C=C str), 1507m (C=C str), 1483m, 1470m, 1427m, 1411m, 1233s, 1216m, 1180s, 1120s, 1109s, 1017s. ¹H-NMR (500 MHz, CDCl₃): δ 2.58 (1H, t, J = 2.4 Hz, -OCH₂C≡CH), 4.79 (2H, d, J = 2.4 Hz, -OCH₂C≡CH), 7.00 (1H, br s, OH), 7.14 (2H, d, J = 9.2 Hz, ArH), 7.42 (1H, t, J = 8.0 Hz, ArH), 7.58 (1H, d, J = 8.4 Hz, ArH), 7.70 (1H, t, J = 8.4 Hz, ArH), 8.25–8.28 (3H, m, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 55.8, 76.0, 78.0, 115.0, 118.2, 120.7, 124.4, 124.4, 125.4, 129.5, 133.4, 137.8, 145.0, 155.3, 158.9, 173.2. LCMS (ES+) m/z = 293.1 ([M + H]⁺, t_R = 1.62 min). HRMS (ESI+) m/z = 315.0618 [M + Na]⁺ found, C₁₈H₁₂O₄Na⁺ required 315.0628.

1-(2-Hydroxy-4-methoxyphenyl)-2-(4-hydroxyphenyl)ethan-1-one (41). A mixture of phenol 37 (8.70 mL, 79.32 mmol) and phenylacetic acid 39 (10.1 g, 66.3 mmol) in BF₃·OEt₂ (85.0 mL, 677 mmol) was reacted according to GP-G. The crude residue was purified by flash column chromatography (SiO₂, CH₂Cl₂) to afford phenylethanone 41 (13.2 g, 78%) as a white powdery solid. m.p. 158–160 °C. TLC R_f = 0.38 (1% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3469w(br) (O-H str), 3221w(br ) (O-H str), 2984w (C-H str), 2904w (C-H str), 1706w (C=O str), 1613s (C=C str), 1518s (C=C str), 1450m, 1437s, 1381m, 1354s, 1291s, 1224s, 1202s, 1127s, 1021m. ¹H-NMR (500 MHz, (CD₃)₂CO): δ 3.85 (3H, s, -OCH₃), 4.19 (2H, s, -COCH₂), 6.42 (1H, d, J = 2.8 Hz, ArH), 6.49 (1H, dd, J = 8.8, 2.4 Hz, ArH), 6.80 (2H, d, J = 8.8 Hz, ArH), 7.16 (2H, d, J = 8.4 Hz, ArH), 7.98 (1H, d, J = 9.2 Hz, ArH), 8.29 (1H, br s, OH), 12.80 (1H, s, OH). ¹³C-NMR (500 MHz, (CD₃)₂CO): δ 43.7, 55.4, 101.0, 107.5, 113.2, 115.6, 125.9, 130.6, 133.1, 156.6, 166.0, 166.5, 203.5. LCMS (ES+) m/z = 259.1 ([M + H]⁺, t_R = 1.47 min). These characterisation data are in accordance with that previously reported in the literature [42].

1-(2,4-Dihydroxyphenyl)-2-(4-methoxyphenyl)ethan-1-one (42). A mixture of phenol 38 (8.00 g, 72.7 mmol) and phenylacetic acid 40 (10.2 g, 61.5 mmol) in BF₃·OEt₂ (70.0 mL, 557 mmol) was reacted according to GP-G. The crude residue was purified by recrystallization from CHCl₃ to afford phenylethanone 42 (5.67 g, 36%) as a pale yellow-white powdery solid. m.p. 168–170 °C. TLC R_f = 0.50 (1% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3349s(br) (O-H str), 2917w (C-H str), 2838w (C-H str), 1614s (C=O str), 1607s (C=C str), 1590s (C=C str), 1510s (C=C str), 1500m (C=C str), 1436m, 1412w, 1351s, 1299m, 1239m, 1174s, 1129m, 1105w, 1023s. ¹H-NMR (500 MHz, (CD₃)₂CO): δ 3.76 (3H, s, -OCH₃), 4.22 (2H, s, -COCH₂), 6.33 (1H, d, J = 2.0 Hz, ArH), 6.44 (1H, dd, J = 9.2, 2.4 Hz, ArH), 6.88 (2H, d, J = 8.8 Hz, ArH), 7.26 (2H, d, J = 8.8 Hz, ArH), 7.96 (1H, d, J = 8.8 Hz, ArH), 9.46 (1H, s, OH), 12.73 (1H, s, OH). ¹³C-NMR (500 MHz, (CD₃)₂CO): δ 43.6, 54.8, 103.0, 108.2, 112.8, 114.1, 127.3, 130.7, 133.7, 159.0, 165.0, 166.1, 203.1. LCMS (ES+) m/z = 259.1 ([M + H]⁺, t_R = 1.52 min). These characterisation data are in accordance with that previously reported in the literature [43].

4′-Hydroxy-7-methoxyisoflavone (43). A mixture of phenylethanone 41 (2.00 g, 7.74 mmol), BF₃·OEt₂ (3.90 mL, 31.1 mmol) and MeSO₂Cl (1.80 mL, 23.3 mmol) in dry DMF (50 mL) was reacted according to GP-H. The crude residue was purified by flash column chromatography (SiO₂, PE/EtOAc; 2:1) to afford isoflavone 43 (1.18 g, 57%) as a white powdery solid. m.p. 232–234 °C. TLC R_f = 0.39 (PE/EtOAc; 1:1). IR ν_max (neat)/cm⁻¹: 3210m(br) (O-H str), 3014w (C-H str), 1621s (C=O str), 1583s (C=C str), 1563m (C=C str), 1517s (C=C str), 1439s, 1373w, 1253s, 1205w, 1170w, 1095m, 1050m, 1019m. ¹H-NMR (500 MHz, (CD₃)₂CO): δ 3.97 (3H, s, -OCH₃), 6.89 (2H, d, J = 8.4 Hz, ArH), 7.04–7.07 (2H, m, ArH), 7.48 (2H, d, J = 8.8 Hz, ArH), 8.10 (1H, d, J = 8.8 Hz, ArH), 8.19 (1H, s, -C=CH), 8.44 (1H, s, OH). ¹³C-NMR (500 MHz, (CD₃)₂CO): δ 55.8, 100.4, 114.7, 115.2, 118.5, 123.7, 124.7, 127.4, 130.4, 152.7, 157.6, 158.2, 164.4, 175.1. LCMS (ES+) m/z = 269.1 ([M + H]⁺, t_R = 1.41 min). These characterisation data are in accordance with that previously reported in the literature [42].

7-Hydroxy-4’-methoxyisoflavone (44). A mixture of phenylethanone 42 (2.02 g, 7.82 mmol), BF₃·OEt₂ (3.90 mL, 31.1 mmol) and MeSO₂Cl (1.80 mL, 23.2 mmol) in dry DMF (50 mL) was reacted according to GP-H. The crude residue was purified by flash column chromatography (SiO₂, PE/EtOAc; 1:1) and recrystallized from CHCl₃ to afford isoflavone 44 (1.62 g, 77%) as a dark yellow powdery solid. m.p. 242–244 °C. TLC R_f = 0.26 (PE/EtOAc; 1:1). IR ν_max (neat)/cm⁻¹: 3126s(br) (O-H str), 2993w (C-H str), 2836w (C-H str), 1637m (C=O str), 1621m, 1594s (C=C str), 1568m (C=C str), 1512s (C=C str), 1451s, 1384m, 1273m, 1178s, 1099m, 1045m, 1025s. ¹H-NMR (500 MHz, (CD₃)₂CO): δ 3.20 (1H, br s, OH), 3.83 (3H, s, -OCH₃), 6.92 (1H, d, J = 2.0 Hz, ArH), 6.98 (2H, d, J = 9.2 Hz, ArH), 7.01 (1H, dd, J = 8.8, 2.4 Hz, ArH), 7.56 (2H, d, J = 8.8 Hz, ArH), 8.07 (1H, d, J = 8.4 Hz, ArH), 8.18 (1H, s, -C=CH). ¹³C-NMR (500 MHz, (CD₃)₂CO): δ 54.9, 102.5, 113.7, 115.1, 117.9, 124.3, 124.9, 127.8, 130.4, 152.8, 158.2, 159.8, 162.6, 175.0. LCMS (ES+) m/z = 269.1 ([M + H]⁺, t_R = 1.47 min). These characterisation data are in accordance with that previously reported in the literature [44].

7-Methoxy-(4′-(prop-2-yn-1-yloxy)isoflavone (45). A mixture of isoflavone 43 (602 mg, 2.25 mmol), propargyl bromide (0.50 mL, 5.61 mmol) and anhydrous K₂CO₃ (1.09 g, 7.91 mmol) in dry acetone (50 mL) was reacted according to GP-C. The crude residue was purified by flash column chromatography (SiO₂, 1% MeOH/CH₂Cl₂) to afford isoflavone 45 (641 mg, 93%) as a white powdery solid. m.p. 162–164 °C. TLC R_f = 0.45 (1% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3289m (C≡C-H str), 3083w (C-H str), 2953w (C-H str), 1645s (C=O str), 1624s, 1606s, 1579m (C=C str), 1513s (C=C str), 1456m, 1442s, 1378s, 1285m, 1262s, 1245s, 1192s, 1176s, 1103s, 1050w, 1017s. ¹H-NMR (500 MHz, CDCl₃): δ 2.54 (1H, t, J = 2.4 Hz, -OCH₂C≡CH), 3.92 (3H, s, -OCH₃), 4.73 (2H, d, J = 2.4 Hz, -OCH₂C≡CH), 6.86 (2H, d, J = 2.0 Hz, ArH), 7.00 (1H, dd, J = 8.8, 2.0 Hz, ArH), 7.05 (2H, d, J = 8.8 Hz, ArH), 7.52 (2H, d, J = 8.8 Hz, ArH), 7.93 (1H, s, -C=CH), 8.21 (2H, d, J = 8.8 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 55.8, 75.6, 78.5, 100.1, 114.5, 114.9, 118.4, 124.7, 125.2, 127.8, 130.1, 152.1, 157.5, 157.9, 164.0, 175.7. LCMS (ES+) m/z = 307.1 ([M + H]⁺, t_R = 1.59 min). HRMS (ESI+) m/z =307.0959 [M + H]⁺ found, C₁₉H₁₅O₄⁺ required 307.0965.

4′-Methoxy-7-(prop-2-yn-1-yloxy)isoflavone (46). A mixture of isoflavone 44 (810 mg, 3.02 mmol), propargyl bromide (0.55 mL, 6.17 mmol) and anhydrous K₂CO₃ (1.25 g, 9.01 mmol) in dry acetone (50 mL) was reacted according to GP-C. The crude residue was purified by flash column chromatography (SiO₂, CH₂Cl₂) to afford isoflavone 46 (550 mg, 60%) as a white powdery solid. m.p. 150–152 °C. TLC R_f = 0.32 (0.5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3281m (C≡C-H str), 3259m, 3078w (C-H str), 2950w (C-H str), 2116w (C≡C str), 1624s (C=O str), 1608s, 1597s (C=C str), 1565m (C=C str), 1513s (C=C str), 1440s, 1373m, 1326w, 1295m, 1271s, 1237s, 1176s, 1109w, 1095s, 1052m, 1033s, 1016s. ¹H-NMR (500 MHz, CDCl₃): δ 2.61 (1H, t, J = 2.0 Hz, -OCH₂C≡CH), 3.85 (3H, s, -OCH₃), 4.81 (1H, d, J = 2.4 Hz, -OCH₂C≡CH), 6.98 (2H, d, J = 8.4 Hz, ArH), 6.98 (1H, d, J = 2.4 Hz, ArH), 7.05 (1H, dd, J = 8.8, 2.4 Hz, ArH), 7.51 (2H, d, J = 8.8 Hz, ArH), 7.93 (1H, s, -C=CH), 8.24 (1H, d, J = 8.8 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 55.3, 56.2, 76.6, 77.3, 101.5, 113.9, 114.8, 119.0, 124.1, 124.9, 127.9, 130.1, 152.1, 157.6, 159.6, 161.6, 175.8. LCMS (ES+) m/z = 307.1 ([M + H]⁺, t_R = 1.62 min). These characterisation data are in accordance with that previously reported in the literature [45].

4-(Prop-2-yn-1-yloxy)-2H-chromen-2-one (48). A mixture of 4-hydroxycoumarin 47 (5.06 g, 31.2 mmol), propargyl bromide (6.20 mL, 69.6 mmol) and anhydrous K₂CO₃ (8.74 g, 63.2 mmol) in dry acetone (100 mL) was reacted according to GP-C. The crude residue was purified by flash column chromatography (SiO₂, CH₂Cl₂) to afford coumarin 48 (3.60 g, 58%) as a white fluffy solid. m.p. 154–156 °C. TLC R_f = 0.24 (CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3281m (C≡C-H str), 3240m, 3078w (C-H str), 2131w (C≡C str), 1714s (C=O str), 1688m, 1622s, 1610m (C=C str), 1568m (C=C str), 1493m, 1453m, 1409m, 1361m, 1329w, 1274s, 1248s, 1194w, 1179m, 1155w, 1145m, 1107s, 1032w. ¹H-NMR (500 MHz, CDCl₃): δ 2.68 (1H, t, J = 2.4 Hz, -OCH₂C≡CH), 4.88 (2H, d, J = 2.4 Hz, -OCH₂C≡CH), 5.84 (1H, s, -C=CH), 7.29–7.34 (2H, m, ArH), 7.57 (1H, t, J = 8.4 Hz, ArH), 7.84 (1H, dd, J = 8.0, 1.2 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 56.8, 75.7, 77.9, 91.7, 115.4, 116.8, 123.1, 124.0, 132.6, 153.3, 162.4, 164.2. LCMS (ES+) m/z = 201.1 ([M + H]⁺, t_R = 1.47 min). These characterisation data are in accordance with that previously reported in the literature [46].

2-(2-Chloro-1-iminoethyl)-1,3,5-benzentriol hydrochloride (50). To a stirred solution of phloroglucinol 49 (5.02 g, 39.8 mmol) and chloroacetonitrile (2.50 mL, 39.5 mmol) in Et₂O (100 mL) was added anhydrous ZnCl₂ (0.558 g, 4.09 mmol). The reaction mixture was cooled to 0 °C and HCl gas was bubbled through the solution for 30 min. The resulting mixture was stirred at 0 °C for 3 h and further 24 h at room temperature. The resulting suspension was filtered and the precipitate was washed with ice-cold Et₂O (2 × 50 mL) and suction-dried to afford hydrochloric salt 50 (1.87 g, 20%) as a pale yellow-white powdery solid and was used without further purification in the next step. m.p. 240–242 °C. IR ν_max (neat)/cm⁻¹: 3389m (N-H str), 3257m(br) (O-H str), 3184s(br) (O-H str), 2968w (C-H str), 1646m, 1616s (C=C str), 1591s (C =C str), 1531w (C=C str), 1457m, 1383m, 1366s, 1291m, 1248s, 1175s, 1128w, 1065m, 1050s, 1024w. ¹H-NMR (500 MHz, DMSO-d₆): δ 5.46 (2H, s, -CH₂-), 6.07 (1H, d, J = 1.2 Hz, ArH), 6.26 (1H, d, J = 1.2 Hz, ArH), 9.90 (1H, s, OH), 10.84 (1H, s, OH), 11.80 (1H, br s, NH), 12.54 (1H, s, OH). ¹³C-NMR (500 MHz, DMSO-d₆): δ 75.3, 90.1, 96.9, 99.3, 160.4, 172.8, 173.7, 176.0. These characterisation data are in accordance with that previously reported in the literature [47].

2,4,6-Trihydroxy-2-chloroacetophenone (51). A mixture of imine salt 50 (1.80 g, 7.56 mmol) and 1 M HCl (100 mL) were heated at reflux with stirring for 1 h. The resulting red solution was blown under a steady stream of nitrogen and the residual solid was re-suspended in H₂O (50 mL). The precipitate was filtered, washed with ice-water (2 × 50 mL), suction-dried and re-dissolved in EtOAc (50 mL). The organic solution was washed with H₂O (2 × 50 mL), brine (2 × 50 mL), dried over anhydrous Na₂SO₄, filtered and evaporated to dryness. The crude residue was purified by flash column chromatography (SiO₂, PE/EtOAc; 1:1) to afford acetophenone 51 (389 mg, 25%) as a white powdery solid. m.p. 236–238 °C. TLC R_f = 0.32 (PE/EtOAc; 1:1). IR ν_max (neat)/cm⁻¹: 3422m (br) (O-H str), 3372s(br) (O-H str), 3068w (C-H str), 2962w (C-H str), 1640m (C=O str), 1598s (C=C str), 1521m (C=C str), 1456s, 1376s, 1331w, 1279m, 1213s, 1164s, 1073s, 1017m. ¹H-NMR (500 MHz, DMSO-d₆): δ 4.98 (2H, s, -COCH₂-), 5.84 (2H, s, ArH), 10.55 (1H, s, OH), 12.07 (2H, s, OH). ¹³C-NMR (500 MHz, DMSO-d₆): δ 51.0, 94.7, 102.5, 163.9, 165.5, 194.7. LCMS (ES+) m/z = 203.0 ([M + H]⁺, t_R = 1.26 min). These characterisation data are in accordance with that previously reported in the literature [26].

Dihydroxybenzofuran-3(2H)-one (52). To a stirred solution of acetophenone 51 (5.00 g, 24.7 mmol) in MeOH (100 mL) was added NaOMe (4.88 g, 90.3 mmol) and the mixture was heated at reflux for 2 h under nitrogen. The reaction mixture was allowed to cool to room temperature, acidified with 1 M HCl and the solvent removed under reduced pressure. The resulting dark residue was then re-dissolved in EtOAc (100 mL). The organic solution was washed with H₂O (2 × 100 mL), brine (2 × 100 mL), dried over anhydrous MgSO₄, filtered and evaporated to dryness. The crude residue was purified by flash column chromatography (SiO₂, PE/EtOAc; 1:1) to afford benzofuranone 52 (2.90 g, 71%) as a pale brown-white powdery solid. m.p. 280–282 °C. TLC R_f = 0.16 (PE/EtOAc; 1:1). IR ν_max (neat)/cm⁻¹: 3331s(br) (O-H str), 3164m(br) (O-H str), 3062w (C-H str), 1671m (C=O str), 1607s (C=C str), 1533w (C=C str), 1457m, 1422w, 1399m, 1369m, 1336m, 1261w, 1227m, 1157s, 1064s, 1042m, 1012m. ¹H-NMR (500 MHz, DMSO-d₆): δ 4.55 (2H, s, -OCH₂CO-), 5.91 (2H, s, ArH), 10.59 (2H, br s, OH). ¹³C-NMR (500 MHz, DMSO-d₆): δ 74.9, 90.1, 96.2, 102.7, 157.5, 167.6, 175.6, 194.0. LCMS (ES+) m/z = 167.1 ([M + H]⁺, t_R = 1.27 min). These characterisation data are in accordance with that previously reported in the literature [26].

4,6-Dimethoxybenzofuran-3(2H)-one (53). To a stirred solution of dihydroxybenzofuranone 52 (2.02 g, 12.2 mmol) in dry DMF (50 mL) were added CH₃I (2.30 mL, 37.0 mmol) and anhydrous K₂CO₃ (3.35 g, 24.2 mmol). The resulting dark red-brown suspension was heated at 80 °C for 1 h under a nitrogen atmosphere. The reaction mixture was then allowed to cool to room temperature, poured into ice-water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layer was washed with H₂O (3 × 100 mL), brine (2 × 100 mL), dried over anhydrous MgSO₄, filtered and evaporated to dryness. The crude residue was purified by flash column chromatography (SiO₂, PE/EtOAc; 1:1) to afford benzofuranone 53 (1.87 g, 79%) as a pale yellow-white powdery solid. m.p. 148–150 °C. TLC R_f = 0.23 (PE/EtOAc; 1:1). IR ν_max (neat)/cm⁻¹: 2979w (C-H str), 2949w (C-H str), 1699s (C=O str), 1616s (C=C str), 1585s (C=C str), 1500m (C=C str), 1463m, 1431m, 1366m, 1342m, 1288m, 1217s, 1186s, 1160s, 1099s, 1052m, 1021m. ¹H-NMR (500 MHz, CDCl₃): δ 3.83 (3H, s, -OCH₃), 3.87 (3H, s, -OCH₃), 4.55 (2H, s, -OCH₂CO-), 5.97 (1H, d, J = 1.6 Hz, ArH), 6.11 (1H, d, J = 2.0 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 55.9, 55.9, 75.4, 88.8, 92.9, 104.7, 158.7, 169.7, 177.0, 194.9. LCMS (ES+) m/z = 195.1 ([M + H]⁺, t_R = 1.52 min). These characterisation data are in accordance with that previously reported in the literature [26].

4,6-Dimethoxy-3′-hydroxyaurone (55). To a stirred solution of benzofuranone 53 (1.01 g, 5.20 mmol) in MeOH (20 mL) was added 3-hydroxybenzaldehyde 54 (0.760 g, 6.22 mmol) followed by the addition of KOH (1.50 g, 26.6 mmol) in H₂O (20 mL). The reaction mixture was stirred at room temperature for 2 h and then poured into H₂O (2 × 100 mL). The resulting suspension was neutralized to pH 7 with 3 M HCl and extracted with CHCl₃ (3 × 50 mL). The combined organic layer was washed with H₂O (3 × 100 mL), brine (100 mL), dried over anhydrous MgSO₄, filtered and evaporated to dryness under reduced pressure. The crude residue was purified by flash column chromatography (SiO₂, PE/EtOAc; 1:1) and recrystallized from MeOH to afford aurone 55 (1.21 g, 78%) as a bright yellow powdery solid. m.p. 178–180 °C. TLC R_f = 0.35 (PE/EtOAc; 1:2). IR ν_max (neat)/cm⁻¹: 3254m(br) (O-H str), 2944w (C-H str), 2842w (C-H str), 1688m (C=O str), 1649m, 1612s (C=C str), 1586s (C=C str), 1501m (C=C str), 1447s, 1430w, 1338m, 1303m, 1249m, 1214s, 1153s, 1138m, 1087s, 1038w. ¹H-NMR (500 MHz, (CD₃)₂CO): δ 3.94 (3H, s, -OCH₃), 3.98 (3H, s, -OCH₃), 6.32 (1H, d, J = 2.0 Hz, ArH), 6.56 (1H, d, J = 1.6 Hz, ArH), 6.56 (1H, s, -C=CH), 6.91 (1H, ddd, J = 8.0, 2.4, 0.8 Hz, ArH), 7.30 (1H, t, J = 8.0 Hz, ArH), 7.40 (1H, d, J = 7.6 Hz, ArH), 7.47 (1H, t, J = 2.0 Hz, ArH), 8.57 (1H, s, OH). ¹³C-NMR (500 MHz, (CD₃)₂CO): δ 55.9, 56.2, 89.7, 94.4, 104.8, 109.4, 116.8, 117.5, 122.8, 130.0, 134.1, 148.1, 157.9, 159.7, 169.2, 169.5, 179.4. LCMS (ES+) m/z = 299.2 ([M + H]⁺, t_R = 1.71 min). These characterisation data are in accordance with that previously reported in the literature [48].

4,6-Dimethoxy-3′-(prop-2-yn-1-yloxy)aurone (56). A mixture of aurone 55 (505 mg, 1.69 mmol), propargyl bromide (0.30 mL, 3.37 mmol) and anhydrous K₂CO₃ (701 mg, 5.07 mmol) in dry acetone (30 mL) was reacted according to GP-C. The crude residue was purified by flash column chromatography (SiO₂, 0.5% MeOH/CH₂Cl₂) to afford aurone 56 (545 mg, 96%) as a pale yellow-white powdery solid. m.p. 152–154 °C. TLC R_f = 0.46 (1% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3219m (C≡C-H str), 3007w (C-H str), 2940w (C-H str), 2110w (C≡C str), 1686s (C=O str), 1654m, 1612s (C=C str), 1589s (C=C str), 1504s (C=C str), 1454m, 1423m, 1347m, 1313m, 1266m, 1215s, 1154m, 1094s, 1040m, 1019w. ¹H-NMR (500 MHz, CDCl₃): δ 2.57 (1H, t, J = 2.5 Hz, -OCH₂C≡CH), 3.91 (3H, s, -OCH₃), 3.95 (3H, s, -OCH₃), 4.75 (2H, d, J = 2.5 Hz, -OCH₂C≡CH), 6.12 (1H, d, J = 2.0 Hz, ArH), 6.37 (1H, d, J = 2.0 Hz, ArH), 6.72 (1H, s, -C=CH), 6.99 (1H, ddd, J = 8.0, 2.5, 1.0 Hz, ArH), 7.35 (1H, t, J = 8.0 Hz, ArH), 7.46 (1H, d, J = 7.5 Hz, ArH), 7.54 (1H, t, J = 1.5 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 55.9, 56.1, 56.2, 75.7, 78.3, 89.2, 94.0, 105.1, 110.3, 115.9, 117.1, 124.6, 129.7, 133.9, 148.0, 157.6, 159.4, 169.0, 180.6. LCMS (ES+) m/z = 337.2 ([M + H]⁺, t_R = 1.83 min). HRMS (ESI+) m/z = 337.1062 [M + H]⁺ found, C₂₀H₁₇O₅⁺ required 337.1071.

4-(2-Bromoethoxy)-2H-chromen-2-one (57). A mixture of 4-hydroxycoumarin 47 (5.14 g, 31.7 mmol), 1,2-dibromoethane (3.19 mL, 37.0 mmol) and anhydrous K₂CO₃ (8.56 g, 61.9 mmol) in dry acetone (100 mL) was reacted according to GP-I. The crude residue was purified by flash column chromatography (SiO₂, CH₂Cl₂) to afford coumarin 57 (1.33g, 16%) as a white powdery solid. m.p. 176–178 °C. TLC R_f = 0.41 (PE/EtOAc 1:1). IR ν_max (neat)/cm⁻¹: 3044w (C-H str), 2982w (C-H str), 1716s (C=O str), 1627s, 1607s, 1566m (C=C str), 1496m, 1454m, 1407s, 1369s, 1330m, 1272m, 1246s, 1225s, 1184s, 1147m, 1111s, 1067w, 1034s. ¹H-NMR (500 MHz, CDCl₃): δ 3.77 (2H, t, J = 6.0 Hz, -OCH₂CH₂Br), 4.46 (2H, t, J = 6.0 Hz, -OCH₂CH₂Br), 5.68 (1H, s, -C=CH), 7.31 (1H, t, J = 8.0 Hz, ArH), 7.34 (1H, dd, J = 8.5, 0.5 Hz, ArH), 7.58 (1H, t, J = 8.5 Hz, ArH), 7.88 (1H, dd, J = 7.5, 1.5 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 27.6, 68.4, 90.9, 115.3, 116.8, 123.1, 124.0, 132.7, 153.3, 162.5, 164.9. LCMS (ES+) m/z = 271.0 ([M + H]⁺, t_R = 1.53 min). These characterisation data are in accordance with that previously reported in the literature [49].

4-(2-Azidoethoxy)-2H-chromen-2-one (58). A mixture of coumarin 57 (679 mg, 2.52 mmol) and NaN₃ (370 mg, 5.69 mmol) in dry DMF (20 mL) was reacted according to GP-J. The reaction mixture was worked up to afford coumarin 58 (571 mg, 98%) as an off-white powdery solid and was used without further purification. m.p. 150–152 °C. TLC R_f = 0.40 (1% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3075w (C-H str), 2947w (C-H str), 2125s (N₃ str), 1732s (C=O str), 1623s, 1609s, 1566s (C=C str), 1495s, 1453m, 1417s, 1371s, 1277m, 1236s, 1180s, 1147s, 1109s, 1032s. ¹H-NMR (500 MHz, CDCl₃): δ 3.75 (2H, t, J = 5.0 Hz, -OCH₂CH₂N₃), 4.32 (2H, t, J = 5.0 Hz, -OCH₂CH₂N₃), 5.70 (1H, s, -C=CH), 7.31 (1H, t, J = 8.0 Hz, ArH), 7.34 (1H, dd, J = 8.5, 0.5 Hz, ArH), 7.58 (1H, t, J = 8.5 Hz, ArH), 7.84 (1H, dd, J = 8.0, 1.5 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 49.6, 68.2, 90.9, 115.2, 116.8, 123.0, 124.1, 132.7, 153.3, 162.5, 165.1. LCMS (ES+) m/z = 232.1 ([M + H]⁺, t_R = 1.70 min). These characterisation data are in accordance with that previously reported in the literature [27].

4-(2-Bomoethoxy)benzaldehyde (59). A mixture of benzaldehyde 33 (20.0 g, 164 mmol), 1,2-dibromoethane (28.5 mL, 331 mmol) and anhydrous K₂CO₃ (46.0 g, 333 mmol) in dry acetone (100 mL) was reacted according to GP-I. The crude residue was purified by flash column chromatography (SiO₂, CH₂Cl₂) to afford benzaldehyde 59 (13.2 g, 35%) as a white powdery solid. m.p. 56–58 °C. TLC R_f = 0.41 (CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 2967w (C-H str), 1679s (C=O str), 1601s (C=C str), 1577s (C=C str), 1508m (C=C str), 1458m, 1422m, 1392m, 1317w, 1300m, 1282m, 1249s, 1229s, 1211s, 1160s, 1107w, 1068s, 1008s. ¹H-NMR (500 MHz, CDCl₃): δ 3.68 (2H, t, J = 6.4 Hz, -OCH₂CH₂Br), 4.39 (2H, t, J = 6.4 Hz, -OCH₂CH₂Br), 7.03 (2H, d, J = 8.8 Hz, ArH), 7.86 (2H, d, J = 8.8 Hz, ArH), 9.91 (1H, s, CHO). ¹³C-NMR (500 MHz, CDCl₃): δ 28.4, 67.9, 114.8, 130.5, 132.0, 163.0, 190.7. LCMS (ES+) m/z = 231.0 ([M + H]⁺, t_R = 1.56 min). These characterisation data are in accordance with that previously reported in the literature [50].

4-(2-Azidoethoxy)benzaldehyde (60). A mixture of benzaldehyde 59 (12.8 g, 56.0 mmol) and NaN₃ (7.36 g, 113 mmol) in dry DMF (100 mL) was reacted according to GP-J. The reaction mixture was worked up to afford benzaldehyde 60 (10.6 g, 99%) as a pale yellow viscous oil and was used without further purification. TLC R_f = 0.38 (CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 2942w (C-H str), 2837w (C-H str), 2100s (N₃ str), 1682s (C=O str), 1598s (C=C str), 1578s (C=C str), 1508s (C=C str), 1427w, 1395w, 1304m, 1247s, 1213s, 1157s, 1110m, 1052m, 1008w. ¹H-NMR (500 MHz, CDCl₃): δ 3.64 (2H, t, J = 5.0 Hz, -OCH₂CH₂N₃), 4.22 (2H, t, J = 5.0 Hz, -OCH₂CH₂N₃), 7.02 (2H, d, J = 8.5 Hz, ArH), 7.84 (2H, d, J = 9.0 Hz, ArH), 9.88 (1H, s, CHO). ¹³C-NMR (500 MHz, CDCl₃): δ 49.9, 67.1, 114.7, 130.3, 131.9, 163.0, 190.7. LCMS (ES+) m/z = 193.2 ([M + H]⁺, t_R = 1.62 min). These characterisation data are in accordance with that previously reported in the literature [50].

(E)-3-(4-(2-Azidoethoxy)phenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one (61). A mixture of benzaldehyde 60 (4.90 g, 25.6 mmol), acetophenone 10 (3.09 mL, 25.7 mmol) and KOH (8.70 g, 155 mmol) in absolute EtOH (100 mL) was reacted according to GP-D. The crude residue was purified by recrystallization from MeOH to afford chalcone 61 (6.13 g, 77%) as a bright yellow powdery solid. m.p. 142–144 °C. TLC R_f = 0.48 (PE/EtOAc; 2:1). IR ν_max (neat)/cm⁻¹: 2932w (C-H str), 2874w (C-H str), 2107m (N₃ str), 2070m, 1636s (C=O str), 1602s, 1575s (C=C str), 1560s (C=C str), 1508s (C=C str), 1488s, 1424m, 1345m, 1299m, 1271m, 1244m, 1201m, 1059m, 1031m. ¹H-NMR (500 MHz, CDCl₃): δ 3.63 (2H, t, J = 5.0 Hz, -OCH₂CH₂N₃), 4.19 (2H, t, J = 5.0 Hz, -OCH₂CH₂N₃), 6.93–6.98 (3H, m, ArH), 7.03 (1H, dd, J = 8.5, 1.0 Hz, ArH), 7.49 (1H, t, J = 8.5 Hz, ArH), 7.54 (1H, d, J = 15.5 Hz, -CH=CHCO-), 7.63 (2H, d, J = 8.5 Hz, ArH), 7.89 (1H, d, J = 15.5 Hz, -CH=CHCO-), 7.92 (1H, dd, J = 8.5, 2.0 Hz, ArH), 12.94 (1H, s, OH). ¹³C-NMR (500 MHz, CDCl₃): δ 50.0, 67.0, 115.0, 117.9, 118.5, 118.7, 120.0, 127.9, 129.5, 130.5, 136.2, 145.0, 160.5, 163.5, 193.5. LCMS (ES+) m/z = 310.1 ([M + H]⁺, t_R = 1.80 min). These characterisation data are in accordance with that previously reported in the literature [51].

1-(4-(2-Bromoethoxy)-3-methoxyphenyl)ethan-1-one (62). A mixture of acetophenone 11 (10.0 g, 60.3 mmol), 1,2-dibromoethane (10.5 mL, 122 mmol) and anhydrous K₂CO₃ (12.6, 91.5 mmol) in dry DMF (100 mL) was reacted according to GP-I. The crude residue was purified by flash column chromatography (SiO₂, CH₂Cl₂) to afford acetophenone 62 (3.90 g, 24%) as a white powdery solid. m.p. 98–100 °C. TLC R_f = 0.16 (CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3075w (C-H str), 2971w (C-H str), 1760w, 1671s (C=O str), 1585s (C=C str), 1507s (C=C str), 1460m, 1412s, 1385w, 1359m, 1263s, 1220s, 1171m, 1144s, 1076s, 1030s, 1008s. ¹H-NMR (500 MHz, CDCl₃): δ 2.58 (3H, s, -COCH₃), 3.70 (2H, t, J = 6.8 Hz, -OCH₂CH₂Br), 3.94 (3H, s, -OCH₃), 4.41 (2H, t, J = 6.8 Hz, -OCH₂CH₂Br), 6.91 (1H, d, J = 8.8 Hz, ArH), 7.55–7.57 (2H, m, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 26.3, 28.2, 56.1, 68.7, 111.0, 112.2, 123.0, 131.4, 149.5, 151.7, 196.7. LCMS (ES+) m/z = 275.0 ([M + H]⁺, t_R = 1.43 min). These characterisation data are in accordance with that previously reported in the literature [52].

1-(4-(2-Azidoethoxy)-3-methoxyphenyl)ethan-1-one (63). A mixture of acetophenone 62 (3.50 g, 12.8 mmol) and NaN₃ (1.25 g, 19.2 mol) in DMF (30 mL) was reacted according to GP-J. The reaction mixture was worked up to afford phenylethanone 63 (2.94 g, 98%) as a pale brown residual oil which solidified upon standing to give a pale brown crystalline solid and used without further purification. m.p. 58–60 °C. TLC R_f = 0.30 (0.5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3088w (C-H str), 2956w (C-H str), 2110s (N₃ str), 2067m, 1742w, 1671s (C=O str), 1589s (C=C str), 1508s (C=C str), 1471m, 1419s, 1355m, 1270s, 1216s, 1177m, 1151s, 1080m, 1036s. ¹H-NMR (500 MHz, CDCl₃): δ 2.56 (3H, s, -COCH₃), 3.68 (2H, t, J = 5.2 Hz, -OCH₂CH₂N₃), 3.91 (3H, s, -OCH₃), 4.23 (2H, t, J = 5.2 Hz, -OCH₂CH₂N₃), 6.89 (1H, d, J = 8.0 Hz, ArH), 7.53–7.55 (2H, m, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 26.2, 50.0, 56.0, 67.7, 110.7, 111.9, 122.9, 131.2, 149.4, 151.9, 196.7. LCMS (ES+) m/z = 236.0 ([M + H]⁺, t_R = 1.45 min). These characterisation data are in accordance with that previously reported in the literature [52].

(E)-1-(4-(2-Azidoethoxy)-3-methoxyphenyl)-3-(3,4-dimethoxyphenyl)prop-2-en-1-one (67). A mixture of benzaldehyde 64 (1.48 g, 8.91 mmol), acetophenone 63 (2.04 g, 8.67 mmol) and KOH (2.41 g, 43.0 mmol) in absolute EtOH (100 mL) was reacted according to GP-D. The crude residue was purified by flash column chromatography (SiO₂, PE/EtOAc; 5:1) and recrystallized from MeOH to afford chalcone 67 (2.61 g, 79%) as a pale yellow-green powdery solid. m.p. 106–108 °C. TLC R_f = 0.28 (PE/EtOAc; 1:1). IR ν_max (neat)/cm⁻¹: 2940w (C-H str), 2838w (C-H str), 2112s (N₃ str), 2068m, 1648s (C=O str), 1595s (C=C str), 1568s (C=C str), 1509s (C=C str), 1458m, 1419m, 1355w, 1312m, 1261s, 1242s, 1199m, 1159m, 1139s, 1036s, 1021s. ¹H-NMR (500 MHz, CDCl₃): δ 3.67 (2H, t, J = 5.2 Hz, -OCH₂CH₂N₃), 3.91 (3H, s, -OCH₃), 3.93 (3H, s, -OCH₃), 3.94 (3H, s, -OCH₃), 4.23 (2H, t, J = 5.2 Hz, -OCH₂CH₂N₃), 6.88 (1H, d, J = 8.4 Hz, ArH), 6.92 (1H, d, J = 8.0 Hz, ArH), 7.15 (1H, d, J = 2.0 Hz, ArH), 7.22 (1H, dd, J = 8.4, 2.0 Hz, ArH), 7.39 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.61–7.65 (2H, m, ArH), 7.75 (1H, d, J = 15.2 Hz, -CH=CHCO-). ¹³C-NMR (500 MHz, CDCl₃): δ 49.9, 55.8, 56.0, 67.7, 110.1, 111.0, 111.4, 111.9, 119.4, 122.4, 122.8, 127.8, 132.2, 144.2, 149.1, 149.6, 151.2, 151.7, 188.5. LCMS (ES+) m/z = 384.2 ([M + H]⁺, t_R = 3.98 min). These characterisation data are in accordance with that previously reported in the literature [52].

(E)-1-(4-(2-Azidoethoxy)-3-methoxyphenyl)-3-(2,3,4-trimethoxyphenyl)prop-2-en-1-one (68). A mixture of benzaldehyde 65 (1.70 g, 8.66 mmol), acetophenone 63 (2.02 g, 8.59 mmol) and KOH (2.39 g, 42.6 mmol) in absolute EtOH (100 mL) was reacted according to GP-D. The crude residue was purified by flash column chromatography (SiO₂, PE/EtOAc; 5:1) and recrystallized from MeOH to afford chalcone 68 (2.61 g, 74%) as a pale yellow-green powdery solid. m.p. 114–116 °C. TLC R_f = 0.35 (PE/EtOAc; 1:1). IR ν_max (neat)/cm⁻¹: 2945w (C-H str), 2836w (C-H str), 2119s (N₃ str), 2072m, 1743w, 1644m (C=O str), 1588m (C=C str), 1560s (C=C str), 1519m (C=C str), 1494s, 1466m, 1420s, 1246s, 1149s, 1093s, 1042s. ¹H-NMR (500 MHz, CDCl₃): δ 3.66 (2H, t, J = 5.2 Hz, -OCH₂CH₂N₃), 3.87 (3H, s, -OCH₃), 3.88 (3H, s, -OCH₃), 3.92 (3H, s, -OCH₃), 3.93 (3H, s, -OCH₃), 4.23 (2H, t, J = 5.0 Hz, -OCH₂CH₂N₃), 6.70 (1H, d, J = 8.8 Hz, ArH), 6.91 (1H, d, J = 8.8 Hz, ArH), 7.37 (1H, d, J = 8.8 Hz, ArH), 7.55 (1H, d, J = 16.0 Hz, -CH=CHCO-), 7.61–7.63 (2H, m, ArH), 7.97 (1H, d, J = 15.6 Hz, -CH=CHCO-). ¹³C-NMR (500 MHz, CDCl₃): δ 49.9, 55.9, 60.8, 61.2, 67.7, 107.5, 111.5, 112.0, 120.8, 121.9, 122.4, 123.7, 132.4, 139.3, 142.3, 149.6, 151.6, 153.6, 155.6, 188.9. LCMS (ES+) m/z = 414.1 ([M + H]⁺, t_R = 1.64 min). HRMS (ESI+) m/z = 414.1653 [M + H]⁺ found, C₂₁H₂₄O₆N₃⁺ required 414.1660.

(E)-1-(4-(2-Azidoethoxy)-3-methoxyphenyl)-3-(2,4,6-trimethoxyphenyl)prop-2-en-1-one (69). A mixture of benzaldehyde 66 (1.69 g, 8.61 mmol), acetophenone 63 (2.06 g, 8.76 mmol) and KOH (2.44 g, 43.5 mmol) in absolute EtOH (100 mL) was reacted according to GP-D. The crude residue was purified by recrystallization from MeOH to afford chalcone 69 (2.91 g, 82%) as a pale yellow-green powdery solid. m.p. 132–134 °C. TLC R_f = 0.29 (PE/EtOAc; 1:1). IR ν_max (neat)/cm⁻¹: 3005w (C-H str), 2939w (C-H str), 2840w (C-H str), 2112m (N₃ str), 1647m (C=O str), 1596m (C=C str), 1567s (C=C str), 1518m (C=C str), 1493w, 1451m, 1417m, 1320s, 1266m, 1213s, 1147s, 1119s, 1026s. ¹H-NMR (500 MHz, CDCl₃): δ 3.70 (2H, t, J = 5.2 Hz, -OCH₂CH₂N₃), 3.87 (3H, s, -OCH₃), 3.92 (6H, s, 2 × -OCH₃), 3.96 (3H, s, -OCH₃), 4.27 (2H, t, J = 5.2 Hz, -OCH₂CH₂N₃), 6.16 (2H, s, ArH), 6.95 (1H, d, J = 8.4 Hz, ArH), 7.62–7.65 (2H, m, ArH), 7.88 (1H, d, J = 16.0 Hz, -CH=CHCO-), 8.24 (1H, d, J = 16.0 Hz, -CH=CHCO-). ¹³C-NMR (500 MHz, CDCl₃): δ 50.1, 55.4, 55.8, 56.1, 67.8, 90.5, 106.6, 111.8, 112.2, 121.8, 122.4, 133.3, 135.4, 149.6, 151.2, 161.6, 163.0, 190.5. LCMS (ES+) m/z = 414.1 ([M + H]⁺, t_R = 1.67 min). HRMS (ESI+) m/z = 414.1654 [M + H]⁺ found, C₂₁H₂₄O₆N₃⁺ required 414.1660.

(E)-1-(4-(2-Azidoethoxy)-3-methoxyphenyl)-3-(1-methyl-1H-pyrrol-2-yl)prop-2-en-1-one (70). A mixture of pyrrole aldehyde 7 (1.40 mL, 13.0 mmol), acetophenone 63 (3.03 g, 12.9 mmol) and KOH (4.33 g, 77.2 mmol) in absolute EtOH (100 mL) was reacted according to GP-D. The crude product was purified by flash column chromatography (SiO₂, PE/EtOAc; 5:1) and recrystallized from MeOH to afford chalcone 70 as a bright yellow powdery solid (1.56 g, 37%). m.p. 124–126 °C. TLC R_f = 0.32 (PE/EtOAc; 1:1). IR ν_max (neat)/cm⁻¹: 2946w (C-H str), 2107m (N₃ str), 2064w, 1739w, 1644m (C=O str), 1595s (C=C str), 1562s (C=C str), 1515m (C=C str), 1485m, 1342s, 1272s, 1238s, 1196s, 1174s, 1125s, 1059m, 1034s. ¹H-NMR (500 MHz, CDCl₃): δ 3.70 (2H, t, J = 5.2 Hz, -OCH₂CH₂N₃), 3.78 (3H, s, -NCH₃), 3.96 (3H, s, -OCH₃), 4.27 (2H, t, J = 4.8 Hz, -OCH₂CH₂N₃), 6.23–6.24 (1H, m, ArH), 6.82 (1H, t, J = 1.6 Hz, ArH), 6.85 (1H, dd, J = 4.0, 1.6 Hz, ArH), 6.94 (1H, d, J = 8.8 Hz, ArH), 7.31 (1H, d, J = 14.8 Hz, -CH=CHCO-), 7.62–7.64 (2H, m, ArH), 7.81 (1H, d, J = 15.2 Hz, -CH=CHCO-). ¹³C-NMR (500 MHz, CDCl₃): δ 34.4, 50.1, 56.1, 67.8, 109.7, 111.5, 112.1, 112.1, 116.4, 122.2, 127.6, 130.3, 131.7, 132.7, 149.7, 151.6, 188.1. LCMS (ES+) m/z = 327.2 ([M + H]⁺, t_R = 1.82 min). HRMS (ESI+) m/z = 327.1447 [M + H]⁺ found, C₁₇H₁₉O₃N₄⁺ required 327.1452.

4-(2-Bromoethoxy)-3-methoxy benzaldehyde (72). A mixture of benzaldehyde 71 (10.0 g, 65.9 mmol), 1,2-dibromoethane (7.40 mL, 85.9 mmol) and anhydrous K₂CO₃ (11.8 g, 85.5 mmol) in dry acetone (100 mL) was reacted according to GP-I. The crude residue was purified by flash column chromatography (SiO₂, CH₂Cl₂) to afford benzaldehyde 72 (4.24 g, 25%) as a white crystalline solid. m.p. 84–86 °C. TLC R_f = 0.37 (CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 2967w (C-H str), 2849w (C-H str), 1697m (C=O str), 1682s, 1672s, 1585s (C=C str), 1508s (C=C str), 1459m, 1444m, 1427m, 1397m, 1349w, 1279m, 1266s, 1233s, 1215w, 1159w, 1134s, 1015s, 1003m. ¹H-NMR (500 MHz, CDCl₃): δ 3.70 (2H, t, J = 6.5 Hz, -OCH₂CH₂Br), 3.94 (3H, s, -OCH₃), 4.42 (2H, t, J = 6.5 Hz, -OCH₂CH₂Br), 6.99 (1H, d, J = 8.0 Hz, ArH), 7.43–7.46 (2H, m, ArH), 9.87 (1H, s, CHO). ¹³C-NMR (500 MHz, CDCl₃): δ 28.1, 56.1, 68.7, 109.8, 112.4, 126.4, 130.8, 150.0, 152.9, 190.8. LCMS (ES+) m/z = 261.0 ([M + H]⁺, t_R = 1.49 min). These characterisation data are in accordance with that previously reported in the literature [53].

3-(2-Bromoethoxy)-4-methoxy benzaldehyde (73). A mixture of isovanillin 1 (10.3 g, 68.0 mmol), 1,2-dibromoethane (7.36 mL, 85.4 mmol) and anhydrous K₂CO₃ (11.8 g, 85.7 mmol) in dry acetone (100 mL) was reacted according to GP-I. The crude residue was purified by flash column chromatography (SiO₂, CH₂Cl₂) to afford benzaldehyde 73 (3.81 g, 22%) as a white powdery solid. m.p. 88–90 °C. TLC R_f = 0.38 (CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 2978w (C-H str), 2840w (C-H str), 1677s (C=O str), 1595m (C=C str), 1582s (C=C str), 1509s (C=C str), 1462w, 1434s, 1392m, 1259s, 1238s, 1162s, 1131s, 1072w, 1013s. ¹H-NMR (500 MHz, CDCl₃): δ 3.69 (2H, t, J = 6.4 Hz, -OCH₂CH₂Br), 3.96 (3H, s, -OCH₃), 4.39 (2H, t, J = 6.4 Hz, -OCH₂CH₂Br), 7.00 (1H, d, J = 8.0 Hz, ArH), 7.41 (1H, d, J = 1.6 Hz, ArH), 7.50 (1H, dd, J = 8.0, 1.6 Hz, ArH), 9.84 (1H, s, CHO). ¹³C-NMR (500 MHz, CDCl₃): δ 28.5, 56.2, 68.8, 111.1, 111.6, 127.4, 130.0, 148.0, 155.0, 190.6. LCMS (ES+) m/z = 261.0 ([M + H]⁺, t_R = 1.47 min). These characterisation data are in accordance with that previously reported in the literature [53].

4-(2-Azidoethoxy)-3-methoxybenzaldehyde (74). A mixture of benzaldehyde 72 (3.40 g, 13.1 mmol) and NaN₃ (1.74 g, 26.8 mmol) in dry DMF (20 mL) was reacted according to GP-J. The reaction mixture was worked up to afford benzaldehyde 74 (2.84 g, 98%) as a pale yellow viscous oil and was used without further purification. TLC R_f = 0.21 (CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 2938w (C-H str), 2831w (C-H str), 2106s (N₃ str), 1679s (C=O str), 1586s (C=C str), 1507s (C=C str), 1457m, 1424m, 1396w, 1339w, 1263s, 1236m, 1194w, 1158w, 1134s, 1051w, 1030m. ¹H-NMR (500 MHz, CDCl₃): δ 3.66 (2H, t, J = 5.2 Hz, -OCH₂CH₂N₃), 3.88 (3H, s, -OCH₃), 4.22 (2H, t, J = 5.2 Hz, -OCH₂CH₂N₃), 6.95 (1H, d, J = 8.0 Hz, ArH), 7.38–7.41 (2H, m, ArH), 9.81 (1H, s, CHO). ¹³C-NMR (500 MHz, CDCl₃): δ 49.8, 55.8, 67.7, 109.5, 112.0, 126.1, 130.6, 149.9, 153.0, 190.7. LCMS (ES+) m/z = 222.0 ([M + H]⁺, t_R = 1.66 min). HRMS (ESI+) m/z = 222.0863 [M + H]⁺ found, C₁₀H₁₂O₃N₃⁺ required 222.0834.

3-(2-Azidoethoxy)-4-methoxybenzaldehyde (75). A mixture of benzaldehyde 73 (3.63 g, 14.0 mmol) and NaN₃ (1.80 g, 27.7 mmol) in dry DMF (20 mL) was reacted according to GP-J. The reaction mixture was worked up to afford benzaldehyde 75 (3.03 g, 98%) as a pale yellow viscous oil and was used without further purification. TLC R_f = 0.26 (CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 2940w (C-H str), 2838w (C-H str), 2094s (N₃ str), 1682s (C=O str), 1596s (C=C str), 1583s (C=C str), 1508s (C=C str), 1435s, 1397w, 1339w, 1261s, 1236s, 1161m, 1134s, 1125s, 1051w, 1019s. ¹H-NMR (500 MHz, CDCl₃): δ 3.68 (2H, t, J = 5.2 Hz, -OCH₂CH₂N₃), 3.96 (3H, s, -OCH₃), 4.25 (2H, t, J = 5.2 Hz, -OCH₂CH₂N₃), 7.00 (1H, d, J = 8.0 Hz, ArH), 7.42 (1H, d, J = 2.0 Hz, ArH), 7.50 (1H, dd, J = 8.4, 2.0 Hz, ArH), 9.85 (1H, s, CHO). ¹³C-NMR (500 MHz, CDCl₃): δ 50.0, 56.1, 67.9, 110.9, 111.1, 127.5, 129.9, 148.3, 155.1, 190.7. LCMS (ES+) m/z = 222.3 ([M + H]⁺, t_R = 1.69 min). HRMS (ESI+) m/z = 244.0683 [M + Na]⁺ found, C₁₀H₁₁O₃N₃Na⁺ required 244.0693.

(E)-3-(4-(2-Azidoethoxy)phenyl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (76). A mixture of benzaldehyde 60 (5.00 g, 26.2 mmol), acetophenone 3 (4.39 g, 26.4 mmol) and KOH (9.42 g, 168 mmol) in absolute EtOH (100 mL) was reacted according to GP-D. The crude residue was purified by recrystallization from MeOH to afford chalcone 76 (5.72 g, 64%) as a bright yellow-orange powdery solid. m.p. 124–126 °C. TLC R_f = 0.36 (PE/EtOAc; 2:1). IR ν_max (neat)/cm⁻¹: 2940w (C-H str), 2873w (C-H str), 2109m (N₃ str), 2073m, 1634m (C=O str), 1604m, 1573s (C=C str), 1513s (C=C str), 1445m, 1426m, 1361s, 1328m, 1307w, 1279s, 1250w, 1209s, 1184s, 1119s, 1057m, 1015s. ¹H-NMR (500 MHz, CDCl₃): δ 3.65 (2H, t, J = 5.2 Hz, -OCH₂CH₂N₃), 3.87 (3H, s, -OCH₃), 4.22 (2H, t, J = 5.2 Hz, -OCH₂CH₂N₃), 6.49–6.51 (2H, m, ArH), 6.98 (2H, d, J = 8.8 Hz, ArH), 7.48 (1H, d, J = 15.2 Hz, -CH=CHCO-), 7.63 (2H, d, J = 8.8 Hz, ArH), 7.84 (1H, d, J = 9.2 Hz, ArH), 7.87 (1H, d, J = 15.6 Hz, -CH=CHCO-), 13.52 (1H, s, OH). ¹³C-NMR (500 MHz, CDCl₃): δ 50.6, 55.6, 67.1, 101.0, 107.7, 114.1, 115.0, 118.3, 128.2, 130.4, 131.1, 144.0, 160.3, 166.1, 166.6, 191.8. LCMS (ES+) m/z = 340.2 ([M + H]⁺, t_R = 1.74 min). HRMS (ESI+) m/z = 340.1295 [M + H]⁺ found, C₁₈H₁₈N₃O₄⁺ required 340.1297.

(E)-3-(4-(2-Azidoethoxy)-3-methoxyphenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one (77). A mixture of benzaldehyde 74 (2.70 g, 12.2 mmol), acetophenone 10 (1.50 mL, 12.5 mmol) and KOH (4.30 g, 76.6 mmol) in absolute EtOH (100 mL) was reacted according to GP-D. The crude residue was purified by flash column chromatography (SiO₂, PE/EtOAc; 5:1) to afford chalcone 77 (1.91 g, 46%) as a bright yellow-orange powdery solid. m.p. 84–86 °C. TLC R_f = 0.25 (PE/EtOAc; 3:1). IR ν_max (neat)/cm⁻¹: 2935w (C-H str), 2876w (C-H str), 2106s (N₃ str), 1635s (C=O str), 1580m (C=C str), 1562s (C=C str), 1508s (C=C str), 1489s, 1462w, 1441w, 1421w, 1372w, 1313w, 1255s, 1201s, 1168w, 1138s, 1057w, 1028s. ¹H-NMR (500 MHz, CDCl₃): δ 3.68 (2H, t, J = 5.5 Hz, -OCH₂CH₂N₃), 3.95 (3H, s, -OCH₃), 4.24 (2H, t, J = 5.5 Hz, -OCH₂CH₂N₃), 6.92 (1H, d, J = 8.0 Hz, ArH), 6.93–6.96 (1H, m, ArH), 7.03 (1H, dd, J = 8.5, 1.5 Hz, ArH), 7.19 (1H, d, J = 2.0 Hz, ArH), 7.25 (1H, dd, J = 8.5, 1.5 Hz, ArH), 7.50 (1H, t, J = 8.5 Hz, ArH), 7.53 (1H, d, J = 15.5 Hz, -CH=CHCO-), 7.87 (1H, d, J = 15.5 Hz, -CH=CHCO-), 7.93 (1H, dd, J = 8.0, 1.5 Hz, ArH), 12.91 (1H, s, OH). ¹³C-NMR (500 MHz, CDCl₃): δ 50.1, 56.1, 67.9, 111.2, 113.4, 118.2, 118.5, 118.7, 120.0, 123.1, 128.5, 129.5, 136.2, 145.4, 149.9, 150.5, 163.5, 193.5. LCMS (ES+) m/z = 340.3 ([M + H]⁺, t_R = 1.96 min). HRMS (ESI+) m/z = 340.1296 [M + H]⁺ found, C₁₈H₁₈N₃O₄⁺ required 340.1297.

(E)-3-(3-(2-Azidoethoxy)-4-methoxyphenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one (78). A mixture of benzaldehyde 75 (3.00 g, 13.6 mmol), acetophenone 10 (1.63 mL, 13.6 mmol) and KOH (4.57 g, 81.4 mmol) in absolute EtOH (100 mL) was reacted according to GP-D. The crude residue was purified by flash column chromatography (SiO₂, PE/EtOAc; 5:1) to afford chalcone 78 (2.72 g, 59%) as a bright yellow powdery solid. m.p. 98–100 °C. TLC R_f = 0.33 (PE/EtOAc; 3:1). IR ν_max (neat)/cm⁻¹: 3009w (C-H str), 2970w (C-H str), 2112m (N₃ str), 2067w, 1738s (C=O str), 1634s, 1567s (C=C str), 1511s (C=C str), 1490s, 1440m, 1374s, 1315m, 1266s, 1227s, 1204s, 1142s, 1024s. ¹H-NMR (500 MHz, CDCl₃): δ 3.66 (2H, t, J = 5.0 Hz, -OCH₂CH₂N₃), 3.89 (3H, s, -OCH₃), 4.22 (2H, t, J = 5.0 Hz, -OCH₂CH₂N₃), 6.90 (1H, d, J = 8.5 Hz, ArH), 6.91 (1H, t, J = 8.5 Hz, ArH), 7.00 (1H, dd, J = 8.5, 1.0 Hz, ArH), 7.19 (1H, d, J = 2.5 Hz, ArH), 7.27 (1H, dd, J = 8.0, 2.0 Hz, ArH, overlain by CDCl₃), 7.46 (1H, t, J = 7.5 Hz, ArH), 7.48 (1H, d, J = 15.0 Hz, -CH=CHCO-), 7.82 (1H, d, J = 15.0 Hz, -CH=CHCO-), 7.90 (1H, dd, J = 8.0, 1.5 Hz, ArH), 12.95 (1H, s, OH). ¹³C-NMR (500 MHz, CDCl₃): δ 50.1, 55.8, 68.2, 111.7, 113.4, 117.7, 118.4, 118.6, 119.9, 124.6, 127.3, 129.4, 136.1, 145.2, 147.9, 152.5, 163.4, 193.3. LCMS (ES+) m/z = 340.3 ([M + H]⁺, t_R = 1.97 min). HRMS (ESI+) m/z = 340.1301 [M + H]⁺ found, C₁₈H₁₈N₃O₄⁺ required 340.1297.

4′-(2-Azidoethoxy)-3-hydroxyflavone (79). A mixture of chalcone 61 (2.02 g, 6.53 mmol), 16% NaOH (12.9 mL) and 15% H₂O₂ (6.47 mL) in MeOH (50 mL) was reacted according to GP-F. The crude residue was purified by flash column chromatography (SiO₂, 1% MeOH/CH₂Cl₂) to afford flavonol 79 (1.68 g, 80%) as an off-white fluffy solid. m.p. 158–160 °C. TLC R_f = 0.39 (0.5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3235w(br) (O-H str), 2957w (C-H str), 2942w (C-H str), 2140m (N₃ str), 2091m, 1739w, 1604s (C=O str), 1574m (C=C str), 1512s (C=C str), 1478m, 1425m, 1406m, 1346m, 1254s, 1201s, 1182s, 1117s, 1107s, 1057s. ¹H-NMR (500 MHz, CDCl₃): δ 3.66 (2H, t, J = 5.2 Hz, -OCH₂CH₂N₃), 4.24 (2H, t, J = 5.2 Hz, -OCH₂CH₂N₃), 7.03 (1H, br s, OH), 7.07 (2H, d, J = 8.8 Hz, ArH), 7.41 (1H, t, J = 7.6 Hz, ArH), 7.58 (1H, d, J = 8.4 Hz, ArH), 7.70 (1H, t, J = 8.4 Hz, ArH), 8.25 (3H, d, J = 8.8 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 50.1, 67.0, 114.6, 118.1, 120.7, 124.2, 124.4, 125.4, 129.6, 133.4, 137.7, 145.0, 155.2, 159.6, 173.1. LCMS (ES+) m/z = 324.1 ([M + H]⁺, t_R = 1.66 min). These characterisation data are in accordance with that previously reported in the literature [51].

4′-(2-Azidoethoxy)-3-hydroxy-7-methoxyflavone (80). A mixture of chalcone 74 (1.06 g, 3.12 mmol), 16% NaOH (5.89 mL) and 15% H₂O₂ (2.95 mL) in MeOH (30 mL) was reacted according to GP-F. The crude residue was purified by flash column chromatography (SiO₂, 1% MeOH/CH₂Cl₂) to afford flavonol 80 (677 mg, 61%) as an off-white powdery solid. m.p. 172–174 °C. TLC R_f = 0.39 (1% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3269w(br) (O-H str), 2932w (C-H str), 2116s (N₃ str), 2073m, 1597s (C=O str), 1561s (C=C str), 1504s (C=C str), 1451m, 1403m, 1256s, 1239s, 1203s, 1171s, 1114m, 1098m, 1050m, 1026m. ¹H-NMR (500 MHz, CDCl₃): δ 3.66 (2H, t, J = 5.2 Hz, -OCH₂CH₂N₃), 3.94 (3H, s, -OCH₃), 4.23 (2H, t, J = 5.2 Hz, -OCH₂CH₂N₃), 6.94 (1H, d, J = 2.0 Hz, ArH), 6.98 (1H, dd, J = 8.8, 2.0 Hz, ArH), 7.04 (1H, br s, OH), 7.05 (2H, d, J = 9.2 Hz, ArH), 8.12 (1H, d, J = 8.8 Hz, ArH), 8.21 (2H, d, J = 8.8 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 50.1, 55.8, 67.0, 99.8, 114.5, 114.6, 114.7, 124.3, 126.6, 129.2, 137.4, 144.3, 157.1, 159.3, 164.1, 172.6. LCMS (ES+) m/z = 354.2 ([M + H]⁺, t_R = 1.90 min). HRMS (ESI+) m/z = 354.1074 [M + H]⁺ found, C₁₈H₁₆O₅N₃⁺ required 354.1084.

4′-(2-Azidoethoxy)-3-hydroxy-3′-methoxyflavone (81). A mixture of chalcone 77 (519 mg, 1.53 mmol), 16% NaOH (2.95 mL) and 15% H₂O₂ (1.47 mL) in MeOH (20 mL) was reacted according to GP-F. The crude residue was purified by flash column chromatography (SiO₂, 1% MeOH/CH₂Cl₂) to afford flavonol 81 (418 mg, 77%) as a pale yellow-white powdery solid. m.p. 118–120 °C. TLC R_f = 0.45 (0.5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3224w(br) (O-H str), 2924w (C-H str), 2125s (N₃ str), 1614s (C=O str), 1567m (C=C str), 1514s (C=C str), 1481m, 1470m, 1409s, 1269s, 1202s, 1183m, 1146s, 1121m, 1035m, 1006m. ¹H-NMR (500 MHz, CDCl₃): δ 3.71 (2H, t, J = 5.2 Hz, -OCH₂CH₂N₃), 3.99 (3H, s, -OCH₃), 4.29 (2H, t, J = 5.2 Hz, -OCH₂CH₂N₃), 7.01 (1H, br s, OH), 7.05 (1H, d, J = 9.2 Hz, ArH), 7.43 (1H, t, J = 7.2 Hz, ArH), 7.60 (1H, d, J = 8.4 Hz, ArH), 7.72 (1H, t, J = 8.4 Hz, ArH), 7.87–7.89 (2H, m, ArH), 8.26 (1H, dd, J = 8.0, 1.2 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 50.1, 56.2, 67.9, 111.6, 113.3, 118.2, 120.6, 121.3, 124.5, 124.8, 125.4, 133.5, 137.9, 144.8, 149.5, 149.5, 155.3, 173.2. LCMS (ES+) m/z = 354.2 ([M + H]⁺, t_R = 1.86 min). HRMS (ESI+) m/z = 354.1095 [M + H]⁺ found, C₁₈H₁₆N₃O₅⁺ required 354.1090.

3′-(2-Azidoethoxy)-3-hydroxy-4′-methoxyflavone (82). A mixture of chalcone 78 (513 mg, 1.51 mmol), 16% NaOH (2.95 mL) and 15% H₂O₂ (1.47 mL) in MeOH (20 mL) was reacted according to GP-F. The crude residue was purified by flash column chromatography (SiO₂, 1% MeOH/CH₂Cl₂) to afford flavonol 82 (419 mg, 78%) as a pale yellow-white powdery solid. m.p. 164–166 °C. TLC R_f = 0.31 (0.5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3199m(br) (O-H str), 2974w (C-H str), 2942w (C-H str), 2105s (N₃ str), 1611s (C=O str), 1599m (C=O str), 1564s (C=C str), 1516s (C=C str), 1480s, 1463m, 1412s, 1350m, 1264s, 1203s, 1179s, 1141s, 1012s. ¹H-NMR (500 MHz, CDCl₃): δ 3.71 (2H, t, J = 5.2 Hz, -OCH₂CH₂N₃), 3.97 (3H, s, -OCH₃), 4.31 (2H, t, J = 5.2 Hz, -OCH₂CH₂N₃), 7.01 (1H, br s, OH), 7.06 (1H, d, J = 8.4 Hz, ArH), 7.43 (1H, t, J = 7.6 Hz, ArH), 7.60 (1H, d, J = 8.4 Hz, ArH), 7.71 (1H, t, J = 8.4 Hz, ArH), 7.91 (1H, d, J = 2.0 Hz, ArH), 7.96 (1H, dd, J = 8.8, 2.0 Hz, ArH), 8.26 (1H, dd, J = 8.0, 1.2 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 50.2, 56.0, 68.3, 111.7, 113.8, 118.2, 120.6, 122.6, 123.7, 124.5, 125.4, 133.5, 137.8, 144.8, 147.6, 151.6, 155.2, 173.1. LCMS (ES+) m/z = 354.2 ([M + H]⁺, t_R = 1.86 min). HRMS (ESI+) m/z = 354.1096 [M + H]⁺ found, C₁₈H₁₆N₃O₅⁺ required 354.1090.

6-(2-Bromoethoxy)flavone (83). A mixture of flavone 28 (1.02 g, 4.28 mmol), 1,2-dibromoethane (0.47 mL, 5.46 mmol) and anhydrous K₂CO₃ (782 mg, 5.66 mmol) in dry acetone (50 mL) was reacted according to GP-I. The crude residue was purified by flash column chromatography (SiO₂, CH₂Cl₂) to afford flavone 83 (328 mg, 22%) as a white powdery solid. m.p. 180–182 °C. TLC R_f = 0.33 (1% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3026w (C-H str), 2938w (C-H str), 2887w (C-H str), 1637s (C=O str), 1617m, 1586m (C=C str), 1568m (C=C str), 1482m, 1468m, 1447s, 1358s, 1313w, 1254m, 1200m, 1084m, 1030m, 1017s. ¹H-NMR (500 MHz, CDCl₃): δ 3.69 (2H, t, J = 6.0 Hz, -OCH₂CH₂Br), 4.41 (2H, t, J = 6.0 Hz, -OCH₂CH₂Br), 6.82 (1H, s, -C=CH), 7.34 (1H, dd, J = 9.2, 3.2 Hz, ArH), 7.50–7.54 (4H, m, ArH), 7.58 (1H, d, J = 3.2 Hz, ArH), 7.91–7.93 (2H, m, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 28.9, 68.4, 105.9, 106.8, 119.8, 124.1, 124.5, 126.2, 129.0, 131.5, 131.7, 151.3, 155.4, 163.2, 178.1. LCMS (ES+) m/z = 347.0 ([M + H]⁺, t_R = 1.66 min). These characterisation data are in accordance with that previously reported in the literature [54].

7-(2-Bromoethoxy)flavone (84). A mixture of flavone 29 (1.59 g, 6.67 mmol), 1,2-dibromoethane (0.71 mL, 8.19 mmol) and anhydrous K₂CO₃ (1.20 g, 8.68 mmol) in dry acetone (50 mL) was reacted according to GP-I. The crude residue was purified by flash column chromatography (SiO₂, 1% MeOH/CH₂Cl₂) to afford flavone 84 (1.50 g, 65%) as a white powdery solid. m.p. 150–152 °C. TLC R_f = 0.22 (1% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3045w (C-H str), 2934w (C-H str), 2864w (C-H str), 1628s (C=O str), 1604s, 1594s (C=C str), 1567m (C=C str), 1494m, 1439m, 1372s, 1356s, 1282s, 1250s, 1227s, 1171s, 1131m, 1089s, 1013m. ¹H-NMR (500 MHz, CDCl₃): δ 3.70 (2H, t, J = 6.0 Hz, -OCH₂CH₂Br), 4.41 (2H, t, J = 6.0 Hz, -OCH₂CH₂Br), 6.76 (1H, s, -C=CH), 6.97 (1H, d, J = 2.4 Hz, ArH), 7.00 (1H, dd, J = 8.8, 2.4 Hz, ArH), 7.49–7.54 (3H, m, ArH), 7.88–7.91 (2H, m, ArH), 8.14 (1H, d, J = 8.8 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 28.3, 68.2, 101.3, 107.5, 114.4, 118.3, 126.1, 127.3, 129.0, 131.4, 131.7, 157.8, 162.4, 163.0, 177.7. LCMS (ES+) m/z = 347.0 ([M + H]⁺, t_R = 1.69 min). These characterisation data are in accordance with that previously reported in the literature [28].

6-(2-Azidoethoxy)flavone (85). A mixture of flavone 83 (824 mg, 2.39 mmol) and NaN₃ (336 mg, 5.17 mmol) in dry DMF (20 mL) was reacted according to GP-J. The reaction mixture was worked up to afford flavone 85 (686 mg, 93%) as a white powdery solid and was used without further purification. m.p. 138–140 °C. TLC R_f = 0.27 (1% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3073w (C-H str), 2930w (C-H str), 2107s (N₃ str), 2063m, 1625s, 1616s (C=O str), 1603s, 1582s (C=C str), 1569s (C=C str), 1480s, 1455s, 1363s, 1291s, 1262m, 1242s, 1203s, 1130s, 1083m. ¹H-NMR (500 MHz, CDCl₃): δ 3.65 (2H, t, J = 4.8 Hz, -OCH₂CH₂N₃), 4.26 (2H, t, J = 4.8 Hz, -OCH₂CH₂N₃), 6.81 (1H, s, -C=CH), 7.34 (1H, dd, J = 8.8, 2.8 Hz, ArH), 7.51–7.54 (4H, m, ArH), 7.59 (1H, d, J = 2.8 Hz, ArH), 7.90–7.93 (2H, m, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 50.0, 67.5, 105.6, 106.9, 119.8, 124.2, 124.5, 126.2, 129.0, 131.5, 131.8, 151.3, 155.5, 163.3, 178.1. LCMS (ES+) m/z = 308.2 ([M + H]⁺, t_R = 1.68 min). HRMS (ESI+) m/z = 330.0836 [M + Na]⁺ found, C₁₇H₁₃O₃N₃Na⁺ required 330.0849.

7-(2-Azidoethoxy)flavone (86). A mixture of flavone 84 (1.03 g, 3.00 mmol) and NaN₃ (444 mg, 6.83 mmol) in dry DMF (20 mL) was reacted according to GP-J. The reaction mixture was worked up to afford flavone 86 (838 mg, 91%) as an off-white powdery solid and was used without further purification. m.p. 108–110 °C. TLC R_f = 0.23 (1% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3073w (C-H str), 2979w (C-H str), 2926w (C-H str), 2105m (N₃ str), 1631s (C=O str), 1601s, 1578m (C=C str), 1569m (C=C str), 1493w, 1447s, 1375m, 1358m, 1303m, 1244s, 1177s, 1130m, 1085s. ¹H-NMR (500 MHz, CDCl₃): δ 3.68 (2H, t, J = 5.0 Hz, -OCH₂CH₂N₃), 4.26 (2H, t, J = 5.0 Hz, -OCH₂CH₂N₃), 6.75 (1H, s, -C=CH), 6.97 (1H, d, J = 2.0 Hz, ArH), 6.99 (1H, dd, J = 8.5, 2.0 Hz, ArH), 7.48–7.54 (3H, m, ArH), 7.88 (2H, dd, J = 8.0, 2.0 Hz, ArH), 8.13 (1H, d, J = 8.5 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 49.8, 67.4, 101.3, 107.5, 114.3, 118.2, 126.1, 127.2, 128.9, 131.4, 131.6, 157.7, 162.6, 163.0, 177.6. LCMS (ES+) m/z = 308.0 ([M + H]⁺, t_R = 4.43 min). These characterisation data are in accordance with that previously reported in the literature [10].

4’-(2-Azidoethoxy)-7-methoxyflavone (87). To a stirred solution of chalcone 76 (1.02 g, 3.01 mmol) in DMSO (20 mL) was added a catalytic amount of I₂ (103 mg, 0.407 mmol). The reaction mixture was heated at 130 °C with stirring for 24 h under a nitrogen atmosphere. The resulting mixture was allowed to cool to room temperature and poured into H₂O (50 mL). The aqueous solution was extracted with CHCl₃ (2 × 100 mL) and the combined organic layer was washed with H₂O (2 × 50 mL), brine (2 × 50 mL), dried over anhydrous MgSO₄, filtered and the solvent removed under reduced pressure. The crude residue was purified by flash column chromatography (SiO₂, 1% MeOH/CH₂Cl₂) to afford flavone 87 (924 mg, 91%) as a pale yellow-white powdery solid. m.p. 128–130 °C. TLC R_f = 0.35 (3% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 2946w (C-H str), 2839w (C-H str), 2097s (N₃ str), 1644s (C=O str), 1626s, 1598s (C=C str), 1510s (C=C str), 1503s (C=C str), 1440s, 1376m, 1355s, 1247s, 1182s, 1164m, 1141w, 1091m, 1023m. ¹H-NMR (500 MHz, CDCl₃): δ 3.65 (2H, t, J = 5.2 Hz, -OCH₂CH₂N₃), 3.92 (3H, s, -OCH₃), 4.22 (2H, t, J = 5.2 Hz, -OCH₂CH₂N₃), 6.66 (1H, s, -C=CH), 6.94 (1H, d, J = 2.4 Hz, ArH), 6.96 (1H, dd, J = 8.8, 2.4 Hz, ArH), 7.02 (2H, d, J = 9.2 Hz, ArH), 7.85 (2H, d, J = 9.2 Hz, ArH), 8.11 (1H, d, J = 8.8 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 50.0, 55.8, 67.1, 100.3, 106.2, 114.2, 114.9, 117.7, 124.7, 126.9, 127.8, 157.8, 160.7, 162.7, 164.0, 177.7. LCMS (ES+) m/z = 338.2 ([M + H]⁺, t_R = 1.84 min). HRMS (ESI+) m/z = 338.1147 [M + H]⁺ found, C₁₈H₁₆N₃O₄⁺ required 338.1141.

4′-(2-Azidoethoxy)aurone (88). A mixture of chalcone 61 (403 mg, 1.30 mmol) and Hg(OAc)₂ (440 mg, 1.38 mmol) in dry pyridine (15 mL) was reacted according to GP-K. The crude residue was purified by flash column chromatography (SiO₂, PE/EtOAc; 3:1) to afford aurone 88 (354 mg, 88%) as a bright yellow powdery solid. m.p. 114–116 °C. TLC R_f = 0.37 (PE/EtOAc; 2:1). IR ν_max (neat)/cm⁻¹: 2945w (C-H str), 2888w (C-H str), 2096s (N₃ str), 2062m, 1699s (C=O str), 1649s, 1592s (C=C str), 1510m (C=C str), 1474m, 1461m, 1395w, 1347m, 1301s, 1257s, 1177s, 1130m, 1111m, 1097w, 1048s, 1009w. ¹H-NMR (500 MHz, CDCl₃): δ 3.65 (2H, t, J = 4.8 Hz, -OCH₂CH₂N₃), 4.22 (2H, t, J = 4.8 Hz, -OCH₂CH₂N₃), 6.89 (1H, s, -C=CH), 7.01 (2H, d, J = 8.8 Hz, ArH), 7.22 (1H, t, J = 7.6 Hz, ArH), 7.33 (1H, d, J = 8.4 Hz, ArH), 7.65 (1H, t, J = 8.4 Hz, ArH), 7.82 (1H, dd, J = 7.6, 0.4 Hz, ArH), 7.91 (2H, d, J = 8.8 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 50.0, 67.0, 112.9, 113.0, 115.0, 121.8, 123.3, 124.6, 125.7, 133.4, 136.6, 146.0, 159.6, 165.9, 184.6. LCMS (ES+) m/z = 308.2 ([M + H]⁺, t_R = 1.73 min). HRMS (ESI+) m/z = 308.1035 [M + H]⁺ found, C₁₇H₁₄O₃N₃⁺ required 308.1035.

4′-(2-Azidoethoxy)-6-methoxyaurone (89). A mixture of chalcone 76 (2.01 g, 5.91 mmol) and Hg(OAc)₂ (1.95 g, 6.13 mmol) in dry pyridine (50 mL) was reacted according to GP-K. The crude residue was purified by flash column chromatography (SiO₂, 0.5% MeOH/CH₂Cl₂) to afford aurone 89 (1.91 g, 96%) as a bright yellow-orange powdery solid. m.p. 108–110 °C. TLC R_f = 0.36 (0.5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3008w (C-H str), 2970w (C-H str), 2092s (N₃ str), 1694m (C=O str), 1652m, 1594s (C=C str), 1570m (C=C str), 1512m (C=C str), 1443m, 1414w, 1349m, 1315w, 1271m, 1248s, 1185m, 1131s, 1110s, 1068w, 1035m. ¹H-NMR (500 MHz, CDCl₃): δ 3.63 (2H, t, J = 4.8 Hz, -OCH₂CH₂N₃), 3.91 (3H, s, -OCH₃), 4.19 (2H, t, J = 4.8 Hz, -OCH₂CH₂N₃), 6.72–6.74 (2H, m, ArH), 6.76 (1H, s, -C=CH), 6.97 (2H, d, J = 8.8 Hz, ArH), 7.68 (1H, d, J = 8.8 Hz, ArH), 7.83 (2H, d, J = 8.8 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 50.0, 55.9, 66.9, 96.5, 111.7, 112.0, 114.9, 115.0, 125.6, 125.7, 133.1, 146.8, 159.3, 167.2, 168.2, 182.8. LCMS (ES+) m/z = 338.2 ([M + H]⁺, t_R = 1.65 min). HRMS (ESI+) m/z = 338.1146 [M + H]⁺ found, C₁₈H₁₆N₃O₄⁺ required 338.1141.

3.3. Synthesis of Triazole-Bridged Flavonoid Dimers and Trimers

(E)-3-(3,4-Dimethoxyphenyl)-1-(3-methoxy-4-(2-(4-((2-methoxy-4-((E)-3-(4-methoxyphenyl)acryloyl))methyl)-1H-1,2,3-triazol-1-yl)ethoxy)phenyl)prop-2-en-1-one (90). A mixture of alkyne chalcone 20 (254 mg, 0.789 mmol), azide chalcone 67 (305 mg, 0.796 mmol), CuSO₄·5H₂O (225 mg, 0.900 mmol) and sodium ascorbate (389 mg, 1.97 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH to afford triazole hybrid 90 (151 mg, 27%) as a pale yellow-brown powdery solid. m.p. 108–110 °C. TLC R_f = 0.41 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 2942w (C-H str), 2837w (C-H str), 1652m (C=O str), 1595m (C=C str), 1572m (C=C str), 1509s (C=C str), 1464m, 1420m, 1335w, 1307w, 1255s, 1195w, 1143s, 1021s. ¹H-NMR (500 MHz, CDCl₃): δ 3.86 (3H, s, -OCH₃), 3.92 (3H, s, -OCH₃), 3.94 (3H, s, -OCH₃), 3.95 (3H, s, -OCH₃), 3.96 (3H, s, -OCH₃), 4.46 (2H, t, J = 5.2 Hz, -OCH₂CH₂N-), 4.84 (2H, t, J = 5.2 Hz, -OCH₂CH₂N-), 5.40 (2H, s, -OCH₂CN-), 6.82 (1H, d, J = 8.0 Hz, ArH), 6.90 (1H, d, J = 8.4 Hz, ArH), 6.93 (2H, d, J = 8.8 Hz, ArH), 7.14–7.17 (2H, m, ArH), 7.24 (1H, dd, J = 8.4, 2.0 Hz, ArH), 7.37 (1H, d, J = 15.2 Hz, -CH=CHCO-), 7.41 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.57–7.62 (6H, m, ArH), 7.75 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.77 (1H, d, J = 15.6 Hz, -CH=CHCO-), 8.04 (1H, s, -CHN-). ¹³C-NMR (500 MHz, CDCl₃): δ 49.8, 55.4, 56.0, 56.0, 62.9, 67.6, 110.2, 111.1, 111.1, 111.5, 112.3, 112.4, 114.4, 119.2, 119.4, 122.5, 122.6, 123.0, 124.7, 127.7, 127.9, 130.1, 132.1, 132.8, 143.7, 144.0, 144.5, 149.2, 149.5, 149.7, 151.2, 151.4, 151.6, 161.5, 188.6. LCMS (ES+) m/z = 706.2 ([M + H]⁺, t_R = 1.65 min). HRMS (ESI+) m/z = 728.2576 [M + Na]⁺ found, C₄₀H₃₉O₉N₃Na⁺ required 728.2579.

(E)-1-(3-Methoxy-4-((1-(2-(2-methoxy-4-((E)-3-(2,4,6-trimethoxyphenyl)acryloyl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (91). A mixture of alkyne chalcone 20 (234 mg, 0.727 mmol), azide chalcone 69 (303 mg, 0.732 mmol), CuSO₄·5H₂O (203 mg, 0.813 mmol) and sodium ascorbate (361 mg, 1.82 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH to afford triazole hybrid 91 (250 mg, 47%) as a pale yellow-white flaky solid. m.p. 206–208 °C. TLC R_f = 0.44 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3150w (C-H str), 2942w (C-H str), 1661m (C=O str), 1601s (C=C str), 1572s (C=C str), 1514s (C=C str), 1459m, 1416m, 1324s, 1295m, 1262s, 1228m, 1166s, 1150s, 1126s, 1053w, 1015s. ¹H-NMR (500 MHz, CDCl₃): δ 3.86 (3H, s, -OCH₃), 3.87 (3H, s, -OCH₃), 3.91 (6H, s, 2 × -OCH₃), 3.92 (3H, s, -OCH₃), 3.95 (3H, s, -OCH₃), 4.46 (2H, t, J = 5.2 Hz, -OCH₂CH₂N-), 4.84 (2H, t, J = 5.2 Hz, -OCH₂CH₂N-), 5.40 (2H, s, -OCH₂CN-), 6.15 (2H, s, ArH), 6.85 (1H, d, J = 8.4 Hz, ArH), 6.94 (2H, d, J = 8.8 Hz, ArH), 7.17 (1H, d, J = 8.8 Hz, ArH), 7.42 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.58–7.65 (6H, m, ArH), 7.78 (1H, d, J = 15.2 Hz, -CH=CHCO-), 7.85 (1H, d, J = 16.0 Hz, -CH=CHCO-), 8.05 (1H, s, -CHN-), 8.23 (1H, d, J = 16.0 Hz, -CH=CHCO-). ¹³C-NMR (500 MHz, CDCl₃): δ 49.8, 55.4, 55.8, 55.9, 56.0, 62.9, 67.5, 90.5, 106.6, 111.1, 111.7, 112.3, 112.4, 114.4, 119.3, 121.6, 122.3, 122.6, 124.7, 127.8, 130.1, 132.1, 133.7, 135.6, 143.7, 143.9, 149.5, 149.5, 150.6, 151.6, 161.5, 161.7, 163.0, 188.6, 190.3. LCMS (ES+) m/z = 736.2 ([M + H]⁺, t_R = 1.67 min). HRMS (ESI+) m/z = 736.2892 [M + H]⁺ found, C₄₁H₄₂O₁₀N₃⁺ required 736.2865.

(E)-1-(2-Hydroxy-4-methoxyphenyl)-3-(4-methoxy-3-((1-(2-(2-methoxy-4-((E)-3-(2,4,6-trimethoxyphenyl)acryloyl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)prop-2-en-1-one (92). A mixture of alkyne chalcone 4 (167 mg, 0.494 mmol), azide chalcone 69 (206 mg, 0.498 mmol), CuSO₄·5H₂O (140 mg, 0.560 mmol) and sodium ascorbate (253 mg, 1.28 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH to afford triazole hybrid 92 (236 mg, 64%) as a bright yellow flaky solid. m.p. 208–210 °C. TLC R_f = 0.48 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 2931w (C-H str), 2842w (C-H str), 1632m (C=O str), 1597m (C=C str), 1568s (C=C str), 1509s (C=C str), 1455w, 1419w, 1371m, 1318m, 1259s, 1232s, 1211s, 1153s, 1123s, 1021m, 1004m. ¹H-NMR (500 MHz, CDCl₃): δ 3.86 (3H, s, -OCH₃), 3.87 (3H, s, -OCH₃), 3.91 (3H, s, -OCH₃), 3.91 (9H, s, 3 × -OCH₃), 4.45 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 4.84 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 5.38 (2H, s, -OCH₂CN-), 6.14 (2H, s, ArH), 6.46 (1H, d, J = 2.4 Hz, ArH), 6.50 (1H, dd, J = 8.8, 2.4 Hz, ArH), 6.81 (1H, d, J = 8.4 Hz, ArH), 6.89 (1H, d, J = 2.4 Hz, ArH), 7.21 (1H, dd, J = 8.0, 2.0 Hz, ArH), 7.45 (1H, d, J = 15.2 Hz, -CH=CHCO-), 7.46 (1H, d, J = 1.6 Hz, ArH), 7.55 (1H, dd, J = 8.4, 1.6 Hz, ArH), 7.61 (1H, d, J = 1.6 Hz, ArH), 7.77 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.85 (1H, d, J = 16.0 Hz, -CH=CHCO-), 7.89 (1H, d, J = 8.8 Hz, ArH), 8.05 (1H, s, -CHN-), 8.23 (1H, d, J = 16.0 Hz, -CH=CHCO-), 13.55 (1H, s, OH). ¹³C-NMR (500 MHz, CDCl₃): δ 49.8, 55.4, 55.5, 55.8, 55.9, 56.0, 63.2, 67.6, 90.5, 101.0, 106.6, 107.6, 111.5, 111.6, 112.3, 113.0, 114.2, 118.4, 121.5, 122.3, 124.3, 124.7, 127.8, 131.3, 133.7, 135.6, 144.0, 144.1, 147.8, 149.4, 150.6, 152.0, 161.7, 163.0, 166.0, 166.6, 190.3, 191.8. LCMS (ES+) m/z = 752.2 ([M + H]⁺, t_R = 1.74 min). HRMS (ESI+) m/z = 752.2822 [M + H]⁺ found, C₄₁H₄₂O₁₁N₃⁺ required 752.2814.

(E)-1-(3-Methoxy-4-((1-(2-(2-methoxy-4-((E)-3-(2,3,4-trimethoxyphenyl)acryloyl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (93). A mixture of alkyne chalcone 20 (235 mg, 0.729 mmol), azide chalcone 68 (303 mg, 0.733 mmol), CuSO₄·5H₂O (271 mg, 1.09 mmol) and sodium ascorbate (414 mg, 2.09 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH to afford triazole hybrid 93 (515 mg, 96%) as a pale yellow-green flaky solid. m.p. 128–130 °C. TLC R_f = 0.30 (4% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 2937w (C-H str), 2836w (C-H str), 1652m (C=O str), 1595s (C=C str), 1572s (C=C str), 1510s (C=C str), 1494s, 1463s, 1415s, 1326w, 1255s, 1193w, 1148s, 1095s, 1021s. ¹H-NMR (500 MHz, CDCl₃): δ 3.86 (3H, s, -OCH₃), 3.90 (3H, s, -OCH₃), 3.92 (6H, s, 2 × -OCH₃), 3.95 (6H, s, 2 × -OCH₃), 4.47 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 4.84 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 5.40 (2H, s, -OCH₂CN-), 6.73 (1H, d, J = 8.8 Hz, ArH), 6.84 (1H, d, J = 8.4 Hz, ArH), 6.94 (2H, d, J = 8.8 Hz, ArH), 7.17 (1H, d, J = 8.8 Hz, ArH), 7.39 (1H, d, J = 8.8 Hz, ArH), 7.42 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.54 (1H, d, J = 16.0 Hz, -CH=CHCO-), 7.59–7.64 (6H, m, ArH), 7.78 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.98 (1H, d, J = 16.0 Hz, -CH=CHCO-), 8.05 (1H, s, -CHN-). ¹³C-NMR (500 MHz, CDCl₃): δ 49.7, 55.4, 56.0, 56.0, 56.1, 60.9, 61.4, 62.9, 67.5, 107.6, 111.1, 111.6, 112.3, 112.4, 114.4, 119.2, 120.8, 122.0, 122.5, 122.6, 123.9, 124.7, 127.7, 130.1, 132.1, 133.0, 139.7, 142.5, 143.7, 144.0, 149.5, 149.7, 151.1, 151.6, 153.8, 155.7, 161.5, 188.6, 189.0. LCMS (ES+) m/z = 736.2 ([M + H]⁺, t_R = 1.66 min). HRMS (ESI+) m/z = 736.2855 [M + H]⁺ found, C₄₁H₄₂O₁₀N₃⁺ required 736.2870.

(E)-1-(3-Methoxy-4-((1-(2-(2-methoxy-4-((E)-3-(2,4,6-trimethoxyphenyl)acryloyl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-3-(1-methyl-1H-pyrrol-2-yl)prop-2-en-1-one (94). A mixture of alkyne chalcone 22 (217 mg, 0.734 mmol), azide chalcone 69 (305 mg, 0.737 mmol), CuSO₄·5H₂O (214 mg, 0.857 mmol) and sodium ascorbate (365 mg, 1.84 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH to afford triazole hybrid 94 (367 mg, 70%) as a bright yellow flaky solid. m.p. 138–140 °C. TLC R_f = 0.31 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 2941w (C-H str), 2838w (C-H str), 1646m (C=O str), 1596m (C=C str), 1566s (C=C str), 1512m (C=C str), 1470m, 1457m, 1414m, 1338w, 1321m, 1257s, 1198m, 1155s, 1146s, 1118s, 1027m. ¹H-NMR (500 MHz, CDCl₃): δ 3.77 (3H, s, -NCH₃), 3.86 (3H, s, -OCH₃), 3.91 (6H, s, 2 × -OCH₃), 3.91 (3H, s, -OCH₃), 3.94 (3H, s, -OCH₃), 4.45 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 4.83 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 5.38 (2H, s, -OCH₂CN-), 6.14 (2H, s, ArH), 6.21–6.23 (1H, m, ArH), 6.80–6.86 (3H, m, ArH), 7.16 (1H, d, J = 8.8 Hz, ArH), 7.29 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.57–7.63 (4H, m, ArH), 7.79 (1H, d, J = 15.2 Hz, -CH=CHCO-), 7.85 (1H, d, J = 16.0 Hz, -CH=CHCO-), 8.05 (1H, s, -CHN-), 8.23 (1H, d, J = 15.6 Hz, -CH=CHCO-). ¹³C-NMR (500 MHz, CDCl₃): δ 34.4, 49.7, 55.4, 55.8, 55.9, 56.0, 62.8, 67.5, 90.5, 106.5, 109.6, 111.1, 111.7, 112.1, 112.3, 112.4, 116.3, 121.5, 122.3, 122.3, 124.7, 127.6, 130.3, 131.6, 132.4, 133.7, 135.6, 143.7, 149.4, 149.5, 150.6, 151.4, 161.6, 163.0, 188.1, 190.3. LCMS (ES+) m/z = 709.3 ([M + H]⁺, t_R = 1.63 min). HRMS (ESI+) m/z = 709.2854 [M + H]⁺ found, C₃₉H₄₁O₉N₄⁺ required 709.2868.

(E)-1-(3-Methoxy-4-((1-(2-(2-methoxy-4-((E)-3-(1-methyl-1H-pyrrol-2-yl)acryloyl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-3-(1-methyl-1H-pyrrol-2-yl)prop-2-en-1-one (95). A mixture of alkyne chalcone 22 (271 mg, 0.918 mmol), azide chalcone 70 (301 mg, 0.924 mmol), CuSO₄·5H₂O (316 g, 1.26 mmol) and sodium ascorbate (499 mg, 2.52 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH to afford triazole hybrid 95 (555 mg, 97%) as a dark yellow-brown flaky solid. m.p. 118–120 °C. TLC R_f = 0.38 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 2941w (C-H str), 2844w (C-H str), 1644m (C=O str), 1594m (C=C str), 1564s (C=C str), 1511m (C=C str), 1480m, 1412m, 1381w, 1330m, 1258s, 1196m, 1153s, 1129m, 1055w, 1025m. ¹H-NMR (500 MHz, CDCl₃): δ 3.76 (3H, s, -NCH₃), 3.77 (3H, s, -NCH₃), 3.92 (3H, s, -OCH₃), 3.95 (3H, s, -OCH₃), 4.46 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 4.84 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 5.39 (2H, s, -OCH₂CN-), 6.22–6.24 (2H, m, ArH), 6.82–6.86 (5H, m, ArH), 7.15 (1H, d, J = 8.0 Hz, ArH), 7.27 (1H, d, J = 15.2 Hz, -CH=CHCO-, overlain by CDCl₃), 7.29 (1H, d, J = 14.0 Hz, -CH=CHCO-), 7.57–7.62 (4H, m, ArH), 7.79 (2H, d, J = 14.8 Hz, 2 × -CH=CHCO-), 8.04 (1H, s, -CHN-). ¹³C-NMR (500 MHz, CDCl₃): δ 34.4, 49.7, 55.9, 56.0, 62.9, 67.5, 109.6, 109.7, 111.1, 111.4, 112.1, 112.2, 112.3, 112.4, 116.2, 116.3, 122.1, 122.3, 124.7, 127.6, 127.7, 130.3, 130.3, 131.6, 131.8, 132.4, 133.1, 143.7, 149.4, 149.6, 150.9, 151.4, 188.0, 188.1. LCMS (ES+) m/z = 622.3 ([M + H]⁺, t_R = 1.62 min). HRMS (ESI+) m/z = 622.2648 [M + H]⁺ found, C₃₅H₃₆O₆N₅⁺ required 622.2660.

(E)-1-(2-Hydroxyphenyl)-3-(4-(2-(4-((2-((E)-3-(1-methyl-1H-pyrrol-2-yl)acryloyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)phenyl)prop-2-en-1-one (96). A mixture of alkyne chalcone 23 (337 mg, 1.27 mmol), azide chalcone 61 (400 mg, 1.29 mmol), CuSO₄·5H₂O (429 mg, 1.72 mmol) and sodium ascorbate (641 mg, 3.23 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) to afford triazole hybrid 96 (399 mg, 55%) as a bright yellow-orange powdery solid. m.p. 98–100 °C. TLC R_f = 0.40 (3% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 2933w (C-H str), 2884w (C-H str), 1635m (C=O str), 1597m (C=C str), 1562s (C=C str), 1509m (C=C str), 1480m, 1447m, 1329m, 1286m, 1268m, 1233m, 1202s, 1174s, 1156s, 1113w, 1055m, 1025s. ¹H-NMR (500 MHz, CDCl₃): δ 3.65 (3H, s, -NCH₃), 4.32 (2H, t, J = 5.2 Hz, -OCH₂CH₂N-), 4.65 (2H, t, J = 5.2 Hz, -OCH₂CH₂N-), 5.33 (2H, s, -OCH₂CN-), 6.16–6.18 (1H, m, ArH), 6.63 (1H, dd, J = 4.0, 1.2 Hz, ArH), 6.76 (1H, t, J = 2.0 Hz, ArH), 6.85 (2H, d, J = 8.8 Hz, ArH), 6.95 (1H, t, J = 8.0 Hz, ArH), 7.03 (1H, dd, J = 8.4, 0.8 Hz, ArH), 7.08 (1H, d, J = 7.6 Hz, ArH), 7.12 (1H, d, J = 8.4 Hz, ArH), 7.16 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.44–7.59 (4H, m, ArH), 7.54 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.60 (1H, d, J = 15.2 Hz, -CH=CHCO-), 7.66 (1H, dd, J = 8.0, 2.0 Hz, ArH), 7.76 (1H, s, -CHN-), 7.86 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.93 (1H, dd, J = 8.4, 1.6 Hz, ArH), 12.89 (1H, s, OH). ¹³C-NMR (500 MHz, CDCl₃): δ 34.3, 49.5, 63.0, 66.2, 109.6, 112.4, 113.0, 114.9, 118.2, 118.5, 118.8, 120.0, 121.4, 122.2, 123.9, 127.7, 128.2, 129.5, 130.0, 130.1, 130.5, 130.6, 132.7, 136.2, 144.1, 144.8, 156.5, 159.9, 163.5, 191.9, 193.5. LCMS (ES+) m/z = 575.3 ([M + H]⁺, t_R = 1.72 min). HRMS (ESI+) m/z = 575.2266 [M + H]⁺ found, C₃₄H₃₁O₅N₄⁺ required 575.2289.

(E)-3-(Ferrocenyl)-1-(4-((1-(2-(4-((E)-3-(2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-3-methoxyphenyl)prop-2-en-1-one (97). A mixture of alkyne chalcone 25 (301 mg, 0.753 mmol), azide chalcone 61 (235 mg, 0.760 mmol), CuSO₄·5H₂O (225 mg, 0.900 mmol) and sodium ascorbate (398 mg, 2.01 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) to afford triazole hybrid 97 (427 mg, 80%) as a dark red-brown powdery solid. m.p. 178–180 °C. TLC R_f = 0.28 (2% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 2937w (C-H str), 1740m (C=O str), 1651m, 1637s, 1596s (C=C str), 1571s (C=C str), 1510s (C=C str), 1487m, 1444m, 1341w, 1300m, 1266s, 1203s, 1179s, 1159s, 1146s, 1048m, 1020s. ¹H-NMR (500 MHz, CDCl₃): δ 3.98 (3H, s, -OCH₃), 4.16 (5H, s, -C₅H₅), 4.42 (2H, t, J = 5.2 Hz, -OCH₂CH₂N-), 4.47 (2H, t, J = 2.0 Hz, -C₅H₄), 4.56 (2H, t, J = 2.0 Hz, -C₅H₄), 4.80 (2H, t, J = 5.2 Hz, -OCH₂CH₂N-), 5.43 (2H, s, -OCH₂CN-), 6.84 (2H, d, J = 8.8 Hz, ArH), 6.97 (1H, t, J = 8.0 Hz, ArH), 7.04 (1H, dd, J = 8.4, 0.8 Hz, ArH), 7.12 (1H, d, J = 15.2 Hz, -CH=CHCO-), 7.12 (1H, d, J = 8.4 Hz, ArH), 7.51 (1H, t, J = 8.4 Hz, ArH), 7.54–7.61 (3H, m, ArH), 7.59 (1H, d, J = 16.0 Hz, -CH=CHCO-), 7.64 (1H, d, J = 1.6 Hz, ArH), 7.74 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.86 (1H, s, -CHN-), 7.86 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.97 (1H, dd, J = 8.0, 1.6 Hz, ArH), 12.90 (1H, s, OH). ¹³C-NMR (500 MHz, CDCl₃): δ 49.7, 56.1, 62.8, 66.3, 68.9, 69.7, 71.3, 79.2, 111.1, 112.3, 114.9, 118.3, 118.5, 118.6, 118.8, 120.0, 122.4, 124.3, 128.4, 129.6, 130.6, 132.3, 136.3, 143.8, 144.7, 146.1, 149.5, 151.2, 159.8, 163.6, 187.9, 193.6. LCMS (ES+) m/z = 710.2 ([M + H]⁺, t_R = 2.09 min). HRMS (ESI+) m/z = 710.1889 [M + H]⁺ found, C₄₀H₃₆N₃O₆Fe⁺ required 710.1875.

(E)-3-((1-(2-(4-(3-(3,4-Dimethoxyphenyl)acryloyl)-2-methoxyphenoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-phenyl-4H-chromen-4-one (98). A mixture of alkyne flavone 30 (806 mg, 2.92 mmol), azide chalcone 67 (1.01 g, 2.64 mmol), CuSO₄·5H₂O (716 mg, 2.87 mmol) and sodium ascorbate (1.29 g, 6.51 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) to afford triazole hybrid 98 (622 mg, 36%) as a pale yellow-green powdery solid. m.p. 102–104 °C. TLC R_f = 0.24 (3% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 2940w (C-H str), 2836w (C-H str), 1644m (C=O str), 1596m (C=C str), 1579m (C=C str), 1510s (C=C str), 1467m, 1420w, 1398w, 1260s, 1237s, 1196m, 1146s, 1138s, 1022s. ¹H-NMR (500 MHz, CDCl₃): δ 3.87 (3H, s, -OCH₃), 3.94 (3H, s, -OCH₃), 3.96 (3H, s, -OCH₃), 4.38 (2H, t, J = 5.2 Hz, -OCH₂CH₂N-), 4.74 (2H, t, J = 5.2 Hz, -OCH₂CH₂N-), 5.32 (2H, s, -OCH₂CN-), 6.84 (1H, d, J = 8.4 Hz, ArH), 6.90 (1H, d, J = 8.4 Hz, ArH), 7.16 (1H, d, J = 1.6 Hz, ArH), 7.24 (1H, dd, J = 8.4, 1.6 Hz, ArH), 7.39 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.39–7.44 (4H, m, ArH), 7.50 (1H, d, J = 8.4 Hz, ArH), 7.59 (1H, d, J = 1.6 Hz, ArH), 7.62 (1H, dd, J = 8.4, 2.0 Hz, ArH), 7.69 (1H, t, J = 8.4 Hz, ArH), 7.77 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.96 (1H, s, -CHN-), 7.97–8.00 (2H, m, ArH), 8.27 (1H, dd, J = 8.0, 1.6 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 49.4, 56.0, 56.0, 65.1, 67.4, 110.2, 111.1, 111.5, 112.2, 118.1, 119.5, 122.4, 123.0, 124.1, 124.8, 125.3, 125.7, 127.9, 128.3, 128.7, 130.6, 130.7, 132.7, 133.5, 139.4, 143.9, 144.5, 149.2, 149.7, 151.3, 151.3, 155.3, 156.4, 175.0, 188.6. LCMS (ES+) m/z = 660.2 ([M + H]⁺, t_R = 1.64 min). HRMS (ESI+) m/z = 660.2325 [M + H]⁺ found, C₃₈H₃₄O₈N₃⁺ required 660.2340.

(E)-3-((1-(2-(2-Methoxy-4-(3-(2,3,4-trimethoxyphenyl)acryloyl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-phenyl-4H-chromen-4-one (99). A mixture of alkyne flavone 30 (205 mg, 0.742 mmol), azide chalcone 68 (306 mg, 0.739 mmol), CuSO₄·5H₂O (204 mg, 0.818 mmol) and sodium ascorbate (365 mg, 1.84 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH to afford triazole hybrid 99 (178 mg, 35%) as an off-white powdery solid. m.p. 120–122 °C. TLC R_f = 0.28 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 2941w (C-H str), 2838w (C-H str), 1740w, 1645s (C=O str), 1581s (C=C str), 1563m (C=C str), 1516w (C=C str), 1494s, 1466s, 1414m, 1403m, 1264s, 1238m, 1195m, 1148m, 1096s, 1039m, 1027m. ¹H-NMR (500 MHz, CDCl₃): δ 3.86 (3H, s, -OCH₃), 3.90 (3H, s, -OCH₃), 3.92 (3H, s, -OCH₃), 3.95 (3H, s, -OCH₃), 4.36 (2H, t, J = 5.2 Hz, -OCH₂CH₂N-), 4.73 (2H, t, J = 5.2 Hz, -OCH₂CH₂N-), 5.33 (2H, s, -OCH₂CN-), 6.73 (1H, d, J = 8.8 Hz, ArH), 6.84 (1H, d, J = 8.0 Hz, ArH), 7.38–7.44 (5H, m, ArH), 7.50 (1H, d, J = 8.4 Hz, ArH), 7.55 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.59–7.62 (2H, m, ArH), 7.69 (1H, t, J = 8.4 Hz, ArH), 7.95 (1H, s, -CHN-), 7.96–7.99 (2H, m, ArH), 7.99 (1H, d, J = 15.6 Hz, -CH=CHCO-), 8.28 (1H, dd, J = 8.0, 1.2 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 49.4, 55.9, 56.1, 60.9, 61.4, 65.1, 67.4, 107.6, 111.5, 112.2, 118.1, 120.9, 122.0, 122.4, 123.9, 124.1, 124.8, 125.3, 125.7, 128.3, 128.7, 130.6, 130.7, 132.8, 133.5, 139.4, 139.7, 142.5, 143.9, 149.6, 151.2, 153.7, 155.3, 155.7, 156.4, 175.0, 189.0. LCMS (ES+) m/z = 690.2 ([M + H]⁺, t_R = 1.95 min). HRMS (ESI+) m/z = 690.2425 [M + H]⁺ found, C₃₉H₃₆O₉N₃⁺ required 690.2446.

(E)-3-((1-(2-(2-Methoxy-4-(3-(2,4,6-trimethoxyphenyl)acryloyl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-phenyl-4H-chromen-4-one (100). A mixture of alkyne flavone 30 (207 mg, 0.749 mmol), azide chalcone 69 (306 mg, 0.741 mmol), CuSO₄·5H₂O (203 mg, 0.814 mmol) and sodium ascorbate (369 mg, 1.86 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH to afford triazole hybrid 100 (342 mg, 67%) as a white powdery solid. m.p. 172–174 °C. TLC R_f = 0.30 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 2941w (C-H str), 2843w (C-H str), 1737w, 1643s (C=O str), 1599s (C=C str), 1575s (C=C str), 1515m (C=C str), 1465m, 1416m, 1322m, 1261m, 1231s, 1216m, 1192m, 1149s, 1125s, 1027s. ¹H-NMR (500 MHz, CDCl₃): δ 3.85 (3H, s, -OCH₃), 3.88 (3H, s, -OCH₃), 3.92 (6H, s, 2 × -OCH₃), 4.35 (2H, t, J = 5.2 Hz, -OCH₂CH₂N-), 4.72 (2H, t, J = 5.2 Hz, -OCH₂CH₂N-), 5.35 (2H, s, -OCH₂CN-), 6.16 (2H, s, ArH), 6.84 (1H, d, J = 8.8 Hz, ArH), 7.38–7.44 (4H, m, ArH), 7.50 (1H, d, J = 8.4 Hz, ArH), 7.60–7.62 (2H, m, ArH), 7.70 (1H, t, J = 8.8 Hz, ArH), 7.87 (1H, d, J = 16.0 Hz, -CH=CHCO-), 7.94 (1H, s -CHN-), 7.95–7.98 (2H, m, ArH), 8.25 (1H, d, J = 16.0 Hz, -CH=CHCO-), 8.29 (1H, dd, J = 8.4, 1.6 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 49.4, 55.4, 55.8, 55.8, 65.0, 67.3, 90.5, 106.5, 111.7, 112.3, 118.1, 121.6, 122.3, 124.1, 124.7, 125.2, 125.7, 128.2, 128.7, 130.6, 130.7, 133.5, 133.5, 135.6, 139.3, 143.8, 149.4, 150.7, 155.2, 156.4, 161.6, 163.0, 175.0, 190.4. LCMS (ES+) m/z = 690.2 ([M + H]⁺, t_R = 1.73 min). HRMS (ESI+) m/z = 690.2476 [M + H]⁺ found, C₃₉H₃₆O₉N₃⁺ required 690.2446.

(E)-6-((1-(2-(4-(3-(3,4-Dimethoxyphenyl)acryloyl)-2-methoxyphenoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-phenyl-4H-chromen-4-one (101). A mixture of alkyne flavone 31 (179 mg, 0.648 mmol), azide chalcone 67 (246 mg, 0.641 mmol), CuSO₄·5H₂O (188 mg, 0.753 mmol) and sodium ascorbate (322 mg, 1.63 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH to afford triazole hybrid 101 (366 mg, 87%) as a bright orange crystalline solid. m.p. 128–130 °C. TLC R_f = 0.34 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 2940w (C-H str), 2831w (C-H str), 1637s (C=O str), 1618m, 1595s (C=C str), 1571s (C=C str), 1510s (C=C str), 1481m, 1454s, 1419m, 1360s, 1257s, 1235m, 1198m, 1140s, 1023s. ¹H-NMR (500 MHz, CDCl₃): δ 3.92 (3H, s, -OCH₃), 3.93 (3H, s, -OCH₃), 3.94 (3H, s, -OCH₃), 4.47 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 4.86 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 5.29 (2H, s, -OCH₂CN-), 6.79 (1H, s, -C=CH), 6.85 (1H, d, J = 8.8 Hz, ArH), 6.89 (1H, d, J = 8.4 Hz, ArH), 7.14 (1H, d, J = 1.6 Hz, ArH), 7.22 (1H, dd, J = 8.4, 2.0 Hz, ArH), 7.33 (1H, dd, J = 9.2, 3.2 Hz, ArH), 7.36 (1H, d, J = 15.2 Hz, -CH=CHCO-), 7.49–7.52 (4H, m, ArH), 7.59–7.61 (2H, m, ArH), 7.71 (1H, d, J = 3.2 Hz, ArH), 7.73 (1H, d, J = 16.0 Hz, -CH=CHCO-), 7.88–7.91 (2H, m, ArH), 8.04 (1H, s, -CHN-). ¹³C-NMR (500 MHz, CDCl₃): δ 49.7, 55.9, 56.0, 62.3, 67.5, 106.3, 106.7, 110.1, 111.1, 111.5, 112.3, 119.4, 119.7, 122.5, 123.0, 123.9, 124.5, 124.6, 126.2, 127.8, 129.0, 131.5, 131.7, 132.7, 143.3, 144.5, 149.2, 149.7, 151.2, 151.2, 151.3, 155.5, 163.2, 178.1, 188.5. LCMS (ES+) m/z = 660.2 ([M + H]⁺, t_R = 1.81 min). HRMS (ESI+) m/z = 682.2153 [M + Na]⁺ found, C₃₈H₃₃O₈N₃Na⁺ required 682.2160.

(E)-6-((1-(2-(2-Methoxy-4-(3-(2,4,6-trimethoxyphenyl)acryloyl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-phenyl-4H-chromen-4-one (102). A mixture of alkyne flavone 31 (211 mg, 0.763 mmol), azide chalcone 69 (317 mg, 0.767 mmol), CuSO₄·5H₂O (211 mg, 0.843 mmol) and sodium ascorbate (382 mg, 1.93 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH to afford triazole hybrid 102 (397 mg, 75%) as a bright yellow-orange flaky solid. m.p. 128–130 °C. TLC R_f = 0.25 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 2941w (C-H str), 2838w (C-H str), 1739w, 1640s (C=O str), 1598s (C=C str), 1569s (C=C str), 1517m (C=C str), 1455s, 1363m, 1320m, 1279m, 1261m, 1201s, 1154s, 1122s, 1035s, 1025s. ¹H-NMR (500 MHz, CDCl₃): δ 3.84 (3H, s, -OCH₃), 3.89 (6H, s, 2 × -OCH₃), 3.92 (3H, s, -OCH₃), 4.45 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 4.85 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 5.28 (2H, s, -OCH₂CN-), 6.12 (2H, s, ArH), 6.79 (1H, s, -C=CH), 6.84 (1H, d, J = 8.4 Hz, ArH), 7.33 (1H, dd, J = 9.2, 3.2 Hz, ArH), 7.48–7.51 (4H, m, ArH), 7.57 (1H, dd, J = 8.0, 1.6 Hz, ArH), 7.61 (1H, d, J = 1.6 Hz, ArH), 7.71 (1H, d, J = 2.8 Hz, ArH), 7.84 (1H, d, J = 16.0 Hz, -CH=CHCO-), 7.88–7.91 (2H, m, ArH), 8.06 (1H, s, -CHN-), 8.21 (1H, d, J = 15.6 Hz, -CH=CHCO-). ¹³C-NMR (500 MHz, CDCl₃): δ 49.7, 55.3, 55.7, 55.9, 62.3, 67.5, 90.5, 106.2, 106.5, 106.7, 111.6, 112.4, 119.6, 121.4, 122.3, 123.9, 124.4, 124.6, 126.2, 128.9, 131.5, 131.7, 133.6, 135.5, 143.3, 149.4, 150.6, 151.2, 155.6, 161.6, 163.0, 163.2, 178.1, 190.3. LCMS (ES+) m/z = 690.3 ([M + H]⁺, t_R = 1.88 min). HRMS (ESI+) m/z = 690.2426 [M + H]⁺ found, C₃₉H₃₆O₉N₃⁺ required 690.2446.

(E)-6-((1-(2-(2-Methoxy-4-(3-(2,3,4-trimethoxyphenyl)acryloyl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)-methoxy)-2-phenyl-4H-chromen-4-one (103). A mixture of alkyne flavone 31 (201 mg, 0.729 mmol), azide chalcone 68 (304 mg, 0.735 mmol), CuSO₄·5H₂O (208 mg, 0.831 mmol) and sodium ascorbate (383 mg, 1.93 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH to afford triazole hybrid 103 (382 mg, 76%) as a pale yellow flaky solid. m.p. 138–140 °C. TLC R_f = 0.32 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 2939w (C-H str), 2839w (C-H str), 1740w, 1640s (C=O str), 1619m, 1593m (C=C str), 1573s (C=C str), 1516m (C=C str), 1495m, 1482m, 1455s, 1415m, 1360s, 1259s, 1200m, 1157m, 1095s, 1026s. ¹H-NMR (500 MHz, CDCl₃): δ 3.89 (3H, s, -OCH₃), 3.90 (3H, s, -OCH₃), 3.93 (3H, s, -OCH₃), 3.94 (3H, s, -OCH₃), 4.47 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 4.86 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 5.29 (2H, s, -OCH₂CN-), 6.72 (1H, d, J = 8.8 Hz, ArH), 6.80 (1H, s, -C=CH), 6.86 (1H, d, J = 8.0 Hz, ArH), 7.34 (1H, dd, J = 9.2, 3.2 Hz, ArH), 7.37 (1H, d, J = 8.8 Hz, ArH), 7.49–7.52 (4H, m, ArH), 7.53 (1H, d, J = 16.0 Hz, -CH=CHCO-), 7.58–7.61 (2H, m, ArH), 7.71 (1H, d, J = 3.2 Hz, ArH), 7.89–7.92 (2H, m, ArH), 7.96 (1H, d, J = 16.0 Hz, -CH=CHCO-), 8.05 (1H, s, -CHN-). ¹³C-NMR (500 MHz, CDCl₃): δ 49.7, 56.0, 56.0, 60.9, 61.3, 62.3, 67.5, 106.3, 106.8, 107.5, 111.5, 112.3, 119.7, 120.8, 122.0, 122.4, 123.8, 123.9, 124.5, 124.6, 126.2, 129.0, 131.5, 131.7, 132.8, 139.6, 142.4, 143.3, 149.6, 151.1, 151.2, 153.7, 155.6, 155.7, 163.2, 178.1, 188.9. LCMS (ES+) m/z = 690.2 ([M + H]⁺, t_R = 1.94 min). HRMS (ESI+) m/z = 690.2452 [M + H]⁺ found, C₃₉H₃₆N₃O₉⁺ required 690.2452.

(E)-7-((1-(2-(2-Methoxy-4-(3-(2,4,6-trimethoxyphenyl)acryloyl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)-methoxy)-2-phenyl-4H-chromen-4-one (104). A mixture of alkyne flavone 32 (202 mg, 0.730 mmol), azide chalcone 69 (304 mg, 0.735 mmol), CuSO₄·5H₂O (218 mg, 0.872 mmol) and sodium ascorbate (386 mg, 1.95 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH to afford triazole hybrid 104 (324 mg, 64%) as a pale yellow-white powdery solid. m.p. 168–170 °C. TLC R_f = 0.25 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 2941w (C-H str), 2841w (C-H str), 1736w, 1634s (C=O str), 1599s (C=C str), 1566s (C=C str), 1512m (C=C str), 1451m, 1441m, 1336s, 1302w, 1279m, 1261m, 1204m, 1175m, 1160w, 1122s, 1092w, 1053w, 1037m, 1016w. ¹H-NMR (500 MHz, CDCl₃): δ 3.87 (3H, s, -OCH₃), 3.91 (6H, s, 2 × -OCH₃), 3.93 (3H, s, -OCH₃), 4.48 (2H, t, J = 5.2 Hz, -OCH₂CH₂N-), 4.87 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 5.35 (2H, s, -OCH₂CN-), 6.14 (2H, s, ArH), 6.77 (1H, s, -C=CH), 6.86 (1H, d, J = 8.0 Hz, ArH), 7.06 (1H, dd, J = 8.8, 2.0 Hz, ArH), 7.14 (1H, d, J = 2.0 Hz, ArH), 7.49–7.53 (3H, m, ArH), 7.59 (1H, dd, J = 8.4, 2.0 Hz, ArH), 7.63 (1H, d, J = 1.6 Hz, ArH), 7.84 (1H, d, J = 16.0 Hz, -CH=CHCO-), 7.90–7.92 (2H, m, ArH), 8.07 (1H, s, -CHN-), 8.15 (1H, d, J = 8.8 Hz, ArH), 8.23 (1H, d, J = 16.0 Hz, -CH=CHCO-). ¹³C-NMR (500 MHz, CDCl₃): δ 49.8, 55.3, 55.7, 55.8, 62.3, 67.4, 90.4, 101.4, 106.4, 107.3, 111.6, 112.4, 114.8, 118.0, 121.3, 122.3, 124.7, 126.1, 127.0, 128.9, 131.4, 131.6, 133.6, 135.6, 143.0, 149.4, 150.5, 157.8, 161.6, 162.6, 163.0, 163.1, 177.7, 190.2. LCMS (ES+) m/z = 690.2 ([M + H]⁺, t_R = 1.70 min). HRMS (ESI+) m/z = 690.2471 [M + H]⁺ found, C₃₉H₃₆O₉N₃⁺ required 690.2446.

(E)-2-(4-(2-(4-((2-(3-(Ferrocenyl)acryloyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)phenyl)-3-hydroxy-7-methoxy-4H-chromen-4-one (105). A mixture of alkyne chalcone 26 (310 mg, 0.838 mmol), azide flavonol 80 (296 mg, 0.838 mmol), CuSO₄·5H₂O (273 mg, 1.09 mmol) and sodium ascorbate (496 mg, 2.50 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) to afford triazole hybrid 105 (238 mg, 40%) as a dark red powdery solid. m.p. 118–120 °C. TLC R_f = 0.44 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3340w (O-H str), 3088w (C-H str), 2929w (C-H str), 1735m (C=O str), 1597s (C=C str), 1541m (C=C str), 1506m (C=C str), 1484m, 1449m, 1403m, 1235s, 1206s, 1171s, 1117m, 1106m, 1044w, 1025s. ¹H-NMR (500 MHz, CDCl₃): δ 3.96 (3H, s, -OCH₃), 4.12 (5H, s, -C₅H₅), 4.35 (2H, t, J = 4.5 Hz, -OCH₂CH₂N-), 4.43 (2H, t, J = 1.5 Hz, -C₅H₄), 4.48 (2H, t, J = 1.5 Hz, -C₅H₄), 4.67 (2H, t, J = 5.0 Hz, -OCH₂CH₂N-), 5.33 (2H, br s, -OCH₂CN-), 6.95–6.97 (4H, m, ArH and OH), 6.96 (1H, d, J = 15.5 Hz, -CH=CHCO-), 7.01 (1H, dd, J = 9.0, 2.0 Hz, ArH), 7.09 (1H, t, J = 7.5 Hz, ArH), 7.14 (1H, d, J = 8.5 Hz, ArH), 7.46 (1H, dd, J = 7.5, 1.0 Hz, ArH), 7.50 (1H, d, J = 16.0 Hz, -CH=CHCO-), 7.60 (1H, dd, J = 7.5, 1.5 Hz, ArH), 7.77 (1H, br s, -CHN-), 8.14 (1H, d, J = 9.0 Hz, ArH), 8.19 (2H, d, J = 8.5 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 49.6, 55.8, 63.0, 66.1, 68.9, 69.8, 71.3, 79.0, 99.9, 113.1, 114.5, 114.6, 114.7, 121.4, 124.0, 124.7, 126.7, 129.3, 130.1, 130.2, 132.4, 137.4, 144.1, 145.5, 156.3, 157.2, 158.8, 164.2, 172.6, 192.3. LCMS (ES+) m/z = 724.2 ([M + H]⁺, t_R = 2.01 min). HRMS (ESI+) m/z = 724.1711 [M + H]⁺ found, C₄₀H₃₄N₃O₇Fe⁺ required 724.1746.

(E)-2-(4-(2-(4-((4-(3-(Ferrocenyl)acryloyl)-2-methoxyphenoxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)phenyl)-3-hydroxy-4H-chromen-4-one (106). A mixture of alkyne chalcone 25 (308 mg, 0.769 mmol), azide flavonol 79 (252 mg, 0.779 mmol), CuSO₄·5H₂O (209 mg, 0.835 mmol) and sodium ascorbate (395 mg, 1.99 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) to afford triazole hybrid 106 (212 mg, 38%) as a dark-red powdery solid. m.p. 158–160 °C. TLC R_f = 0.26 (3% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3429w (O-H str), 2943w (C-H str), 2873w (C-H str), 1735m (C=O str), 1645w, 1596s (C=C str), 1568s (C=C str), 1509s (C=C str), 1469m, 1418m, 1409m, 1348w, 1292w, 1254s, 1200w, 1180m, 1151m, 1108m, 1027m. ¹H-NMR (500 MHz, CDCl₃): δ 3.97 (3H, s, -OCH₃), 4.17 (5H, s, -C₅H₅), 4.46–4.48 (4H, m, -C₅H₄ and -OCH₂CH₂N-), 4.57 (2H, t, J = 2.0 Hz, -C₅H₄), 4.83 (2H, t, J = 5.0 Hz, -OCH₂CH₂N-), 5.43 (2H, s, -OCH₂CN-), 6.94 (1H, br s, OH), 6.98 (2H, d, J = 9.0 Hz, ArH), 7.12 (1H, d, J = 15.0 Hz, -CH=CHCO-), 7.15 (1H, d, J = 8.5 Hz, ArH), 7.43 (1H, t, J = 8.0 Hz, ArH), 7.57 (1H, dd, J = 8.0, 1.5 Hz, ArH), 7.59 (1H, d, J = 8.5 Hz, ArH), 7.63 (1H, d, J = 2.0 Hz, ArH), 7.71 (1H, t, J = 8.0 Hz, ArH), 7.73 (1H, d, J = 15.5 Hz, -CH=CHCO-), 7.90 (1H, br s, -CHN-), 8.22 (2H, d, J = 9.0 Hz, ArH), 8.25 (1H, dd, J = 8.0, 1.5 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 49.7, 56.1, 62.9, 66.3, 68.9, 69.7, 71.2, 79.3, 111.2, 112.3, 114.5, 118.2, 118.5, 120.7, 122.4, 124.3, 124.5, 124.6, 125.4, 129.6, 132.3, 133.5, 137.8, 143.8, 144.7, 146.0, 149.5, 151.3, 155.2, 159.0, 173.2, 187.9. LCMS (ES+) m/z = 724.2 ([M + H]⁺, t_R = 2.04 min). HRMS (ESI+) m/z = 724.1723 [M + H]⁺ found, C₄₀H₃₄N₃O₇Fe⁺ required 724.1746.

(E)-2-(3-(2-(4-((4-Bromo-2-(3-(1-methyl-1H-indol-3-yl)acryloyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-ethoxy)-4-methoxyphenyl)-3-hydroxy-4H-chromen-4-one (107). A mixture of alkyne chalcone 21 (339 mg, 0.859 mmol), azide flavonol 82 (301 mg, 0.853 mmol), CuSO₄·5H₂O (542 mg, 2.17 mmol) and sodium ascorbate (202 mg, 1.02 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH to afford triazole hybrid 107 (258 mg, 40%) as a brown powdery solid. m.p. 158–160 °C. TLC R_f = 0.44 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3351w (O-H str), 2920m (C-H str), 2852w (C-H str), 1640m (C=O str), 1589s (C=C str), 1559m (C=C str), 1514m (C=C str), 1492m, 1471m, 1397m, 1374m, 1333w, 1269s, 1204m, 1180m, 1130s, 1074w, 1047m, 1020m. ¹H-NMR (500 MHz, CDCl₃): δ 3.64 (3H, s, -NCH₃), 3.83 (3H, s, -OCH₃), 4.02 (2H, t, J = 4.5 Hz, -OCH₂CH₂N-), 4.49 (2H, t, J = 4.5 Hz, -OCH₂CH₂N-), 5.36 (2H, br s, -OCH₂CN-), 6.96 (1H, d, J = 9.0 Hz, ArH), 7.02 (1H, br s, OH), 7.07 (1H, d, J = 8.5 Hz, ArH), 7.10–7.13 (1H, m, ArH), 7.18 (1H, s, ArH), 7.23 (2H, d, J = 3.5 Hz, ArH), 7.38 (1H, d, J = 15.5 Hz, -CH=CHCO-), 7.45 (1H, t, J = 7.5 Hz, ArH), 7.50 (1H, d, J = 1.5 Hz, ArH), 7.53 (1H, d, J = 7.5 Hz, ArH), 7.56 (1H, dd, J = 8.5, 2.5 Hz, ArH), 7.60 (1H, d, J = 8.5 Hz, ArH), 7.73 (1H, t, J = 7.0 Hz, ArH), 7.77 (1H, d, J = 16.0 Hz, -CH=CHCO-), 7.83 (1H, d, J = 2.5 Hz, ArH), 7.90 (1H, dd, J = 8.5, 1.5 Hz, ArH), 8.06 (1H, br s, -CHN-), 8.27 (1H, d, J = 8.0 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 33.0, 49.5, 55.9, 63.5, 67.1, 109.9, 111.4, 112.6, 113.2, 114.0, 114.8, 118.1, 120.5, 120.6, 121.4, 121.6, 122.6, 123.0, 123.3, 123.7, 124.6, 124.8, 125.4, 125.7, 131.9, 133.3, 133.6, 134.8, 134.9, 137.7, 137.8, 138.0, 144.5, 146.9, 151.3, 155.1, 155.8, 173.0, 190.5. LCMS (ES+) m/z = 749.2 ([M + H]⁺, t_R = 1.99 min). HRMS (ESI+) m/z = 769.1232 [M + Na]⁺ found, C₃₉H₃₁O₇N₄BrNa⁺ required 769.1268.

(E)-2-(4-(2-(4-((4-Bromo-2-(3-(furan-2-yl)acryloyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)-3-methoxyphenyl)-3-hydroxy-4H-chromen-4-one (108). A mixture of alkyne chalcone 24 (289 mg, 0.872 mmol), azide flavonol 81 (304 mg, 0.860 mmol), CuSO₄·5H₂O (234 mg, 0.936 mmol) and sodium ascorbate (476 mg, 2.40 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH to afford triazole hybrid 108 (245 mg, 42%) as a dark yellow-brown powdery solid. m.p. 118–120 °C. TLC R_f = 0.41 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3275w (O-H str), 3110w (C-H str), 2926w (C-H str), 1650m (C=O str), 1598s (C=C str), 1549m (C=C str), 1515s (C=C str), 1481s, 1422w, 1398m, 1267s, 1232m, 1207s, 1177m, 1145s, 1111m, 1041m, 1017m, 1008m. ¹H-NMR (500 MHz, CDCl₃): δ 3.90 (3H, s, -OCH₃), 4.43 (2H, t, J = 4.0 Hz, -OCH₂CH₂N-), 4.75 (2H, t, J = 4.0 Hz, -OCH₂CH₂N-), 5.33 (2H, br s, -OCH₂CN-), 6.47 (1H, d, J = 1.5 Hz, ArH), 6.64 (1H, d, J = 3.0 Hz, ArH), 6.89 (1H, d, J = 8.5 Hz, ArH), 7.01 (1H, s, ArH), 7.06–7.08 (1H, m, ArH), 7.25 (1H, d, J = 16.0 Hz, -CH=CHCO-, overlain by CDCl₃), 7.36 (1H, d, J = 15.5 Hz, -CH=CHCO-), 7.44 (1H, t, J = 7.5 Hz, ArH), 7.52 (1H, s, ArH), 7.54 (1H, d, J = 6.5 Hz, ArH), 7.61 (1H, d, J = 8.5 Hz, ArH), 7.72 (1H, d, J = 7.0 Hz, ArH), 7.74 (1H, d, J = 2.0 Hz, ArH), 7.82 (1H, d, J = 8.5 Hz, ArH), 7.84 (1H, s, -CHN-), 8.09 (1H, br s, OH), 8.26 (1H, d, J = 7.5 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 49.9, 55.8, 63.2, 67.5, 111.4, 112.7, 113.6, 113.9, 115.1, 116.1, 118.2, 120.6, 121.1, 124.0, 124.5, 125.2, 125.4, 129.6, 131.1, 133.0, 133.5, 135.4, 137.9, 144.6, 145.0, 148.7, 149.4, 151.4, 155.2, 155.7, 173.1, 190.2. LCMS (ES+) m/z = 686.2 ([M + H]⁺, t_R = 2.00 min). HRMS (ESI+) m/z = 684.0955 [M + H]⁺ found, C₃₄H₂₇O₈N₃Br⁺ required 684.0976.

6-(2-(4-(((4-Oxo-2-phenyl-4H-chromen-3-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)-2-phenyl-4H-chromen-4-one (109). A mixture of alkyne flavone 30 (277 mg, 1.00 mmol), azide flavone 85 (307 mg, 0.998 mmol), CuSO₄·5H₂O (303 mg, 1.21 mmol) and sodium ascorbate (492 mg, 2.48 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) to afford triazole hybrid 109 (534 mg, 92%) as a white powdery solid. m.p. 234–236 °C. TLC R_f = 0.36 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3145w (C-H str), 2940w (C-H str), 1736w, 1643s (C=O str), 1627s, 1600m, 1570m (C=C str), 1561m (C=C str), 1482m, 1470m, 1455s, 1398m, 1361s, 1293m, 1197s, 1187m, 1148m, 1087m, 1047m, 1026w. ¹H-NMR (500 MHz, CDCl₃): δ 4.41 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 4.73 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 5.34 (2H, s, -OCH₂CN-), 6.83 (1H, s, -C=CH), 7.25 (1H, dd, J = 9.2, 3.2 Hz, ArH, overlain by CDCl₃), 7.41–7.46 (4H, m, ArH), 7.51–7.55 (5H, m, ArH), 7.58 (1H, d, J = 3.2 Hz, ArH), 7.70 (1H, t, J = 7.2 Hz, ArH), 7.81 (1H, s, -CHN-), 7.92–7.94 (2H, m, ArH), 8.01–8.04 (2H, m, ArH), 8.29 (1H, d, J = 7.2 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 49.4, 65.1, 66.7, 105.9, 106.9, 118.0, 119.9, 123.8, 124.1, 124.5, 124.8, 125.7, 126.2, 128.3, 128.7, 129.0, 130.7, 131.6, 131.7, 133.5, 139.5, 144.0, 151.4, 155.1, 155.3, 156.4, 163.3, 175.1, 178.0. LCMS (ES+) m/z = 584.1 ([M + H]⁺, t_R = 1.91 min). HRMS (ESI+) m/z = 606.1610 [M + Na]⁺ found, C₃₅H₂₅O₆N₃Na⁺ required 606.1636.

3-Hydroxy-2-(4-(2-(4-(((4-oxo-2-phenyl-4H-chromen-3-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)phenyl) -4H-chromen-4-one (110). A mixture of alkyne flavone 30 (272 mg, 0.984 mmol), azide flavonol 79 (311 mg, 0.961 mmol), CuSO₄·5H₂O (274 mg, 1.10 mmol) and sodium ascorbate (557 mg, 2.81 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH to afford triazole hybrid 110 (272 mg, 47%) as an off-white powdery solid. m.p. 148–150 °C. TLC R_f = 0.34 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3254w(br) (O-H str), 2964w (C-H str), 1602s (C=O str), 1564m (C=C str), 1549m (C=C str), 1509s (C=C str), 1481m, 1469s, 1427m, 1403s, 1282m, 1250s, 1198m, 1183s, 1150w, 1116m, 1109m, 1041m. ¹H-NMR (500 MHz, CDCl₃): δ 4.39 (2H, t, J = 5.5 Hz, -OCH₂CH₂N-), 4.73 (2H, t, J = 5.5 Hz, -OCH₂CH₂N-), 5.33 (2H, s, -OCH₂CN-), 6.99 (3H, d, J = 9.0 Hz, ArH and OH), 7.41–7.46 (5H, m, ArH), 7.53 (1H, dd, J = 8.0, 0.5 Hz, ArH), 7.59 (1H, d, J = 8.0 Hz, ArH), 7.68–7.72 (2H, m, ArH), 7.85 (1H, s, -CHN-), 8.01–8.03 (2H, m, ArH), 8.23 (2H, d, J = 9.0 Hz, ArH), 8.25 (1H, dd, J = 8.0, 1.5 Hz, ArH), 8.29 (1H, dd, J = 8.0, 1.5 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 49.5, 65.1, 66.2, 114.5, 118.1, 118.2, 120.7, 124.1, 124.5, 124.5, 124.8, 125.0, 125.4, 125.7, 128.4, 128.7, 129.6, 130.7, 133.5, 133.6, 137.8, 139.5, 144.1, 144.8, 155.3, 155.3, 156.4, 159.1, 173.2, 175.1. LCMS (ES+) m/z = 600.0 ([M + H]⁺, t_R = 1.75 min). HRMS (ESI+) m/z = 600.1755 [M + H]⁺ found, C₃₅H₂₆O₇N₃⁺ required 600.1765.

3-Hydroxy-2-(4-((1-(2-(4-(3-hydroxy-4-oxo-4H-chromen-2-yl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)-methoxy)phenyl)-4H-chromen-4-one (111). A mixture of alkyne flavonol 36 (273 mg, 0.933 mmol), azide flavonol 79 (310 mg, 0.958 mmol), CuSO₄·5H₂O (296 mg, 1.19 mmol) and sodium ascorbate (461 mg, 2.33 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH to afford triazole hybrid 111 (82.7 mg, 14%) as a dark brown powdery solid. m.p. 218–220 °C. TLC R_f = 0.41 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3284w (O-H str), 3087w (C-H str), 2924w (C-H str), 1600s (C=O str), 1563m (C=C str), 1543m (C=C str), 1508s (C=C str), 1491s, 1424s, 1409s, 1248s, 1209m, 1180s, 1108s, 1043m, 1014w. ¹H-NMR (500 MHz, DMSO-d₆): δ 4.53 (2H, t, J = 4.5 Hz, -OCH₂CH₂N-), 4.85 (2H, t, J = 4.5 Hz, -OCH₂CH₂N-), 5.29 (2H, s, -OCH₂CN-), 7.11 (2H, d, J = 8.5 Hz, ArH), 7.25 (2H, d, J = 8.5 Hz, ArH), 7.43–7.47 (2H, m, ArH), 7.71–7.80 (4H, m, ArH), 8.09 (2H, t, J = 6.5 Hz, ArH), 8.17 (2H, d, J = 9.0 Hz, ArH), 8.21 (2H, d, J = 9.0 Hz, ArH), 8.39 (1H, s, -CHN-), 9.47 (1H, s, OH), 9.48 (1H, s, OH). ¹³C-NMR (500 MHz, DMSO-d₆): δ 49.0, 61.1, 66.3, 114.6, 114.8, 115.4, 118.3, 121.3, 123.9, 124.1, 124.5, 124.7, 125.4, 129.4, 129.6, 133.4, 133.5, 138.2, 142.4, 145.3, 145.4, 154.4, 158.9, 159.1, 172.6. LCMS (ES+) m/z = 616.1 ([M + H]⁺, t_R = 1.68 min). HRMS (ESI+) m/z = 616.1722 [M + H]⁺ found, C₃₅H₂₆N₃O₈⁺ required 616.1720.

3-(4-Methoxyphenyl)-7-((1-(2-((4-oxo-2-phenyl-4H-chromen-6-yl)oxy)ethyl)-1H-1,2,3-triazol-4-yl)-methoxy)-4H-chromen-4-one (112). A mixture of alkyne isoflavone 46 (280 mg, 0.914 mmol), azide flavone 85 (282 mg, 0.919 mmol), CuSO₄·5H₂O (279 mg, 1.12 mmol) and sodium ascorbate (503 mg, 2.54 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH to afford triazole hybrid 112 (531 mg, 95%) as a white powdery solid. m.p. 234–236 °C. TLC R_f = (3% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3082w (C-H str), 2941w (C-H str), 1641s, 1625s (C=O str), 1608s, 1567s (C=C str), 1515s (C=C str), 1497w, 1483w, 1456s, 1443s, 1359s, 1292s, 1252s, 1204m, 1192m, 1185s, 1137w, 1099m, 1084m, 1047s, 1032s. ¹H-NMR (500 MHz, CDCl₃): δ 3.83 (3H, s, -OCH₃), 4.50 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 4.86 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 5.36 (2H, s, -OCH₂CN-), 6.82 (1H, s, -C=CH), 6.95 (2H, d, J = 8.4 Hz, ArH), 7.01 (1H, d, J = 2.0 Hz, ArH), 7.07 (1H, dd, J = 8.8, 2.0 Hz, ArH), 7.18 (1H, dd, J = 8.8, 3.2 Hz, ArH), 7.48–7.56 (6H, m, ArH), 7.59 (1H, d, J = 3.2 Hz, ArH), 7.86 (1H, s, -CHN-), 7.90–7.92 (3H, m, -C=CH and ArH), 8.22 (1H, d, J = 8.4 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 49.8, 55.3, 62.4, 66.8, 101.3, 106.2, 106.9, 113.9, 115.0, 118.8, 119.9, 123.4, 124.0, 124.1, 124.6, 124.9, 126.3, 127.9, 129.1, 130.1, 131.7, 143.3, 151.5, 152.1, 155.0, 157.7, 159.6, 162.3, 163.5, 175.8, 178.0. LCMS (ES+) m/z = 614.2 ([M + H]⁺, t_R = 1.94 min). HRMS (ESI+) m/z = 614.1942 [M + H]⁺ found, C₃₆H₂₈N₃O₇⁺ required 614.1927.

(E)-7-Methoxy-3-(4-((1-(2-(2-methoxy-4-(3-(2,4,6-trimethoxyphenyl)acryloyl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-4H-chromen-4-one (113). A mixture of alkyne isoflavone 45 (236 mg, 0.770 mmol), azide chalcone 69 (308 mg, 0.744 mmol), CuSO₄·5H₂O (210 mg, 0.843 mmol) and sodium ascorbate (363 mg, 1.83 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH/PE to afford triazole hybrid 113 (167 mg, 31%) as a pale yellow-orange powdery solid. m.p. 118–120 °C. TLC R_f = 0.33 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 2942w (C-H str), 2840w (C-H str), 1637m (C=O str), 1595s (C=C str), 1559s (C=C str), 1511s (C=C str), 1438m, 1418m, 1336m, 1300m, 1244s, 1201m, 1153s, 1177s, 1118s, 1037s, 1024s. ¹H-NMR (500 MHz, CDCl₃): δ 3.86 (3H, s, -OCH₃), 3.90 (6H, s, 2 × -OCH₃), 3.90 (3H, s, -OCH₃), 3.93 (3H, s, -OCH₃), 4.46 (2H, t, J = 5.2 Hz, -OCH₂CH₂N-), 4.84 (2H, t, J = 5.2 Hz, -OCH₂CH₂N-), 5.26 (2H, s, -OCH₂CN-), 6.13 (2H, s, ArH), 6.83 (1H, d, J = 0.4 Hz, ArH), 6.84 (1H, d, J = 6.0 Hz, ArH), 6.97 (1H, dd, J = 8.8, 2.4 Hz, ArH), 7.04 (2H, d, J = 8.8 Hz, ArH), 7.48 (2H, d, J = 8.8 Hz, ArH), 7.58 (1H, dd, J = 8.4, 2.0 Hz, ArH), 7.62 (1H, d, J = 2.0 Hz, ArH), 7.84 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.88 (1H, s, -CHN-), 8.02 (1H, s, -C=CH), 8.19 (1H, d, J = 8.8 Hz, ArH), 8.21 (1H, d, J = 15.6 Hz, -CH=CHCO-). ¹³C-NMR (500 MHz, CDCl₃): δ 49.7, 55.0, 55.4, 55.8, 55.9, 62.1, 67.6, 90.5, 100.0, 106.6, 111.7, 112.5, 114.5, 114.8, 118.4, 121.6, 122.3, 122.9, 124.4, 127.7, 130.1, 133.7, 135.6, 144.3, 149.5, 150.7, 152.1, 157.9, 158.2, 158.3, 161.6, 163.0, 163.9, 175.7, 190.3. LCMS (ES+) m/z = 720.3 ([M + H]⁺, t_R = 1.69 min). HRMS (ESI+) m/z = 720.2529 [M + H]⁺ found, C₄₀H₃₈O₁₀N₃⁺ required 720.2552.

(E)-7-((1-(2-(2-Methoxy-4-(3-(2,3,4-trimethoxyphenyl)acryloyl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)-methoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (114). A mixture of alkyne isoflavone 46 (226 mg, 0.738 mmol), azide chalcone 68 (301 mg, 0.728 mmol), CuSO₄·5H₂O (204 mg, 0.818 mmol) and sodium ascorbate (393 mg, 1.98 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH to afford triazole hybrid 114 (331 mg, 63%) as a pale yellow-green powdery solid. m.p. 98–100 °C. TLC R_f = 0.39 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 2937w (C-H str), 2838w (C-H str), 1623s (C=O str), 1594s (C=C str), 1576s (C=C str), 1512s (C=C str), 1494s, 1463m, 1442m, 1416m, 1247s, 1196m, 1178m, 1094s, 1027m. ¹H-NMR (500 MHz, CDCl₃): δ 3.83 (3H, s, -OCH₃), 3.89 (3H, s, -OCH₃), 3.91 (3H, s, -OCH₃), 3.93 (3H, s, -OCH₃), 3.95 (3H, s, -OCH₃), 4.47 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 4.86 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 5.32 (2H, s, -OCH₂CN-), 6.72 (1H, d, J = 8.4 Hz, ArH), 6.85 (1H, d, J = 8.4 Hz, ArH), 6.95 (2H, d, J = 8.8 Hz, ArH), 7.01 (1H, d, J = 2.0 Hz, ArH), 7.04 (1H, dd, J = 8.8, 2.0 Hz, ArH), 7.38 (1H, d, J = 8.8 Hz, ArH), 7.49 (2H, d, J = 8.8 Hz, ArH), 7.53 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.60 (1H, d, J = 8.4, 1.6 Hz, ArH), 7.62 (1H, d, J = 0.8 Hz, ArH), 7.90 (1H, s, -C=CH), 7.98 (1H, d, J = 16.0 Hz, -CH=CHCO-), 8.06 (1H, s, -CHN-), 8.20 (1H, d, J = 9.2 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 49.8, 55.3, 56.0, 56.0, 60.9, 61.4, 62.4, 67.5, 101.2, 107.6, 111.5, 112.4, 113.9, 114.8, 118.7, 120.7, 122.0, 122.4, 123.9, 124.1, 124.7, 124.8, 127.9, 130.1, 133.0, 139.7, 142.4, 143.1, 149.6, 151.0, 152.1, 153.7, 155.7, 157.7, 159.5, 162.4, 175.7, 188.9. LCMS (ES+) m/z = 720.3 ([M + H]⁺, t_R = 1.84 min). HRMS (ESI+) m/z = 720.2533 [M + H]⁺ found, C₄₀H₃₈O₁₀N₃⁺ required 720.2552.

3-Hydroxy-2-(4-(2-(4-(((3-(4-methoxyphenyl)-4-oxo-4H-chromen-7-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)-ethoxy)phenyl)-4H-chromen-4-one (115). A mixture of alkyne isoflavone 46 (183 mg, 0.597 mmol), azide flavonol 79 (189 mg, 0.585 mmol), CuSO₄·5H₂O (271 mg, 1.09 mmol) and sodium ascorbate (493 mg, 2.49 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH to afford triazole hybrid 115 (42.9 mg, 12%) as a yellow-green powdery solid. m.p. 252–254 °C. TLC R_f = 0.30 (3% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3371w(br) (O-H str), 3064w (C-H str), 2928w (C-H str), 1640m, 1626m (C=O str), 1601s, 1563m (C=C str), 1512m (C=C str), 1484w, 1444m, 1409m, 1290w, 1247s, 1201m, 1183m, 1121m, 1049m, 1027m. ¹H-NMR (500 MHz, CDCl₃): δ 3.83 (3H, s, -OCH₃), 4.48 (2H, t, J = 5.0 Hz, -OCH₂CH₂N-), 4.86 (2H, t, J = 5.0 Hz, -OCH₂CH₂N-), 5.36 (2H, s, -OCH₂CN-), 6.92 (2H, d, J = 9.0 Hz, ArH), 6.97 (3H, d, J = 9.0 Hz, ArH and OH), 7.00 (1H, d, J = 1.5 Hz, ArH), 7.07 (1H, dd, J = 8.5, 2.0 Hz, ArH), 7.42 (1H, t, J = 7.5 Hz, ArH), 7.47 (2H, d, J = 8.5 Hz, ArH), 7.57 (1H, d, J = 8.0 Hz, ArH), 7.70 (1H, t, J = 8.5 Hz, ArH), 7.89 (2H, s, -C=CH and -CHN-), 8.21–8.25 (4H, m, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 49.8, 55.3, 62.4, 66.3, 101.3, 113.9, 114.5, 115.0, 118.2, 118.8, 120.6, 124.1, 124.5, 124.7, 124.9, 125.4, 127.9, 129.6, 130.0, 133.5, 137.8, 144.6, 152.1, 155.3, 157.7, 159.0, 159.5, 162.3, 173.2, 175.8. LCMS (ES+) m/z = 630.2 ([M + H]⁺, t_R = 1.77 min). HRMS (ESI+) m/z = 630.1861 [M + H]⁺ found, C₃₆H₂₈O₈N₃⁺ required 630.1871.

2-((Z)-4-(2-(4-((2-Methoxy-4-((E)-3-(4-methoxyphenyl)acryloyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-ethoxy)benzylidene)benzofuran-3(2H)-one (116). A mixture of alkyne chalcone 20 (192 mg, 0.595 mmol), azide aurone 88 (187 mg, 0.609 mmol), CuSO₄·5H₂O (289 mg, 1.16 mmol) and sodium ascorbate (548 mg, 2.77 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH to afford triazole hybrid 116 (148 mg, 40%) as a bright yellow powdery solid. m.p. 128–130 °C. TLC R_f = 0.33 (3% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 2941w (C-H str), 2835w (C-H str), 1695m (C=O str), 1647m, 1590s (C=C str), 1571s (C=C str), 1509s (C=C str), 1461m, 1422m, 1296m, 1250s, 1174s, 1147s, 1128s, 1110s, 1098m, 1025s. ¹H-NMR (500 MHz, CDCl₃): δ 3.85 (3H, s, -OCH₃), 3.97 (3H, s, -OCH₃), 4.43 (2H, t, J = 5.0 Hz, -OCH₂CH₂N-), 4.80 (2H, t, J = 5.0 Hz, -OCH₂CH₂N-), 5.42 (2H, s, -OCH₂CN-), 6.83 (1H, s, -C=CH), 6.89 (2H, d, J = 9.0 Hz, ArH), 6.91 (2H, d, J = 9.0 Hz, ArH), 7.12 (1H, d, J = 8.0 Hz, ArH), 7.22 (1H, t, J = 8.0 Hz, ArH), 7.33 (1H, d, J = 8.0 Hz, ArH), 7.39 (1H, d, J = 15.5 Hz, -CH=CHCO-), 7.56 (2H, d, J = 8.5 Hz, ArH), 7.60 (1H, dd, J = 8.5, 2.0 Hz, ArH), 7.64–7.67 (2H, m, ArH), 7.77 (1H, d, J = 16.0 Hz, -CH=CHCO-), 7.79–7.81 (1H, m, ArH), 7.86 (2H, d, J = 9.0 Hz, ArH), 7.87 (1H, br s, -CHN-). ¹³C-NMR (500 MHz, CDCl₃): δ 49.7, 55.4, 56.1, 62.9, 66.3, 111.1, 112.3, 112.6, 112.9, 114.3, 114.9, 119.1, 121.8, 122.6, 123.3, 124.3, 124.6, 126.1, 127.7, 130.1, 132.2, 133.1, 133.4, 136.6, 144.0, 146.1, 149.6, 151.4, 158.9, 161.5, 165.9, 184.5, 188.6. LCMS (ES+) m/z = 630.0 ([M + H]⁺, t_R = 1.72 min). HRMS (ESI+) m/z = 630.2217 [M + H]⁺ found, C₃₇H₃₂O₇N₃⁺ required 630.2235.

2-((Z)-4-(2-(4-((2-((E)-3-(Ferrocenyl)acryloyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)benzylidene)benzofuran-3(2H)-one (117). A mixture of alkyne chalcone 26 (286 mg, 0.772 mmol), azide aurone 88 (248 mg, 0.806 mmol), CuSO₄·5H₂O (236 mg, 0.943 mmol) and sodium ascorbate (426 mg, 2.15 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) to afford triazole hybrid 117 (409 mg, 78%) as a dark red-purple microcrystalline solid. m.p. 108–110 °C. TLC R_f = 0.48 (3% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3090w (C-H str), 1699m (C=O str), 1646m, 1594s (C=C str), 1569m (C=C str), 1509s (C=C str), 1476w, 1459m, 1347w, 1297m, 1247m, 1208m, 1178s, 1127s, 1109s, 1097s, 1044m, 1025m, 1001w. ¹H-NMR (500 MHz, CDCl₃): δ 4.11 (5H, s, -C₅H₅), 4.32 (2H, t, J = 5.2 Hz, -OCH₂CH₂N-), 4.42 (2H, t, J = 2.0 Hz, -C₅H₄), 4.47 (2H, t, J = 2.0 Hz, -C₅H₄), 4.65 (2H, t, J = 5.2 Hz, -OCH₂CH₂N-), 5.32 (2H, s, -OCH₂CN-), 6.85 (1H, s, -C=CH), 6.88 (2H, d, J = 8.8 Hz, ArH), 6.95 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.08 (1H, t, J = 7.6 Hz, ArH), 7.13 (1H, d, J = 8.4 Hz, ArH), 7.22 (1H, t, J = 7.6 Hz, ArH), 7.34 (1H, d, J = 8.4 Hz, ArH), 7.44–7.46 (1H, m, ArH), 7.49 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.60 (1H, dd, J = 7.6, 1.6 Hz, ArH), 7.65 (1H, t, J = 8.4 Hz, ArH), 7.74 (1H, s, -CHN-), 7.81 (1H, dd, J = 7.6, 0.8 Hz, ArH), 7.86 (2H, d, J = 8.8 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 49.5, 62.9, 66.1, 68.9, 69.8, 71.2, 79.0, 112.8, 112.9, 113.1, 115.0, 121.4, 121.8, 123.3, 123.9, 124.6, 124.7, 125.9, 130.1, 130.2, 132.4, 133.4, 136.6, 144.1, 145.4, 146.0, 156.3, 159.0, 165.8, 184.5, 192.3. LCMS (ES+) m/z = 678.2 ([M + H]⁺, t_R = 2.11 min). HRMS (ESI+) m/z = 678.1677 [M + H]⁺ found, C₃₉H₃₂N₃O₅Fe⁺ required 678.1691.

6-Methoxy-2-((Z)-4-(2-(4-((2-methoxy-5-((E)-3-(1-methyl-1H-pyrrol-2-yl)acryloyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)benzylidene)benzofuran-3(2H)-one (118). A mixture of alkyne chalcone 22 (265 mg, 0.898 mmol), azide aurone 89 (304 mg, 0.900 mmol), CuSO₄·5H₂O (264 mg, 1.06 mmol) and sodium ascorbate (474 mg, 2.39 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) to afford triazole hybrid 118 (270 mg, 48%) as a bright yellow powdery solid. m.p. 138–140 °C. TLC R_f = 0.46 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 2934w (C-H str), 2884w (C-H str), 1700m (C=O str), 1656m, 1638m, 1596s (C=C str), 1562s (C=C str), 1510m (C=C str), 1483m, 1412m, 1330m, 1267s, 1198m, 1152s, 1132s, 1099s, 1056m, 1042s, 1022s. ¹H-NMR (500 MHz, CDCl₃): δ 3.74 (3H, s, -NCH₃), 3.94 (3H, s, -OCH₃), 3.96 (3H, s, -OCH₃), 4.42 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 4.79 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 5.41 (2H, s, -OCH₂CN-), 6.19–6.21 (1H, m, ArH), 6.74–6.80 (4H, m, ArH), 6.78 (1H, s, -C=CH), 6.87 (2H, d, J = 8.8 Hz, ArH), 7.11 (1H, d, J = 8.4 Hz, ArH), 7.27 (1H, d, J = 15.2 Hz, -CH=CHCO-, overlain by CDCl₃), 7.58 (1H, dd, J = 8.4, 1.6 Hz, ArH), 7.64 (1H, d, J = 2.0 Hz, ArH), 7.69 (1H, d, J = 8.8 Hz, ArH), 7.78 (1H, d, J = 15.2 Hz, -CH=CHCO-), 7.82 (2H, d, J = 8.8 Hz, ArH), 7.87 (1H, s, -CHN-). ¹³C-NMR (500 MHz, CDCl₃): δ 34.3, 49.7, 56.0, 56.0, 62.8, 66.2, 96.6, 109.6, 111.0, 111.4, 112.0, 112.1, 112.3, 114.8, 114.9, 116.2, 122.3, 124.3, 125.6, 126.1, 127.6, 130.2, 131.6, 132.4, 133.1, 143.8, 147.0, 149.4, 151.2, 158.6, 167.2, 168.2, 182.8, 188.0. LCMS (ES+) m/z = 633.3 ([M + H]⁺, t_R = 1.94 min). HRMS (ESI+) m/z = 633.2352 [M + H]⁺ found, C₃₆H₃₃N₄O₇⁺ required 633.2349.

2-((Z)-4-(2-(4-((4-Bromo-2-((E)-3-(1-methyl-1H-indol-3-yl)acryloyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)benzylidene)benzofuran-3(2H)-one (119). A mixture of alkyne chalcone 21 (308 mg, 0.781 mmol), azide aurone 88 (239 mg, 0.779 mmol), CuSO₄·5H₂O (261 mg, 1.04 mmol) and sodium ascorbate (397 mg, 2.00 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH to afford triazole hybrid 119 (117 mg, 21%) as a pale yellow-brown powdery solid. m.p. 138–140 °C. TLC R_f = 0.44 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 2930w (C-H str), 1699m (C=O str), 1644m, 1590s (C=C str), 1525m (C=C str), 1508m (C=C str), 1460m, 1395w, 1373m, 1249m, 1177s, 1126m, 1096w, 1045w. ¹H-NMR (500 MHz, CDCl₃): δ 3.74 (3H, s, -NCH₃), 4.03 (2H, t, J = 5.2 Hz, -OCH₂CH₂N-), 4.37 (2H, t, J = 5.2 Hz, -OCH₂CH₂N-), 5.32 (2H, s, -OCH₂CN-), 6.71 (2H, d, J = 8.8 Hz, ArH), 6.82 (1H, s, -C=CH), 7.04 (1H, d, J = 8.8 Hz, ArH), 7.16–7.21 (1H, m, ArH), 7.23 (1H, t, J = 7.6 Hz, ArH), 7.29–7.30 (2H, m, ArH), 7.33–7.35 (2H, m, ArH), 7.38 (1H, d, J = 16.0 Hz, -CH=CHCO-), 7.54 (1H, dd, J = 8.8, 2.4 Hz, ArH), 7.64–7.69 (2H, m, ArH), 7.73 (1H, s, -CHN-), 7.77 (2H, d, J = 8.8 ArH), 7.80–7.82 (2H, m, ArH), 7.85 (1H, d, J = 15.6 Hz, -CH=CHCO-). ¹³C-NMR (500 MHz, CDCl₃): δ 33.2, 49.2, 63.3, 65.7, 110.0, 112.7, 112.7, 112.9, 114.0, 114.7, 114.9, 120.6, 121.7, 121.7, 121.8, 123.1, 123.4, 124.1, 124.6, 125.7, 125.8, 132.0, 133.1, 133.2, 134.8, 135.0, 136.7, 138.1, 138.1, 143.7, 146.0, 155.5, 158.8, 165.8, 184.5, 190.8. LCMS (ES+) m/z = 703.1 ([M + H]⁺, t_R = 5.05 min). HRMS (ESI+) m/z = 723.1189 [M + Na]⁺ found, C₃₈H₂₉O₅N₄BrNa⁺ required 723.1214.

(Z)-3-((1-(2-(4-((6-Methoxy-3-oxobenzofuran-2(3H)-ylidene)methyl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)-methoxy)-2-phenyl-4H-chromen-4-one (120). A mixture of alkyne flavone 30 (250 mg, 0.906 mmol), azide aurone 89 (316 mg, 0.936 mmol), CuSO₄·5H₂O (284 mg, 1.14 mmol) and sodium ascorbate (447 mg, 2.26 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH to afford triazole hybrid 120 (351 mg, 63%) as a pale yellow-white powdery solid. m.p. 186–188 °C. TLC R_f = 0.38 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3056w (C-H str), 1698m (C=O str), 1654w, 1608s, 1595s (C=C str), 1509m (C=C str), 1470m, 1434m, 1397m, 1342m, 1272s, 1245s, 1198s, 1176m, 1147m, 1128s, 1109s, 1091s, 1042m. ¹H-NMR (500 MHz, CDCl₃): δ 3.93 (3H, s, -OCH₃), 4.35 (2H, t, J = 5.0 Hz, -OCH₂CH₂N-), 4.71 (2H, t, J = 4.5 Hz, -OCH₂CH₂N-), 5.33 (2H, s, -OCH₂CN-), 6.74–6.77 (3H, m, ArH and -C=CH), 6.90 (2H, d, J = 9.0 Hz, ArH), 7.40–7.45 (4H, m, ArH), 7.52 (1H, dd, J = 8.5, 0.5 Hz, ArH), 7.69 (1H, t, J = 8.5 Hz, ArH), 7.70 (1H, d, J = 8.5 Hz, ArH), 7.83 (2H, d, J = 9.0 Hz, ArH), 7.83 (1H, s, -CHN-), 8.01–8.03 (2H, m, ArH), 8.28 (1H, dd, J = 8.0, 1.5 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 49.5, 56.0, 65.1, 66.2, 96.6, 111.5, 112.0, 114.9, 115.0, 118.1, 124.1, 124.8, 124.9, 125.7, 126.1, 128.3, 128.7, 130.7, 133.1, 133.5, 139.5, 144.0, 147.0, 155.3, 156.4, 158.8, 167.3, 168.3, 175.1, 182.8. LCMS (ES+) m/z = 614.2 ([M + H]⁺, t_R = 1.91 min). HRMS (ESI+) m/z = 614.1926 [M + H]⁺ found, C₃₆H₂₈N₃O₇⁺ required 614.1927.

(Z)-6-((1-(2-(4-((6-Methoxy-3-oxobenzofuran-2(3H)-ylidene)methyl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-phenyl-4H-chromen-4-one (121). A mixture of alkyne flavone 31 (249 mg, 0.900 mmol), azide aurone 89 (309 mg, 0.916 mmol), CuSO₄·5H₂O (247 mg, 0.989 mmol) and sodium ascorbate (482 mg, 2.43 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH to afford triazole hybrid 121 (269 mg, 49%) as a bright yellow-orange powdery solid. m.p. 148–150 °C. TLC R_f = 0.30 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3065w (C-H str), 2925w (C-H str), 1695m (C=O str), 1640s, 1594s (C=C str), 1568s (C=C str), 1510m (C=C str), 1496m, 1481m, 1454s, 1442s, 1360m, 1270m, 1250s, 1181s, 1131s, 1110s, 1095s, 1043m, 1027m. ¹H-NMR (500 MHz, CDCl₃): δ 3.92 (3H, s, -OCH₃), 4.43 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 4.82 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 5.30 (2H, s, -OCH₂CN-), 6.72–6.74 (2H, m, ArH), 6.75 (1H, s, -C=CH), 6.79 (1H, s, -C=CH), 6.89 (2H, d, J = 8.8 Hz, ArH), 7.33 (1H, dd, J = 9.2, 3.2 Hz, ArH), 7.48–7.52 (4H, m, ArH), 7.68 (1H, d, J = 9.2 Hz, ArH), 7.71 (1H, d, J = 3.2 Hz, ArH), 7.80 (2H, d, J = 8.8 Hz, ArH), 7.88–7.90 (3H, m, ArH and -CHN-). ¹³C-NMR (500 MHz, CDCl₃): δ 49.7, 56.0, 62.2, 66.3, 96.5, 106.4, 106.8, 111.4, 112.0, 114.8, 114.9, 120.0, 123.9, 124.2, 124.5, 125.7, 126.1, 126.2, 129.0, 131.5, 131.7, 133.1, 143.4, 146.9, 151.2, 155.4, 158.7, 163.2, 167.2, 168.2, 178.1, 182.8. LCMS (ES+) m/z = 614.2 ([M + H]⁺, t_R = 1.77 min). HRMS (ESI+) m/z = 614.1906 [M + H]⁺ found, C₃₆H₂₈O₇N₃⁺ required 614.1922.

(Z)-3-Hydroxy-2-(4-((1-(2-(4-((3-oxobenzofuran-2(3H)-ylidene)methyl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-4H-chromen-4-one (122). A mixture of alkyne flavonol 36 (391 mg, 1.34 mmol), azide aurone 88 (408 mg, 1.33 mmol), CuSO₄·5H₂O (435 mg, 1.74 mmol) and sodium ascorbate (682 mg, 3.44 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH to afford triazole hybrid 122 (335 mg, 42%) as a yellow-brown powdery solid. m.p. 208–210 °C. TLC R_f = 0.32 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3300w (O-H str), 3073w (C-H str), 2951w (C-H str), 1694m (C=O str), 1646w, 1604s, 1596s (C=C str), 1567w (C=C str), 1509s (C=C str), 1458w, 1426w, 1407w, 1299m, 1256s, 1178s, 1109s, 1051s. ¹H-NMR (500 MHz, CDCl₃): δ 4.46 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 4.84 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 5.34 (2H, s, -OCH₂CN-), 6.82 (1H, s, -C=CH), 6.92 (2H, d, J = 8.8 Hz, ArH), 6.96 (1H, br s, OH), 7.15 (2H, d, J = 8.8 Hz, ArH), 7.22 (1H, t, J = 7.6 Hz, ArH), 7.31 (1H, d, J = 8.4 Hz, ArH), 7.39 (1H, t, J = 7.6 Hz, ArH), 7.56 (1H, d, J = 8.8 Hz, ArH), 7.63–7.71 (2H, m, ArH), 7.80 (1H, d, J = 7.6 Hz, ArH), 7.86 (3H, d, J = 8.4 Hz, ArH and -CHN-), 8.21–8.25 (3H, m, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 49.8, 62.1, 66.4, 112.6, 112.9, 114.9, 114.9, 118.1, 120.6, 121.8, 123.4, 124.1, 124.4, 124.6, 125.4, 126.1, 129.5, 133.0, 133.4, 136.5, 136.7, 137.7, 145.0, 146.1, 155.3, 157.4, 158.9, 159.5, 165.9, 173.1, 184.5. LCMS (ES+) m/z = 600.0 ([M + H]⁺, t_R = 4.68 min). HRMS (ESI+) m/z = 600.1751 [M + H]⁺ found, C₃₅H₂₆O₇N₃⁺ required 600.1765.

(Z)-2-(4-(2-(4-((3-((4,6-Dimethoxy-3-oxobenzofuran-2(3H)-ylidene)methyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)phenyl)-3-hydroxy-7-methoxy-4H-chromen-4-one (123). A mixture of alkyne aurone 56 (192 mg, 0.571 mmol), azide flavonol 80 (210 mg, 0.595 mmol), CuSO₄·5H₂O (234 mg, 0.939 mmol) and sodium ascorbate (362 mg, 1.83 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH to afford triazole hybrid 123 (54.3 mg, 14%) as a pale yellow-brown powdery solid. m.p. 178–180 °C. TLC R_f = 0.29 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3302w (O-H str), 2939w (C-H str), 2845w (C-H str), 1692w, 1614s (C=O str), 1599s (C=C str), 1510m (C=C str), 1503m (C=C str), 1452m, 1403w, 1361w, 1346w, 1251m, 1215s, 1187w, 1156m, 1121w, 1092s, 1036w. ¹H-NMR (500 MHz, CDCl₃): δ 3.91 (3H, s, -OCH₃), 3.92 (3H, s, -OCH₃), 3.95 (3H, s, -OCH₃), 4.46 (2H, t, J = 4.5 Hz, -OCH₂CH₂N-), 4.83 (2H, t, J = 4.5 Hz, -OCH₂CH₂N-), 5.34 (2H, s, -OCH₂CN-), 6.08 (1H, s, ArH), 6.41 (1H, s, ArH), 6.70 (1H, s, -C=CH), 6.93–6.95 (4H, m, ArH and OH), 6.99–7.03 (2H, m, ArH), 7.34 (1H, t, J = 8.0 Hz, ArH), 7.40 (1H, d, J = 7.5 Hz, ArH), 7.55 (1H, s, ArH), 7.85 (1H, br s, -CHN-), 8.12 (1H, d, J = 9.0 Hz, ArH), 8.16 (2H, d, J = 8.5 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 49.8, 55.9, 56.2, 56.2, 62.2, 66.4, 89.3, 94.1, 99.9, 105.1, 110.3, 114.4, 114.6, 114.8, 116.2, 116.7, 121.9, 123.9, 124.5, 124.8, 126.7, 129.3, 129.8, 134.0, 137.4, 144.0, 148.0, 157.2, 158.3, 158.8, 159.3, 164.2, 169.1, 172.6, 180.6. LCMS (ES+) m/z = 690.2 ([M + H]⁺, t_R = 4.59 min). HRMS (ESI+) m/z = 690.2062 [M + H]⁺ found, C₃₈H₃₂O₁₀N₃⁺ required 690.2082.

(Z)-7-((1-(2-(4-((6-Methoxy-3-oxobenzofuran-2(3H)-ylidene)methyl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)-methoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (124). A mixture of alkyne isoflavone 46 (276 mg, 0.901 mmol), azide aurone 89 (301 mg, 0.892 mmol), CuSO₄·5H₂O (348 mg, 1.39 mmol) and sodium ascorbate (496 mg, 2.50 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH to afford triazole hybrid 124 (317 mg, 55%) as a bright yellow powdery solid. m.p. 228–230 °C. TLC R_f = 0.43 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3085w (C-H str), 2935w (C-H str), 1705m (C=O str), 1651m, 1629s, 1596s (C=C str), 1567m (C=C str), 1510s (C=C str), 1441s, 1347m, 1295m, 1249s, 1202m, 1179s, 1147s, 1098s, 1020s. ¹H-NMR (500 MHz, CDCl₃): δ 3.83 (3H, s, -OCH₃), 3.93 (3H, s, -OCH₃), 4.44 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 4.83 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 5.34 (2H, s, -OCH₂CN-), 6.74–6.77 (2H, m, ArH), 6.76 (1H, s, -C=CH), 6.88 (2H, d, J = 8.8 Hz, ArH), 6.93 (2H, d, J = 8.8 Hz, ArH), 6.97 (1H, d, J = 2.4 Hz, ArH), 7.06 (1H, dd, J = 8.8, 2.4 Hz, ArH), 7.47 (2H, d, J = 8.8 Hz, ArH), 7.69 (1H, d, J = 8.4 Hz, ArH), 7.82 (2H, d, J = 8.8 Hz, ArH), 7.87 (1H, s, -CHN-), 7.89 (1H, s, -C=CH), 8.23 (1H, d, J = 8.8 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 49.8, 55.3, 56.0, 62.4, 66.3, 96.7, 101.3, 111.3, 112.1, 113.9, 114.8, 114.9, 118.8, 124.1, 124.2, 124.9, 125.7, 126.3, 127.9, 130.0, 133.1, 143.2, 147.0, 152.1, 157.7, 158.6, 159.5, 162.3, 167.3, 168.3, 175.8, 182.8. LCMS (ES+) m/z = 644.2 ([M + H]⁺, t_R = 1.86 min). HRMS (ESI+) m/z = 644.2011 [M + H]⁺ found, C₃₇H₃₀O₈N₃⁺ required 644.2027.

4,6-Dimethoxy-2-((Z)-3-((1-(2-(4-(((Z)-3-oxobenzofuran-2(3H)-ylidene)methyl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)benzylidene)benzofuran-3(2H)-one (125). A mixture of alkyne aurone 56 (303 mg, 0.902 mmol), azide aurone 88 (278 mg, 0.905 mmol), CuSO₄·5H₂O (263 mg, 1.05 mmol) and sodium ascorbate (462 mg, 2.33 mmol) in t-BuOH/H₂O (1:1, 20 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH to afford triazole hybrid 125 (491 mg, 85%) as a bright yellow-brown powdery solid. m.p. 148–150 °C. TLC R_f = 0.36 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 2942w (C-H str), 2843w (C-H str), 1694m (C=O str), 1651m, 1587s (C=C str), 1508m (C=C str), 1458m, 1423w, 1345m, 1298m, 1251m, 1234m, 1214s, 1177s, 1154s, 1128s, 1091s, 1036m. ¹H-NMR (500 MHz, CDCl₃): δ 3.90 (3H, s, -OCH₃), 3.92 (3H, s, -OCH₃), 4.42 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 4.81 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 5.31 (2H, s, -OCH₂CN-), 6.09 (1H, d, J = 1.6 Hz, ArH), 6.40 (1H, d, J = 1.2 Hz, ArH), 6.68 (1H, s, -C=CH), 6.81 (1H, s, -C=CH), 6.88 (2H, d, J = 8.4 Hz, ArH), 7.00 (1H, dd, J = 8.0, 2.4 Hz, ArH), 7.21 (1H, t, J = 7.6 Hz, ArH), 7.30–7.34 (2H, m, ArH), 7.39 (1H, d, J = 8.0 Hz, ArH), 7.54 (1H, s, ArH), 7.64 (1H, t, J = 7.6 Hz, ArH), 7.79 (1H, d, J = 7.6 Hz, ArH), 7.82–7.85 (3H, m, ArH and -CHN-). ¹³C-NMR (500 MHz, CDCl₃): δ 49.7, 56.2, 62.2, 66.3, 89.3, 94.1, 105.1, 110.3, 112.7, 112.9, 114.3, 114.8, 116.3, 116.6, 121.8, 123.3, 123.9, 124.5, 124.5, 126.0, 129.8, 133.0, 133.4, 133.9, 136.7, 144.3, 146.1, 148.0, 158.3, 158.9, 159.3, 165.9, 169.0, 180.6, 184.5. LCMS (ES+) m/z = 644.2 ([M + H]⁺, t_R = 2.02 min). HRMS (ESI+) m/z = 644.2006 [M + H]⁺ found, C₃₇H₃₀O₈N₃⁺ required 644.2027.

(E)-4-((1-(2-(4-(3-(2-Hydroxyphenyl)-3-oxoprop-1-en-1-yl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2H-chromen-2-one (126). A mixture of alkyne coumarin 48 (207 mg, 1.03 mmol), azide chalcone 61 (302 mg, 0.975 mmol), CuSO₄·5H₂O (292 mg, 1.17 mmol) and sodium ascorbate (508 mg, 2.56 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH to afford triazole hybrid 126 (387 mg, 78%) as a bright yellow powdery solid. m.p. 194–196 °C. TLC R_f = 0.43 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3083w (C-H str), 2929w (C-H str), 1725s (C=O str), 1641m, 1625m, 1607m, 1560s (C=C str), 1511s (C=C str), 1489s, 1424m, 1382m, 1273m, 1249s, 1202s, 1175s, 1156s, 1107m, 1056m, 1030m. ¹H-NMR (500 MHz, CDCl₃): δ 4.47 (2H, t, J = 5.2 Hz, -OCH₂CH₂N-), 4.87 (2H, t, J = 5.2 Hz, -OCH₂CH₂N-), 5.36 (2H, s, -OCH₂CN-), 5.87 (1H, s, -C=CH), 6.91–6.97 (3H, m, ArH), 7.03 (1H, d, J = 8.4 Hz, ArH), 7.23 (1H, t, J = 8.0 Hz, ArH), 7.31 (1H, d, J = 8.4 Hz, ArH), 7.48–7.54 (2H, m, ArH), 7.54 (1H, d, J = 15.2 Hz, -CH=CHCO-), 7.61 (2H, d, J = 8.4 Hz, ArH), 7.78 (1H, dd, J = 8.0, 1.6 Hz, ArH), 7.86 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.91 (1H, dd, J = 8.0, 1.2 Hz, ArH), 7.94 (1H, s, -CHN-), 12.87 (1H, s, OH). ¹³C-NMR (500 MHz, CDCl₃): δ 49.9, 62.5, 66.3, 91.2, 115.0, 115.4, 116.8, 118.4, 118.6, 118.8, 120.0, 123.1, 123.9, 124.7, 128.5, 129.5, 130.6, 132.6, 136.3, 141.6, 144.7, 153.3, 159.8, 162.6, 163.5, 164.9, 193.6. LCMS (ES+) m/z = 510.2 ([M + H]⁺, t_R = 1.65 min). HRMS (ESI+) m/z = 510.1651 [M + H]⁺ found, C₂₉H₂₄O₆N₃⁺ required 510.1660.

4-((1-(2-(4-(3-Hydroxy-4-oxo-4H-chromen-2-yl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2H-chromen-2-one (127). A mixture of alkyne coumarin 48 (186 mg, 0.931 mmol), azide flavonol 79 (302 mg, 0.933 mmol), CuSO₄·5H₂O (318 mg, 1.27 mmol) and sodium ascorbate (497 mg, 2.51 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH to afford triazole hybrid 127 (77.9 mg, 16%) as an off-white powdery solid. m.p. 228–230 °C. TLC R_f = 0.46 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3271w (O-H str), 3015w (C-H str), 2923w (C-H str), 1714s (C=O str), 1622m, 1603s, 1565s (C=C str), 1509m (C=C str), 1480m, 1470w, 1428m, 1406w, 1376w, 1262s, 1228m, 1177m, 1140w, 1106m, 1043m. ¹H-NMR (500 MHz, CDCl₃): δ 4.52 (2H, t, J = 5.0 Hz, -OCH₂CH₂N-), 4.89 (2H, t, J = 5.0 Hz, -OCH₂CH₂N-), 5.37 (2H, s, -OCH₂CN-), 5.89 (1H, s, -C=CH), 6.97 (1H, br s, OH), 7.03 (2H, d, J = 9.0 Hz, ArH), 7.24 (1H, t, J = 8.0 Hz, ArH), 7.31 (1H, dd, J = 8.5, 1.0 Hz, ArH), 7.43 (1H, t, J = 8.0 Hz, ArH), 7.54 (1H, t, J = 8.5 Hz, ArH), 7.59 (1H, d, J = 8.5 Hz, ArH), 7.72 (1H, t, J = 8.5 Hz, ArH), 7.78 (1H, dd, J = 8.0, 1.5 Hz, ArH), 7.96 (1H, s, -CHN-), 8.23–8.27 (3H, m, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 49.9, 62.6, 66.3, 91.2, 114.5, 115.4, 116.8, 118.2, 120.7, 123.1, 123.9, 124.5, 124.7, 124.8, 125.4, 129.7, 132.5, 133.5, 137.8, 141.7, 144.6, 153.3, 155.3, 159.0, 162.6, 164.9, 173.2. LCMS (ES+) m/z = 524.2 ([M + H]⁺, t_R = 1.55 min). HRMS (ESI+) m/z = 524.1476 [M + H]⁺ found, C₂₉H₂₂N₃O₇⁺ required 524.1458.

4-(2-(4-(((4-Oxo-2-phenyl-4H-chromen-3-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)-2H-chromen-2-one (128). A mixture of alkyne flavone 30 (310 mg, 1.12 mmol), azide coumarin 58 (256 mg, 1.11 mmol), CuSO₄·5H₂O (399 mg, 1.60 mmol) and sodium ascorbate (578 mg, 2.92 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) to afford triazole hybrid 128 (354 mg, 63%) as a white fluffy solid. m.p. 268–270 °C. TLC R_f = 0.30 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3082w (C-H str), 2926w (C-H str), 1723s (C=O str), 1626s, 1567m (C=C str), 1494w, 1465m, 1400w, 1385m, 1274m, 1239s, 1197s, 1182s, 1148s, 1140m, 1111m, 1058w, 1030w. ¹H-NMR (500 MHz, CDCl₃): δ 4.47 (2H, t, J = 5.0 Hz, -OCH₂CH₂N-), 4.85 (2H, t, J = 5.0 Hz, -OCH₂CH₂N-), 5.31 (2H, s, -OCH₂CN-), 5.65 (1H, s, -C=CH), 7.24 (1H, t, J = 7.5 Hz, ArH, overlain by CDCl₃), 7.33 (1H, d, J = 8.5 Hz, ArH), 7.41–7.46 (4H, m, ArH), 7.51 (1H, d, J = 8.5 Hz, ArH), 7.55 (1H, t, J = 8.0 Hz, ArH), 7.68–7.73 (2H, m, ArH), 7.93 (1H, s, -CHN-), 8.02–8.04 (2H, m, ArH), 8.25 (1H, d, J = 7.5 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 48.7, 65.2, 67.0, 91.1, 115.0, 116.8, 118.1, 122.9, 124.0, 124.2, 124.7, 124.9, 125.6, 128.4, 128.7, 130.7, 130.8, 132.8, 133.7, 139.7, 144.7, 153.3, 155.3, 156.3, 162.2, 164.6, 175.1. LCMS (ES+) m/z = 508.3 ([M + H]⁺, t_R = 1.81 min). HRMS (ESI+) m/z = 508.1506 [M + H]⁺ found, C₂₉H₂₂N₃O₆⁺ required 508.1509.

(Z)-4-((1-(2-(4-((6-Methoxy-3-oxobenzofuran-2(3H)-ylidene)methyl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2H-chromen-2-one (129). A mixture of alkyne coumarin 48 (181 mg, 0.902 mmol), azide aurone 89 (302 mg, 0.895 mmol), CuSO₄·5H₂O (250 mg, 1.00 mmol) and sodium ascorbate (459 mg, 2.32 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and recrystallized from MeOH to afford triazole hybrid 129 (253 mg, 53%) as a bright yellow-orange microcrystalline solid. m.p. 138–140 °C. TLC R_f = 0.40 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3077w (C-H str), 2926w (C-H str), 1719s (C=O str), 1650m, 1623m, 1593s (C=C str), 1565m (C=C str), 1511m (C=C str), 1442m, 1399m, 1269m, 1247s, 1182s, 1130s, 1096s, 1042m, 1019m. ¹H-NMR (500 MHz, CDCl₃): δ 3.94 (3H, s, -OCH₃), 4.48 (2H, t, J = 4.5 Hz, -OCH₂CH₂N-), 4.87 (2H, t, J = 4.5 Hz, -OCH₂CH₂N-), 5.36 (2H, s, -OCH₂CN-), 5.88 (1H, s, -C=CH), 6.75–6.78 (2H, m, ArH), 6.76 (1H, s, -C=CH), 6.94 (2H, d, J = 9.0 Hz, ArH), 7.23 (1H, t, J = 8.0 Hz, ArH), 7.31 (1H, dd, J = 8.5, 1.0 Hz, ArH), 7.53 (1H, t, J = 8.5 Hz, ArH), 7.71 (1H, d, J = 9.0 Hz, ArH), 7.77 (1H, dd, J = 8.0, 1.5 Hz, ArH), 7.84 (2H, d, J = 8.5 Hz, ArH), 7.95 (1H, s, -CHN-). ¹³C-NMR (500 MHz, CDCl₃): δ 49.9, 56.0, 62.5, 66.3, 91.2, 96.6, 111.3, 112.1, 114.8, 115.0, 115.4, 116.8, 123.1, 123.9, 124.7, 125.8, 126.3, 132.5, 133.1, 141.6, 147.1, 153.3, 158.6, 162.6, 164.9, 167.3, 168.3, 182.8. LCMS (ES+) m/z = 538.2 ([M + H]⁺, t_R = 1.78 min). HRMS (ESI+) m/z = 538.1617 [M + H]⁺ found, C₃₀H₂₄N₃O₇⁺ required 538.1614.

4-(2-(4-(((3-(4-Methoxyphenyl)-4-oxo-4H-chromen-7-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)-2H-chromen-2-one (130). A mixture of alkyne isoflavone 46 (301 mg, 0.983 mmol), azide coumarin 58 (232 mg, 1.00 mmol), CuSO₄·5H₂O (288 mg, 1.15 mmol) and sodium ascorbate (503 mg, 2.54 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) to afford triazole hybrid 130 (363 mg, 69%) as an off-white powdery solid. m.p. 208–210 °C. TLC R_f = 0.28 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3085w (C-H str), 2927w (C-H str), 1730s (C=O str), 1621s, 1566m (C=C str), 1513m (C=C str), 1495w, 1444m, 1379m, 1330w, 1279w, 1241s, 1198m, 1181s, 1144m, 1109m, 1031m. ¹H-NMR (500 MHz, CDCl₃): δ 3.85 (3H, s, -OCH₃), 4.58 (2H, t, J = 4.4 Hz, -OCH₂CH₂N-), 4.95 (2H, t, J = 4.4 Hz, -OCH₂CH₂N-), 5.35 (2H, s, -OCH₂CN-), 5.69 (1H, s, -C=CH), 6.97–6.99 (3H, m, ArH), 7.03 (1H, dd, J = 8.8, 2.0 Hz, ArH), 7.23 (1H, d, J = 7.6 Hz, ArH), 7.31 (1H, d, J = 8.0 Hz, ArH), 7.50 (2H, d, J = 8.4 Hz, ArH), 7.56 (1H, t, J = 8.0 Hz, ArH), 7.65 (1H, d, J = 8.0 Hz, ArH), 7.84 (1H, s, -CHN-), 7.90 (1H, s, -C=CH), 8.20 (1H, d, J = 8.8 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 49.0, 55.3, 62.4, 67.0, 91.3, 101.2, 114.0, 114.8, 114.9, 117.0, 118.9, 120.2, 122.4, 123.5, 124.0, 124.1, 125.0, 128.0, 130.1, 132.9, 143.7, 152.1, 153.3, 157.7, 159.6, 162.2, 164.4, 175.7. LCMS (ES+) m/z = 538.0 ([M + H]⁺, t_R = 4.19 min). HRMS (ESI+) m/z = 538.1624 [M + H]⁺ found, C₃₀H₂₄N₃O₇⁺ required 538.1614.

(E)-4-((1-(2-(4-(3-Oxo-3-(2-(prop-2-yn-1-yloxy)phenyl)prop-1-en-1-yl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2H-chromen-2-one (131). A mixture of biflavonoid 126 (264 mg, 0.517 mmol), propargyl bromide (0.130 mL, 1.46 mmol) and anhydrous K₂CO₃ (291 mg, 2.10 mmol) in dry acetone (50 mL) was reacted according to GP-B. The crude residue was purified by flash column chromatography (SiO₂, 1% MeOH/CH₂Cl₂) to afford alkyne biflavonoid 131 (229 mg, 81%) as a pale yellow-white powdery solid. m.p. 164–166 °C. TLC R_f = 0.15 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3239w (C≡C-H str), 3074w (C-H str), 2973w (C-H str), 2165w (C≡C str), 1723s (C=O str), 1651m, 1624m, 1600s (C=C str), 1566m (C=C str), 1510m (C=C str), 1482w, 1452m, 1401s, 1372m, 1328m, 1231s, 1175w, 1105m, 1028m. ¹H-NMR (500 MHz, CDCl₃): δ 2.54 (1H, t, J = 2.0 Hz, -OCH₂C≡CH), 4.45 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 4.79 (2H, d, J = 2.0 Hz, -OCH₂C≡CH), 4.85 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 5.35 (2H, s, -OCH₂CN-), 5.87 (1H, s, -C=CH), 6.88 (2H, d, J = 8.8 Hz, ArH), 7.09–7.13 (2H, m, ArH), 7.23 (1H, t, J = 7.6 Hz, ArH), 7.29 (1H, d, J = 13.2 Hz, -CH=CHCO-, overlain by CDCl₃), 7.32 (1H, t, J = 4.4 Hz, ArH), 7.49 (1H, t, J = 8.8 Hz, ArH), 7.53–7.58 (3H, m, ArH), 7.56 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.64 (1H, dd, J = 7.6, 1.2 Hz, ArH), 7.77 (1H, dd, J = 8.4, 0.8 Hz, ArH), 7.93 (1H, s, -CHN-). ¹³C-NMR (500 MHz, CDCl₃): δ 49.9, 56.4, 62.5, 66.3, 76.1, 78.1, 91.2, 113.3, 114.8, 115.4, 116.8, 121.8, 123.1, 123.9, 124.6, 125.6, 129.0, 130.0, 130.2, 130.5, 132.6, 132.6, 141.6, 142.7, 153.3, 155.8, 159.3, 162.5, 164.9, 192.5. LCMS (ES+) m/z = 548.0 ([M + H]⁺, t_R = 4.38 min). HRMS (ESI+) m/z = 548.1803 [M + H]⁺ found, C₃₂H₂₆O₆N₃⁺ required 548.1816.

(Z)-2-(4-((1-(2-(4-((3-Oxobenzofuran-2(3H)-ylidene)methyl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-3-(prop-2-yn-1-yloxy)-4H-chromen-4-one (132). A mixture of biflavonoid 122 (212 mg, 0.354 mmol), propargyl bromide (0.063 mL, 0.707 mmol) and anhydrous K₂CO₃ (153 mg, 1.11 mmol) in dry acetone (20 mL) was reacted according to GP-B. The crude residue was purified by flash column chromatography (SiO₂, 1% MeOH/CH₂Cl₂) to afford alkyne biflavonoid 132 (168 mg, 74%) as a bright yellow powdery solid. m.p. 150–152 °C. TLC R_f = 0.50 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3233w (C≡C-H str), 2939w (C-H str), 2115w (C≡C str), 1697s (C=O str), 1635m, 1606s, 1598s (C=C str), 1566m (C=C str), 1508s (C=C str), 1472m, 1395m, 1343w, 1301m, 1250s, 1198m, 1184s, 1148m, 1133w, 1047m, 1017w. ¹H-NMR (500 MHz, CDCl₃): δ 2.34 (1H, t, J = 2.4 Hz, -OCH₂C≡CH), 4.46 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 4.84 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 5.00 (2H, d, J = 2.4 Hz, -OCH₂C≡CH), 5.33 (2H, s, -OCH₂CN-), 6.83 (1H, s, -C=CH), 6.93 (2H, d, J = 8.8 Hz, ArH), 7.12 (2H, d, J = 9.2 Hz, ArH), 7.22 (1H, t, J = 7.6 Hz, ArH), 7.31 (1H, d, J = 8.4 Hz, ArH), 7.38 (1H, t, J = 7.6 Hz, ArH), 7.51 (1H, d, J = 8.4 Hz, ArH), 7.63–7.69 (2H, m, ArH), 7.80 (1H, d, J = 7.6 Hz, ArH), 7.86 (2H, d, J = 6.8 Hz, ArH), 7.87 (1H, s, -CHN-), 8.16 (2H, d, J = 8.8 Hz, ArH), 8.22 (1H, dd, J = 8.0, 1.6 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 49.8, 59.0, 62.0, 66.3, 76.0, 78.7, 112.6, 112.9, 114.6, 114.9, 117.9, 121.8, 123.4, 123.8, 123.9, 124.1, 124.6, 124.7, 125.7, 126.1, 130.7, 133.4, 136.7, 138.0, 146.1, 155.1, 156.4, 158.9, 160.1, 165.8, 174.7, 184.5. LCMS (ES+) m/z = 638.1 ([M + H]⁺, t_r = 4.82 min). HRMS (ESI+) m/z = 638.1902 [M + H]⁺ found, C₃₈H₂₈O₇N₃⁺ required 638.1922.

(E)-1-(4-Methoxy-2-(prop-2-yn-1-yloxy)phenyl)-3-(4-methoxy-3-((1-(2-(2-methoxy-4-((E)-3-(2,4,6-trimethoxyphenyl)acryloyl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)prop-2-en-1-one (133). A mixture of biflavonoid 92 (111 mg, 0.148 mmol), propargyl bromide (0.050 mL, 0.561 mmol) and anhydrous K₂CO₃ (113 mg, 0.815 mmol) in dry acetone (50 mL) was reacted according to GP-B. The crude residue was purified by flash column chromatography (SiO₂, 1% MeOH/CH₂Cl₂) to afford alkyne biflavonoid 133 (107 mg, 92%) as a bright yellow powdery solid. m.p. 170–172 °C. TLC R_f = 0.29 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3286w (C≡C-H str), 3002w (C-H str), 2936w (C-H str), 2841w (C-H str), 2160w (C≡C str), 1650m (C=O str), 1599s (C=C str), 1511m (C=C str), 1458m, 1441w, 1432w, 1418w, 1399w, 1377w, 1337m, 1321m, 1301m, 1259s, 1205w, 1159m, 1124m, 1027m. ¹H-NMR (500 MHz, CDCl₃): δ 2.64 (1H, t, J = 2.4 Hz, -OCH₂C≡CH), 3.87 (6H, s, 2 × -OCH₃), 3.89 (3H, s, -OCH₃), 3.91 (9H, s, 3 × -OCH₃), 4.45 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 4.83 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 4.84 (2H, d, J = 2.4 Hz, -OCH₂C≡CH), 5.33 (2H, s, -OCH₂CN-), 6.15 (2H, s, ArH), 6.61–6.63 (2H, m, ArH), 6.83 (1H, d, J = 8.0 Hz, ArH), 6.87 (1H, d, J = 8.0 Hz, ArH), 7.18 (1H, dd, J = 8.4, 2.0 Hz, ArH), 7.39 (1H, d, J = 1.6 Hz, ArH), 7.46 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.56–7.64 (2H, m, ArH), 7.61 (1H, d, J = 16.0 Hz, -CH=CHCO-), 7.79 (1H, d, J = 9.2 Hz, ArH), 7.85 (1H, d, J = 15.6 Hz, -CH=CHCO-), 8.03 (1H, s, -CHN-), 8.23 (1H, d, J = 16.0 Hz, -CH=CHCO-). ¹³C-NMR (500 MHz, CDCl₃): δ 49.7, 55.6, 55.8, 55.9, 55.9, 56.5, 63.1, 67.5, 76.3, 78.1, 90.5, 100.1, 106.4, 106.6, 111.5, 111.7, 112.4, 112.8, 121.6, 122.3, 122.8, 124.0, 124.6, 125.3, 128.5, 132.9, 133.7, 135.6, 142.1, 144.1, 147.7, 149.5, 150.6, 151.5, 158.2, 158.3, 161.6, 163.0, 163.8, 190.0, 190.3. LCMS (ES+) m/z = 790.3 ([M + H]⁺, t_R = 4.71 min). HRMS (ESI+) m/z = 790.2949 [M + H]⁺ found, C₄₄H₄₄O₁₁N₃⁺ required 790.2970.

2-(4-(2-(4-(((4-Oxo-2-phenyl-4H-chromen-3-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)phenyl)-3-(prop-2-yn-1-yloxy)-4H-chromen-4-one (134). A mixture of biflavonoid 110 (161 mg, 0.268 mmol), propargyl bromide (0.045 mL, 0.500 mmol) and anhydrous K₂CO₃ (111 mg, 0.803 mmol) in dry acetone (20 mL) was reacted according to GP-B. The crude residue was purified by flash column chromatography (SiO₂, 1% MeOH/CH₂Cl₂) to afford alkyne biflavonoid 134 (161 mg, 94%) as a pale yellow-white powdery solid. m.p. 118–120 °C. TLC R_f = 0.34 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3233w (C≡C-H str), 2939w (C-H str), 2116w (C≡C str), 1631s (C=O str), 1613s, 1600s, 1559m (C=C str), 1508m (C=C str), 1467s, 1392s, 1287w, 1252m, 1239m, 1184s, 1146m, 1123w, 1109w, 1042w. ¹H-NMR (500 MHz, CDCl₃): δ 2.33 (1H, t, J = 2.4 Hz, -OCH₂C≡CH), 4.39 (2H, t, J = 5.2 Hz, -OCH₂CH₂N-), 4.73 (2H, t, J = 5.2 Hz, -OCH₂CH₂N-), 4.99 (2H, d, J = 2.4 Hz, -OCH₂C≡CH), 5.33 (2H, s, -OCH₂CN-) 6.97 (2H, d, J = 9.2 Hz, ArH), 7.39–7.45 (5H, m, ArH), 7.53 (1H, d, J = 8.0 Hz, ArH), 7.54 (1H, d, J = 8.0 Hz, ArH), 7.67–7.72 (2H, m, ArH), 7.85 (1H, s, -CHN-), 8.02–8.04 (2H, m, ArH), 8.15 (2H, d, J = 9.2 Hz, ArH), 8.25 (1H, dd, J = 8.0, 1.2 Hz, ArH), 8.28 (1H, dd, J = 8.0, 1.2 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 49.5, 59.0, 65.1, 66.2, 76.1, 78.6, 114.3, 117.9, 118.1, 124.0, 124.1, 124.3, 124.7, 124.8, 124.9, 125.7, 128.3, 128.7, 130.7, 130.8, 133.4, 133.6, 138.1, 139.5, 144.1, 155.1, 155.3, 156.2, 156.4, 159.6, 174.7, 175.1. LCMS (ES+) m/z = 638.1 ([M + H]⁺, t_R = 4.70 min). HRMS (ESI+) m/z = 638.1905 [M + H]⁺ found, C₃₈H₂₈O₇N₃⁺ required 638.1922.

(E)-2-(4-(2-(4-((4-(3-(Ferrocenyl)acryloyl)-2-methoxyphenoxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)phenyl)-3-(prop-2-yn-1-yloxy)-4H-chromen-4-one (135). A mixture of biflavonoid 106 (190 mg, 0.263 mmol), propargyl bromide (0.047 mL, 0.526 mmol) and anhydrous K₂CO₃ (127 mg, 0.920 mmol) in dry acetone (20 mL) was reacted according to GP-B. The crude residue was purified by flash column chromatography (SiO₂, 1% MeOH/CH₂Cl₂) to afford alkyne biflavonoid 135 (95.5 mg, 48%) as a dark red powdery solid. m.p. 108–110 °C. TLC R_f = 0.37 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3292w (C≡C-H str), 2937w (C-H str), 2245w (C≡C str), 1636m (C=O str), 1598s (C=C str), 1576s (C=C str), 1509s (C=C str), 1467m, 1419m, 1395m, 1349w, 1258s, 1198m, 1184m, 1150m, 1029w, 1000w. ¹H-NMR (500 MHz, CDCl₃): δ 2.33 (1H, t, J = 2.5 Hz, -OCH₂C≡CH), 3.96 (3H, s, -OCH₃), 4.17 (5H, s, -C₅H₅), 4.45–4.47 (4H, m, -C₅H₄ and -OCH₂CH₂N-), 4.57 (2H, t, J = 2.0 Hz, -C₅H₄), 4.82 (2H, t, J = 5.0 Hz, -OCH₂CH₂N-), 4.98 (2H, d, J = 2.5 Hz, -OCH₂C≡CH), 5.42 (2H, s, -OCH₂CN-), 6.96 (2H, d, J = 9.0 Hz, ArH), 7.13 (1H, d, J = 15.5 Hz, -CH=CHCO-), 7.15 (1H, d, J = 8.5 Hz, ArH), 7.41 (1H, t, J = 8.5 Hz, ArH), 7.54 (1H, dd, J = 8.5, 0.5 Hz, ArH), 7.58 (1H, dd, J = 8.5, 2.0 Hz, ArH), 7.63 (1H, d, J = 2.0 Hz, ArH), 7.69 (1H, t, J = 8.5 Hz, ArH), 7.73 (1H, d, J = 15.0 Hz, -CH=CHCO-), 7.90 (1H, s, -CHN-), 8.14 (2H, d, J = 9.0 Hz, ArH), 8.25 (1H, dd, J = 8.0, 1.5 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 49.7, 56.1, 59.0, 62.8, 66.2, 68.9, 69.7, 71.2, 76.1, 78.6, 79.3, 111.2, 112.3, 114.2, 117.9, 118.5, 122.4, 124.0, 124.3, 124.4, 124.7, 125.7, 130.8, 132.3, 133.4, 138.1, 143.8, 146.0, 149.5, 151.3, 155.1, 156.1, 159.5, 174.7, 187.9. LCMS (ES+) m/z = 762.1 ([M + H]⁺, t_R = 4.88 min). HRMS (ESI+) m/z = 762.1878 [M + H]⁺ found, C₄₃H₃₆O₇N₃Fe⁺ required 762.1897.

(E)-4-((1-(2-(4-(3-Oxo-3-(2-((1-(2-((4-oxo-2-phenyl-4H-chromen-7-yl)oxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)prop-1-en-1-yl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2H-chromen-2-one (136). A mixture of alkyne biflavonoid 131 (205 mg, 0.375 mmol), azide flavone 86 (123 mg, 0.399 mmol), CuSO₄·5H₂O (115 mg, 0.459 mmol) and sodium ascorbate (192 mg, 0.969 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) to afford triazole hybrid 136 (214 mg, 67%) as a pale yellow-white powdery solid. m.p. 78–80 °C. TLC R_f = 0.37 (7% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3080w (C-H str), 2923w (C-H str), 1708s (C=O str), 1622s, 1597s (C=C str), 1567s (C=C str), 1509w (C=C str), 1493w, 1449m, 1356m, 1274w, 1237m, 1173m, 1139w, 1105w, 1043w, 1026w. ¹H-NMR (500 MHz, CDCl₃): δ 4.38 (2H, t, J = 5.2 Hz, -OCH₂CH₂N-), 4.41 (2H, t, J = 5.2 Hz, -OCH₂CH₂N-), 4.70 (2H, t, J = 5.2 Hz, -OCH₂CH₂N-), 4.82 (2H, t, J = 5.2 Hz, -OCH₂CH₂N-), 5.34 (2H, s, -OCH₂CN-), 5.34 (2H, s, -OCH₂CN-), 5.85 (1H, s, -C=CH), 6.75 (1H, s, -C=CH), 6.77–6.80 (3H, m, ArH), 6.85 (1H, d, J = 2.4 Hz, ArH), 7.08 (1H, t, J = 7.6 Hz, ArH), 7.14 (1H, d, J = 8.4 Hz, ArH), 7.20 (1H, t, J = 8.0 Hz, ArH), 7.26 (1H, d, J = 16.0 Hz, -CH=CHCO-, overlain by CDCl₃), 7.28 (1H, d, J = 4.0 Hz, ArH), 7.38 (2H, d, J = 8.4 Hz, ArH), 7.46–7.54 (5H, m, ArH), 7.50 (1H, d, J = 16.0 Hz, -CH=CHCO-), 7.62 (1H, dd, J = 8.8, 1.6 Hz, ArH), 7.74 (1H, dd, J = 8.0, 1.2 Hz, ArH), 7.77 (1H, s, -CHN-), 7.89 (2H, dd, J = 7.6, 1.6 Hz, ArH), 7.96 (1H, s, -CHN-), 8.03 (1H, d, J = 8.8 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 49.4, 49.8, 62.5, 62.8, 66.2, 66.6, 91.2, 101.4, 107.5, 113.1, 114.1, 114.8, 115.4, 116.7, 118.5, 121.5, 123.1, 123.9, 124.0, 124.8, 125.7, 126.2, 127.3, 128.7, 129.1, 129.8, 130.1, 130.4, 131.6, 131.6, 132.5, 132.9, 141.6, 142.4, 144.1, 153.3, 156.5, 157.6, 159.3, 161.9, 162.5, 163.2, 164.9, 177.6, 192.6. LCMS (ES+) m/z = 855.3 ([M + H]⁺, t_R = 4.57 min). HRMS (ESI+) m/z = 855.2743 [M + H]⁺ found, C₄₉H₃₉O₉N₆⁺ required 855.2773.

(Z)-7-(2-(4-(((4-Oxo-2-(4-((1-(2-(4-((3-oxobenzofuran-2(3H)-ylidene)methyl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-4H-chromen-3-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)-2-phenyl-4H-chromen-4-one (137). A mixture of alkyne biflavonoid 132 (145 mg, 0.227 mmol), azide flavone 86 (73.5 mg, 0.239 mmol), CuSO₄·5H₂O (70.1 mg, 0.281 mmol) and sodium ascorbate (129 mg, 0.651 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) to afford triazole hybrid 137 (106 mg, 49%) as a bright yellow powdery solid. m.p. 198–200 °C. TLC R_f = 0.33 (7% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 2931w (C-H str), 2874w (C-H str), 1698w, 1628s (C=O str), 1602s, 1594s (C=C str), 1508s (C=C str), 1466m, 1449m, 1423w, 1396w, 1374m, 1299w, 1288w, 1249s, 1178s, 1148w, 1128w, 1110w, 1096w, 1041m. ¹H-NMR (500 MHz, CDCl₃): δ 4.44–4.46 (4H, m, 2 × -OCH₂CH₂N-), 4.78 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 4.83 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 5.28 (2H, s, -OCH₂CN-), 5.33 (2H, s, -OCH₂CN-), 6.75 (1H, s, -C=CH), 6.81 (1H, s, -C=CH), 6.91–6.94 (4H, m, ArH), 7.04 (2H, d, J = 9.2 Hz, ArH), 7.21 (1H, d, J = 7.6 Hz, ArH), 7.30 (1H, d, J = 8.4 Hz, ArH), 7.37 (1H, d, J = 7.6 Hz, ArH), 7.47–7.53 (4H, m, ArH), 7.62–7.67 (2H, m, ArH), 7.79 (1H, d, J = 7.6 Hz, ArH), 7.84 (2H, d, J = 8.8 Hz, ArH), 7.87–7.90 (3H, m, -CHN- and ArH), 7.94 (1H, s, -CHN-), 8.04 (2H, d, J = 8.8 Hz, ArH), 8.11 (1H, d, J = 8.8 Hz, ArH), 8.23 (1H, dd, J = 8.0, 1.2 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 49.3, 49.7, 61.9, 65.0, 66.3, 66.7, 101.5, 107.6, 112.7, 112.9, 114.2, 114.7, 114.9, 117.9, 118.5, 121.8, 123.4, 123.6, 124.0, 124.1, 124.6, 124.7, 125.0, 125.6, 126.1, 126.2, 127.4, 129.0, 130.5, 131.5, 131.7, 133.4, 133.4, 136.7, 139.0, 143.7, 144.3, 146.1, 155.1, 156.1, 157.7, 159.0, 160.0, 162.1, 163.2, 165.9, 174.9, 177.7, 184.5. LCMS (ES+) m/z = 945.4 ([M + H]⁺, t_R = 4.89 min). HRMS (ESI+) m/z = 945.2851 [M + H]⁺ found, C₅₅H₄₁O₁₀N₆⁺ required 945.2879.

7-Methoxy-2-(4-(2-(4-((5-methoxy-2-((E)-3-(4-methoxy-3-((1-(2-(2-methoxy-4-((E)-3-(2,4,6-trimethoxyphenyl)acryloyl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)acryloyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)phenyl)-4H-chromen-4-one (138). A mixture of alkyne biflavonoid 133 (107 mg, 0.135 mmol), azide flavone 87 (49.3 mg, 0.146 mmol), CuSO₄·5H₂O (66.0 mg, 0.264 mmol) and sodium ascorbate (72.8 mg, 0.367 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) to afford triazole hybrid 138 (8.00 mg, 5%) as a pale yellow-white powdery solid. m.p. 128–130 °C. TLC R_f = 0.19 (5% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 2927w (C-H str), 2846w (C-H str), 1736w, 1627m (C=O str), 1600s (C=C str), 1510s (C=C str), 1454m, 1439m, 1423m, 1375w, 1355w, 1338w, 1258s, 1204m, 1162m, 1123s, 1023s. ¹H-NMR (500 MHz, DMSO-d₆): δ 3.76 (6H, s, 2 × -OCH₃), 3.85 (6H, s, 2 × -OCH₃), 3.90 (9H, s, 3 × -OCH₃), 4.38 (2H, t, J = 4.4 Hz, -OCH₂CH₂N-), 4.50 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 4.71 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 4.82 (2H, t, J = 4.8 Hz, -OCH₂CH₂N-), 5.24 (2H, s, -OCH₂CN-), 5.38 (2H, s, -OCH₂CN-), 6.29 (2H, s, ArH), 6.57–6.66 (1H, m, ArH), 6.81 (1H, s, -C=CH), 6.82–6.85 (1H, m, ArH), 6.92–6.98 (3H, m, ArH), 7.02–7.11 (3H, m, ArH), 7.20 (1H, d, J = 8.8 Hz, ArH), 7.27 (1H, dd, J = 5.6, 2.4 Hz, ArH), 7.47 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.48 (1H, d, J = 8.0 Hz, ArH), 7.54–7.64 (2H, m, ArH), 7.56 (1H, d, J = 15.2 Hz, -CH=CHCO-), 7.82 (1H, d, J = 16.0 Hz, -CH=CHCO-), 7.87–8.06 (3H, m, ArH and -CHN-), 8.02 (1H, d, J = 16.0 Hz, -CH=CHCO-), 8.28 (1H, d, J = 6.4 Hz, ArH), 8.31 (1H, s, -CHN-). ¹³C-NMR (500 MHz, DMSO-d₆): δ 48.9, 49.0, 55.5, 55.7, 56.0, 61.5, 61.7, 66.2, 67.1, 91.0, 99.8, 100.9, 105.1, 105.4, 106.6, 111.0, 111.3, 111.8, 112.0, 112.7, 114.5, 114.9, 114.9, 115.0, 115.0, 117.1, 120.2, 122.1, 123.8, 125.3, 126.1, 127.6, 127.9, 128.0, 132.0, 132.1, 134.4, 137.4, 141.4, 142.3, 142.7, 147.7, 148.9, 149.8, 151.0, 151.1, 157.4, 157.9, 158.6, 160.4, 161.3, 162.0, 163.2, 163.7, 176.3, 188.3, 189.1. LCMS (ES+) m/z = 1128.0 ([M + H]⁺, t_R = 1.87 min). HRMS (ESI+) m/z = 1127.4014 [M + H]⁺ found, C₆₂H₅₉O₁₅N₆⁺ required 1127.4033.

(Z)-3-((1-(2-(4-((6-Methoxy-3-oxobenzofuran-2(3H)-ylidene)methyl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-2-(4-(2-(4-(((4-oxo-2-phenyl-4H-chromen-3-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)phenyl)-4H-chromen-4-one (139). A mixture of alkyne biflavonoid 134 (134 mg, 0.210 mmol), azide aurone 89 (83.5 mg, 0.248 mmol), CuSO₄·5H₂O (70.8 mg, 0.284 mmol) and sodium ascorbate (131 mg, 0.659 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) to afford triazole hybrid 139 (73.9 mg, 36%) as a bright yellow powdery solid. m.p. 98–100 °C. TLC R_f = 0.39 (7% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 3001w (C-H str), 2929w (C-H str), 2874w (C-H str), 1693m (C=O str), 1632m, 1600s (C=C str), 1509m (C=C str), 1466m, 1444w, 1395m, 1343w, 1248s, 1181s, 1146m, 1129m, 1110m, 1096w, 1044m. ¹H-NMR (500 MHz, CDCl₃): δ 3.93 (3H, s, -OCH₃), 4.34–4.37 (4H, m, 2 × -OCH₂CH₂N-), 4.69–4.72 (4H, m, 2 × -OCH₂CH₂N-), 5.32 (4H, s, 2 × -OCH₂CN-), 6.77 (1H, d, J = 5.6 Hz, ArH), 6.77 (1H, s, -C=CH), 6.88 (2H, d, J = 8.8 Hz, ArH), 6.90 (2H, d, J = 8.8 Hz, ArH), 7.40–7.45 (6H, m, ArH), 7.51 (1H, d, J = 3.6 Hz, ArH), 7.53 (1H, d, J = 3.6 Hz, ArH), 7.67–7.72 (3H, m, ArH), 7.81 (2H, d, J = 9.2 Hz, ArH), 7.84 (1H, s, -CHN-), 7.88 (1H, s, -CHN-), 8.01–8.05 (4H, m, ArH), 8.27 (2H, dd, J = 8.0, 1.6 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 49.4, 49.5, 56.0, 64.9, 65.2, 66.2, 66.3, 96.6, 111.5, 112.1, 114.3, 114.9, 115.0, 118.0, 118.1, 124.0, 124.1, 124.1, 124.8, 124.8, 124.9, 125.0, 125.7, 125.7, 125.7, 126.1, 128.4, 128.7, 130.6, 130.7, 133.1, 133.4, 133.6, 139.0, 139.6, 144.0, 144.1, 147.0, 155.2, 155.3, 156.0, 156.4, 158.8, 159.5, 167.3, 168.3, 175.0, 175.1, 182.8. LCMS (ES+) m/z = 975.4 ([M + H]⁺, t_R = 4.94 min). HRMS (ESI+) m/z = 975.2956 [M + H]⁺ found, C₅₆H₄₃O₁₁N₆⁺ required 975.2984.

2-(4-(2-(4-((4-((E)-3-(Ferrocenyl)acryloyl)-2-methoxyphenoxy)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)phenyl)-3-((1-(2-(4-(((Z)-6-methoxy-3-oxobenzofuran-2(3H)-ylidene)methyl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)-4H-chromen-4-one (140). A mixture of alkyne biflavonoid 135 (71.6 mg, 0.0940 mmol), azide aurone 89 (38.1 mg, 0.113 mmol), CuSO₄·5H₂O (46.1 mg, 0.185 mmol) and sodium ascorbate (58.0 mg, 0.293 mmol) in t-BuOH/H₂O (1:1, 40 mL) was reacted according to GP-A. The crude residue was purified by flash column chromatography (SiO₂, 1%–5% MeOH/CH₂Cl₂) and further purified by preparative HPLC to afford triazole hybrid 140 (2.80 mg, 3%) as a bright red powdery solid. m.p. 158–160 °C. TLC R_f = 0.35 (7% MeOH/CH₂Cl₂). IR ν_max (neat)/cm⁻¹: 2917w (C-H str), 2852w (C-H str), 1737w, 1605s (C=O str), 1509m (C=C str), 1465m, 1443w, 1378w, 1353w, 1260s, 1198m, 1151m, 1133w, 1113w, 1042w, 1015w. ¹H-NMR (500 MHz, CDCl₃): δ 3.94 (3H, s, -OCH₃), 3.96 (3H, s, -OCH₃), 4.17 (5H, br s, -C₅H₅), 4.38 (2H, t, J = 5.0 Hz, -OCH₂CH₂N-), 4.42 (2H, t, J = 5.0 Hz, -OCH₂CH₂N-), 4.47 (2H, br s, -C₅H₄), 4.57 (2H, br s, -C₅H₄), 4.73 (2H, t, J = 5.0 Hz, -OCH₂CH₂N-), 4.80 (2H, t, J = 4.5 Hz, -OCH₂CH₂N-), 5.30 (2H, s, -OCH₂CN-), 5.41 (2H, s, -OCH₂CN-), 6.76–6.79 (2H, m, ArH and -C=CH), 6.77 (1H, d, J = 14.5 Hz, -CH=CHCO-), 6.89 (2H, d, J = 9.0 Hz, ArH), 6.90 (2H, d, J = 8.5 Hz, ArH), 7.14 (1H, d, J = 8.0 Hz, ArH), 7.43 (1H, t, J = 8.0 Hz, ArH), 7.53 (1H, d, J = 8.5 Hz, ArH), 7.58 (1H, d, J = 8.2 Hz, ArH), 7.62 (1H, s, ArH), 7.70 (1H, t, J = 8.5 Hz, ArH), 7.70 (1H, d, J = 16.0 Hz, -CH=CHCO-), 7.71 (2H, d, J = 8.5 Hz, ArH), 7.84 (2H, d, J = 9.0 Hz, ArH), 7.89 (1H, s, -CHN-), 7.94 (1H, s, -CHN-), 8.05 (2H, d, J = 9.0 Hz, ArH), 8.27 (1H, dd, J = 8.0, 1.5 Hz, ArH). ¹³C-NMR (500 MHz, CDCl₃): δ 49.6, 49.7, 56.1, 61.2, 62.8, 66.2, 66.3, 68.9, 69.8, 71.3, 79.3, 96.6, 111.2, 111.6, 111.8, 112.1, 112.3, 114.3, 114.3, 114.9, 118.0, 118.6, 121.3, 122.5, 122.5, 124.1, 124.1, 124.3, 124.4, 124.8, 125.1, 125.7, 125.7, 125.8, 130.6, 133.0, 133.2, 133.5, 138.3, 144.0, 146.0, 149.6, 151.4, 155.1, 157.4, 158.8, 159.5, 167.5, 167.7, 179.2, 182.9, 187.9. LCMS (ES+) m/z = 1098.8 ([M + H]⁺, t_R = 2.02 min). HRMS (ESI+) m/z = 1099.2960 [M + H]⁺ found, C₆₁H₅₁FeN₆O₁₁⁺ required 1099.2921.

3.4. Biological Screening

3.4.1. Aβ Preparation

Aβ₄₂ (1 mg) was purchased from Eurogentec Ltd. (Hampshire, UK) as a lyophilised powder. The peptide was dissolved in trifluroacetic acid (TFA, 1 mL), sonicated in an ice-water bath for 60 s, then the TFA removed in a vacuum desiccator. Ice cold 1,1,1,3,3,3-hexafluro-2-propanol (HFIP, 1 mL) was added to re-suspend the lyophilised peptide. The sample was sonicated for 60 s at 0 °C, then aliquoted into 20 μL portions. The HFIP was removed in the vacuum desiccator overnight and the lyophilised samples were stored at −80 °C until use. The required concentration of Aβ₄₂ was prepared by dissolving the sample in dimethyl sulfoxide (DMSO) (5% of total solvent volume), then adding sodium phosphate buffer (50 mM, pH 7.4). The solution was sonicated at 0 °C for 3 min, then centrifuged at 13,400 rpm for 30 min at 0 °C to separate any aggregated species.

3.4.2. Thioflavin T (THT) Assay

ThT was purchased from AbCam (Cambridge, UK). Final concentrations of 10 μM Aβ₄₂, 20 μM ThT and 50 μM compound in sodium phosphate buffer (50 mM, pH 7.4) were used for all samples. The assay samples (100 μL) were mixed in a black non-binding 96-well plate (Greiner Bio-One, Stonehouse, UK) which was sealed (Nunc™ polyolefin acrylate film Nunc, ThermoFisher) and loaded into the fluorescence plate reader (Tecan, Männedorf, Switzerland) at 37 °C. Fluorescence kinetics were measured at 5 min reading intervals, with 15 s shaking before each read. The excitation and emission wavelengths were 440 and 480 nm respectively.

4. Conclusions

Herein, we have described a highly modular branching-type strategy for the synthesis of biologically interesting and rare triazole-linked flavonoid dimers and trimers by the varied combination of readily-accessible flavonoid building blocks. Application of this strategy enabled concise and highly step-efficient access to a structurally diverse library of 46 final compounds, with six different biologically-relevant flavonoid structural subclasses (chalcone, flavonol, aurone, flavone, coumarin and isoflavone) successfully incorporated into the library. Each library member features structural motifs that are associated with biological activity (at least two flavonoid units and a 1,2,3-triazole linkage) and many also incorporate additional potential biomolecular-interacting elements (for example, hydrogen-bonding motifs). Many library compounds also feature groups that could provide synthetic handles for further elaboration or diversification. The synthetic strategy could conceivably be applied on a larger scale using a greater range of building blocks. However, this current strategy is limited to the installation of one linker type between the flavonoid units. It may be possible to adapt the strategy to allow for greater variation in the linker motif (for example, the use of an alternate type of building block may allow the alkyl chain length to be varied and 1,5-triazole linkages could conceivably be accessed though ruthenium-mediated ‘click’ cycloaddition conditions). Such variety may be of value in the context of biological screening; for example, previous studies of flavonoid dimers have suggested that linker length variation had a significant effect upon biological activity [14,16]. Preliminary biological screening of a representative sub-set of compounds has revealed that a selection of the triazole-linked dimers exhibit moderate inhibitory activity against the aggregation of Aβ₄₂, a process closely linked with the development of Alzheimer’s disease. Such findings prompt for continued screening of the entire library and further study of the active scaffolds identified. Milligram (typically multimilligram) quantities of most final library compounds were isolated, which should provide ample material for screening in a wider range of biological assays; the systematic modification of any compounds with interesting properties should be facilitated by the conciseness and inherent modularity of the synthetic strategy [55]. More detailed biological assessment of the compound library is currently ongoing and notable results will be reported in due course.