Name: 117-39-5|2-(3,4-Dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one|97%
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SKU: A292006
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1
[ 117-39-5 ]
[ 108-24-7 ]
[ 1064-06-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	With pyridine at 130 - 140℃;
97.5%	With pyridine at 140 - 145℃; for 4h;
95%	With pyridine at 70℃; for 6h;	5.1.1 2-(3,4-Diacetoxyphenyl)-4-oxo-4H-chromene-3,5,7-triyl triacetate (8) Acetic anhydride (1mL, 10.7mmol) was added to a solution of 1 (604mg, 2mmol) in anhydrous pyridine (8mL) at room temperature. The reaction mixture was stirred for 6h at 70°C. After the completion of reaction, the resultant mixture was cooled to room temperature (rt). After concentration, the crude product was recrystallized with acetone to afford 8 as a white solid (973mg, 95% yield). 1H NMR (300MHz, CDCl3): δ 7.75-7.67 (m, 2H), 7.36 (s, 1H), 7.33 (d, J=1.8Hz, 1H), 6.87 (d, J=2.1Hz, 1H), 2.42 (s, 3H), 2.37-2.31 (m, 12H)

93%	With sodium acetate at 160℃; for 0.166667h; Microwave irradiation;
88%	With pyridine for 0.133333 - 0.166667h; Microwave irradiation;
86%	With pyridine Ambient temperature;
84%	With dmap In N,N-dimethyl-formamide at 45℃; for 0.5h;	3. General method for peracetylation of polyphenols: General procedure: Polyphenols, acetic or butyric anhydride (6.0 equivalents per -OH group) andDMAP (0.3 equivalent) were completely dissolved in DMF in a round bottom flask to afinal concentration of 15 mM polyphenols. The reaction was kept at 45°C under stirringand monitored by analytical TLC (hexanes:ethyl acetate 3:1). After 0.5 - 2 h, cold 10%NaCl (aq) was added, and soluble fractions were extracted at 3 20 mL with ethyl acetate.The pooled organic phase was then washed with 3 20 mL 10% NH4Cl(aq) and 3 20mL 10% NaHCO3(aq), dried over anhydrous Na2SO4 and evaporated under reducedpressure to yield peracetylated (1a-8a) or perbutyrylated (2b, 4b, 6b) products. Meltingpoints were measured for solid products and compared to data from the literature, ifavailable. Structures were confirmed by 1H NMR, 13C NMR and LCMS(ESI+).
83%	With triethylamine In N,N-dimethyl-formamide at 20℃; for 3h;	1 Compound 2a: Quercetin 1 (500 mg, 1.65 mmol) was dissolved in 15 mL DMF and acetic anhydride (1.25 mL,13.24 mmol), triethylamine (2.76 mL, 20 mmol),The reaction system was stirred at room temperature for 3 h and TLC showed that the reaction of the raw materials completely disappeared. The reaction mixture was poured into ice water to precipitate a white solid.The suspension is filtered to obtain a crude product.The crude product was recrystallized from methanol to give white compound 2a in a yield of 83%.
82%	With pyridine at 80℃; for 3h;	3,3′,4′,5,7-Pentaacetoxyflavone (5c) To a solution of 5a (quercetin, 2.90g, 9.60mmol) in pyridine(10mL) was added an acetic anhydride (7.5mL)and the mixture was stirred for 3h at 80°C. e reactionwas poured into ice. e precipitates were collectedby fltration and washed with ethanol, ethyl acetate anddiethyl ether and then dried in vacuo to give 5c [22]as a colorless solid (4.05g, 82%). 1H-NMR (500MHz,CDCl3) δ: 2.33 (3H, s), 2.34 (3H, s), 2.34 (3H, s), 2.35(3H, s), 2.43 (3H, s), 6.87 (1H, d, J=2.2Hz), 7.33 (1H,d, J = 2.2Hz), 7.35 (1H, d, J = 8.5Hz), 7.68 (1H, d,J = 2.2Hz), 7.72 (1H, dd, J = 2.2, 8.5Hz). is wasemployed for the next step without further purication.
80%	With pyridine Reflux;
80%	With pyridine at 70℃; for 6h;
79%	With pyridine for 5h; Reflux;
79%	With pyridine for 6h; Inert atmosphere; Reflux;	3.2. Synthesis of 2-(3,4-Diacetoxyphenyl)-4-oxo-4H-chromene-3,5,7-triyl triacetate (5) Quercetin (2, 1.0 g, 3.0 mmol), acetic anhydride (6.1 g, 60.0 mmol), and pyridine (15 mL) were heated to reflux under argon atmosphere for 6 h. After cooling down to room temperature, the mixture was poured into 50 mL of ice water and filtered to give the product 5 in 79% yield. 1H-NMR (DMSO-d6): δ 7.85-7.88 (m, 2H, -ArH), 7.65 (d, J = 2.0 Hz, 1H, -ArH), 7.53 (d, J = 8.0 Hz, 1H, -ArH),7.18 (d, J = 2.0 Hz, 1H, -ArH), 2.32-2.34 (m, 15H, -CH3-C=O); ESI-MS (m/z) 513.1 [M+H]+.
79%	With pyridine for 5h; Reflux; Inert atmosphere;	4.2.2 Procedure b): Synthesis of 2-(3,4-diacetoxyphenyl)-4-oxo-4H-chromene-3,5,7-triyl triacetate Que1 Quercetin (1 equiv.), acetic anhydride (20 equiv.), and pyridine (15mL) were stirred at reflux for 5h. Then, a mixture of ice-water (50g) was added. The resulting precipitate was filtered and washed with cold EtOAc to obtain Que1. White solid, 79% yield. Spectroscopic data are in agreement with those previously reported [40].
73%	With dmap at 150℃; for 24h;	2.2. Synthesis of Quercetin Pentaacetate Quercetin pentaacetate was synthesized from quercetinby a previously described procedure with slightmodifications.21 DMAP (0.44 mmol) was added to a solutionof quercetin (3.3 mmol) in previously distilled acetic anhydride (25 ml) and the mixture was left under reflux(150 C) overnight. The reaction was followed by thinlayer chromatography. After 24 h, the warm mixture was added to ice-water and filtered. The resulting precipitatewas dissolved in chloroform. This organic phase was 3×extracted with 0.1 M NaHCO3 aqueous solution, driedwith anhydrous MgSO4 and purified by column chromatography(Silica gel 60, 70-230 mesh) using chloroformas eluent. The isolated product was obtained asa yellow-white solid (73% of yield) presenting a meltingpoint of 194.9 C (Büchi Melting Point B-545equipment). The product was assigned the structure of3,3,4,5,7-pentaacetyl quercetin (Fig. 1) based on ATR-IRspectroscopy (Bruker Alpha-P equipment) and 1H-NMR analysis (Bruker equipment operating at 400 MHz) aspreviously stated.21
72%	With pyridine at 20℃; for 0.25h;	14 Penta-O-acetylquercetin (20) A suspension of quercetin (10.0 g, 33.2 mmol) in acetic anhydride (50 mL, 530 mmol) and pyridine (25 mL) was stirred at room temperature for 15 min. The mixture was poured into ice-water (500 mL) and stirred for 15 min, and the solid that formed was collected by vacuum filtration and washed with ice-cold ethanol (20 mL). The crude material was recrystallized from EtOAc/petroleum spirits to afford the pentaacetate as pale beige needles (12.3 g, 72%), m.p. 195-196° C. 1H NMR (399.7 MHz, CDCl3) d 2.32, 2.33, 2.34, 2.43 (4 s, 15H, 5*Me); 6.88, 7.33 (2 d, J6,8 2.4 Hz, H6,8); 7.35 (d, J5',6' 8.4 Hz, H5'); 7.7 (d, J2',6' 2.0 Hz, H2'); 7.63 (dd, H6'). 13C NMR (100.5 MHz, CDCl3) δ 20.43, 20.56, 20.94, 21.06 (5C, Me);108.94, 113.82, 114.63, 123.75, 123.86, 126.33, 127.62, 133.93, 142.09, 144.29, 150.26, 153.65, 154.17, 156.73 (14C, Ar); 167.71, 167.78, 169.19, 169.95 (6C, C=O).
70%	With pyridine for 5h; Heating;
67%	With pyridine for 5h; Heating;
54%	With pyridine at 70℃;
54%	With pyridine at 80℃; for 4h;
54%	With pyridine at 20℃;	4.2.1 Acetic acid 3,5-diacetoxy-2-(3,4-diacetoxy-phenyl)-4-oxo-4H-chromen-7-yl ester (8) To a stirred mixture of 8 (3 g, 5.85 mmol) and imidazole (80 mg, 1.17 mmol) in NMP (30 mL) was slowly added PhSH (0.48 mL, 4.69 mmol) at 0 °C. The reaction mixture was stirred for 2 h at rt. The mixture was diluted with EtOAc and washed with 2 N HCl. The organic layer was concentrated under reduced pressure and dried over MgSO4. The crude product was purified by column chromatography on silica gel (2:1:1 = hexane/acetone/EtOAc) as eluent and was recrystallized from CH2Cl2 to give 9 (2 g, 4.25 mmol, 73% yield) as white powder; mp 204 °C (rec. CH2Cl2); 1H NMR (400 MHz, DMSO-d6) δ (ppm) 11.33 (s, 1H), 7.83-7.80 (m, 2H), 7.51 (d, J = 8.5 Hz, 1H), 6.94 (s, 1H), 6.65 (s, 1H), 2.33 (s, 6H), 2.30 (s, 6H); 13C NMR (100 MHz, DMSO-d6) δ (ppm); 169.0, 168.8, 168.3, 168.1, 168.0, 162.9, 157.6, 152.4, 150.2, 144.2, 142.2, 132.8, 127.4, 126.5, 124.5, 123.6, 109.4, 109.1, 101.0, 20.9, 20.5, 20.4, 20.3; HR-FABMS (m/z): Found: 471.0926 [M+H]+; Calcd for C23H18O11: 470.0847.
49%	With potassium carbonate In tetrahydrofuran at 55℃; for 15h;	74 Example 74: [2-acetoxy-4-(3,5,7-triacetoxy-4-oxo-ch romen-2-yl)phenyl] acetate To a mixture of 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-chromen-4-one (1 g) and aceticanhydride (2.36 g) in THE (40 mL) was added K2003 (3.2 g) at 25°C, then the mixture was stirred at 5500 for 12 h. Additional acetic anhydride was added (3 eq) and the mixture and stirred for another 3 h.The reaction mixture was concentrated in vacuum and purified by reverse phase prep-HPLC (018; water(0.05%HCI)-aceton itri le gradient) to give [2-acetoxy-4-(3,5,7-triacetoxy-4-oxo-chromen-2-yl)phenyl] acetate (0.837 g, 49%) as a white solid. LOMS: 513.2 (M÷H÷) 1H NMR (400 MHz, 0D013): O 7.742 -7.703 (m, 2H), 7.373 - 7.346 (m, 2H), 6.888 (s, 1 H), 2.443, (s, 3H), 2.356 (s, 6H), 2.350(s, 6H) ppm
49%	With potassium carbonate In tetrahydrofuran at 25 - 55℃; for 12h;	1 Compound 4: [2-acetoxy-4-(3,5,7-triacetoxy-4-oxo-chromen-2-yl)phenyl] acetate To a mixture of 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-chromen-4-one (1 g) and acetic anhydride (2.36 g) in THF (40 ml_) was added K2CO3 (3.2 g) at 25°C, then the mixture was stirred at 55 °C for 12 h. Additional acetic anhydride was added (3 equiv.) and the mixture and stirred for another 3 h. The reaction mixture was concentrated in vacuum and purified by reverse phase prep-HPLC (C18; water (0.05% HCI)-ACN gradient) to give compound 4 (0.837 g, 49%) as a white solid. LCMS: 513.2 (M+H+) 1 H NMR (400 MHz, CDCIs). 7.742 - 7.703 (m, 2H), 7.373 - 7.346 (m, 2H), 6.888 (s, 1 H), 2.443, (s, 3H), 2.356 (s, 6H), 2.350(s, 6H).
49%	With potassium carbonate In tetrahydrofuran at 25 - 55℃; for 15h;	1 Compound 14: [2-acetoxy-4-(3,5,7-triacetoxy-4-oxo-chromen-2-yl)phenyl] acetate To a mixture of 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-chromen-4-one (1 g) and acetic anhydride (2.36 g) in THF (40 mL) was added K2CO3 (3.2 g) at 25°C, then the mixture was stirred at 55 °C for 12 h. Additional acetic anhydride was added (3 equiv.) and the mixture and stirred for another 3 h. The reaction mixture was concentrated in vacuum and purified by reverse phase prep-HPLC (C1 8; water (0.05%HCI)-ACN gradient) to give compound 14 (0.837 g,49%) as a white solid. LCMS: 513.2 (M+H+) (0776) NMR (400 MHz, CDC ). d 7.742 - 7.703 (m, 2H), 7.373 - 7.346 (m, 2H),6.888 (s,1 H), 2.443, (s,3H), 2.356 (s,6H), 2.350(s,6H).
49%	With potassium carbonate In tetrahydrofuran at 55℃; for 15h;	Compound 4: [2-acetoxy-4-(3,5,7-triacetoxy-4-oxo-chromen-2-yl)phenyl]acetate To a mixture of 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-chromen-4-one (1 g) and acetic anhydride (2.36 g) in THF (40 ml_) was added K2CO3 (3.2 g) at 25C, then the mixture was stirred at 55 C for 12 h. Additional acetic anhydride was added (3 equiv.) and the mixture and stirred for another 3 h. The reaction mixture was concentrated in vacuum and purified by reverse phase prep-HPLC (C18; water(0.05%HCI)-ACN gradient) to give compound 4 (0.837 g, 49%) as a white solid. LCMS: 513.2 (M+H+) 1H NMR (400 MHz, CDCI3). 7.742 - 7.703 (m, 2H), 7.373 - 7.346 (m, 2H), 6.888 (s, 1H), 2.443, (S,3H), 2.356 (s, 6H), 2.350(s, 6H).
39.3%	With pyridine at 0 - 25℃; for 16h; Large scale;	1 Compound 5 Eight reactions were carried out in parallel. To a solution of quercetin (300 g, 992 mmol, 1.00 equiv.) in pyridine (1 .60 L) was added dropwise acetyl acetate (1 .52 kg, 14.9 mol, 1.39 L, 15.0 equiv.) at 0 °C. After addition, the mixture was stirred at 25 °C for 16 h. TLC (dichloromethane/methanol = 10/1 , Rf = 0.63) indicated complete consumption of quercetin. The eight reaction mixtures were combined, poured into ice-water (w/w = 1/1 , 24.0 L) and stirred for 1 h. The suspensions were filtered to give a yellow solid. The solid was dried under vacuum and was combined with another batch of compound 5 (300 g). The combined crude product was dissolved in MeCN (10.0 L) and heated to 65 °C. EtOH (12.0 L) was added drop-wise at 65°C, and then the suspension was stirred at 65 °C for 1 h. White solid formed and was filtered. The filter cake was rinsed with EtOH (2.00 L), collected and dried under vacuum (40 °C, -0.09 MPa) to give the compound 5 (2005 g, 3.91 mol, 39.3% total yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.68-7.73 (m, 2H), 7.33-7.36 (m, 2H), 6.87 (d, J = 2.0 Hz, 1 H), 2.43 (s, 3H), 2.33-2.34 (m, 12H) ppm.
35%	With pyridine at 140℃; for 5h;
	With sodium acetate
	With sulfuric acid
	With pyridine at 20℃;
	With pyridine at 20℃; for 24h;
0.6 mg	With pyridine Ambient temperature;
	In pyridine
	With pyridine; dmap
10 mg	With pyridine for 2h; Heating;
	With pyridine at 20℃;
	With pyridine at 20℃;
	With pyridine at 20℃;
	With pyridine at 130 - 140℃; Inert atmosphere;
	With pyridine; dmap
	With pyridine at 70℃;	1 For introducing a carboxylic acid linker into quercetin without affecting its function, the inventors chose to address the 7-hydroxy group, as also illustrated In Figure 1A. This was achieved by first completely acetylating quercetin with an excess of acetic anhydride in pyridine at 70 °C. It was then regioselectively deprotected with imidazole and thiophenol in N- Methyl-2-pyrrolidone (NMP) as described by Kim et al. to give the 7-O-monodeacetyiated product (Kim et al., J Med Chem, 2014, 57(17): 7216-33). Subsequently the carboxylic acid linker was introduced by addition of ethyl iodoacetate. The fully protected intermediate 3 (see Figure 1A) was then deprotected using hydrochloric acid in refluxing acetone as described by Mattarei et al. (11 % yield over 4 steps; Mattarei et al., Molecules, 2010, 15(7): 4722-36).
2005 g	With pyridine at 0 - 25℃; for 16h; Large scale;	1 Compound 5 Eight reactions were carried out in parallel. To a solution of quercetin (300 g, 992 mmol, 1.00 equiv.) in pyridine (1.60 L) was added dropwise acetyl acetate (1.52 kg, 14.9 mol, 1.39 L, 15.0 equiv.) at 0 °C. After addition, the mixture was stirred at 25 °C for 16 h. TLC (dichloromethane/methanol = 10/1, Rf= 0.63) indicated complete consumption of quercetin. The eight reaction mixtures were combined, poured into ice-water (w/w = 1/1, 24.0 L) and stirred for 1 h. The suspensions were filtered to give a yellow solid. The solid was dried under vacuum and was combined with another batch of compound 5 (300 g). The combined crude product was dissolved in MeCN (10.0 L) and heated to 65 °C. EtOH (12.0 L) was added drop-wise at 65°C, and then the suspension was stirred at 65 °C for 1 h. White solid formed and was filtered. The filter cake was rinsed with EtOH (2.00 L), collected and dried under vacuum (40 °C, -0.09 MPa) to give the compound 5 (2005 g, 3.91 mol, 39.3% total yield) as a white solid.1H NMR (400 MHz, CDCl3): δ 7.68-7.73 (m, 2H), 7.33-7.36 (m, 2H), 6.87 (d, J = 2.0 Hz, 1H), 2.43 (s, 3H), 2.33-2.34 (m, 12H) ppm
	With pyridine

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2
[ 117-39-5 ]
[ 98-88-4 ]
[ 120036-90-0 ]

Yield	Reaction Conditions	Operation in experiment
97%	With pyridine In dichloromethane at 20℃; for 3h;
92%	With pyridine at 22 - 24℃; for 4h;	Quercetin 3,3,4,5,7-Penta-O-benzoate (6) [9]. Compound 1 (0.30 g, 1 mmol) was dissolved in anhydrous Py (20 mL),treated with benzoylchloride (1.15 mL, 10 mmol), refluxed for 4 h, left overnight at 22-24°C, and diluted on the following daywith cold H2O. The resulting precipitate (0.92 g) was filtered off, dried, and recrystallized from CHCl3-MeOH. Yield 0.76 g(92%), mp 170-172°C. IR spectrum (max, cm-1): 3472, 1742, 1582, 1506. 1 NMR spectrum (300 MHz, CDCl3, , ppm):7.18-7.54 (17H, m, 365CO, -8, 6), 7.88-8.15 (13H, m, 265CO, -6, 5, 2). 13C NMR spectrum (75.5 MHz, CDCl3,, ppm): 169.8 (-4), 164.9 (-7), 163.8, 163.4, 157.0, 154.5, 153.6, 150.7, 145.0, 142.8, 134.4, 134.2, 133.8, 133.5, 130.7,130.4, 130.2, 129.2, 128.8, 128.5, 128.0, 126.7, 124.0, 123.7, 115.3, 114.4, 109.4. MS: m/z 823 [M + H]+. 503012. [] 822.8.
56%	With pyridine at 60℃;

With sodium hydroxide

Reference： [1]Location in patent: experimental part Mattarei, Andrea; Biasutto, Lucia; Rastrelli, Federico; Garbisa, Spiridione; Marotta, Ester; Zoratti, Mario; Paradisi, Cristina [Molecules, 2010, vol. 15, # 7, p. 4722 - 4736]
[2]Karimova; Baltina; Spirikhin; Kondratenko; Farkhutdinov; Petrova [Chemistry of Natural Compounds, 2015, vol. 51, # 5, p. 851 - 855][Khim. Prir. Soedin., 2015, vol. 51, # 5, p. 851 - 855]
[3]Li, Ming; Han, Xiuwen; Yu, Biao [Journal of Organic Chemistry, 2003, vol. 68, # 17, p. 6842 - 6845]
[4]Wunderlich [Archiv der Pharmazie, 1908, vol. 246, p. 246]

3
[ 117-39-5 ]
[ 75-03-6 ]
[ 82547-03-3 ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium carbonate In N,N-dimethyl-formamide at 45℃; for 12h; Inert atmosphere;	2-(3,4-diethoxyphenyl)-3,7-diethoxy-5-hydroxy-4H-chromen-4-one(8) K2CO3 (6.08 g, 44 mmol) and CH3CH2I (6.86 g, 44 mmol) were added to a stirred solution of quercetin (3.02 g, 10 mmol) in dry DMF (25 mL). After the addition, themixture was heated to 45°C and stirred for 12 h. The reaction was cooled toroom temperature, filtered and diluted with ethyl acetate (100 mL) and theresulting solution was poured into aqueous HCl (1 M, 100 mL). The organic layerwas separated, washed with saturated NaCl (3×100 mL) and dried over anhydrousNa2SO4. After concentrated to dryness under reducedpressure, the crude product was purified by column chromatography on silica (dichloromethane /methanol 100:1) to afford the known compound 8 (3.52 g, 85%) as a yellow . Datafor 8: 1HNMR(400 MHz, CDCl3): δ 7.74(s, 1H), 7.69 (d, J = 8.8 Hz, 1H),6.97 (d, J = 8.8 Hz, 1H), 6.42(s, 1H), 6.41 (s, 1H), 4.05-4.21 (m, 8H), 1.50 (m, 6H), 1.44 (m, 3H), 1.34 (m,3H); 13CNMR (100 MHz, CDCl3): δ 14.6,14.7, 14.8, 15.6, 64.2, 64.5, 64.8, 68.6, 92.6, 98.1, 105.9, 112.3, 113.8,122.2, 123.1, 137.9, 148.2, 151.2, 156.2, 156.8, 162.0, 164.8, 178.9.
56%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 10h; Inert atmosphere;	Quercetin 3,7,3',4'-tetraethyl ether (9) To a stirred solution of quercetin(302 mg, 1.0 mmol) in dry DMF (5 mL) was added K2CO3 (621mg, 4.5 mmol) and CH3CH2I (780 mg, 5.0 mmol). After theaddition, the mixture was stirred for 10 h at roomtemperature.The reaction mixture was then diluted with CH2Cl2 (20 mL)and poured into aqueous HCl (0.1 M) (10 mL). The organic layer was separated,washed with H2O (3×10 mL) and dried over Mg2SO4.After concentrated to dryness under reduced pressure, the crude product was purifiedby column chromatography on silica (petroleum ether/ethyl acetate 5:1) toafford compound 92 (233 mg, 56%) as a yellow solid.
40%	With potassium hydroxide In methanol for 20h; Heating;

With potassium hydroxide; ethanol

Reference： [1]Pan, Guojun; Yang, Ke; Ma, Yantao; Zhao, Xia; Lu, Kui; Yu, Peng [Bulletin of the Korean Chemical Society, 2015, vol. 36, # 5, p. 1460 - 1466]
[2]Lu, Kui; Chu, Jie; Wang, Haomeng; Fu, Xiaoli; Quan, Dewu; Ding, Hongxia; Yao, Qingwei; Yu, Peng [Tetrahedron Letters, 2013, vol. 54, # 47, p. 6345 - 6348]
[3]Picq; Prigent; Nemoz; Andre; Pacheco [Journal of Medicinal Chemistry, 1982, vol. 25, # 10, p. 1192 - 1198]
[4]Herzig [Monatshefte fur Chemie, 1884, vol. 5, p. 75][Monatshefte fuer Chemie, 1888, vol. 9, p. 541]

4
[ 117-39-5 ]
[ 75-03-6 ]
[ 82547-07-7 ]

Yield	Reaction Conditions	Operation in experiment
87%	With potassium carbonate In N,N-dimethyl-formamide at 45℃; for 12h; Inert atmosphere;	2-(3,4-diethoxyphenyl)-3,5,7-triethoxy-4H-chromen-4-one (16) K2CO3 (8.29 g, 60 mmol) and CH3CH2I (10.9 g, 70 mmol) were added to a stirred solution of quercetin (3.02 g, 10 mmol) in dry DMF (25 mL). After the addition, themixture was heated to 45°C and stirred for 12 h. The reaction was cooled toroom temperature, filtered and diluted with ethyl acetate (100 mL) and theresulting solution was poured into aqueous HCl (1 M, 100 mL). The organic layerwas separated, washed with saturated NaCl (3×100 mL) and dried over anhydrousNa2SO4. After concentrated to dryness under reducedpressure, the crude product was purified by column chromatography on silica (petroleum ether/ethyl acetate 1:1) to afford the known compound 16 (3.84 g, 87%) as a white solid * MERGEFORMAT . Data for 16: 1HNMR(400 MHz, CDCl3): δ 7.76 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 6.95(d, J = 8.4 Hz, 1H), 6.45 (s, 1H), 6.32 (s,1H), 4.07-4.20 (m, 10H), 1.55 (m, 3H), 1.44-1.51 (m, 9H), 1.32 (m, 3H); 13CNMR(100 MHz, CDCl3): δ 14.6, 14.8, 14.9, 15.7, 64.1, 64.4, 64.8,65.0, 68.0, 92.8, 97.0, 109.6, 112.3, 113.7, 121.6, 123.7, 140.1, 148.1, 150.5,152.8, 158.8, 160.4, 163.0, 174.1.
82%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 15h; Inert atmosphere;	Quercetin 3,5,7,3',4'-pentaethyl ether (11) To a stirred solution of quercetin(302 mg, 1.0 mmol) in dry DMF (5 mL) was added K2CO3 (829mg, 6.0 mmol) and CH3CH2I (1.09 g, 7.0 mmol). After theaddition, the mixture was stirred for 15 h at room temperature. The reactionmixture was then diluted with CH2Cl2 (20 mL) and pouredinto aqueous HCl (0.1 M) (10 mL). The organic layer was separated, washed withH2O (3×10 mL) and dried over Mg2SO4. Afterconcentrated to dryness under reduced pressure, the crude product was purifiedby column chromatography on silica (petroleum ether/ethyl acetate 1:1) toafford the known compound 112 (362 mg, 82%).
70%	With tetraethylammonium fluoride In N,N-dimethyl-formamide for 20h;

With potassium hydroxide

Reference： [1]Pan, Guojun; Yang, Ke; Ma, Yantao; Zhao, Xia; Lu, Kui; Yu, Peng [Bulletin of the Korean Chemical Society, 2015, vol. 36, # 5, p. 1460 - 1466]
[2]Lu, Kui; Chu, Jie; Wang, Haomeng; Fu, Xiaoli; Quan, Dewu; Ding, Hongxia; Yao, Qingwei; Yu, Peng [Tetrahedron Letters, 2013, vol. 54, # 47, p. 6345 - 6348]
[3]Picq, M.; Prigent, A. F.; Chabannes, B.; Pacheco, H.; Parent, P.; Pichat, L. [Tetrahedron Letters, 1984, vol. 25, # 21, p. 2227 - 2230]
[4]Perkin [Proceedings of the Chemical Society, London, 1913, vol. 28, p. 328][Journal of the Chemical Society, 1913, vol. 103, p. 1637]

5
[ 117-39-5 ]
[ 77-78-1 ]
[ 1245-15-4 ]

Yield	Reaction Conditions	Operation in experiment
74%	With triethylamine In acetone at 0 - 60℃; for 3.08333h;	1 Compound 3b: Quercetin 1 (200 mg, 0.66 mmol) was dissolved in 10 mL of acetone and K2CO3 (375 mg) was added.2.71mmol), Me2SO4 (0.25mL, 2.65mmol) was added dropwise at 0°C. After 5min reaction, the mixture was stirred at 60°C for 3h. TLCDetection of the disappearance of raw materials. The reaction solution was filtered to remove inorganic salts, and the filtrate was spin-dried to give a crude product, which was purified by column chromatography to give compound 3b.The rate is 74%.
61%	With potassium carbonate In acetone at 0℃; for 3h; Inert atmosphere; Reflux;	8 Example 8 synthesis of 2-(3,4-dimethoxyphenyl)-5-hydroxy-3,7-dimethoxy-4H-chromen-4-one (5) To a solution of commercial quercetin dihydrate (5.0 g, 14.78 mmol, 1 eq) in acetone (200 mL), potassium carbonate (8.4 g, 60.60 mmol, 4.1 eq) and dimethylsulfate (5.61 mL, 59.12 mmol, 4 eq) were added under argon at 0°C. After vigorous stirring at reflux for 3h, the resulting mixture was filtered and the filtrate concentrated in vacuo. The residue was recristallized from water /ethanol (1/1) (150 mL) then washed with diethyl ether (50 mL) to afford 3.23 g (61%) of a pale yellow solid. Molecular Weight: 358.34 (C19H18O7). 1H-NMR δ (CDCl3, 300 MHz) ppm (J in Hz): 3.86 (s, 3H, MeO), 3.87 (s, 3H, MeO), 3.96 (s, 3H, MeO), 3.97 (s, 3H, MeO), 6.35 (d, 1H, J=2.1, H-6), 6.44 (d, 1H, J=2.1, H-8), 6.98 (d, 1H, J=8.7, H-5'), 7.68 (d, 1H, J=2.1, H-2'), 7.73 (dd, 1H, J=8.7, 2.1, H-6').
51%	Stage #1: quercetol With potassium hydroxide In water; acetone for 0.166667h; Reflux; Stage #2: dimethyl sulfate With potassium hydroxide In water; acetone for 1.83333h; Reflux;	4.6 General procedure for synthesis of tetramethyl ethers of quercetin and morin General procedure: Quercetin hydrate or morin (10mmol) was added to a mixture of acetone (150ml) and water (75ml). To the resulting mixture, 30% aqueous KOH (6ml) was added and refluxed for 10min. Dimethyl sulphate (2.4ml) was added and refluxed for 20min. More amount of KOH (3ml) was added producing dark brown solution. To this solution an additional amount of dimethyl sulphate (2.4ml) was added and refluxed for 20min. Finally, again KOH (3.0ml) and dimethyl sulphate (3.5ml) were added, refluxed further for 1.5h and allowed to cool to room temperature. Evaporation of acetone gave a dark yellow to brown residue. This residue was purified bycolumn chromatography using hexan:ethylacetate (1:3) as mobile phase. The first two fractions were combined to give pure 12 or 13.

	With potassium carbonate
0.6 mg	With potassium carbonate In acetone for 1h; Heating;
	With potassium carbonate In acetone at 50℃; for 7h;
	In acetone Heating;
	With sodium hydride; potassium carbonate In acetone Heating; regiospecific reaction;
1.82 g	Stage #1: quercetol With potassium hydroxide In water; acetone for 0.166667h; Reflux; Stage #2: dimethyl sulfate In water; acetone Reflux;	2 4.2. Synthesis of 3,3',4',7-O-tetramethylquercetin (7) This compound was synthesized by a modified method of Manthey and Guthrie. Quercetin (3.0 g, 10 mmol) was added to a solution of acetone (150 mL), water (75 mL) and 30% aqueous KOH solution (6 mL) in a three-neck round bottom flask. The reaction mixture was refluxed for 10 min. Dimethyl sulfate (2.4 mL) was added, and the mixture was refluxed for 20 min. KOH solution (3 mL) was added, producing a dark brown solution. An additional 2.4 mL of dimethyl sulfate was added, and the solution was again refluxed for 20 min. KOH (3.0 mL) was added, followed by dimethyl sulfate (0.6 mL). An additional aliquot of dimethyl sulfate (3.0 mL) was added and the mixture was refluxed for 1.5 h and allowed to cool down and stand at room temperature overnight. Yellow crystals (1.82 g) were collected and directly used for the next step reaction.
	With potassium hydroxide In water; acetone

Reference： [1]Current Patent Assignee: NANJING HUITELAI PHARMACEUTICAL - CN104557891, 2017, B Location in patent: Paragraph 0027
[2]Current Patent Assignee: AXOGLIA THERAPEUTICS - EP2112145, 2009, A1 Location in patent: Page/Page column 13
[3]Juvale, Kapil; Stefan, Katja; Wiese, Michael [European Journal of Medicinal Chemistry, 2013, vol. 67, p. 115 - 126]
[4]Gomm; Nierenstein [Journal of the American Chemical Society, 1931, vol. 53, p. 4408] Waljaschko [Archiv der Pharmazie, 1904, vol. 242, p. 241][Chemische Berichte, 1909, vol. 42, p. 727] Wunderlich [Archiv der Pharmazie, 1908, vol. 246, p. 246] Herzig [Monatshefte fur Chemie, 1912, vol. 33, p. 697]
[5]Guerrero; Puebla; Carron; Martin; San Roman [Journal of Pharmacy and Pharmacology, 2002, vol. 54, # 10, p. 1373 - 1378]
[6]Location in patent: experimental part Chen, Lei; He, Ting; Han, Yi; Sheng, Ji-Zhong; Jin, Si; Jin, Man-Wen [Molecules, 2011, vol. 16, # 7, p. 5754 - 5768]
[7]Martins, Inês L.; Charneira, Catarina; Gandin, Valentina; Ferreira Da Silva, João L.; Justino, Gonçalo C.; Telo, João P.; Vieira, Abel J. S. C.; Marzano, Cristina; Antunes, Alexandra M. M. [Journal of Medicinal Chemistry, 2015, vol. 58, # 10, p. 4250 - 4265]
[8]Li, Xue-Li; Zhang, Yan-Hua; Wang, Cai-Fang; Wang, Qiu-An [Natural Product Research, 2017, p. 1 - 8]
[9]Rajaram, Pravien; Jiang, Ziran; Chen, Guanglin; Rivera, Alyssa; Phasakda, Alison; Zhang, Qiang; Zheng, Shilong; Wang, Guangdi; Chen, Qiao-Hong [Bioorganic Chemistry, 2019, vol. 87, p. 227 - 239]
[10]Chen, Hongping; Ding, Haiyan; Hu, Yuan; Li, Dan; Liu, Youping; You, Qiang [Journal of Agricultural and Food Chemistry, 2021, vol. 69, # 43, p. 12705 - 12716]

6
[ 117-39-5 ]
[ 77-78-1 ]
[ 1247-97-8 ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium hydroxide In dimethyl sulfoxide at 10 - 20℃; for 2h;	Methylation of quercetin (2) with the Me2SO4/KOH/DMSO system (run 2 in Table 2): QPE [2-(3,4-Dimethoxyphenyl)-3,5,7-trimethoxy-4H-1-benzopyran-4-one] (1) To a suspensionof powdered KOH (1.66 g, 29.7×10-3 mol) in DMSO(8 mL) was slowly added quercetin (2, 1 g, 3.3 × 10-3 mol), followedby Me2SO4 (2.5 mL, 26.4 × 10-3 mol), with control ofthe temperature to less than 10 °C (CAUTION: The reaction isexothermic). The resulting dark brown solution was stirred at rtfor 2 h, during which time the color changed to light brown.The reaction was quenched with H2O (80 mL), and the resultingsuspension was extracted with EtOAc (50/20/20 mL) TheEtOAc solution was successively washed with 5% NaOH aq(10 mL × 4), H2O (10 mL × 3), and brine (10 mL), dried oversodium sulfate, and evaporated under reduced pressure to giveQPE (1) as a light brown solid (1.05 g), which was homogeneouson TLC and showed a single peak at the same retentiontime as that of an authentic sample. Recrystallizationfrom MeOH gave colorless prisms, mp 147-149 °C(lit. mp 136-137 °C [34]; mp 151 °C [39]; mp 151.2 °C [51]:1H NMR δ 3.88 (s, 3H, OMe), 3.90 (s, 3H, OMe), 3.95 (s, 9H,OMe × 3), 6.34 (d, J = 2.2 Hz, 1H, 6- or 8-H), 6.49 (d,J = 2.2 Hz, 1H, 6- or 8-H), 6.97 (d, J = 8.4 Hz, 1H, 5'-H), 7.71 (dd, J = 8.4, 2.0 Hz, 1H, 6'-H), 7.72 (s-like, 1H, 2'-H);13C NMR δ 55.9, 56.1, 56.3, 56.6, 60.1, 92.7, 96.0, 109.8,111.2, 111.8, 121.8, 123.8, 141.4, 149.0, 151.2, 152.6, 159.0,161.3, 164.1, 174.1
85%	With potassium hydroxide In dimethyl sulfoxide at 10 - 20℃; for 2h;	1; 2 Example 1 Dimethyl sulfoxide (DMSO) (8 mL) was added to powdered potassium (1.66 g, 29.7 mmol), and they were stirred at room temperature. Quercetin (1 g, 3.3 mmol) and dimethyl sulfate were added successively to the suspension at lower than 10-degree centigrade, and the mixture was stirred at room temperature for 2 hours. In the above reaction, the color of the suspension was changed from dark brown to light brown. After the reaction, water (80 mL) was added, and extraction was performed three times with ethyl acetate (50 mL, 20 mL, 20 mL for each). The ethyl acetate solution was washed by 5% sodium hydroxide aqueous solution (10 mL×4), water (10 mL×3), and brine (10 mL×1), respectively. After being dried over sodium sulfate, the ethyl acetate solution was evaporated under a reduced pressure to give a light brown solid (1.05 g). The solid showed a single spot on thin-layer chromatography, and recrystallization from methanol afforded colorless prisms. The melting point of the solid (147-149 degree centigrade) was the same as the value which was described in non-patent document 1. Further, based on the NMR data described below, it was confirmed that all hydroxyl groups of the quercetin were substituted for methoxy groups. 1H-NMR δ 3.88 (3H, s, OMe), 3.90 (3H, s, OMe), 3.95 (9H, s, OMe×3), 6.34 (1H, d, J=2.2 Hz, 6- or 8-H), 6.49 (1H, d, J=2.2 Hz, 6- or 8-H), 6.97 (1H, d, J=8.4 Hz, 5′-H), 7.71 (1H, dd, J=8.4, 2.0 Hz, 6′-H), 7.72 (1H, s-like, 2′-H); 13C-NMR δ 55.9, 56.1, 56.3, 56.6, 60.1, 92.7, 96.0, 109.8, 111.2, 111.8, 121.8, 123.8, 141.4, 149.0, 151.2, 152.6, 159.0, 161.3, 164.1, 174.1. As a result of the reaction, it was confirmed that the yield was 85% and the method of the present invention was effectual.
80%	With potassium carbonate In acetone at 60℃; for 5h;	1 Compound 3a: Quercetin 1 (200 mg, 0.66 mmol) was dissolved in 10 mL of acetone and K2CO3 (503 mg) was added.3.64 mmol), Me2SO4 (0.35 mL, 3.64 mmol). The reaction was stirred at 60°C for 5 h. TLC showed the disappearance of starting material. anti-The solution was filtered to remove inorganic salts, and the filtrate was spin-dried to give a crude product, which was recrystallized from ethyl acetate to give a yellow solid.Compound 3a, yield 80%

72%	With potassium carbonate In acetone for 21h; Heating;
65.7%	With potassium carbonate In acetone for 10h; Reflux;	General procedure for alkylation of flavonoids General procedure: To a stirred solution of flavonoid (1 mmol), K2CO3 (552 mg,4 mmol) in acetone (50 mL) was added dimethyl sulfate(5.5 mmol) or allyl bromide (5.5 mmol). The mixture was stirredand refluxed for 10 h, monitoring by TLC. After removing potassiumcarbonate, the solvent was evaporated in reduced pressure.The residue was purified by column chromatography on silicagel.
60%	With potassium hydroxide In water at 20 - 90℃;	1.1 4.1.1.1. Synthesis of 2-(3,4-dimethoxyphenyl)-3,5,7-trimethoxy-4H-chromen-4-one (2) 4.1.1.1 Synthesis of 2-(3,4-dimethoxyphenyl)-3,5,7-trimethoxy-4H-chromen-4-one (2) Quercetin (1) (1 g, 3.30 mmol) was dissolved in KOH (15%, 10 mL) at ambient temperature. Dimethyl sulfate (2.29 g, 1.7 mL, 18.15 mmol, 5.5 eq., d = 1.33 g/mL) was added slowly over 10 min and the reaction was stirred at ambient temperature for 1 h. After 1 h, further dimethyl sulfate (5.5 eq.) and KOH (15%, 10 mL) were added and the mixture was heated to 90 °C. After 3 h, further dimethyl sulfate (5.5 eq.) and KOH (15%, 10 mL) were added and the reaction was stirred overnight at 90 °C. KOH (15%, 15 mL) was then added and the reaction was stirred for another 5 h at 90 °C. The reaction was cooled to room temperature, and acidified to pH 5 by the addition of 2 M HCl (20 mL). The precipitate was filtered and washed with water. The 2-(3,4-dimethoxyphenyl)-3,5,7-trimethoxy-4H-chromen-4-one (2) was obtained as an off white solid in a pure form after purification by column chromatography [Solvent system: EtOAc (100%)]. Yield: 60%; m.p: 155-7 °C (lit [35] -150-52 °C);1H NMR: (DMSO-d6,400 MHz) δ 3.88, 3.90, 3.96 (15H, s, -OCH3), 6.34 (1H, s, H-6), 6.50 (1H, s, H-8), 6.97 (1H, d, J = 8.0 Hz, H-5'), 7.69 (1H, d, J = 8.0 Hz, H- 6'), 7.71 (1H, s, H-2'); 13C NMR: (DMSO-d6, 100 MHz) δ 56.3 (4 x-OCH3), 59.9 (-OCH3), 92.3 (C8), 95.8 (C6), 109.4 (C10), 110.7 (C2'), 111.5 (C5'), 121.6 (C6'), 123.7 (C1'), 141.3 (C3), 148.8 (C4'), 150.8 (C3'), 152.6 (C2), 158.9 (C9), 161.3 (C5), 164.1 (C7), 174.0 (C=O); IR νmax[cm-1]: 1651(C=O, ν, s), 1291 (-OCH3, ν, s), 1097 (C-O, ν, m); m/z (FTMS + ESI): M + H (C20H21O7) requires 373.1282, found 373.1277. HPLC purity: 96.1%
	With alkali
	With potassium carbonate
	With potassium carbonate
	With potassium carbonate In acetone
	Stage #1: quercetol With potassium hydroxide In acetone Heating; Stage #2: dimethyl sulfate In water; acetone for 1h; Heating;
	With potassium hydroxide at 20 - 90℃;
1.827 g	Stage #1: quercetol; dimethyl sulfate In acetone at 60℃; for 12h; Stage #2: dimethyl sulfate With sodium hydride at 60℃; for 12h;	7 Add 15mL of acetone (which can dissolve the above powder)Add 30 tubes of dimethyl sulfate (59.95g,475.3mmoL),The reflux was stirred at 60 °C.once in a while,Add dimethyl sulfate 5-10 tube,Add twice.When the reaction proceeds to 12h,Stop heating,Lower the temperature to room temperature,Add an appropriate amount of NaH powder (a small amount is appropriate, can not be added, pay attention to a small amount to prevent bumping),After adding NaH,Add 10 tubes of dimethyl sulfate,Start heating to 60 ° C,Continue to react for 12 h.After the reaction is completed, add ammonia water (dropped from above the condenser),Until it is no longer boiling (alkaline, this step is mainly to remove dimethyl sulfate).Spin the above reaction solution,add water,Methylene chloride extraction layering,The organic layer was obtained by liquid separation using a 250 mL separatory funnel.Decompressed under reduced pressure,The crude product was separated and purified by silica gel column chromatography (200 mesh silica gel).The eluent is (petroleum ether/ethyl acetate),The desired product (1.827 g, 30.60%) was obtained.
	With potassium hydroxide In water; acetone for 3h; Reflux;
	With potassium hydroxide In water; acetone

Reference： [1]Tatsuzaki, Jin; Ohwada, Tomohiko; Otani, Yuko; Inagi, Reiko; Ishikawa, Tsutomu [Beilstein Journal of Organic Chemistry, 2018, vol. 14, p. 3112 - 3121]
[2]Current Patent Assignee: TOKIWA PHYTOCEMICAL CO LTD - US10889557, 2021, B1 Location in patent: Page/Page column 5; 6
[3]Current Patent Assignee: NANJING HUITELAI PHARMACEUTICAL - CN104557891, 2017, B Location in patent: Paragraph 0026
[4]Picq; Prigent; Nemoz; Andre; Pacheco [Journal of Medicinal Chemistry, 1982, vol. 25, # 10, p. 1192 - 1198]
[5]Hoang, T. Kim-Dung; Huynh, T. Kim-Chi; Nguyen, Thanh-Danh [Bioorganic Chemistry, 2015, vol. 63, p. 45 - 52]
[6]Ravishankar, Divyashree; Watson, Kimberly A.; Boateng, Samuel Y.; Green, Rebecca J.; Greco, Francesca; Osborn, Helen M.I. [European Journal of Medicinal Chemistry, 2015, vol. 97, p. 259 - 274]
[7]Herzig; Hofmann [Chemische Berichte, 1909, vol. 42, p. 157] Tasaki [Acta Phytochimica, 1924, vol. 2, p. 127][Acta Phytochimica, 1927, vol. 3, p. 14][Chemisches Zentralblatt, 1926, vol. 97, # I, p. 956] Freudenberg [Justus Liebigs Annalen der Chemie, 1923, vol. 433, p. 236]
[8]Brandt, Edward V.; Ferreira, Daneel; Roux, David G. [Journal of the Chemical Society. Perkin transactions I, 1981, p. 514 - 521]
[9]Joseph-Nathan, P.; Abramo-Bruno, D.; Torres, Ma. A. [Phytochemistry, 1981, vol. 20, p. 313 - 318]
[10]Yuldashev [Chemistry of Natural Compounds, 1996, vol. 32, # 6, p. 925 - 925]
[11]Ko, Wun-Chang; Kuo, Shih-Wu; Sheu, Joen-Rong; Lin, Chien-Huang; Tzeng, Shu-Huey; Chen, Chi-Ming [Planta Medica, 1999, vol. 65, # 3, p. 273 - 275]
[12]Manthey, John A.; Guthrie, Najla [Journal of Agricultural and Food Chemistry, 2002, vol. 50, # 21, p. 5837 - 5843]
[13]Ravishankar, Divyashree; Watson, Kimberly A.; Greco, Francesca; Osborn, Helen M. I. [RSC Advances, 2016, vol. 6, # 69, p. 64544 - 64556]
[14]Current Patent Assignee: TIANJIN UNIVERSITY OF SCIENCE AND TECHNOLOGY - CN108276374, 2018, A Location in patent: Paragraph 0040; 0041
[15]Dudek, Bettina; Schnurrer, Florian; Dahse, Hans-Martin; Paetz, Christian; Warskulat, Anne-Christin; Weigel, Christiane; Voigt, Kerstin; Schneider, Bernd [Molecules, 2018, vol. 23, # 12]
[16]Chen, Hongping; Ding, Haiyan; Hu, Yuan; Li, Dan; Liu, Youping; You, Qiang [Journal of Agricultural and Food Chemistry, 2021, vol. 69, # 43, p. 12705 - 12716]

7
[ 117-39-5 ]
[ 74-88-4 ]
[ 1245-15-4 ]

Yield	Reaction Conditions	Operation in experiment
73%	With potassium carbonate In N,N-dimethyl-formamide at 35℃; for 12h; Inert atmosphere;	2-(3,4-dimethoxyphenyl)-5-hydroxy-3,7-dimethoxy-4H-chromen-4-one (1) K2CO3 (6.08 g, 44 mmol) and CH3I(6.25 g, 44 mmol) were added to a stirred solution of quercetin (3.02 g, 10 mmol) in dry DMF (25 mL). After the addition, themixture was heated to 35°C and stirred for 12 h. The reaction was cooled toroom temperature, filtered and diluted with ethyl acetate (100 mL) and theresulting solution was poured into aqueous HCl (1 M, 100 mL). The organic layerwas separated, washed with saturated NaCl (3×100 mL) and dried over anhydrousNa2SO4. After concentrated to dryness under reducedpressure, the crude product was purified by column chromatography on silica (dichloromethane /methanol 100:1) to afford the known compound 1 (2.62 g, 73%) as a yellow. Datafor 1: 1HNMR(400 MHz, CDCl3): δ 7.82(s, 1H), 7.79 (d, J = 8.4 Hz, 1H),7.00(d, J = 8.4 Hz, 1H), 6.55 (s,1H), 6.35 (s, 1H), 3.99 (s, 6H), 3.96 (s, 3H), 3.93 (s, 3H); 13CNMR(100 MHz, CDCl3): δ 55.8,55.9, 56.0, 56.4, 92.4, 95.7, 106.2, 110.4, 110.9, 120.6, 123.8, 137.6, 142.1,148.9, 150.3, 158.9, 160.6, 164.4, 171.9.
68%	With sodium carbonate In N,N-dimethyl-formamide at 20℃; for 10h; Inert atmosphere;	Quercetin 3,7,3',4'-tetramethyl ether (5) To a stirred solution of quercetin (302 mg, 1.0 mmol) in dry DMF (5 mL) was addedNa2CO3 (477 mg, 4.5 mmol) CH3I (639 mg, 4.5mmol). After the addition, the mixture was stirred for 10 h at roomtemperature. After diluted with CH2Cl2 (20 mL), the reactionmixture was poured into aqueous HCl (0.1 M, 10 mL). The organic layer wasseparated, washed with H2O (3×10 mL) and dried over Mg2SO4.After concentrated to dryness under reduced pressure, the crude product waspurified by column chromatography on silica (petroleum ether/ethyl acetate 4:1)to afford the known compound 51(244 mg, 68%) as a yellow solid.
48%	With potassium carbonate

9%	With potassium carbonate In N,N-dimethyl-formamide at 35℃; Inert atmosphere;	2-(3,4-dimethoxyphenyl)-5-hydroxy-3,7-dimethoxy-4H-chromen-4-one (13) Methyl iodide (1.00 g, 7.10 mmol) was added to a solution of quercetin (0.30 g, 1.00 mmol)and potassium carbonate (0.83 g, 7.24 mmol) in DMF (2.5 mL). The reaction mixture wasstirred at 35 °C overnight under inert atmosphere. The reaction mixture was quenched byaddition of 5% HCl aqueous solution (30 mL) and extracted with EtOAc (3 × 20 mL). Thecombined organic layers were washed with brine (20 mL), dried over MgSO4 and evaporate todryness under reduced pressure. The residue was purified by column chromatography (EtOAc).Subsequent crystallization (ethanol) afforded yellow solid (0.035 g, 9%).
	With potassium hydroxide

Reference： [1]Pan, Guojun; Yang, Ke; Ma, Yantao; Zhao, Xia; Lu, Kui; Yu, Peng [Bulletin of the Korean Chemical Society, 2015, vol. 36, # 5, p. 1460 - 1466]
[2]Lu, Kui; Chu, Jie; Wang, Haomeng; Fu, Xiaoli; Quan, Dewu; Ding, Hongxia; Yao, Qingwei; Yu, Peng [Tetrahedron Letters, 2013, vol. 54, # 47, p. 6345 - 6348]
[3]Cormier, Michelle; Ghouili, Firas; Roumaud, Pauline; Martin, Luc J.; Touaibia, Mohamed [Toxicology in Vitro, 2017, vol. 44, p. 111 - 121]
[4]Albiñana, Carlos Berenguer; Brynda, Jiří; Fanfrlík, Jindřich; Flieger, Miroslav; Hodek, Jan; Karlukova, Elena; Kožíšek, Milan; Konvalinka, Jan; Machara, Aleš; Majer, Pavel; Radilová, Kateřina; Weber, Jan; Zima, Václav [European Journal of Medicinal Chemistry, 2020, vol. 208]
[5]Herzig [Monatshefte fur Chemie, 1884, vol. 5, p. 75][Monatshefte fuer Chemie, 1888, vol. 9, p. 541]

8
[ 117-39-5 ]
[ 74-88-4 ]
[ 1247-97-8 ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium carbonate In N,N-dimethyl-formamide at 35℃; for 12h; Inert atmosphere;	2-(3,4-dimethoxyphenyl)-3,5,7-trimethoxy-4H-chromen-4-one (14) K2CO3 (8.28 g, 60 mmol) and CH3I(9.94 g, 70 mmol) were added to a stirred solution of quercetin(3.02 g, 10 mmol) in dry DMF (25 mL). After the addition, the mixture washeated to 35°C and stirred for 12h. The reaction was cooled to roomtemperature, filtrated and diluted with ethyl acetate (100 mL) and theresulting solution was poured into aqueous HCl (1 M, 100 mL). The organic layerwas separated, washed with saturated NaCl (3×100 mL) and dried over anhydrousNa2SO4. After concentrated to dryness under reducedpressure, the crude product was purified by column chromatography on silica (petroleum ether/ethyl acetate 4:1) to afford the known compound 14 (3.19 g, 86%) as a white solid. Data for 14: 1HNMR(400 MHz, CDCl3): δ 7.72 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 8.8 Hz, 1H), 6.50 (s, 1H), 6.35 (s,1H), 3.97 (s, 9H), 3.91 (s, 3H), 3.88 (s, 3H); 13CNMR (100 MHz, CDCl3):δ 56.0,56.1, 56.9, 60.2, 69.5, 90.2, 106.1, 110.9, 111.3, 122.3, 122.6, 138.9, 148.8,151.6, 156.1, 157.1, 160.9, 163.2, 177.9.
84%	With sodium hydride In N,N-dimethyl-formamide at 20℃; for 12h;
82%	With potassium carbonate In acetone for 24h; Reflux;	4.5 General procedure for the synthesis of pentamethyl ethers of quercetin and morin General procedure: To a solution of quercetin hydrate or morin (10mmol) in acetone (50ml), K2CO3 (30mmol) and methyl iodide (70mmol, excess) were added. The resulting mixture was refluxed for 24h. After completion of the reaction, acetone and methyl iodide were removed under reduced pressure. To the resulting solid water was added, the precipitated product was filtered and washed with water to remove traces of K2CO3. The product was dried at room temperature and recrystallized from ethanol to yield compounds 10 and 11.

80%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 10h; Inert atmosphere;	Quercetin 3,5,7,3',4'-pentamethyl ether (7) To a stirred solution of quercetin (302 mg, 1.0 mmol) in dry DMF (5 mL) was added K2CO3(828 mg, 6.0 mmol) and CH3I (994 mg, 7.0 mmol). After the addition,the mixture was stirred for 10 h at room temperature. After diluted with CH2Cl2(20 mL), the reaction mixture was poured into aqueous HCl (0.1 M, 10 mL). The organic layer was separated, washed withH2O (3×10 mL) and dried over Mg2SO4. Afterconcentrated to dryness under reduced pressure, the crude product was purified by column chromatography on silica(petroleum ether/ethyl acetate 4:1) to afford the known compound 71 (297 mg, 80%) as a whites olid.
75%	With tetraethylammonium fluoride In N,N-dimethyl-formamide for 2h;
67%	With potassium hydroxide In dimethyl sulfoxide at 10 - 20℃; for 1.5h;	3 Comparative Example 3 Dimethyl sulfoxide (DMSO) (4 mL) was added to powdered potassium hydroxide (0.83 g, 14.8 mmol), and the mixture was stirred at room temperature. Quercetin (0.51 g, 1.67 mmol) and methyl iodide were added successively to the suspension at lower than 10-degree centigrade, and they were stirred at room temperature for 1.5 hours. The reaction mixture was quenched by adding water, acidified with 20% sulfuric acid, and extracted with ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate and evaporated. The obtained residue (0.492 g) was washed with acetone to give the pentamethoxy derivative (0.394 g). After evaporating the acetone washings under a reduced pressure and purifying the residue by preparative chromatography, a pentamethoxy derivative 0.02 g (totally 0.418 g, 67%) was additionally obtained. Further, by preparative chromatography, a 6-methylpentametoxy derivative (0.007 g, 1%) was obtained as byproduct. As a result, it is found that the method which uses methyl iodide was very complicated.
52%	With potassium carbonate
14%	With potassium carbonate In N,N-dimethyl-formamide at 40℃; Inert atmosphere;	2-(3,4-Dimethoxyphenyl)-3,5,7-trimethoxy-4H-chromen-4-one (14) Methyl iodide (1.80 g, 12.68 mmol) was added to a solution of quercetin (0.30, 0.99 mmol) andpotassium carbonate (1.00 g, 7.24 mmol) in DMF (6 mL). The reaction mixture was stirred at40 °C overnight under inert atmosphere. The reaction mixture was quenched by addition ofaqueous solution of HCl 5% (30 mL) and extracted with EtOAc (3 × 20 mL). The combinedorganic layers were washed with brine (10 mL), dried over MgSO4 and evaporate to drynessunder reduced pressure. The residue was purified by column chromatography (EtOAc).Subsequent crystallization (ethanol) afforded yellow solid (0.050 g, 14%).
	With potassium hydroxide

Reference： [1]Pan, Guojun; Yang, Ke; Ma, Yantao; Zhao, Xia; Lu, Kui; Yu, Peng [Bulletin of the Korean Chemical Society, 2015, vol. 36, # 5, p. 1460 - 1466]
[2]Matsuda, Hisashi; Morikawa, Toshio; Toguchida, Iwao; Yoshikawa, Masayuki [Chemical and Pharmaceutical Bulletin, 2002, vol. 50, # 6, p. 788 - 795]
[3]Juvale, Kapil; Stefan, Katja; Wiese, Michael [European Journal of Medicinal Chemistry, 2013, vol. 67, p. 115 - 126]
[4]Lu, Kui; Chu, Jie; Wang, Haomeng; Fu, Xiaoli; Quan, Dewu; Ding, Hongxia; Yao, Qingwei; Yu, Peng [Tetrahedron Letters, 2013, vol. 54, # 47, p. 6345 - 6348]
[5]Picq, M.; Prigent, A. F.; Chabannes, B.; Pacheco, H.; Parent, P.; Pichat, L. [Tetrahedron Letters, 1984, vol. 25, # 21, p. 2227 - 2230]
[6]Current Patent Assignee: TOKIWA PHYTOCEMICAL CO LTD - US10889557, 2021, B1 Location in patent: Page/Page column 6
[7]Cormier, Michelle; Ghouili, Firas; Roumaud, Pauline; Martin, Luc J.; Touaibia, Mohamed [Toxicology in Vitro, 2017, vol. 44, p. 111 - 121]
[8]Albiñana, Carlos Berenguer; Brynda, Jiří; Fanfrlík, Jindřich; Flieger, Miroslav; Hodek, Jan; Karlukova, Elena; Kožíšek, Milan; Konvalinka, Jan; Machara, Aleš; Majer, Pavel; Radilová, Kateřina; Weber, Jan; Zima, Václav [European Journal of Medicinal Chemistry, 2020, vol. 208]
[9]Perkin [Journal of the Chemical Society, 1913, vol. 103, p. 1634]

9
[ 117-39-5 ]
[ 95412-48-9 ]

Yield	Reaction Conditions	Operation in experiment
80%	With hydrogen bromide; dihydrogen peroxide In methanol; water at 0 - 5℃; for 5h;
78.95%	With bromine In acetic acid at 35 - 40℃; for 1h;
50%	With 2,3-dibromo-3-phenylpropanoic acid; potassium carbonate In N,N-dimethyl-formamide at 60℃; for 16h; Inert atmosphere;

	With bromine; acetic acid
	With hypobromous acid In ethanol; water at 20℃; aq. phosphate buffer;
	Stage #1: quercetol With N-Bromosuccinimide In methanol; water at 20℃; for 0.166667h; Green chemistry; Stage #2: With sodium dithionite In methanol; water at 20℃; for 0.166667h; Green chemistry;	A solution of NBS (500 mg in 60 mL of H2O) was poured into a solutionof quercetin (250mg in 50 mL of methanol)at room temperatureunder stirring. The final violet solution was allowed to stand forapproximately 10 minutes.Then, the solution was treated with Na2S2O4 (400 mg in 40 mL of H2O)which caused an immediate color change from violet to yellow and the formationof a precipitate. After another 10 minutes, the solution was filtrated and the precipitatewashed repeatedly with distilled water. The solid was then solubilized with 50mL of acetone and the solvent successively removed till dryness using arotavapor pump. Final yield ca. 70%. 1HNMR (acetone-d6): d = 7.03 (d, J = 8.4 Hz, 1H, H-5’), 7.86 (dd, J= 1.6, 8.4 Hz, 1H, H-6’), 7.98 (d, J = 1.6 Hz, 1H, H-2’), 8.44 (OH-3), 8.54(OH-3’), 8.80 (OH-4’), 9.65 (OH-7), 13.15 (OH-5). Addition of traces of HClrendered the signals of all OHs very sharp. 13C NMR (acetone-d6): d = 87.01 (C-8), 92.75(C-6), 104.18 (C-10), 114.89 (C-2’), 115.38 (C-5’), 120.96 (C-6’), 122.43(C-1’), 136.09 (C-3), 145.07 (C-3’), 147.21 (C-4’), 147.90 (C-2), 151.32 (C-5),156.56 (C-7), 156.84 (C-9), 175.13 (C-4). The ESI-MS spectrum of 2 (MeOH) in the negative ion-modeshowed a peak at m/z 459 [M -H]- and the typical isotopic pattern1:2:1 for 2 Br atoms (M-1, M+1, M+3).

Reference： [1]Peng, Mei; Liu, Fengxian; Feng, Xin; Yang, Fan; Yang, Xiaoping [Asian Journal of Chemistry, 2014, vol. 26, # 15, p. 4701 - 4703]
[2]Nagimova; Zbusupova; Erzhanova [Chemistry of Natural Compounds, 1996, vol. 32, # 5, p. 695 - 697]
[3]Hurtová, Martina; Biedermann, David; Kuzma, Marek; Křen, Vladimír [Journal of Natural Products, 2020, vol. 83, # 11, p. 3324 - 3331]
[4]Liebermann [Chemische Berichte, 1884, vol. 17, p. 1682] Herzig [Monatshefte fur Chemie, 1885, vol. 6, p. 872]
[5]Location in patent: experimental part Justino, Goncalo C.; Rodrigues, Margarida; Florencio, M. Helena; Mira, Lurdes [Journal of Mass Spectrometry, 2009, vol. 44, # 10, p. 1459 - 1468]
[6]Foti, Mario C.; Rocco, Concetta [Tetrahedron Letters, 2014, vol. 55, # 9, p. 1602 - 1607]

10
[ 117-39-5 ]
[ 528-58-5 ]

Reference： [1]Chemische Berichte,1934,vol. 67,p. Abt. A, S. 85
[2]Journal of the American Chemical Society,1930,vol. 52,p. 2864,2868

11
[ 110-91-8 ]
[ 50-00-0 ]
[ 117-39-5 ]
[ 30987-77-0 ]

Yield	Reaction Conditions	Operation in experiment
65%	In ethanol; water at 20℃; for 4h;	General procedure for aminomethylation of flavonoids General procedure: To a stirred solution of flavonoid (3.31 mmol) in ethanol (50 mL) was slowly added amines (33.3 mmol) and a 37% formaldehyde solution (2.48 g, 35 mmol). The mixture was stirred at room temperature for 4 h, monitoring by TLC. The residue was fltered of, washed with 50 mL of ethanol, and then dried in the vacuum.
	In ethanol at 20℃; regioselective reaction;
	In ethanol; water	3 EXAMPLE 3 Synthesis of 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-8-(morpholinomethyl)- 4H-chromen-4-one (compound 4) To a solution of quercetin dihydrate and morpholine in ethanol was added 37% aqueous formaldehyde. The reaction was filtered to provide the product as a solid.

In ethanol at 60℃;

Reference： [1]Hoang, T. Kim-Dung; Huynh, T. Kim-Chi; Do, T. Hong-Tuoi; Nguyen, Thanh-Danh [Chemical Papers, 2018, vol. 72, # 6, p. 1399 - 1406]
[2]Jerzmanowska,Z.; Jurkowska-Kowalczyk,E. [Roczniki Chemii, 1970, vol. 44, p. 1395 - 1402] Jerzmanowska,Z.; Jurkowska-Kowalczyk,E. [Roczniki Chemii, 1972, vol. 46, p. 1039 - 1046]
[3]Joshi, Dharati; Field, James; Murphy, John; Abdelrahim, Mohammed; Schoenherr, Heike; Sparrow, Janet R.; Ellestad, George; Nakanishi, Koji; Zask, Arie [Journal of Natural Products, 2013, vol. 76, # 3, p. 450 - 454]
[4]Current Patent Assignee: COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK - WO2014/110551, 2014, A1 Location in patent: Paragraph 0057
[5]Bagavieva; Yagunov; Kholshin; Prosenko [Russian Chemical Bulletin, 2019, vol. 68, # 1, p. 194 - 196][Izv. Akad. Nauk, Ser. Khim., 2019, vol. 68, # 1, p. 194 - 196,3]

12
[ 133-89-1 ]
[ 117-39-5 ]
[ 482-35-9 ]

Yield	Reaction Conditions	Operation in experiment
43%	With oleandomycin glucosyltransferase In dimethyl sulfoxide at 37℃; Enzymatic reaction;	Determination of the reaction product by 1H NMR and HRMS Spectra General procedure: The OleDPSA-catalyzed reaction was carried out at 37 °C in 100 mL of Tris-HCl buffer (100 mM, pH 8.0) containing quercetin (15.1 mg, 50 μmol), UDP-Glc (152.6 mg, 250 μmol), OleDPSA (9.8 mg) and 10% DMSO. The reaction was incubated overnight and quenched by adding an equal volume of ice-cold ethanol. The precipitates were removed by centrifugation, and the supernatant was concentrated. The crude product was purified via C-18 reverse phase chromatography (water: acetonitrile from 8:1 to 3:1) to give the product as light yellow solid in 43% yield. 1H NMR (400 MHz, MeOD-d4)  7.73 (d, J = 2.0 Hz, 1H), 7.62 (dd, J1 = 2.0 Hz, J2 = 8.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.43 (d, J = 2.0 Hz, 1H), 6.23 (d, J = 2.0 Hz,1H), 5.29 (d, J = 7.6 Hz, 1H), 3.74 (dd, J1 = 2.0 Hz, J2 = 11.6 Hz, 1H), 3.60 (dd, J1 = 5.4 Hz, J2 = 11.8 Hz, 1H), 3.53-3.40 (m, 3H), 3.26 -3.22 (m, 1H); HRMS(+MALDI) calcd for C21H20NaO12 [M+Na]+ 487.0847 found 487.0853.
	With UDP glucose:flavonol glucosyltransferase enzyme preparation from Norway spruce needles In water for 0.75h; pH 8.0 bicine buffer;
	With uridine diphosphate glycosyltransferase UGT₇₈D₁ In aq. buffer at 30℃; for 0.75h; Enzymatic reaction; regioselective reaction;

	With O-glycosyltransferase TwUGT₂ from Tripterygium wilfordii In aq. buffer at 35℃; for 24h; Enzymatic reaction;	3.5. Enzyme assay General procedure: Enzyme assays were performed in 100 ll of the reaction mixture, containing 100mM Tris-HCl buffer (pH 7.5), 0.5mM sugar donor (uridine diphosphate glucose, UDPG), 50 lM substrate and 50 mg purified recombinant TwUGT2 protein. The reaction mixture with the addition of the purified empty vector protein was set as a control. The reactions were incubated at 35 °C for 24 h and terminated by the addition of 200 ll of UPLC-grade methanol. After centrifuging at 10,000 g for 2 min, the supernatant was filtered through a 0.22-mm nylon syringe filter and temporarily stored at 4 °C.
	With glycosyltransferases from Glycine max In aq. buffer at 37℃; Enzymatic reaction;	3.3.1. Synthesis of quercetin 3-O-β-D-glucoside The one-pot reaction mixture for the synthesis of quercetin 3-O-β-D-glucosides (QG) contained100 mM Tris buffer, 20 mM MgCl2, 150 mM acetyl phosphate, 50 mM glucose 1-phosphate,1 mM ATP, 2 mM UMP, 8 mM quercetin, and ~50 μg/mL of each crude enzyme (UMK,ACK, GalU, and UGT78K1). The reactions were incubated at 37 °C for an appropriate time,and 10 μL reaction sample was diluted in 500 μL methanol at different times, to check for conversion of the product.

Reference： [1]Wang, Lu; Han, Weiqing; Xie, Chenying; Hou, Jingli; Fang, Qinghong; Gu, Jianchun; Wang, Peng George; Cheng, Jiansong [Carbohydrate Research, 2013, vol. 368, p. 73 - 77]
[2]Strack, Dieter; Heilemann, Juergen; Wray, Victor; Dirks, Herbert [Phytochemistry, 1989, vol. 28, # 8, p. 2071 - 2078]
[3]Ren, Guangxiang; Hou, Jingli; Fang, Qinghong; Sun, Hong; Liu, Xiaoyan; Zhang, Lianwen; Wang, Peng George [Glycoconjugate Journal, 2012, vol. 29, # 5-6, p. 425 - 432]
[4]Lu, Yun; Ma, Bao-Wei; Gao, Jie; Tu, Li-Chan; Hu, Tian-Yuan; Zhou, Jia-Wei; Liu, Yuan; Tu, Yu-He; Lin, Zhao-Shou; Huang, Lu-Qi; Gao, Wei [Journal of Asian Natural Products Research, 2020, vol. 22, # 6, p. 537 - 546]
[5]Bae, Jae Yoon; Darsandhari, Sumangala; Han, Jang Mi; Jung, Hye Jin; Pandey, Ramesh Prasad; Rha, Chan-Su; Shrestha, Biplav; Sohng, Jae Kyung; Yamaguchi, Tokutaro [Natural Product Research, 2019, vol. 33, # 13, p. 1944 - 1952]

13
[ 106-31-0 ]
[ 117-39-5 ]
[ 82546-97-2 ]

Yield	Reaction Conditions	Operation in experiment
97%	With dmap In N,N-dimethyl-formamide at 45℃; for 1h;	3. General method for peracetylation of polyphenols: General procedure: Polyphenols, acetic or butyric anhydride (6.0 equivalents per -OH group) andDMAP (0.3 equivalent) were completely dissolved in DMF in a round bottom flask to afinal concentration of 15 mM polyphenols. The reaction was kept at 45°C under stirringand monitored by analytical TLC (hexanes:ethyl acetate 3:1). After 0.5 - 2 h, cold 10%NaCl (aq) was added, and soluble fractions were extracted at 3 20 mL with ethyl acetate.The pooled organic phase was then washed with 3 20 mL 10% NH4Cl(aq) and 3 20mL 10% NaHCO3(aq), dried over anhydrous Na2SO4 and evaporated under reducedpressure to yield peracetylated (1a-8a) or perbutyrylated (2b, 4b, 6b) products. Meltingpoints were measured for solid products and compared to data from the literature, ifavailable. Structures were confirmed by 1H NMR, 13C NMR and LCMS(ESI+).
82%	With pyridine for 5h; Heating;

Reference： [1]Castro, Rosane Nora; Freire de Lima, Marco Edilson; Pitasse-Santos, Paulo; de Alcântara Pinto, Douglas Chaves; de Souza, Gabriela Alves [Natural Product Research, 2022]
[2]Picq; Prigent; Nemoz; Andre; Pacheco [Journal of Medicinal Chemistry, 1982, vol. 25, # 10, p. 1192 - 1198]

14
[ 117-39-5 ]
[ 100-39-0 ]
[ 13157-90-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 72h;
89%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 4h;
80%	Stage #1: quercetol; benzyl bromide With potassium carbonate In N,N-dimethyl-formamide at 20 - 70℃; for 15h; Stage #2: With water In N,N-dimethyl-formamide at 20℃; for 1h;	1 To a solution of quercetin [9] (5 g) in dimethylformamide (30 ml) was added potassium carbonate (34.3 gm) followed by drop wise addition of benzyl bromide (23.7 ml) at room temperature. The reaction mixture was heated at 70 °C for 15 hours and then cooled to room temperature, to which was added water (60 ml) and the stirring was continued for an additional hour. The precipitated solid was filtered, washed five times with water and twice with ethyl acetate to give 10 g (80%) of desired product [11].Analytical Data: t ESIMS: 753 (M++l)

80%	With potassium carbonate In N,N-dimethyl-formamide at 20 - 70℃; for 15h;	1 Synthesis of Pentabenzylated Quercetin Example 1 Synthesis of Pentabenzylated Quercetin To a solution of quercetin [9] (5 g) in dimethylformamide (30 ml) was added potassium carbonate (34.3 gm) followed by drop wise addition of benzyl bromide (23.7 ml) at room temperature. The reaction mixture was heated at 70° C. for 15 hours and then cooled to room temperature, to which was added water (60 ml) and the stirring was continued for an additional hour. The precipitated solid was filtered, washed five times with water and twice with ethyl acetate to give 10 g (80%) of desired product [11]. Analytical Data: ESIMS: 753 (M++1)
60%	With tetraethylammonium fluoride In N,N,N,N,N,N-hexamethylphosphoric triamide for 48h;
	With potassium carbonate In N,N-dimethyl-formamide
	With potassium carbonate In N,N-dimethyl-formamide at 80℃;

Reference： [1]Villaume, Sydney A.; Fu, Jian; N'Go, Inès; Liang, Hui; Lou, Huayong; Kremer, Laurent; Pan, Weidong; Vincent, Stéphane P. [Chemistry - A European Journal, 2017, vol. 23, # 43, p. 10423 - 10429]
[2]Caldwell, Stuart T.; Crozier, Alan; Hartley, Richard C. [Tetrahedron, 2000, vol. 56, # 24, p. 4101 - 4106]
[3]Current Patent Assignee: EPIRIUM BIO - WO2012/101652, 2012, A2 Location in patent: Page/Page column 29-30
[4]Current Patent Assignee: EPIRIUM BIO - US2014/31421, 2014, A1 Location in patent: Paragraph 0034; 0142; 0143; 0144; 0145
[5]Picq, M.; Prigent, A. F.; Chabannes, B.; Pacheco, H.; Parent, P.; Pichat, L. [Tetrahedron Letters, 1984, vol. 25, # 21, p. 2227 - 2230]
[6]Bouktaib, Mohamed; Lebrun, Stéphane; Atmani, Aziz; Rolando, Christian [Tetrahedron, 2002, vol. 58, # 50, p. 10001 - 10009]
[7]Current Patent Assignee: KONKUK UNIVERSITY; KYUNG HEE UNIVERSITY - KR2020/46287, 2020, A Location in patent: Paragraph 0097-0099

15
[ 117-39-5 ]
[ 107-30-2 ]
[ 143724-67-8 ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: quercetol With potassium carbonate In acetone at 20℃; for 0.5h; Stage #2: chloromethyl methyl ether In acetone at 20℃;	General procedure for the synthesis of MOM protected group General procedure: A solution of diosmetin, luteolin or quercetin (5 mmol) and anhydrous K2CO3 (45 mmol) in 50 mL acetone was stirred for 30 min at room temperature. Then chloromethyl methyl ether (10-20 mmol) was added dropwise, and the mixture was stirred for another 4-6 h. The reaction mixture was filtered and solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography respectively.
78%	Stage #1: quercetol; chloromethyl methyl ether With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 2h; Stage #2: With hydrogenchloride In methanol; N,N-dimethyl-formamide at 0℃; for 3h;
55%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 15h; Inert atmosphere;

38%	With potassium carbonate In acetone for 2h; Ambient temperature;
	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 15h; Inert atmosphere;	General procedure for protection of flavonoid by MOM (61) To a solution of flavonoid (1.0 equiv) in DCM, N,N'-diisopropylethylamine (8.0 equiv) and MOM chloride (3.5 equiv) was added under nitrogen. After vigorous stirring at 0 °C for 1 h, the reaction mixture was allowed to warm to room temperature over 2 h and the stirring was maintained for 12 h. The resulting mixture was diluted with water (100 mL), extracted with EtOAC (200 mL), and then the organic layer was washed with water (100 mL) and dried over Na2SO4. The residue obtained after removal of the solvent was purified by flash column chromatography.

Reference： [1]Li, Wei; Shu, Liang; Liu, Kexiong; Wang, Qiuan [Tetrahedron Letters, 2019, vol. 60, # 41]
[2]Sun, Hua; Li, Yashan; Zhang, Xiaoting; Lei, Yanan; Ding, Weina; Zhao, Xue; Wang, Haomeng; Song, Xiaotong; Yao, Qingwei; Zhang, Yongmin; Ma, Ying; Wang, Runling; Zhu, Tao; Yu, Peng [Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 20, p. 4567 - 4571]
[3]Afosah, Daniel K.; Al-Horani, Rami A.; Sankaranarayanan, Nehru Viji; Desai, Umesh R. [Journal of Medicinal Chemistry, 2017, vol. 60, # 2, p. 641 - 657]
[4]Fukai, Toshio; Nomura, Taro [Heterocycles, 1992, vol. 34, # 6, p. 1213 - 1225]
[5]Al-Horani, Rami A.; Karuturi, Rajesh; White, Domonique T.; Desai, Umesh R. [Molecules, 2015, vol. 20, # 1, p. 608 - 624]

16
[ 215257-15-1 ]
[ 117-39-5 ]

Yield	Reaction Conditions	Operation in experiment
50%	With potassium metabisulphite In ethanol at 100℃;	(d) Flavonols 6, 6a, 6b, 6c and 6d General procedure: Dihydroflavonols (5, 0.3 mmol) in ethanol (2.5 ml) was added to potassium metabisulphite, (5.0 ml, 20%) and heated at 100 °C (5-8 h). The reaction mixture is poured into crushed ice. The centrifuged product was purified by column (SiO2) chromatography. The purity of final products were analyzed by HPLC and NMR (Supplementary data).
	With pyridine; air for 20h; Heating;
	With FLAVONOL SYNTHASE Enzymatic reaction;

Reference： [1]Location in patent: experimental part Pandurangan; Bose, Chinchu; Banerji [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5328 - 5330]
[2]Zanarotti, Antonio [Heterocycles, 1982, vol. 19, # 9, p. 1585 - 1586]
[3]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2022/45091, 2022, A1 Location in patent: Paragraph 0092

17
[ 522-12-3 ]
[ 117-39-5 ]

Yield	Reaction Conditions	Operation in experiment
		The water phases were dried and then desalted by SPE (Oasis HLB 30 mg). Methanol SPE eluates,containing deacylated flavonoids, were dried and subjected to acid hydrolysis (1 mL of 2M HCl, 2 h,100 C). Aglycones were then extracted with ethyl acetate (3 × 1 mL), dried with a stream of nitrogen,dissolved in 50% methanol, and identified by UPLC-ESI-MS. Chromatographic separations wereperformed on a ACQUITY BEH C18 (100 × 2.1 mm, 1.7 mum; Waters) column (40 C). The mobile phases were water with 0.1% FA (A) and in acetonitrile with 0.1% FA (B). Samples were separated (400 muL·min-1) with the following gradient: 0-1 min, 15% B; 1-11 min, 15%-95% B; 11-13 min, 95%B; 13-13.1 min, 95%-15% B; 13.1-15 min, 15% B. Mass spectra were obtained in negative ionization mode, MS parameters were as follows: capillary voltage 2.8 kV; cone voltage 45 V; source temperature 140 C, desolvation temperature 350 C, cone gas flow (nitrogen) 100 L·h-1 desolvation gas flow 800 L·h-1.Sugar-containing aqueous layers were neutralized with Amberlite IRA-400 (OH- form) [33]. After drying, the samples were used to determine the absolute configuration of the constituent monosaccharides.

Reference： [1]Chemical and pharmaceutical bulletin,1988,vol. 36,p. 1180 - 1184
[2]Biological and Pharmaceutical Bulletin,2003,vol. 26,p. 1042 - 1044
[3]Molecules,2014,vol. 19,p. 18152 - 18178
[4]RSC Advances,2016,vol. 6,p. 84616 - 84626

18
[ 522-12-3 ]
[ 6014-42-2 ]
[ 117-39-5 ]

Reference： [1]Phytochemistry,1985,vol. 24,p. 347 - 350
[2]Phytochemistry,1985,vol. 24,p. 371 - 372

19
[ 153-18-4 ]
[ 117-39-5 ]

Yield	Reaction Conditions	Operation in experiment
96%	With hydrogenchloride; methanol for 3h; Heating;
95.6%	With sulfuric acid In lithium hydroxide monohydrate at 100℃; for 3h;	2.5.2. Quercetin (2) A solution of the rutin (15 g, 24.57 mmol) in 6% H2SO4 /H2O (v/v,500 mL) and the reaction mixture was heated at 100 °C for 3 h. At the end of the reaction period, the solution was cooled and the precipitated solid was filtration and collection. The residue was dissolved in ethanol (40 mL) and reflux for 1 h. The reaction solution was cooled and poured into ice water (200 mL). A solid was precipitated, filtration, collection and dried. Quercetin was obtained as a light green solid (7.1 g, 95.6%). 1H NMR (400 MHz, (CD3)2SO) δ 12.46 (s, 1H), 7.64 (d, J = 2.1 Hz, 1H), 7.52 (dd, J = 8.5, 2.1 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 6.40 (d, J = 2.0Hz, 1H), 6.17 (d, J = 2.0 Hz, 1H). 13C NMR (100 MHz, (CD3)2SO) δ 176.3, 164.3, 161.1, 156.6, 148.1, 147.3, 145.5, 136.2, 122.4, 120.5,116.1, 115.5, 103.5, 98.7, 93.8.
95.6%	With sulfuric acid In lithium hydroxide monohydrate at 100℃; for 3h;	2.5.2. Quercetin (2) A solution of the rutin (15 g, 24.57 mmol) in 6% H2SO4 /H2O (v/v,500 mL) and the reaction mixture was heated at 100 °C for 3 h. At the end of the reaction period, the solution was cooled and the precipitated solid was filtration and collection. The residue was dissolved in ethanol (40 mL) and reflux for 1 h. The reaction solution was cooled and poured into ice water (200 mL). A solid was precipitated, filtration, collection and dried. Quercetin was obtained as a light green solid (7.1 g, 95.6%). 1H NMR (400 MHz, (CD3)2SO) δ 12.46 (s, 1H), 7.64 (d, J = 2.1 Hz, 1H), 7.52 (dd, J = 8.5, 2.1 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 6.40 (d, J = 2.0Hz, 1H), 6.17 (d, J = 2.0 Hz, 1H). 13C NMR (100 MHz, (CD3)2SO) δ 176.3, 164.3, 161.1, 156.6, 148.1, 147.3, 145.5, 136.2, 122.4, 120.5,116.1, 115.5, 103.5, 98.7, 93.8.

90%	With lithium hydroxide monohydrate at 100℃; Ionic liquid;
89%	With sulfuric acid; lithium hydroxide monohydrate at 20℃; for 0.166667h;	Typical hydrolysis procedure General procedure: Sulfuric acid (2.0mL, 0.037mmol) was added dropwise to a beaker (100 mL) containing scutellarin (50 mg, 0.11 mmol). It was shaken or agitated by ultrasound agitated to dissolve the substrate in the acid at room temperature. Water (2.0 mL) was then added carefully dropwise. When the evolution of heat ceased (in 10 minutes), the mixture was added to water (15 mL) in one portion with stirring with a glass rod. The yellow crystals that were deposited were collected by suction filtration and washed by water (5 mL). In most cases, such products were pure enough for direct use. Moreover, it could be further purified by recrystallisation from aqueous methanol (70%, v/v) or column chromatography on silica gel (eluent:ethyl acetate/formic acid/water=100/4/3, v/v/v, Rfs of SCU and SCUE were 0.1 and 0.8 on silica gel GF254 respectively). Light yellow crystals were obtained after recrystallisation (28.5mg, 93% yield); m.p. 285-287°C (>300°C)27. IR (KBr, cm-1): νmax 3442, 3331, 3098, 1671, 1619, 1587, 1509. 1H NMR (500MHz, DMSO-d6): δ 12.80 (s, 1H, 5-OH), 10.48 (s, 1H, 7-OH), 10.33 (s, 1H, 4′-OH), 8.75 (s, 1H, 6-OH), 7.92 (d, 2H, J=8.6Hz, C2′, C6′-H), 6.92 (d, 2H, J=8.6Hz, C3′, C5′-H), 6.75 (s, 1H, C3-H), 6.58 (s, 1H, C8-H). HR-ESI-MS (m/z): 309.0363 for [M+Na]+, calcd 309.0370.
6.788%	With sulfuric acid Reflux;	1.3 Embodiment 1 3, was prepared from the resulting quercetin rutin Take half of the above step retained rutin filtrate was added 1mol / L sulfuric acid, in a water bath at reflux for 1 ~ 1.5h, until total hydrolysis of steam to ethanol, cooled, the precipitated quercetin, filtration.Quercetin precipitate after washing, after drained, dried, and weighed to give quercetin 6.788g, calculate the yield of 6.788%, and then recrystallized from ethanol to give yellow needles, quercetin boutique.
	With hydrogenchloride In hydrogenchloride for 1h; Heating;
	With phosphate buffer; β-glucosidase from rat small intestinal mucosa of duodenum; phenylmethylsulphonyl fluoride; 2-hydroxyethanethiol In lithium hydroxide monohydrate at 37℃; for 0.333333h; rate of hydrolysis in mol/hr/mg protein; other proteins;
	With sulfuric acid for 2h;
	With hydrogenchloride; ethanol for 4h; Heating;
	With hydrogenchloride In ethanol; lithium hydroxide monohydrate for 2h; Reflux;
	With rutin hydrolyzing enzyme from fagopyrum tataricum In ethanol; lithium hydroxide monohydrate at 37℃; for 0.25h;
	With formic acid; α-L-rhamnosyl-β-D-glucosidase from Aspergillus niger K2 in Pichia pastoris In methanol; lithium hydroxide monohydrate; acetonitrile at 25℃; for 0.5h;
	With hydrogenchloride In lithium hydroxide monohydrate at 39.84 - 59.84℃; for 6h;	Forced studies of rutin For the determination of concentration changes of rutin in the presence of its impurities and degradation products (quercetin and isoquercetin) as a result of factors affecting action, changes in the absorption spectra of rutin were examined. The degradation of rutin was studied in aqueous solutions: in hydrochloric acid (pH = 0.3) at 333 K up to 360 min, sodium hydroxide (pH = 13.3) at 313 K up to 15 min and in hydrogen peroxide (10%) at 353 K up to 200 min. Samples were prepared by dissolving an accurately weighed 5.0 mg of rutin in 25.0 mL of the equilibrated solution to 313 K in glass stoppered flasks. At specified times, samples of the reaction solutions (1.0 mL) were collected and instantly cooled with a mixture of ice and water, neutralized with 0.8 ml of NaOH or HCl solutions of suitable concentrations and assayed. The ionic strength of all solutions was adjusted to 0.5 mol/L with a solution of sodium chloride (4 mol/L).
	With hydrogenchloride In lithium hydroxide monohydrate for 0.5h; Reflux;
	With hydrogenchloride; potassium carbonate In lithium hydroxide monohydrate at 70℃; for 3h;	7 Preparation of 2-(3,4-dimethoxyphenyl)-3,5,7-trimethoxy-4H-benzopyran-4-one A clean and dry 500 mL round bottom flask was taken, and the analytical balance was weighed into rutin (6 g, 9.828 mmoL) and K2CO3 (20 g, 144.8 mmoL).Add 10% HCl solution to dissolve,Then a small amount of ethanol can be added to the inner wall of the flask.Dissolve the solid on the inner wall.After processing,Heated to 70 ° C for 3 h,hydrolysis,Getting a flocculent solid,Filtering,Get a rough product.
	With lithium hydroxide monohydrate at 50℃; for 1h; Irradiation; Green chemistry; Enzymatic reaction;
	With rutinosidase from Aspergillus niger K₂; lithium hydroxide monohydrate In dimethyl sulfoxide Enzymatic reaction;
	With Prunus dulcis beta-glucosidase at 59.84℃; Enzymatic reaction;
	With trifluoroacetic acid at 100℃; for 0.5h;

Reference： [1]Matsuda, Hisashi; Morikawa, Toshio; Toguchida, Iwao; Yoshikawa, Masayuki [Chemical and Pharmaceutical Bulletin, 2002, vol. 50, # 6, p. 788 - 795]
[2]Zhang, Yinan; Zhang, Xiaoting; Xiao, Zhiyi; Zhang, Xinying; Sun, Hua [Fitoterapia, 2022, vol. 156]
[3]Zhang, Yinan; Zhang, Xiaoting; Xiao, Zhiyi; Zhang, Xinying; Sun, Hua [Fitoterapia, 2022, vol. 156]
[4]Yang, Chang; Zeng, Hao; Song, Hang; Yao, Shun; Ma, Hongyan [Asian Journal of Chemistry, 2013, vol. 25, # 13, p. 7327 - 7331]
[5]Zhang, Wei; Yi, Dong; Gao, Kai; Liu, Manshuo; Yang, Jian; Liao, Xiali; Yang, Bo [Journal of Chemical Research, 2014, vol. 38, # 7, p. 396 - 398]
[6]Current Patent Assignee: Zhang, Tingting - CN105541776, 2016, A Location in patent: Paragraph 0016; 0021; 0022; 0023; 0024; 0025-0041
[7]Hasan, Aurangzeb; Ahmed, Iftikar; Jay, Maurice; Voirin, Bernard [Phytochemistry, 1995, vol. 39, # 5, p. 1211 - 1214]
[8]Ioku, Kana; Pongpiriyadacha, Yutana; Konishi, Yotaro; Takei, Yoko; Nakatani, Nobuji; Terao, Junji [Bioscience, Biotechnology and Biochemistry, 1998, vol. 62, # 7, p. 1428 - 1431]
[9]Rizk; Al-Nagdy; El-Missiry [Pharmazie, 1982, vol. 37, # 10, p. 737 - 738]
[10]Bondarenko, O. M.; Chagovets, R. K.; Soboleva, V. A. [Chemistry of Natural Compounds, 1983, vol. 19, # 5, p. 613 - 614][Khimiya Prirodnykh Soedinenii, 1983, # 5, p. 647]
[11]Location in patent: experimental part Anam, Edet M. [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2009, vol. 48, # 3, p. 423 - 429]
[12]Location in patent: experimental part Cui, Xiao-Dong; Wang, Zhuan-Hua [Food Chemistry, 2012, vol. 132, # 1, p. 60 - 66]
[13]imkov, Daniela; Kotik, Michael; Weignerov, Lenka; Halada, Petr; Pelantov, Helena; Adamcov, Kateina; Ken, Vladimr [Advanced Synthesis and Catalysis, 2015, vol. 357, # 1, p. 107 - 117]
[14]Paczkowska, Magdalena; Lewandowska, Kornelia; Bednarski, Waldemar; Mizera, Mikołaj; Podborska, Agnieszka; Krause, Anna; Cielecka-Piontek, Judyta [Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 2015, vol. 140, p. 132 - 139]
[15]Oliveira, Andreia P.; Sá, Ivone; Pereira, David M.; Gonçalves, Rui F.; Andrade, Paula B.; Valentão, Patrícia [Chemistry and biodiversity, 2017, vol. 14, # 6]
[16]Current Patent Assignee: TIANJIN UNIVERSITY OF SCIENCE AND TECHNOLOGY - CN108276374, 2018, A Location in patent: Paragraph 0040
[17]Zang, Yuan-Yuan; Yang, Xi; Chen, Zhi-Gang; Wu, Tao [Process Biochemistry, 2020, vol. 89, p. 193 - 198]
[18]Pachl, Petr; Kapešová, Jana; Brynda, Jiří; Biedermannová, Lada; Pelantová, Helena; Bojarová, Pavla; Křen, Vladimír; Řezáčová, Pavlína; Kotik, Michael [FEBS Journal, 2020, vol. 287, # 15, p. 3315 - 3327]
[19]Adhikari, Aniruddha; Biswas, Pritam; Choudhury, Sudeshna Shyam; Das, Monojit; Das, Ranjan; Pal, Samir Kumar; Pal, Uttam; Saha-Dasgupta, Tanusri; Singh, Priya [Soft Matter, 2020, vol. 16, # 12, p. 3050 - 3062]
[20]Daowtak, Krai; Khonkarn, Ruttiros; Mueller, Monika; Naksuriya, Ornchuma; Okonogi, Siriporn; Tima, Singkome; Toegel, Stefan [Molecules, 2022, vol. 27, # 10]

20
[ 522-12-3 ]
[ 73-34-7 ]
[ 117-39-5 ]

Reference： [1]Phytochemistry,1995,vol. 39,p. 1211 - 1214

21
[ 117-39-5 ]
6-bromo-2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86.1%	With bromine In 1,4-dioxane at 20 - 22℃; for 2h;
400 mg	Stage #1: quercetol With N-Bromosuccinimide; sodium hydroxide In methanol; water at 20℃; for 0.166667h; Inert atmosphere; Green chemistry; Stage #2: With hydrogenchloride; sodium dithionite In methanol; water at 20℃; Inert atmosphere; Green chemistry;	1 g of NBS in 250 mL of water was treated with 8mL of NaOH 2N undernitrogen. This solution was mixed (under nitrogen) with a solution of quercetin(1 g in 200 mL methanol) yielding a deep green solution (occasionally the colorwas violet) which was allowed to stand for 10 minutes. Then, the solution wastreated with 1.5 g of Na2S2O4in 80 mL of water and successively with excess HCl 2N. The precipitate obtained was filtered andwashed with distilled water, and the filtrate left overnight. A second crop ofprecipitate was filtrated and washed with distilled water. The two cropscollected were combined and purified over Polyamid SC6 (polycaprolactam, byMacherey-Nagel, Germany) with methanol to give 400 mg of 3 (final yield 32%). 1HNMR (acetone-d6): d = 6.70 (s, 1H, H-8),6.95 (d, J = 8.4 Hz, 1H, H-5’), 7.66 (dd, J=2, 8.4 Hz, 1H, H-6’), 7.77 (d, J =2 Hz, 1H, H-2’), 8.21 (OH-3), 8.45 (OH-3’), 8.76 (OH-4’), 10.56 (OH-7), 13.05(OH-5). 13C NMR(acetone-d6): 92.13 (C-6), 93.8 (C-8), 103.46 (C-10), 114.8 (C-2’), 115.22(C-5’), 120.63 (C-6’), 122.3 (C-1’), 135.76 (C-3), 144.81 (C-3’), 146.60 (C-2),147.50 (C-4’), 155.13 (C-5), 157.78 (C-9), 159.99 (C-7), 175.14 (C-4). TheESI-MS spectrum of 3 (methanol)showed - in the negative ion mode - isotopic peaks at m/z 378.9 and at 380.9 ina 1:1 ratio corresponding to [M-H]- with 1 bromine atom. Also, thedimer with isotopic peaks at m/z 759.0, 761.0 and 763.1 (ratio 1:2:1) waspresent.
	Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 12 h / 60 °C / Inert atmosphere 2: N-Bromosuccinimide / dichloromethane / -40 °C / Inert atmosphere 3: boron trichloride / dichloromethane; hexane / 2.5 h / -20 °C / Inert atmosphere; Reflux

With bromine In 1,4-dioxane at 24.84℃;

The synthesis of bromine derivative of querce-tin was carried out by the simple method described in the literature (Nagimova etal. 1996): 1g of quercetin was bro-minated in dioxane at 298K without stirring (Scheme1). The precipitated orange crystals were washed with water and crystallized three times from ethanol. The test by paper chromatography demonstrates the absence of initial querce-tin in the final products.The characteristic IR absorption bands for identification of obtained compound are given in Supplementary Material (TableS1).

Reference： [1]Nagimova; Zbusupova; Erzhanova [Chemistry of Natural Compounds, 1996, vol. 32, # 5, p. 695 - 697]
[2]Foti, Mario C.; Rocco, Concetta [Tetrahedron Letters, 2014, vol. 55, # 9, p. 1602 - 1607]
[3]Pan, Guojun; Yang, Ke; Ma, Yantao; Zhao, Xia; Lu, Kui; Yu, Peng [Bulletin of the Korean Chemical Society, 2015, vol. 36, # 5, p. 1460 - 1466]
[4]Lutoshkin, Maxim A.; Levdanskiy, Vladimir A.; Baryshnikov, Sergey V.; Kuznetsov, Boris N. [Chemical Papers, 2019, vol. 73, # 7, p. 1731 - 1741]

22
[ 7647-01-0 ]
[ 117-39-5 ]
magnesium [ No CAS ]
[ 528-58-5 ]

Reference： [1]Journal of the American Chemical Society,1930,vol. 52,p. 2864,2868

23
[ 2051-90-3 ]
[ 117-39-5 ]
[ 357194-03-7 ]

Yield	Reaction Conditions	Operation in experiment
89%	In diphenylether at 175℃; for 2h;
89%	In diphenylether at 175℃; for 2h;
86%	In diphenylether at 175℃; for 0.5h; Inert atmosphere; regioselective reaction;

86%	In diphenylether at 175℃; for 0.5h; Inert atmosphere;	3.1.4. 2-(2,2-Diphenylbenzo[d][1,3]dioxol-5-yl)-3,5,7-trihydroxy-4H-chromen-4-one (9) To a stirring mixture of quercetin (1) (302 mg, 1 mmol) in diphenyl ether (20 ml) was added dichlorodiphenylmethane (0.30 ml, 1.5 mmol, 1.5 equiv.), and the reaction mixture was heated at 175 °C for 30 min. The mixture was cooled to room temperature and the solid compound was obtained as the petroleum ether (50 ml) was added, then the solid was filtered, purified by column chromatography (25% ethyl acetate in petroleum ether) to yield 9 (400 mg, 86%) as a yellow solid [16]. Mp 218-219 °C (lit. [16] 222-224 °C). 1H NMR (DMSO-d6, 300 MHz) δ: 6.20 (d, J = 2.0 Hz, 1H, 6-H), 6.47 (d, J = 2.0 Hz, 1H, 8-H), 7.22 (d, J = 8.8 Hz, 1H, 5'-H), 7.46 (m, 6H, aromatic H), 7.58 (m, 4H, aromatic H), 7.79 (dd, J = 1.8, 8.8 Hz, 1H, 6'-H), 7.82 (d, J = 1.8 Hz, 1H, 2'-H), 9.61 (s, 1H, 3-OH), 10.81 (s, 1H, 7-OH), 12.37 (s, 1H, 5-OH). ESI-MS m/z: 467 [M + H]+, 489 [M + Na]+.
86%	In diphenylether at 175℃;
86%	In diphenylether at 180℃; for 0.5h;
86%	In diphenylether at 175℃; for 0.5h;	2 Compound 5: Quercetin 1 (302 mg, 1.00 mmol) was dissolved in 20 mL of diphenyl ether,L, 1.50 mmol). The reaction was stirred at 175°C for 0.5 h.The TLC test material disappeared. After the reaction solution was cooled to room temperature, a dark red solid precipitated out after adding 50 mL of petroleum ether. The crude product was filtered and the crude product was subjected to column chromatography (PE:EtOAc=4:1) to give Compound 5 in a yield of 86%
86%	In diphenylether at 170 - 180℃; for 0.5h;	1 Preparation of compound A-1: Diphenyl ether 30 mL (Tokyo Chemical Industry Co., Ltd.)In the quercetin 1.0 g (3.48 mmol, Sigma Aldrich Co., Ltd.) dissolved,Dichlorodiphenylmethane 1.38 mL (6.96 mmol, Alpha Eisa)After adding, acetalize quercetin by reacting for 30 minutes at a temperature of 170-180 °C while stirring,It was cooled to room temperature. Then, 200 ml of petroleum ether was added to precipitate a solid and the solvent was removed.The solid was purified by column chromatography (a mixed solution of n-hexane and ethyl acetate (4:1 by volume) was used) to obtain compound A-1 (Yield: 86%).
78%	In Diphenylmethane at 180℃; for 1h;	General method for Synthesis of 2-(2,2-diphenylbenzo[1,3]dioxol-5-yl)-3,5,7-trihydroxy-4H -chromen-4-one (Qr-1) Quercetin (1.66 mmol) and 1,1-dichlorodiphenylmethane (2.50 mmol) were dissolved in diphenyl ether (20 mL). The mixture was warmed at 180 °C with stirring to react for 1 h. After the reaction, the mixture was cooled to room temperature, petroleum ether (50 mL) was added, and the yellow crude product was obtained by filtration. Ethyl acetate/petroleum ether (v:v, 1:5) was selected as the eluent, and a yellow solid QR-1 was obtained by pressure column chromatography; yield 78.0%; m.p. 221.3-222.2 °C (lit.22 230-232 °C).
71%	In diphenylether at 180℃; for 3h;	3′,4′-O-Diphenylmethane quercetin: This synthesis followed the procedure of Li et al. (40). 6.15 g (18.2 mmol) of quercetin hydrate was dried at 110° C. under high vacuum for 1 hour. 250 mL of diphenyl ether was then added, along with 5.4 mL (27.3 mmol) of Ph2CCl2. The mixture was heated to 180° C. and stirred for 3 hours. The material was precipitated by adding 800 mL of pet ether, then filtered and purified by silica gel chromatography with 5% EtOAc/toluene. The material was further purified by recrystallization in chloroform. 6.02 g (12.91 mmol) of 3′,4′-O-diphenylmethane quercetin was isolated as a yellow powder (71% yield). 1H NMR (300 MHz, CDCl3; δ 12.10 (s, 1H), 9.70 (br, 1H), 8.22 (br, 1H), 7.34 (m, 12H), 6.96 (d, J=6.9 Hz, 1H), 6.33 (d, J=1.8 Hz, 1H), 6.26 (d, J=1.7 Hz, 1H); 13C NMR (150 MHz, acetone-d6) δ 176.6, 165.0, 162.3, 157.7, 149.3, 148.2, 145.9, 140.8, 137.1, 130.2, 129.3, 126.9, 126.2, 123.9, 118.4, 109.5, 108.7, 104.1, 99.1, 94.5; ESI-MS: m/z: 467 [M+H]+
68%	In diphenylether at 180℃; for 0.5h;
68%	In diphenylether at 175℃; for 24h;	2-(20,20-Diphenylbenzo[d][10,30]dioxol-5-yl)-3,5,7-trihydroxy-4H-chromen-4-one (2): To a stirredsolution of quercetin 1 (3.0 g, 9.93 mmol) in diphenylether (60 mL) at 60 C was addeddichlorodiphenylmethane (2.85 mL, 14.89 mmol). The reaction mixture was then stirredat 175 C for 24 h. The mixture was cooled to r.t. and petroleum ether (50 mL) wasadded to precipitate the crude product. The precipitate was filtered and further washedwith petroleum ether (60 mL). The crude solid was dissolved in EtOAc and the solventremoved in vacuo. The resulting crude product was purified by flash chromatography (4:1Petroleum ether:EtOAc) to give the title compound 2 (3.13 g, 68%) as a yellow solid. Rf: 0.30(4:1 Petroleum ether:EtOAc). M.P.: 240-242 C (literature 218-219 C) [17]. H (400 MHz;d6-DMSO): 6.20 (1H, d, J = 2.0 Hz, 6-H), 6.47 (1H, d, J = 2.0 Hz, 8-H), 7.22 (1H, d, J = 8.3 Hz,70-H), 7.43-7.49 (6H, m, Ar-H), 7.55-7.58 (4H, m, Ar-H), 7.80-7.83 (2H, m, 40-H and 60-H),9.63 (1H, s, 3-OH), 10.82 (1H, s, 7-OH), 12.38 (1H, s, 5-OH). C (100 MHz; d6-DMSO): 93.6(C-8), 98.3 (C-6), 103.1 (C-4a), 107.8 (C-40), 108.8 (C-70), 117.0 (C-20), 123.0 (C-60), 125.2 (C-50),125.8 (C-200), 128.6, 129.5 (C-300 and C-400), 136.4 (C-3), 139.4 (C-100), 145.6 (C-2), 146.7 (C-30a),147.6 (C-70a), 156.2 (C-8a), 160.7 (C-5), 164.1 (C-7), 176.0 (C-4). IR: max/cm1; 696, 730,747, 757, 775, 817, 827, 850, 871, 906, 951, 987, 1003, 1019, 1044, 1093, 1122, 1155, 1190, 1209,1237, 1256, 1316, 1347, 1389, 1439, 1487, 1522, 1566, 1596, 1614, 1631, 1653, 2586, 3064, 3334.HRMS (ESI+): Found (MNa+) 489.0929, C28H18NaO7 requires 489.0945. The 1H NMR values are in agreement with literature [17].
66%	In diphenylether at 175℃; for 0.5h;	3',4'-O-Diphenylmethane Quercetin (2) compound 1(302 mg, 1 mmol, 1 equiv) and dichlorodiphenylmethane(0.3 mL, 1.5 mmol, 1.5 equiv) in diphenyl ether (15 mL)were mixed and heated at 175 °C for 30 min. The residuewas cooled to room temperature and petroleum ether (30mL) was added to give a solid compound. Then solid wascollected by filteration and purified by a silica gel columnchromatography using petroleum ether/ethyl acetate (4:1) aseluent to afford a yellow solid 2. Yield = 66% (306 mg). Rf (petroleum ether/ethyl acetate 4:1) 0.50. mp 219-220 °C(lit.21 222-224 °C). 1H NMR (400 MHz, DMSO-d6) 12.35(s, 1H), 10.79 (s, 1H), 9.60 (s, 1H), 7.81 (d, J = 1.8 Hz, 1H),7.77 (dd, J = 8.8, 1.8 Hz, 1H), 7.58 (m, 4H), 7.46 (m, 6H),7.23 (d, J = 8.8 Hz, 1H), 6.47 (d, J = 2.0 Hz, 1H), 6.21 (d, J= 2.0 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) 178.2,164.5, 161.4, 156.6, 155.4, 148.7, 146.8, 139.4, 137.4,129.8, 128.8, 126.0, 124.3, 124.2, 117.5, 109.1, 108.8,104.5, 98.9, 94.1. Anal. calcd. for C28H18O7: C, 72.10; H,3.89; O, 24.01; Found: C, 72.12; H, 3.88; O, 24.00.
62%	In diethyl ether at 175℃; for 6h;
56%	In diethylene glycol dimethyl ether for 2h; Reflux; Inert atmosphere;	Synthesis of 2-(2,2-diphenylbenzo[1,3]dioxol-5-yl)-3,5,7-trihydroxy-4H-chromen-4-one (7) Quercetin (2.0 g, 6.6 mmol) and 1,1-dichlorodiphenylmethane (2.0 mL,10.4 mmol) were dissolved in bis(2-methoxyethyl) ether (20 mL). Themixture was warmed to reflux under an atmosphere of nitrogen for2 h. The reaction solution was concentrated in vacuo to give a yellowsolid which was purified on silica gel eluting with hexane/EtOAc toafford 7 as a yellow solid; yield 1.73 g (56%); m.p. 230-232 °C (lit.17222-224 °C); 1H NMR (300 MHz, CDCl3): δ 11.77 (s, 1H, 5OH),7.83-7.75 (m, 2H, H6′, H2′), 7.66-7.52 (m, 4H, Ph), 7.47-7.32 (m, 6H,Ph), 7.02 (d, J = 8.2 Hz, 1H, H5′), 6.43 (d, J = 2.1 Hz, 1H, H8), 6.29 (d,J = 2.1 Hz, 1H, H6).
40%	at 170℃;	1.1 (Example 1-1) Synthesis of intermediate 2 for glucose derivative () 2-(2,2-Diphenylbenzo[d][1,3]dioxol-5-yl)-3,5,7-trihydroxy-4H-c hromen-4-one (2) A mixture of a compound 1 (quercetin, 1 g, 3 mmol) and Ph2CCl2 (1.7 mL, 8.9 mmol) was stirred at 170°C for 7 to 8 minutes, and an oily composition was dissolved in AcOEt (3 ml) in as small an amount as possible. Further, the solution was added to n-hexane (20 mL), and a gray solid precipitated was separated by filtration. The resultant gray solid was subjected to silica gel flash column chromatography, and a yellow solid 2 (0.62 g, 40%) was obtained from a fraction eluted with AcOEt:n-hexane (1:4, v/v). Melting point (m.p.) 238-239°C (lit. 239-240°C). Rf=0.15 (AcOEt:n-hexane (1:4, v/v)). IR (KBr) cm-1; 1600 (C=C), 1638 (C=O). 1HNMR (DMSO-d6, 300 MHz) δ 6.20 (d, 4J=1.8 Hz, 1H, 8-H), 6.46 (d, 4J=1.8 Hz, 1H, 6-H), 7.21 (d, J=8.1 Hz, 1H, 3'-H), 7.44-7.50 (m, 6H, Ar-H), 7.54-7.59 (m, 4H, Ar-H), 7.59-7.82 (m, 2H, 7.79-7.82 (m, 2H, 2'-H, 6'-H), 9.63 [s, 1H, 3-OH (exchangeable with D2O)], 10.81 [s, 1H, 7-OH (exchangeable with D2O)], 12.37 [s, 1H, 5-OH (exchangeable with D2O)].
39%	at 180℃; for 0.166667h;	4.2.1. 2-(2,2-Diphenylbenzo[1,3]dioxol-5-yl)-3,5,7-trihydroxy-4H-chromen-4-one 2 A mixture of quercetin 1 (3.00 g, 8.87 mmol) and dichlorodiphenylmethane (4.3 ml, 22.5 mmol) was intimately mixed, and then heated at 180 °C for 10 min. The crude reaction mixture was then purified by flash column chromatography using CH2Cl2/EtOAc (85:15) as eluent and was recrystallized from CHCl3 to afford 2 (1.62 g, 39% yield). Mp 222-224 °C (lit.21 218-219 °C; lit.18 222-224 °C). 1H NMR (DMSO-d6): 6.20 (d, J=1.9 Hz, 1H), 6.47 (d, J=1.9 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 7.44-7.58 (m, 10H), 7.79 (dd, J=8.3, 1.6 Hz, 1H), 7.81 (d, J=1.6 Hz, 1H). 13C NMR (DMSO-d6): 93.6, 98.3, 103.1, 107.8, 108.8, 117.0, 123.0, 125.2, 125.7, 128.6, 129.5, 136.4, 139.4, 145.5, 146.7, 147.6, 156.2, 160.7, 164.2, 177.8. Elemental analysis: calculated for C28H18O7 C, 72.10; H, 3.89; O, 24.09. Observed C, 71.83; H, 3.74; O, 23.89.
38%	In diphenylether at 180℃; for 0.333333h;	5.1.62 2-(2,2-Diphenylbenzo[d][1,3]dioxol-5-yl)-3,5,7-trihydroxy-4H-chromen-4-one (30) A mixture of 1 (2g, 6.57mmol) and dichlorodiphenylmethane (2mL, 10.42mmol) in 5mL diphenyl ether was heated at 180°C for 20min. The reaction mixture was washed by ether and diluted with hot acetone. Then, the filtrate was purified by flash column chromatography using petroleum ether/ EtOAc (6:1 to 1:1) as eluent to give 30 (1.25g, 38% yield) as a yellow solid. 1H NMR (300MHz, d6-DMSO): δ 7.86-7.79 (m, 2H), 7.67-7.53 (m, 4H), 7.53-7.42 (m, 6H), 7.24 (d, J=8.7Hz, 1H), 6.59 (d, J=2.1Hz, 1H), 6.21 (s, 1H).
37%	at 180℃; for 0.166667h;
37%	at 180℃; for 0.166667h;	1.1 A mixture of quercetin IXa (5 g, 15 mraol) and PI12CCI2 (8.5 mL, 45 mmol) in a 50 mL round bottom flask was stirred at 180 0C for 10 min. The reaction mixture was purified by flash chromatography on silica gel and eluted with a mixture of EtOAc/petroleum ether (1:4, v/v) to afford IXb (2.5 g, 37 %) as a yellow solid: Mp 239-240 0C, 1H-NMR (DMSO-d6) δ: 6.22 (IH, d) , 6.50 (IH, d) , 7.26 (IH, d) , 7.44-7.60 (1OH, m) , 7.80-7.83 (2H, m) .
35%	at 180℃; for 0.5h;
35%	at 180℃; for 0.5h;
35%	at 180℃; for 0.5h;	4.2.4 2-(2,2-Diphenyl-benzo[1,3]dioxol-5-yl)-3,5,7-trihydroxy-chromen-4-one (10) A mixture of quercetin (1) (5 g, 14.8 mmol) and dichlorodiphenylmethane (8.5 mL, 44.3 mmol) was stirred for 30 min at 180 °C. The reaction mixture was taken with CHCl3 and concentrated under reduced pressure. The residue was purified by column chromatography (hexane/EtOAc = 4:1) on silica gel as eluent and was recrystallized from CHCl3 to afford 10 (2.4 g, 5.2 mmol, 35% yield) as yellow powder; mp 222-224 °C (rec. CHCl3) (lit.14 mp 222-224 °C); 1H NMR (400 MHz, acetone-d6) δ (ppm) 12.18 (s, 1H), 7.89-7.92 (m, 2H), 7.63-7.69 (m, 5H), 7.45-7.49 (m, 5H), 7.19 (d, J = 10.5 Hz, 1H), 6.58 (s, 1H), 6.28 (s,1H); 13C NMR (100 MHz, DMSO-d6) δ (ppm) 176.1, 164.2, 160.8, 156.3, 147.7, 146.8, 145.6, 139.5, 136.5, 129.5, 128.7, 125.8, 125.3, 123.1, 117.1, 108.9, 107.9, 101.1, 98.4, 93.7; HR-FABMS (m/z): Found: 467.1135 [M+H]+; Calcd for C28H18O7: 466.1056.
33%	With pyridine at 170℃; for 0.25h;
7%	In diphenylether at 175℃; for 5h;
	at 180℃; for 0.0833333h;
		1; 2; 3; 4; 5; 6 EXAMPLE 1; Synthesis Of Quercetin-3-Curcumin (Compound 8)Preparation of diphenyl ketal aminoαuercetin (compound 3)[0073] Quercetin (compound 1 ) was reacted with Ph2CCI2 to form diphenylketalquercetin (compound 2).
	at 190℃; for 0.25h;
	at 170℃;
	at 170 - 180℃; for 0.166667h;

Reference： [1]Current Patent Assignee: UNIVERSITY OF MONTPELLIER; CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE; ECOLE NATIONALE SUPERIEURE DE CHIMIE DE MONTPELLIER; NATIONAL INSTITUTE OF HEALTH AND MEDICAL RESEARCH - EP3594209, 2020, A1 Location in patent: Paragraph 0114
[2]Moine, Espérance; Boukhallat, Manel; Cia, David; Jacquemot, Nathalie; Guillou, Laurent; Durand, Thierry; Vercauteren, Joseph; Brabet, Philippe; Crauste, Céline [Free Radical Biology and Medicine, 2021, vol. 162, p. 367 - 382]
[3]Location in patent: experimental part Li, Nian-Guang; Tang, Yu-Ping; Yang, Jian-Ping; Duan, Jin-Ao; Shi, Zhi-Hao [Beilstein Journal of Organic Chemistry, 2009, vol. 5]
[4]Location in patent: experimental part Shi, Zhi-Hao; Li, Nian-Guang; Tang, Yu-Ping; Wei-Li; Lian-Yin; Yang, Jian-Ping; Hao-Tang; Duan, Jin-Ao [European Journal of Medicinal Chemistry, 2012, vol. 54, p. 210 - 222]
[5]Shi, Zhi-Hao; Li, Nian-Guang; Tang, Yu-Ping; Shi, Qian-Ping; Tang, Hao; Li, Wei; Zhang, Xu; Fu, Hai-An; Duan, Jin-Ao [Drug Development Research, 2014, vol. 75, # 7, p. 455 - 462]
[6]Jang, Jongyun; Kang, Dong Wook [Journal of the Korean Chemical Society, 2018, vol. 62, # 1, p. 19 - 23]
[7]Current Patent Assignee: NANJING HUITELAI PHARMACEUTICAL - CN104557891, 2017, B Location in patent: Paragraph 0032
[8]Current Patent Assignee: CATHOLIC UNIVERSITY OF DAEGU - KR2021/4643, 2021, A Location in patent: Paragraph 0122-0130
[9]Sun, Lei; Lu, Bo; Liu, Yandan; Wang, Qian; Li, Gao; Zhao, Longxuan; Zhao, Chunhui [Synthetic Communications, 2021, vol. 51, # 19, p. 2944 - 2953]
[10]Current Patent Assignee: UNIVERSITY OF BRITISH COLUMBIA - US2020/79810, 2020, A1 Location in patent: Paragraph 0110
[11]Kim, Mi Kyoung; Choo, Hyunah; Chong, Youhoon [Journal of Medicinal Chemistry, 2014, vol. 57, # 17, p. 7216 - 7233]
[12]Barker, David; Fedrizzi, Bruno; Leung, Euphemia; Lo, Stephen [Molecules, 2021, vol. 26, # 6]
[13]Lu, Chenjuan; Huang, Feng; Li, Zexin; Ma, Jinshuo; Li, Huanhuan; Fang, Lizhen [Bulletin of the Korean Chemical Society, 2014, vol. 35, # 2, p. 518 - 520]
[14]Adamczyk-Grochala, Jagoda; Błoniarz, Dominika; Lewińska, Anna; Litwinienko, Grzegorz; Przybylski, Paweł; Wnuk, Maciej [Cancers, 2022, vol. 14, # 3]
[15]Cao, Zhiling; Chen, Jing; Zhu, Dandan; Yang, Zongnan; Teng, Wenqi; Liu, Gaofeng; Liu, Bing; Tao, Chuanzhou [Journal of Chemical Research, 2018, vol. 42, # 4, p. 189 - 193]
[16]Current Patent Assignee: OKAYAMA UNIVERSITY - EP2460810, 2012, A1 Location in patent: Page/Page column 13
[17]Kajjout, Mohammed; Rolando, Christian [Tetrahedron, 2011, vol. 67, # 25, p. 4731 - 4741]
[18]Li, Bo-Wen; Zhang, Feng-Hua; Serrao, Erik; Chen, Huan; Sanchez, Tino W.; Yang, Liu-Meng; Neamati, Nouri; Zheng, Yong-Tang; Wang, Hui; Long, Ya-Qiu [Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 12, p. 3146 - 3158]
[19]Bouktaib, Mohamed; Lebrun, Stéphane; Atmani, Aziz; Rolando, Christian [Tetrahedron, 2002, vol. 58, # 50, p. 10001 - 10009] Chen, Lili; Li, Jian; Luo, Cheng; Liu, Hong; Xu, Weijun; Chen, Gang; Liew, Oi Wah; Zhu, Weiliang; Puah, Chum Mok; Shen, Xu; Jiang, Hualiang [Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 24, p. 8295 - 8306]
[20]Current Patent Assignee: SINGAPORE POLYTECHNIC; CHINESE ACADEMY OF SCIENCES; Shanghai Institute of Materia Medica (in: CAS) - WO2007/75145, 2007, A1 Location in patent: Page/Page column 31
[21]Location in patent: experimental part Kim, Mi Kyoung; Park, Kwang-Su; Lee, Chaewoon; Park, Hye Ri; Choo, Hyunah; Chong, Youhoon [Journal of Medicinal Chemistry, 2010, vol. 53, # 24, p. 8597 - 8607]
[22]Location in patent: scheme or table Kim, Mi Kyoung; Park, Kwang-Su; Chong, Youhoon [ChemMedChem, 2012, vol. 7, # 2, p. 229 - 232]
[23]Cho, Suh Young; Kim, Mi Kyoung; Park, Kwang-Su; Choo, Hyunah; Chong, Youhoon [Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 7, p. 1671 - 1679]
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[25]Grande, Fedora; Parisi, Ortensia I.; Mordocco, Roberta A.; Rocca, Carmine; Puoci, Francesco; Scrivano, Luca; Quintieri, Anna M.; Cantafio, Patrizia; Ferla, Salvatore; Brancale, Andrea; Saturnino, Carmela; Cerra, Maria C.; Sinicropi, Maria S.; Angelone, Tommaso [European Journal of Pharmaceutical Sciences, 2016, vol. 82, p. 161 - 170]
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[27]Current Patent Assignee: COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK - WO2009/64485, 2009, A1 Location in patent: Page/Page column 39; 41; 42; 43; 44; 45
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[29]Location in patent: scheme or table Hossion, Abugafar M.L.; Otsuka, Nao; Kandahary, Rafiya K.; Tsuchiya, Tomofusa; Ogawa, Wakano; Iwado, Akimasa; Zamami, Yoshito; Sasaki, Kenji [Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 17, p. 5349 - 5352]
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24
[ 117-39-5 ]
[ 100-39-0 ]
[ 1486-63-1 ]
[ 40554-92-5 ]

Yield	Reaction Conditions	Operation in experiment
1: 56% 2: 20%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16h; Inert atmosphere;	5.1.56 3,7-Bis(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)-5-hydroxy-4H-chromen-4-one (26) (0073) and 5.1.57 3,7-Bis(benzyloxy)-2-(4-(benzyloxy)-3-hydroxyphenyl)-5-hydroxy-4H-chromen-4-one (27) To a solution of quercetin (5.00g, 14.79mmol) in DMF (40mL), were added potassium carbonate (7.14g, 51.77mmol) and benzyl bromide (6.19mL, 51.77mmol) under argon. The reaction mixture was stirred vigorously at room temperature for 16h. The resulting mixture was diluted with 400mL of AcOEt and washed with water. The residue obtained after evaporation of the solvent was purified by column chromatography on silica gel (hexanes/DCM=1:1) to afford 26 (5.51g, 56% yield) as a yellow solid. 1H NMR (300MHz, CDCl3): δ 7.72 (d, J=2.1Hz, 1H), 7.55 (dd, J=8.6, 2.2Hz, 1H), 7.51-7.20 (m, 20H), 6.96 (d, J=8.7Hz, 1H), 6.46 (d, J=2.2Hz, 1H), 6.44 d, J=2.2Hz, 1H), 5.26 (s, 2H), 5.13 (s, 2H), 5.04 (s, 2H), 5.00 (s, 2H); 27 (1.68g, 20%) as a yellow solid. 1H NMR (300MHz, CDCl3): δ 7.66-7.60 (m, 2H), 7.48-7.27 (m, 15H), 6.95 (d, J=9.1Hz, 1H), 6.53-6.41 (m, 2H), 5.24-5.17 (m, 2H), 5.17-5.10 (s, 2H), 5.08 (s, 2H).
1: 40% 2: 14%	With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 36h;
35%	With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere;	2 Compound 10: Quercetin 1 (500 mg, 1.66 mmol) was dissolved in 20 mL of DMF and K2CO3 (714 mg) was added.5.17mmol), BnBr (0.62mL, 5.81mmol), N2 protection, the reaction system was allowed to react at 0°C for 2h and then warmed to room temperature and stirred.At night, TLC detected that the raw material completely disappeared. The reaction solution was added with 150 mL of water and extracted with ethyl acetate (3×100 mL).After washing with saturated saline, it was dried over anhydrous sodium sulfate. After spin-drying the solution, a mixture of compounds 10 and 11 was obtained and the column was chromatographed.(PE:CH2Cl2=1.5:1) The compound was obtained in a yield of 35%.

1: 18.2% 2: 20.9%	Stage #1: quercetol With potassium hydroxide In dimethyl sulfoxide for 0.333333h; Stage #2: benzyl bromide In dimethyl sulfoxide at 20 - 22℃; for 4h;
	With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 12h;	1.A Example 1 3,7-dihydroxy-2-[4-hydroxy-3-(2,6-cis-dimethylmorpholin-4-yl-2-hydroxy-propyl)oxyphenyl]-5-hydroxy-chromen-4-one hydrochloride Step A Synthesis of 3,7-bis-benzyloxy-2-(4-benzyloxy-3-hydroxy-phenyl)-5-hydroxy-chromen-4-one and 3,7-bis-benzyloxy-2-(3,4-bisbenzyloxy-3-hydroxy-phenyl)-5-hydroxy-chromen-4-one Benzyl bromide (55.6 g) was added to a mixture of quercetin (31.8 g) and potassium carbonate (52.5 g) in DMF (500ml). Reaction mixture was stirred for 12 h at 25 °C. The reaction mixture was diluted with water (1.2 1) and ethyl acetate (250 ml) was added. The organic layer was separated, washed with water, dried over anhydrous magnesium sulphate and evaporated to give crude product. The crude products were separated by column chromatography using ethyl acetate/hexane (1:1.5 v/v) as eluent to furnish 3,7-bis-benzyloxy-2-(4-benzyloxy-3-hydroxy-phenyl)-5-hydroxy-chromen-4-one, 19.5 g, m.p.=151-152 °C and 3,7-bis-benzyloxy-2-(3,4-bisbenzyloxy-3-hydroxy-phenyl)-5-hydroxy-chromen-4-one 22.8 g, m.p.=128-132 °C.

Reference： [1]Li, Bo-Wen; Zhang, Feng-Hua; Serrao, Erik; Chen, Huan; Sanchez, Tino W.; Yang, Liu-Meng; Neamati, Nouri; Zheng, Yong-Tang; Wang, Hui; Long, Ya-Qiu [Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 12, p. 3146 - 3158]
[2]Alluis, Bertrand; Dangles, Olivier [Helvetica Chimica Acta, 2001, vol. 84, # 5, p. 1133 - 1156]
[3]Current Patent Assignee: NANJING HUITELAI PHARMACEUTICAL - CN104557891, 2017, B Location in patent: Paragraph 0037; 0038
[4]Karimova; Spirikhin; Baltina; Abdullin [Russian Journal of General Chemistry, 2014, vol. 84, # 9, p. 1711 - 1715][Zh. Obshch. Khim., 2014, vol. 84, # 9, p. 1471 - 1475,5]
[5]Current Patent Assignee: EUROFINS SCIENTIFIC SA - EP2468741, 2012, A1 Location in patent: Page/Page column 8

25
[ 21637-25-2 ]
[ 117-39-5 ]

Reference： [1]Chemistry of Natural Compounds,2001,vol. 37,p. 226 - 227

26
[ 117-39-5 ]
[ 100-39-0 ]
[ 1486-63-1 ]
[ 13157-90-9 ]
[ 40554-92-5 ]

Yield	Reaction Conditions	Operation in experiment
1: 60% 2: 20% 3: 3%	With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 16h;
1: 60% 2: 20% 3: 3%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16h; Inert atmosphere; regioselective reaction;	4.3.1. 3,7-Bisbenzyloxy-2-(3,4-bisbenzyloxyphenyl)-5-hydroxyl-4H-chromen-4-one 3 To a solution of quercetin 1 (5.00 g, 14.79 mmol) in DMF (40 ml), potassium carbonate (7.14 g, 51.77 mmol) and benzyl bromide (6.19 ml, 51.77 mmol) were added under argon. The reaction mixture was agitated vigorously at room temperature for 16 h. The resulting mixture was diluted with 200 ml of AcOEt and was washed with water (2×150 ml). The residue obtained after evaporation of the solvent was purified by flash column chromatography using CH2Cl2 as eluent, to afford 3 (5.88 g, 60% yield), 4 (1.69 g, 20% yield) and 5 (0.33 g, 3% yield), respectively. Mp 140-142 °C (lit.18 140-142 °C; lit.50 128 °C). 1H NMR (CDCl3): 4.96 (s, 2H), 5.01 (s, 2H), 5.12 (s, 2H), 5.25 (s, 2H), 6.44 (d, J=2.1 Hz, 1H), 6.46 (d, J=2.1 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 7.21-7.45 (m, 20H), 7.54 (dd, J=8.7, 2.1 Hz, 1H), 7.72 (d, J=2.1 Hz, 1H). 13C NMR (CDCl3): 70.4, 70.8, 71.0, 74.3, 93.0, 98.5, 106.1, 113.6, 115.2, 122.6, 123.4, 127.2, 127.4, 127.6, 127.9, 128.0, 128.3, 128.4, 128.5, 128.6, 128.8, 129.0, 135.8, 136.05, 136.7, 136.9, 137.4, 148.2, 151.1, 156.2, 156.7, 162.0, 164.4, 178.8. Elemental analysis: calculated for C43H34O7 C, 77.94; H, 5.14; O, 16.92. Observed C, 77.97; H, 5.16; O, 16.95.

Reference： [1]Bouktaib, Mohamed; Lebrun, Stéphane; Atmani, Aziz; Rolando, Christian [Tetrahedron, 2002, vol. 58, # 50, p. 10001 - 10009]
[2]Kajjout, Mohammed; Rolando, Christian [Tetrahedron, 2011, vol. 67, # 25, p. 4731 - 4741]

27
[ 117-39-5 ]
[ 74-88-4 ]
[ 1245-15-4 ]
[ 1247-97-8 ]

Yield	Reaction Conditions	Operation in experiment
1: 30% 2: 56%	With potassium carbonate In methanol; acetonitrile at 60℃; for 10h;
1: 56% 2: 38%	With potassium carbonate In methanol; acetonitrile at 60℃; for 10h;
1: 40% 2: 55%	Stage #1: quercetol With potassium hydroxide In dimethyl sulfoxide for 0.5h; Stage #2: methyl iodide In dimethyl sulfoxide for 4h;	Methylation of Q by CH3I (1:10) in DMSO A solution of 1 (0.30 g, 1 mmol) in DMSO (10 mL) was treated withpowdered KOH (0.56 g, 10 mmol), stirred for 30 min, treated dropwise with CH3I (0.62 mL, 10 mmol), and stirred for 4 h withTLC monitoring. The resulting solution was poured into H2O and acidified (pH 2-3) with HCl. The precipitate was filteredoff, rinsed with H2O until neutral, and dried. The dry product (0.37 g) was chromatographed over a column of SG with elutionby C6H6 and a C6H6-EtOH gradient (100:0.150:1, v/v). Homogeneous TLC fractions were combined and evaporated toafford two principal fractions with Rf 0.77 and 0.73 that were recrystallized from EtOH. The first fraction was identified aspenta-O-methyl ether 2 (0.15 g, 40% yield). The second fraction turned out to be tetra-O-methyl ether 3 (0.20 g, 55% yield).

1: 21.2% 2: 35.6%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 12h;	4.1.3. 2-(3,4-Dimethoxyphenyl)-5-hydroxy-3,7-dimethoxy-4H-chromen-4-one (9) and 2-(3,4-dimethoxyphenyl)-3,5,7-trimethoxy-4H-chromen-4-one (10) Method 1: A solution of quercetin (100 mg, 0.33 mmol) in DMF (10 mL) and anhydrous potassium carbonate (69 mg, 0.50 mmol) was treated with methyl iodide (187 mg, 1.32 mmol) at 0 °C, and the solution was stirred at room temperature for 12 h until TLC showed that the reaction had been completed. The mixture was poured into ice-water (30 mL), and the solution was extracted with ethyl acetate, and then the extract was washed with saturated aqueous NaHCO3 and brine, and then was dried over anhydrous MgSO4. The solvent was evaporated and the residue was purified by flash chromatography on silica gel to afford the desired compounds 9 (25.1 mg, 21.2% yield) and 10 (43.7 mg, 35.6% yield).Method 2: When 10 equivalents methyl iodide were used in the above reaction, trace of compound 9 and 57.6% of 10 were obtained.The melting point of compounds 9 and 10 were identical to the literature [32].Compound 9: mp 156-157 °C; 1H NMR (CDCl3, 600 MHz) δ: 12.65 (s, 1H), 7.74 (dd, J = 8.7, 2.3 Hz), 7.69 (d, J = 1.8 Hz, 1H), 6.99 (d, J = 8.7 Hz, 1H), 6.45 (d, J = 1.9 Hz, 1H), 6.36 (d, 2.3 Hz, 1H), 3.98, 3.97, 3.88, and 3.86 (4s, 12H); 13C NMR (CDCl3, 150 MHz) δ: 178.8, 165.5, 162.1, 156.8, 155.9, 151.4, 148.8, 139.0, 123.0, 122.3, 111.3, 110.9, 106.1, 97.9, 92.3, 60.3, 56.1, 56.0, 55.9; HRMS calcd for (C19H18O7 + H)+ 359.1131, found 359.1145. Compound 10: mp 150-152 °C; 1H NMR (CDCl3, 600 MHz) δ: 7.68-7.66 (m, 2H), 6.94 (d, J = 8.8 Hz, 1H), 6.46 (d, J = 2.2 Hz, 1H), 6.30 (d, J = 1.6 Hz, 1H), 3.93-3.92 (m, 9H), 3.87 (s, 3H) 3.84 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ: 178.9, 165.5, 162.1, 156.8, 155.7, 148.8, 145.6, 139.3, 123.7, 121.7, 114.5, 110.5, 106.2, 97.9, 92.2, 60.3, 56.1, 55.9; HRMS calcd for (C20H20O7 + H)+ 373.1287, found 373.1264.
28%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 72h;	Synthesis of 2-(3,4-dimethoxyphenyl)-5-hydroxy-3,7-dimethoxy-4H-chromen-4-one (8e) To a solution of quercetin (10) (0.604 g, 2.0 mmol, 1.0 equiv) in dry DMF (10 mL) was added K2CO3 (1.24 g, 9.0 mmol, 4.5 equiv). The suspension was stirred for 30 minutes at room temperature, then MeI was added slowly (1.28 g, 9.0 mmol, 4.5 equiv), and the resulting reaction mixture was stirred for 3 days. The reaction mixture was checked by TLC (eluent:hexane-EtOAc (1:1)) and the formation of two major products was discovered. The reaction mixture was poured on water and the precipitate was filtered. The aqueous phase contained the majority of the permethylated product and some more of 8e. The aqueous phase was acidified with HCl and the precipitate was filtered. The combined solid material was washed with acetone and hexane to obtain the pure product as a yellow solid; yield: 0.201 g (28%), 156-158 °C [Lit. 158-159 °C].

Reference： [1]De La Torre, Maria D.L.; Tomé, Augusto C.; Silva, Artur M.S.; Cavaleiro, José A.S. [Tetrahedron Letters, 2002, vol. 43, # 26, p. 4617 - 4620]
[2]De La Torre, Maria D. L.; Rodrigues, Andrea G. P.; Tomé, Augusto C.; Silva, Artur M. S.; Cavaleiro, José A. S. [Tetrahedron, 2004, vol. 60, # 16, p. 3581 - 3592]
[3]Karimova; Baltina; Spirikhin; Kondratenko; Farkhutdinov; Petrova [Chemistry of Natural Compounds, 2015, vol. 51, # 5, p. 851 - 855][Khim. Prir. Soedin., 2015, vol. 51, # 5, p. 851 - 855]
[4]Location in patent: experimental part Yuan, Jian; Wong, Iris L.K.; Jiang, Tao; Wang, Si Wen; Liu, Tao; Jin Wen, Bin; Chow, Larry M.C.; Wan Sheng, Biao [European Journal of Medicinal Chemistry, 2012, vol. 54, p. 413 - 422]
[5]Sipos, Zoltán; Kónya, Krisztina [Synthesis, 2018, vol. 50, # 8, p. 1610 - 1620]

28
[ 133-89-1 ]
[ 117-39-5 ]
[ 482-35-9 ]
[ 6892-74-6 ]

Reference： [1]Phytochemistry,2006,vol. 67,p. 1598 - 1612

29
[ 480-18-2 ]
[ 117-39-5 ]

Reference： [1]Phytochemistry,2008,vol. 69,p. 66 - 75

30
[ 482-36-0 ]
[ 59-23-4 ]
[ 117-39-5 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In water; at 100℃; for 0.5h;	General procedure: Acid hydrolysis of flavonoids was carried out in 2M HCl, at 100C for 30min. After cooling, HCl was removed by evaporation and the hydolysate was dried under a stream of N2. Aglycones formed by acid hydrolysis were analyzed by LC-MS as described above using commercially available standards. Sugars released by hydrolysis were analyzed by a glucose assay kit and a galactose assay kit according to the manufactures procedures to determine their absolute configuration.

Reference： [1]Chemistry of Natural Compounds,2009,vol. 45,p. 422 - 423
[2]Chemistry of Natural Compounds,2008,vol. 44,p. 370 - 371
[3]Chemistry of Natural Compounds,2009,vol. 45,p. 87 - 88
[4]Chemistry of Natural Compounds,2013,vol. 49,p. 106 - 107
Khim. Prir. Soedin.,2013,p. 94 - 95,2
[5]Phytochemistry,2013,vol. 94,p. 108 - 112
[6]Chemistry of Natural Compounds,2014,vol. 50,p. 737 - 738
Khim. Prir. Soedin.,2014,p. 639 - 639,1

31
(S)-tert-butyl 2-(((4-Nitrophenoxy)carbonyl)amino)propanoate [ No CAS ]
[ 117-39-5 ]
[ 1791-13-5 ]
C₃₁H₃₆N₂O₁₃ [ No CAS ]
C₃₁H₃₆N₂O₁₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 1164 - 1171

32
(S)-tert-butyl 2-(((4-Nitrophenoxy)carbonyl)amino)propanoate [ No CAS ]
[ 117-39-5 ]
[ 1791-13-5 ]
[ 1138406-34-4 ]
[ 1138406-36-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 1164 - 1171

33
[ 117-39-5 ]
[ 100-39-0 ]
[ 40554-92-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium carbonate In N,N-dimethyl-formamide at 0 - 25℃; Inert atmosphere; regioselective reaction;	3.1.1. 3,7-Bis(benzyloxy)-2-(4-(benzyloxy)-3-hydroxyphenyl)-5-hydroxy-4H-chromen-4-one (7) To a solution of quercetin 1 (1.00 g, 2.96 mmol) in DMF (50 ml) was added K2CO3 (1.22 g, 8.87 mmol, 3.0 equiv.) and benzyl bromide (1.06 ml, 8.87 mmol, 3.0 equiv.). After vigorous stirring at 0 °C for 2 h, the reaction mixture was allowed to warm to room temperature and the stirring was maintained for 12 h. The resulting mixture was diluted with water (100 ml), extracted with ethyl acetate (100 ml), then the organic layer was washed with brine (100 ml), dried over MgSO4, filtered and concentrated. The crude material was purified by column chromatography (33% ethyl acetate in petroleum ether) to yield the tribenzylether 7 (1.35 g, 80% yield) as a yellow solid [16]. Mp 149-150 °C (lit. [16] 150-152 °C). 1H NMR (CDCl3, 500 MHz): 5.07 (s, 2H, -OCH2Ph), 5.13 (s, 2H, -OCH2Ph), 5.19 (s, 2H, -OCH2Ph), 6.43 (d, J = 2.2 Hz, 1H, 6-H), 6.49 (d, J = 2.2 Hz, 1H, 8-H), 6.95 (d, J = 9.2 Hz, 1H, 5'-H), 7.21-7.47 (m, 15H, aromatic H), 7.60 (dd, J = 2.1, 9.2 Hz, 1H, 6'-H), 7.62 (d, J = 2.1 Hz, 1H, 2'-H), 12.68 (s, 1H, 5-OH). ESI-MS m/z: 573 [M + H]+, 595 [M + Na]+.
70%	Stage #1: quercetol With potassium carbonate In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Inert atmosphere; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 20℃; Inert atmosphere;
45%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 13h; Inert atmosphere; Cooling with ice;

38.4%	With potassium carbonate In N,N-dimethyl-formamide at 60 - 62℃; for 3h; Inert atmosphere;	1 Benzyl bromide (174.5 g, 1.02 mol) was added drop wise to a solution of Quercetin (II, 100 g, 0.3 mol) in DMF (1.4 lt), potassium carbonate (165.6 gm, 1.2 mol) at 60° C. under nitrogen. Reaction mixture stirred for 3 h at 60-62° C. The reaction mixture was diluted with ethyl acetate (3.5 lt) and water (2 lt). The organic layer was separated, washed with water, dried over anhydrous sodium sulphate and evaporated to give crude product. The crude product was purified by column chromatography (60-120 mesh silica gel) using Methylene chloride/Hexane as eluent to furnish the required product.Yield 65 g (38.4%).Rf 0.67 (30% Ethyl acetate/Petroleum ether);1HNMR (DMSO-d6): δ 5.0 (s, 2H), 5.20 (s, 2H), 5.22 (s, 2H), 6.45-6.46 (d, 1H), 6.79-6.80 (d, 1H), 7.10-7.13 (d, 1H), 7.27-7.54 (m, 18H), 9.4 (s, 1H); MS (ES+) m/z 573.3 (M+H).
35.5%	With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃;	1.1 Step 1: Synthesis of compound 1 [3,7-bis(benzyloxy)-2-(4-(benzyloxy)-3-hydroxyphenyl)-5-hydroxy-4H-benzopyran-4-one] 2g (6.6mmol) of quercetin, potassium carbonate 2.76g (3eq, 19.8mmol) was added to 30mL DMF solution, and stirred to dissolve. A DMF solution (10 mL) of 3.39 g (2.36 mL, 3 eq, 19.8 mmol) of benzyl bromide was added dropwise under an ice bath, and the mixture was stirred at 0° C for 2 h, and then returned to room temperature to react overnight. After the reaction is complete, add 50 mL of saturated brine to the reaction system, 60 mL of ethyl acetate was added for extraction twice, and the obtained organic layer was dried with anhydrous sodium sulfate, purification by column chromatography (petroleum ether/ethyl acetate=3/1) gave compound 1 (1.336 g) as a yellow solid with a yield of 35.5%.
35.5%	With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 14h; Inert atmosphere;
	With potassium carbonate In N,N-dimethyl-formamide at 25℃;

Reference： [1]Location in patent: experimental part Shi, Zhi-Hao; Li, Nian-Guang; Tang, Yu-Ping; Wei-Li; Lian-Yin; Yang, Jian-Ping; Hao-Tang; Duan, Jin-Ao [European Journal of Medicinal Chemistry, 2012, vol. 54, p. 210 - 222]
[2]Kato, Komei; Ninomiya, Masayuki; Tanaka, Kaori; Koketsu, Mamoru [Journal of Natural Products, 2016, vol. 79, # 7, p. 1808 - 1814]
[3]Location in patent: experimental part Liu, Pei-Yan; Li, Kun; Zhang, Ji; Zhang, Da-Wei; Lin, Hong-Hui; Yu, Xiao-Qi [Chemistry and biodiversity, 2010, vol. 7, # 1, p. 236 - 244]
[4]Current Patent Assignee: FRESENIUS SE & CO. KGAA - US2011/34413, 2011, A1 Location in patent: Page/Page column 6-7
[5]Current Patent Assignee: SHANGHAI JIAO TONG UNIVERSITY - CN112300191, 2021, A Location in patent: Paragraph 0044-0049
[6]Yang, Zhuojin; Zheng, Yi; Tursumamat, Nafisa; Zhu, Mingyan [Chemistry and biodiversity, 2021, vol. 18, # 11]
[7]Shi, Zhi-Hao; Li, Nian-Guang; Tang, Yu-Ping; Shi, Qian-Ping; Tang, Hao; Li, Wei; Zhang, Xu; Fu, Hai-An; Duan, Jin-Ao [Drug Development Research, 2014, vol. 75, # 7, p. 455 - 462]

34
[ 21637-25-2 ]
[ 50-99-7 ]
[ 117-39-5 ]

Reference： [1]Journal of Agricultural and Food Chemistry,2009,vol. 57,p. 5843 - 5852
[2]Chemistry of Natural Compounds,2010,vol. 46,p. 799 - 800

35
[ 117-39-5 ]
[ 100-44-7 ]
[ 13157-90-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate at 20℃; for 35h; Inert atmosphere;
93%	With tetrabutylammomium bromide; potassium carbonate In 1-methyl-pyrrolidin-2-one; acetone at 85 - 90℃; for 24h;	2.1 Synthesis of Pentabenzylated quercetin from Quercetin using Benzyl chloride. To a stirred solution of Quercetin dihydrate [1] (25 g, 0.074 mol) in N-methyl pyrrrolidone[NMP] (125 ml) and acetone(375 ml), potassium carbonate (122.5 gm, 0.89 mol) was added followed by slow addition of benzyl chloride (85.9 ml, 0.75 mol) and tetrabutyl ammonium bromide[TBAB] (1.19 gm, 3.7 mmol)at room temperature. The reaction mixture was heated at 85-90° C. and stirred for 24 hours. After completion of the reaction, acetone was evaporated and the reaction mass was cooled to 0-5° C. followed by addition ofwater (1250 ml) and the stirring was continued for an additional hour. The precipitated solid was filtered, washed three times with water and then 1:1 mixture of methanol : water to give 52 g (93%; HPLC purity-95%), off white colored desired product [2] (0118) Analytical Data: (0119) ESIMS: 753[M++1]: (0120) 1H NMR (300 MHz, CDCl3): δ (ppm) 7.72(d, 1H, Ar-H); 7.60-7.62(d, 1H, Ar-H); 7.14-7.50(m, 25H, 5-Ar-H); 6.93(d, 1H, Ar-H); 6.52(d, 1H, Ar-H); 6.45(d, 1H, Ar-H); 5.24-5.28(s, 4H, 2×CH2); 5.08-5.09(s, 4H, 2×CH2); 4.96(s, 2H, CH2).
90%	With potassium carbonate; Aethyl-dipropyl-benzyl-ammonium In N,N,N,N,N,N-hexamethylphosphoric triamide for 35h; Inert atmosphere;	Quercetin 3,5,7,3',4'-pentabenzyl ether This compound was synthesizedaccording to a literature: a mixture of quercetin (302 mg, 1.0mmol), benzyl chloride (886 mg, 7.0 mol), HMPA (5 mL), K2CO3(967 mg, 7.0 mmol) and BnN+(Et3)Cl- (23 mg,0.10 mmol) was stirred at room temperature under N2 for 35 h. H2O(30 mL) was then added and the resulting precipitate was filtered. The crudeproduct was washed with H2O (3 x 30 mL) to give a yellow solid thatwas crystallized (EtOAc) to give the known compound 153(677 mg, 90%) as a white solid.

87%	With tetrabutylammomium bromide; potassium carbonate In 1-methyl-pyrrolidin-2-one; acetone at 75℃; for 24h; Inert atmosphere;	Synthesis of 2-[3, 4-bis(phenylmethoxy)phenyl]-3, 5, 7-tris (phenylmethoxy)chromen-4-one, 2 In a 3-neck, 1 L round bottomed flask fitted with a mechanicalstirrer, quercetin dehydrate 1, (25 g) was added, followed by additionof acetone (80 mL) and N-methylpyrrolidone (40 mL). Solid anhydrouspotassium carbonate (81.5 g, 8 eq.) and tetra-butylammonium bromide(1.19 g, 0.05 eq.) was then added followed by benzyl chloride (52 mL,6.2 eq.) under inert atmosphere, at 25-30 °C with constant but slowstirring to maintain effective mixing. The resulting reaction mixturewas refluxed at 75 °C with constant stirring (180-200 RPM) for 24 h.After completion of the reaction, the reaction mixture was cooled toroom temperature. Ice cold water (500 mL) was slowly added to thereaction mixture yielding a pale brown precipitate. The reaction masswas stirred for an additional 30 min at room temperature followed byfiltration using a Buchner funnel. The solid product was washed with anadditional 100 mL of ice-cold water. The wet cake was semi-dried undervacuum. The semi-dried cake was treated with methanol (300 mL) andstirred for 5 min followed by filtration. The solid mass was washed withan additional 100 mL of methanol and dried under vacuum at ambienttemperature to yield 2 (54.0 g, 87 % yield) as an off-white solid.Analytical Data: ESIMS: 753[M+1]; 1H NMR (300 MHz, CDCl3): δ(ppm) 7.72 (d, 1 H, Ar-H), 7.60-7.62 (d, 1 H, Ar-H), 7.14-7.50 (m, 25H, 5-Ar-H), 6.93 (d, 1 H, Ar-H), 6.52 (d, 1 H, Ar-H), 6.45 (d, 1 H, Ar-H),5.24-5.28 (s, 4 H, 2 x CH2), 5.08-5.09 (s, 4 H, 2 x CH2), 4.96 (s, 2 H,CH2); 13C NMR (75 MHz, CDCl3): δ 158.64, 157.93, 157.04, 153.89,151.87, 150.99, 149.72, 148.89, 148.51, 148.18, 148.13, 137.69,137.26, 137.16, 137.09, 136.95, 136.70, 136.62, 136.24, 133.47,131.93, 128.49, 128.47, 128.43, 128.33, 128.25, 127.92, 127.77,127.62, 127.54, 127.49, 127.43, 127.26, 127.15, 127.08, 126.40,120.32, 120.19, 114.21, 114.14, 113.72, 105.14, 101.73, 95.36, 94.79,94.31, 93.92, 89.34, 70.94, 70.25, 70.07, 69.93, 69.56, 22.
15%	With potassium carbonate; N,N-dimethyl-formamide at 20℃; for 12h;

Reference： [1]Location in patent: experimental part Zhou, Zhong-Hua; Fang, Zhuan; Jin, Hui; Chen, Yue; He, Ling [Synthesis, 2010, # 23, p. 3980 - 3986]
[2]Current Patent Assignee: EPIRIUM BIO - US2015/368223, 2015, A1 Location in patent: Paragraph 0116; 0117; 0118; 0119; 0120
[3]Lu, Kui; Chu, Jie; Wang, Haomeng; Fu, Xiaoli; Quan, Dewu; Ding, Hongxia; Yao, Qingwei; Yu, Peng [Tetrahedron Letters, 2013, vol. 54, # 47, p. 6345 - 6348]
[4]Dugar, Sundeep; Villarreal, Francisco; Hollinger, Frank H.; Mahajan, Dinesh; Ramirez-Sanchez, Israel; Moreno-Ulloa, Aldo; Ceballos, Guillermo; Schreiner, George [Pharmacological Research, 2020, vol. 151]
[5]Grande, Fedora; Parisi, Ortensia I.; Mordocco, Roberta A.; Rocca, Carmine; Puoci, Francesco; Scrivano, Luca; Quintieri, Anna M.; Cantafio, Patrizia; Ferla, Salvatore; Brancale, Andrea; Saturnino, Carmela; Cerra, Maria C.; Sinicropi, Maria S.; Angelone, Tommaso [European Journal of Pharmaceutical Sciences, 2016, vol. 82, p. 161 - 170]

36
[ 133-89-1 ]
[ 117-39-5 ]
[ 482-35-9 ]

Reference： [1]Phytochemistry,2010,vol. 71,p. 1253 - 1263
[2]Journal of Agricultural and Food Chemistry,2018,vol. 66,p. 11701 - 11708
[3]Organic Letters,2019,vol. 21,p. 2241 - 2245

37
[ 482-35-9 ]
[ 50-99-7 ]
[ 117-39-5 ]

Reference： [1]Chemistry of Natural Compounds,2011,vol. 46,p. 968 - 970
[2]Chemistry of Natural Compounds,2012,vol. 48,p. 470 - 471

38
[ 327-97-9 ]
[ 117-39-5 ]
[ 1219698-63-1 ]
[ 1219698-62-0 ]

Yield	Reaction Conditions	Operation in experiment
	Laccase DAIWA Y120; In water; at 50℃; for 0.516667h;Enzymatic reaction;	Quercetin 2 hydrate (500 mg) and <strong>[327-97-9]chlorogenic acid</strong> (250 mg) were dissolved in purified water (1000 mL), and the mixture was warmed in an incubator at 50 C. for 1 minute. Laccase DAIWA Y120 (100 mL, Amano Enzyme Inc.) prepared to 5 mg/mL was added and the mixture was stirred for 1 minute. Ethanol (1000 mL) was further added to quench the enzyme reaction. This reaction mixture was concentrated to dryness under reduced pressure, the sample was dissolved in purified water, and the solution was loaded on Sep-Pak C18 (Waters), washed with purified water, and eluted with 30% aqueous ethanol solution (100 mL). 40% Ethanol-eluted fraction was concentrated to dryness under reduced pressure, the fraction was dissolved in 50% aqueous ethanol solution (2 mL), and the solution (500 muL) was injected in 4 portions and purified by HPLC. Two components (10 mg and 3 mg) having a molecular weight of 654 were obtained from the fractions with retention time 33.7 minutes and 34.4 minutes. The apparatus and measurement conditions of HPLC are shown below. LC/MS was used for the detection of the component having a molecular weight of 654 by HPLC, and UV spectrum was simultaneously measured by a photodiode array detector (see FIGS. 7 to 9). The apparatus and measurement conditions of LC/MS and photodiode array detector are shown below.HPLC apparatus:pump: PU-2087 PLUS (manufactured by JASCO Corporation) detector: Hitachi Lachrom Elite L-2455 (manufactured by Hitachi, Ltd.)autoinjector: AS-2057 PLUS (manufactured by JASCO Corporation) fraction collector: ADVANTEC SF-3120 (manufactured by ADVANTEC)HPLC measurement condition:column: CAPCELL PAK AQ S-5 mum, 50×250 mm (manufactured by Shiseido Co., Ltd.)solvent: solution of 0.05% trifluoroacetic acid and 25% acetonitrile in waterflow rate: 30 mL/minutedetection wavelength: 280 nmLC/MS analysis conditions:column: CAPCELL PAK AQ S-3 mum, 2×250 mm (manufactured by Shiseido Co., Ltd.)gradient conditions: 0 minute (SOLUTION A/SOLUTION B=100:0), 100 minutes (SOLUTION A/SOLUTION B=0:100), injection volume: 1 muL, flow rate: 0.2 mL/minute, solvent: SOLUTION A solution of 0.05% trifluoroacetic acid-10% acetonitrile in water, SOLUTION B solution of 0.05% trifluoroacetic acid and 80% acetonitrile in water1H-NMR (400 MHz, MeOH-d4): shown in Table 1.13C-NMR (100 MHz, MeOH-d4): shown in Table 2.As the NMR measurement device, Bruker Avance 400 (400 MHz, Bruker BioSpin KK) was used. The attribution of which carbon to which each proton is bonded was determined on the basis of the measurement by two-dimensional NMR (HSQC), and the assumed whole structure was attributed by two-dimensional NMR (HMBC). From the results of NMR analysis of each component, the difference was assumed to be any of (compound 5) or (compound 6) in a flat plane structure; however, (compound 5) and (compound 6) cannot be distinguished by NMR analysis

Reference： [1]Patent: US2011/237533,2011,A1 .Location in patent: Page/Page column 19; 20

39
[ 482-35-9 ]
[ 2280-44-6 ]
[ 117-39-5 ]

Reference： [1]Chemistry of Natural Compounds,2011,vol. 47,p. 812 - 813

40
[ 117-39-5 ]
[ 74-88-4 ]
[ 572-32-7 ]
[ 1245-15-4 ]
[ 1247-97-8 ]

Yield	Reaction Conditions	Operation in experiment
1: 49% 2: 22% 3: 21%	With potassium carbonate In N,N-dimethyl-formamide at 35℃; for 24h;	Reaction with MeI/K2CO3/DMF (run 1 in Table 1) According to the reported conditions[1] a suspension of quercetin (2) (0.146 g, 4.8 × 10-4 mol), K2CO3 (0.418 g, 30 × 10-4 mol),and MeI (0.5 g, 35 × 10-4 mol) in DMF (1.3 mL) was stirred at 35 °C for 24 h. After quenchedwith H2O and acidified with 20% H2SO4 (pH ca 5) the mixture was extracted. Purification ofthe residue (0.157 g) by preparative TLC (CHCl3) afforded quercetin tetramethyl ether 4 (Rf= 0.30-0.56, 0.084 g, 49%), quercetin trimethyl ether 3 (Rf = 0.12-0.24, 0.036 g, 22%), andquercetin pentamethyl ether 1 (Rf = 0.02-0.12, 0.039 g, 21%)
1: 20% 2: 32% 3: 41%	With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 12h; Inert atmosphere;	3.1.35. Synthesis of trimethylether 31, tetramethylether 34 and pentamethylether 37 To a solution of 1 (151 mg, 0.5 mmol) in dry DMF (20 ml) was added K2CO3 (414 mg, 3.0 mmol, 6.0 equiv.) and iodomethane (0.17 ml, 2.75 mmol, 5.5 equiv.) at room temperature. After 12 h, the reaction mixture was then partitioned between 100 ml ethyl acetate and 100 ml water. The ethyl acetate layer was then washed with brine (100 ml), dried over MgSO4, filtered and concentrated. The crude material was purified by column chromatography (25% ethyl acetate in petroleum ether) to yield trimethylether 31 (34 mg, 20% yield) tetramethylether 34 (57 mg, 32% yield) and pentamethylether 37 (76 mg, 41% yield) as yellow solids.3.1.36. 2-(3,4-Dimethoxyphenyl)-5-hydroxy-3,7-dimethoxy-4H-chromen-4-one (34)Mp 156-157 °C. 1H NMR (CDCl3, 300 MHz) δ 3.87 (s, 3H, -OCH3), 3.88 (s, 3H, -OCH3), 3.97 (s, 3H, -OCH3), 3.98 (s, 3H, -OCH3), 6.36 (d, J = 2.2 Hz, 1H, 6-H), 6.45 (d, J = 2.2 Hz, 1H, 8-H), 6.99 (d, J = 8.6 Hz, 1H, 5'-H), 7.69 (d, J = 2.0 Hz, 1H, 2'-H), 7.74 (dd, J = 2.0, 8.6 Hz, 1H, 6'-H), 12.64 (s, 1H, 5-OH). ESI-MS m/z: 359 [M + H]+, 381 [M + Na]+.3.1.37. 2-(3,4-Dimethoxyphenyl)-3,5,7-trimethoxy-4H-chromen-4-one (37)Mp 136-137 °C. 1H NMR (CDCl3, 300 MHz) δ 3.85 (s, 3H, -OCH3), 3.90 (s, 3H, -OCH3), 3.97 (s, 9H, 3×-OCH3), 6.35 (d, J = 2.2 Hz, 1H, 6-H), 6.51 (d, J = 2.2 Hz, 1H, 8-H), 6.98 (d, J = 9.2 Hz, 1H, 5'-H), 7.69 (dd, J = 2.0, 9.2 Hz, 1H, 6'-H), 7.72 (d, J = 2.0 Hz, 1H, 2'-H). ESI-MS m/z: 373 [M + H]+, 395 [M + Na]+.
	With potassium carbonate In N,N-dimethyl-formamide at 25℃;

Reference： [1]Tatsuzaki, Jin; Ohwada, Tomohiko; Otani, Yuko; Inagi, Reiko; Ishikawa, Tsutomu [Beilstein Journal of Organic Chemistry, 2018, vol. 14, p. 3112 - 3121]
[2]Location in patent: experimental part Shi, Zhi-Hao; Li, Nian-Guang; Tang, Yu-Ping; Wei-Li; Lian-Yin; Yang, Jian-Ping; Hao-Tang; Duan, Jin-Ao [European Journal of Medicinal Chemistry, 2012, vol. 54, p. 210 - 222]
[3]Shi, Zhi-Hao; Li, Nian-Guang; Tang, Yu-Ping; Shi, Qian-Ping; Tang, Hao; Li, Wei; Zhang, Xu; Fu, Hai-An; Duan, Jin-Ao [Drug Development Research, 2014, vol. 75, # 7, p. 455 - 462]

41
[ 117-39-5 ]
[ 107-30-2 ]
[ 1427579-73-4 ]
[ 143724-67-8 ]

Yield	Reaction Conditions	Operation in experiment
1: 50% 2: 50%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 15h; Inert atmosphere;
1: 50% 2: 50%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 15h; Inert atmosphere;	2 Quercetin Protection. Synthesis of compounds 21a and 21b: To a solution of quercetin (1.0 equiv) in DCM, N,N-diisopropylethylamine (8.0 equiv) and MOM chloride (3.5 equiv) was added under nitrogen. After vigorous stirring at 0 °C for 1 h, the reaction mixture was allowed to warm to room temperature over 2 h and the stirring was maintained for 12 h. The resulting mixture was diluted with water (100 ml), extracted with EtOAC (200 ml), and then the organic layer was washed with water (100 ml) and dried over NaSO4. The residue obtained after removal of the solvent was purified by flash column chromatography to afford two products: the tri protected ether 21a (50% yield) and tetra protected ether 21b (50% yield). Spectral (e.g. 1H NMR) characteristics of the following compounds were consistent with their predicted formulas: 2-(3,4-bis(methoxymethoxy)phenyl)-5-hydroxy-3,7-bis(methoxymethoxy)-4H-chromen-4-one (21a); and 5-hydroxy-2-(3-hydroxy-4-(methoxymethoxy)phenyl)-3,7-bis(methoxymethoxy)-4H-chromen-4-one (21b).
1: 50% 2: 50%	In dichloromethane at 0 - 20℃; for 15h; Inert atmosphere;	2 Example 2Synthesis of Protected Quercetin General procedure: Synthesis10125] The protection of quercetin using methoxy methyl chloride as a protecting group giving two products 3, 7, 4’-tri- and 3, 7, 3’, 4’-O-tetra methoxy methylated quercetin (FIG. 7).General Procedure for Protection:10126] To a solution of quercetin (1.0 equiv) in DCM, N, N-diisopropylethylamine (8.0 equiv) and MOM chloride (3.5 equiv) was added under nitrogen. After vigorous stirring at 0° C. for 1 h, the reaction mixture was allowed to warm to room temperature over 2 h and the stirring was maintained for 12 h. The resulting mixture was diluted with water (100 ml), extracted with EtOAC (200 ml), and then the organic layer was washed with water (100 ml) and dried over Na504. The residue obtained afier removal of the solvent was purified by flash column chromatography to afford two products: the tri protected ether 2a (50% yield) and tetra protected ether 2b (50% yield).

Reference： [1]Karuturi, Rajesh; Al-Horani, Rami A.; Mehta, Shrenik C.; Gailani, David; Desai, Umesh R. [Journal of Medicinal Chemistry, 2013, vol. 56, # 6, p. 2415 - 2428]
[2]Current Patent Assignee: VIRGINIA COMMONWEALTH UNIVERSITY - WO2014/75045, 2014, A1 Location in patent: Page/Page column 47; 48
[3]Current Patent Assignee: VIRGINIA COMMONWEALTH UNIVERSITY - US2016/280676, 2016, A1 Location in patent: Paragraph 0126

42
[ 522-12-3 ]
[ 3615-41-6 ]
[ 117-39-5 ]

Reference： [1]Egyptian Journal of Chemistry,2011,vol. 54,p. 99 - 113

43
[ 117-39-5 ]
[ 100-39-0 ]
[ 183067-65-4 ]

Yield	Reaction Conditions	Operation in experiment
57%	Stage #1: quercetol With potassium carbonate In N,N-dimethyl-formamide at 0℃; for 0.25h; Inert atmosphere; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 0 - 20℃; for 16h; Inert atmosphere;	1.1 Preparation of 3′,4′,7-tribenzylated quercetin from Quercetin To a stirred of [1] (3.0 g, 9.9 mmol) in DMF was added K2CO3 (1.3 g, 29.7 mmol) at 0° C. under nitrogen atmosphere. After stirring at this temperature for 15 min, was added Benzyl bromide drop-wise. The temperature of reaction mixture was allowed to rise to room temperature and stirred it for overnight. TLC showed complete consumption of [1]. Reaction mixture was quenched with water (50 ml) and extracted with ethyl acetate (2*100 ml). The combined organic layer was washed with water, brine and dried over sodium sulphate. The organic layer was rotary evaporated to afford light brown sticky material. This crude product was loaded on to silica gel column and eluted with 8% ethyl acetate/hexane to afford yellowish green powder [2] (3.2 g, 57%).Analytical Data: ESIMS: 573[M++1]
50%	With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃;	7-(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)-3,5-dihydroxy-4H-chromen-4-one (2) Quercetin (0.977 g, 3.23 mmol, 1.0 equiv) was dissolved in DMF (26 ml, 0.125M) and was cooled to 0°C. To this mixture was added potassium carbonate (1.43 g, 10.34mmol, 3.2 equiv) and benzyl bromide (1.23 ml, 3.13 mmol, 3.5equiv). The reaction mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction was diluted with ethyl acetate and washed with copious amounts of 1N HCl. The ethyl acetate layer was dried over sodium sulfate and concentrated in vacuo. The crude was purified by column chromatography (silica gel, acetone/hexane, 20% v/v) to give the desired compound 2 (0.925 g, 1.62 mmol, 50%). 1H NMR (400MHz, DMSO-d6) δ 7.9 (d, J=2, 1H), 7.84 (dd, J1=2, J2=2, 1H),7.51-7.32 (m, 15H), 7.25 (d, J=9, 1H), 6.85 (d, J=2, 1H), 6.44(d, J=2, 1H), 5.24 (s, 4H), 5.2 (s, 2H).

Reference： [1]Current Patent Assignee: EPIRIUM BIO - US2015/368223, 2015, A1 Location in patent: Paragraph 0094; 0095
[2]Verghese, Jenson; Nguyen, Thuy; Oppegard, Lisa M.; Seivert, Lauren M.; Hiasa, Hiroshi; Ellis, Keith C. [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 21, p. 5874 - 5877]

44
[ 117-39-5 ]
[ 100-44-7 ]
[ 1486-63-1 ]

Yield	Reaction Conditions	Operation in experiment
60%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 10h; Inert atmosphere;	Quercetin 3,7,3',4'-tetrabenzyl ether (13) To a stirred solution of quercetin (302 mg, 1.0mmol) in dry DMF (5 mL) was added K2CO3 (690 mg, 5.0mmol) and benzyl chloride (633mg, 5.0 mmol). After the addition, the mixture was stirred for 10 h at roomtemperature. The reaction mixture was then diluted with CH2Cl2 (20mL) and poured into aqueous HCl (0.1 M) (10 mL). The organic layer wasseparated, washed with H2O (3×10 mL) and dried over Mg2SO4.After concentrated to dryness under reduced pressure, the crude product waspurified by column chromatography on silica (petroleum ether/ethyl acetate 4:1) to afford the known compound 133 (398 mg, 60%) as a yellow solid.
	With dmap In tetrahydrofuran at 20℃; for 10h; Inert atmosphere;	1.1; 2.1; 3.1 Step 1: Preparation of Compound A 20 mL of THF was added to a 100 mL three-necked flask, then 604 mg of quercetin was added, 580 mg of DMAP and 550 μl of benzyl chloride were added to the reaction solution, and the whole process was nitrogen-protected, stirred at room temperature for 10 hours, and 30 mL of ethyl acetate and 10 ml of purified water were added. The mixture was extracted and separated, and the aqueous layer was extracted twice with 30 mL of ethyl acetate. The organic layer obtained by combined extraction was filtered, dried, and purified by silica gel column chromatography on 200-300 mesh to obtain compound A, ie, 3,7-bis ( Benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)-5-hydroxy-4H-pyran-4-one;The yield was 57%, the purity was 97%, and Rf was 0.484.

Reference： [1]Lu, Kui; Chu, Jie; Wang, Haomeng; Fu, Xiaoli; Quan, Dewu; Ding, Hongxia; Yao, Qingwei; Yu, Peng [Tetrahedron Letters, 2013, vol. 54, # 47, p. 6345 - 6348]
[2]Current Patent Assignee: ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN110078695, 2019, A Location in patent: Paragraph 0017; 0033; 0035-0036; 0041; 0043-0044; 0049

45
[ 117-39-5 ]
[ 814-49-3 ]
[ 1266147-87-8 ]

Yield	Reaction Conditions	Operation in experiment
56%	With dmap; triethylamine In tetrahydrofuran at 70℃; for 3.5h; Cooling with ice; Inert atmosphere;	4.1.1 General procedure for the synthesis of compound 2 General procedure: Compound 1 (1.0mmol) was added to a solution of 20mL THF, DMAP (3.0mmol per OH group) and Et3N (3.0mmol per OH group), and the mixture was stirred until dissolved. A solution of ClP(O)(OEt)2 (4.0mmol per OH group) with 5mL THF was then added dropwise with vigorous stirring in an ice-water bath over 30min. After stirring at 70°C for 3h under nitrogen, the reaction mixture was concentrated, diluted with EtOAc (3×30mL), washed with 0.5M HCl (3×15mL), 5% (w/v) NaOH (3×15mL) and brine, and dried over anhydrous Na2SO4. After removal of the solvent in vacuo, the residue was purified by column chromatography on deactivated silica gel with petroleum ether/EtOAc (1:1-1:4), CH2Cl2/MeOH (100:1-60:1) as eluant to give the corresponding product 2.
	With dmap; triethylamine In tetrahydrofuran for 24.5h; Inert atmosphere; Cooling with ice;	2.2 2.2- Method General procedure: QP was synthesized based on the reported literature, with some modification.Briefly, 3 mmol quercetin, DMAP (2.0 mmol per -OH group), and Et3N (2.0 mmol per-OH group) were dissolved in 100 mL anhydrous THF. Then a solution ofClP(O)(OEth (90 mmol) in anhydrous THF (50 mL) was added dropwise under stirringin an ice-water bath over 30 min. The reaction was continued at room temperature for 24 h under nitrogen. The reaction mixture was diluted with EtOAc, washed with 0.5 MHCl, 5% (w/v) NaOH, brine and water, and then dried over anhydrous Na2S04. Afterremoval of the solvent by rotary evaporation, the residue was purified using columnchromatography on deactivated silica gel with petroleum ether/EtOAc ( 4:1 - 2:1) and dichloromethan/methanol (5:1 - 2:1) as eluent to give the ethyl protected QP, whichwas characterized by HPLC-MS.

Reference： [1]Wei, Yingling; Peng, Ai-Yun; Wang, Bo; Ma, Lin; Peng, Guoping; Du, Yidan; Tang, Jingming [European Journal of Medicinal Chemistry, 2014, vol. 74, p. 751 - 758]
[2]Current Patent Assignee: UNIVERSITY OF NORTH CAROLINA SYSTEM - WO2018/172942, 2018, A1 Location in patent: Page/Page column 49; 50

46
[ 50329-91-4 ]
[ 117-39-5 ]
[ 1614253-88-1 ]

Yield	Reaction Conditions	Operation in experiment
65%	With triethylamine In ethanol at 20℃; for 0.25h;	(I) Synthesis of chromeno [4, 3-d] pyrimidine 3-oxidederivatives (3a-o): General procedure: A solution of 4-chloro-3-formyl coumarin (1mmol), resorcinol derivatives (1 mmol) and triethylamine (1 equivalent) in 3ml ethanolwere stirred at room temperature for 15 min. After completion of the reaction,the precipitate obtained was filtered and washed thoroughly with absoluteethanol and re-crystallized from ethanol to afford pure products 3a-o.

Reference： [1]Jaggavarapu, Satyanarayana Reddy; Kamalakaran, Anand Solomon; Nanubolu, Jagadeesh Babu; Jalli, Venkata Prasad; Gangisetty, Sravan Kumar; Gaddamanugu, Gopikrishna [Tetrahedron Letters, 2014, vol. 55, # 27, p. 3670 - 3673]

47
[ 50-00-0 ]
[ 117-39-5 ]
[ 52721-69-4 ]
8-(2-fluorophenethylaminomethyl)quercetin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	In ethanol; water; at 20℃; for 16h;	General procedure: General Procedure for the synthesis of Compounds 4-20. To a suspension of quercetin (0.35mmol) in EtOH (5mL)was added 37% wt formaldehyde in H2O (0.35mmol) and amine (0.35mmol).The resulting suspension was allowed to stir for 16h. Product was isolated viavacuum filtration as a yellow solid.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 327 - 332

48
[ 50-00-0 ]
[ 117-39-5 ]
[ 13078-79-0 ]
8-(3-chlorophenethylaminomethyl)quercetin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	In ethanol; water; at 20℃; for 16h;	General procedure: General Procedure for the synthesis of Compounds 4-20. To a suspension of quercetin (0.35mmol) in EtOH (5mL)was added 37% wt formaldehyde in H2O (0.35mmol) and amine (0.35mmol).The resulting suspension was allowed to stir for 16h. Product was isolated viavacuum filtration as a yellow solid.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 327 - 332

49
[ 50-00-0 ]
[ 404-70-6 ]
[ 117-39-5 ]
8-(3-fluorophenethylaminomethyl)quercetin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	In ethanol; water; at 20℃; for 16h;	General procedure: General Procedure for the synthesis of Compounds 4-20. To a suspension of quercetin (0.35mmol) in EtOH (5mL)was added 37% wt formaldehyde in H2O (0.35mmol) and amine (0.35mmol).The resulting suspension was allowed to stir for 16h. Product was isolated viavacuum filtration as a yellow solid.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 327 - 332

50
[ 117-39-5 ]
2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromene-4-thione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium hydroxide / water / 20 - 90 °C 2: Lawessons reagent / toluene / 4 h / 110 °C 3: boron tribromide / dichloromethane / 40 °C
	Multi-step reaction with 3 steps 1: acetone / Heating 2: tetraphosphorus decasulfide / tetrahydrofuran / 72 h / 20 °C 3: boron tribromide / dichloromethane / 24 h / -78 - 20 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: potassium hydroxide / 20 - 90 °C 2: Lawessons reagent / toluene / 4 h / 110 °C 3: boron tribromide / dichloromethane / 40 °C

With Lawessons reagent In toluene at 110℃; for 6h; Inert atmosphere;

General procedure for the synthesis of thioxoflavonoids. General procedure: A flask was charged with a flavone (5 mmol) and Lawesson's reagent (2.5 mmol) under nitrogen atmosphere, after 5 min, 35 mL of dry methylbenzene was added by syringe and the mixture was stirred while being brought to reflux. The mixture was heated to 110℃ for 6h and then cooled to room temperature. The methylbenzene is removed and concentrated in vacuo. The residue was purified by column chromatography methods to obtain target products.

Reference： [1]Ravishankar, Divyashree; Watson, Kimberly A.; Boateng, Samuel Y.; Green, Rebecca J.; Greco, Francesca; Osborn, Helen M.I. [European Journal of Medicinal Chemistry, 2015, vol. 97, p. 259 - 274]
[2]Martins, Inês L.; Charneira, Catarina; Gandin, Valentina; Ferreira Da Silva, João L.; Justino, Gonçalo C.; Telo, João P.; Vieira, Abel J. S. C.; Marzano, Cristina; Antunes, Alexandra M. M. [Journal of Medicinal Chemistry, 2015, vol. 58, # 10, p. 4250 - 4265]
[3]Ravishankar, Divyashree; Watson, Kimberly A.; Greco, Francesca; Osborn, Helen M. I. [RSC Advances, 2016, vol. 6, # 69, p. 64544 - 64556]
[4]Li, Wei; Han, Peipei; Cai, Shuanglian; Wang, Qiuan [Natural Product Research, 2019, vol. 33, # 17, p. 2440 - 2445]

51
[ 75-30-9 ]
[ 117-39-5 ]
2-(3,4-diisopropoxyphenyl)-3,5,7-triisopropoxy-4H-chromen-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With potassium carbonate In N,N-dimethyl-formamide for 30h; Inert atmosphere; Heating;	6 5.1.6 5,7-diisopropoxy-2-phenyl-4H-chromen-4-one (20) General procedure: K2CO3 (3.45 g, 24.98 mmol) and (CH3)2CHI (4.25 g, 24.98 mmol) were added to a stirred solution of 17 (2.54 g, 9.99 mmol) in dry DMF (10 mL). After the addition, the mixture was heated to 45 °C and stirred for 30 h. The reaction was cooled to room temperature, filtered and diluted with ethyl acetate (100 mL) and the resulting solution was poured into aqueous HCl (1 M, 100 mL). The organic layer was separated, washed with brine (3 * 100 mL) and dried over anhydrous Na2SO4. After concentrated to dryness under reduced pressure, the crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 100:1) to afford the known compound 20 (3.08 g, 91%) as a pale yellow solid.
75%	With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 12h; Inert atmosphere;	2-(3,4-diisopropoxyphenyl)-3,5,7-triisopropoxy-4H-chromen-4-one (18) K2CO3 (8.29g, 60 mmol) and (CH3)2CHI(11.9 g, 70 mmol) were added to a stirred solution of quercetin(3.02 g, 10 mmol) in dry DMF (25 mL). After the addition, the mixture washeated to 60°C and stirred for 12 h. The reaction was cooled to roomtemperature, filtered and diluted with ethyl acetate (100 mL) and the resultingsolution was poured into aqueous HCl (1 M, 100 mL). The organic layer wasseparated, washed with saturated NaCl (3×100 mL) and dried over anhydrous Na2SO4.After concentrated to dryness under reduced pressure, the crude product waspurified by column chromatography on silica (petroleum ether/ethylacetate 4:1) to afford the known compound 18(3.84 g, 75%) as a yellow solid * MERGEFORMAT . Data for 18: 1HNMR(400 MHz, CDCl3): δ 7.77(s, 1H), 7.67 (d, J = 8.4 Hz, 1H),6.97 (d, J = 8.4 Hz, 1H), 6.46 (s,1H), 6.32 (s, 1H), 4.49-4.80 (m, 5H), 1.45 (d, J = 6.0 Hz, 6H), 1.37-1.40 (m, 18H),1.15 (d, J = 6.0 Hz, 6H).

Reference： [1]Pan, Guojun; Zhao, Lianbo; Xiao, Na; Yang, Ke; Ma, Yantao; Zhao, Xia; Fan, Zhenchuan; Zhang, Yongmin; Yao, Qingwei; Lu, Kui; Yu, Peng [European Journal of Medicinal Chemistry, 2016, vol. 122, p. 674 - 683]
[2]Pan, Guojun; Yang, Ke; Ma, Yantao; Zhao, Xia; Lu, Kui; Yu, Peng [Bulletin of the Korean Chemical Society, 2015, vol. 36, # 5, p. 1460 - 1466]

52
[ 75-30-9 ]
[ 117-39-5 ]
2-(3,4-diisopropoxyphenyl)-5-hydroxy-3,7-diisopropoxy-4H-chromen-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 12h; Inert atmosphere;	2-(3,4-diisopropoxyphenyl)-5-hydroxy-3,7-diisopropoxy-4H-chromen-4-one(11): K2CO3 (6.08g, 44 mmol) and (CH3)2CHI (7.48g, 70 mmol) were added to a stirred solution of quercetin(3.02 g, 10 mmol) in dry DMF (25 mL). After the addition, the mixture was heatedto 60°C and stirred for 12 h. The reaction was cooled to room temperature,filtered and diluted with ethyl acetate (100 mL) and the resulting solution waspoured into aqueous HCl (1 M, 100 mL). The organic layer was separated, washedwith saturated NaCl (3×100 mL) and dried over anhydrous Na2SO4.After concentrated to dryness under reduced pressure, the crude product waspurified by column chromatography on silica (petroleum ether/ethylacetate 20:1) to afford a new compound 11(3.39 g, 72%) as a yellow solid. Datafor 11: 1HNMR(400 MHz, CDCl3): δ 7.77 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.41 (s, 1H), 6.31 (s,1H), 4.59-4.66 (m, 3H), 4.47-4.55 (m, 1H), 1.37-1.40 (m, 18H), 1.20 (d, J = 8.4 Hz, 6H); 13CNMR (100MHz, CDCl3): δ 21.9, 22.2, 22.3, 70.7, 71.7, 72.8, 74.9,93.4, 98.8, 105.7, 115.7, 119.5, 123.1, 123.8, 136.6, 148.0, 151.6, 156.6,156.8, 162.1, 163.8, 179.2; LRMS (ESI) m/z 471 [M + H]+;HRMS (ESI)m/z: Calcdfor C27H35O7[M+H]+471.2377;found, 471.2370; m.p.: 68.4-70.2.

Reference： [1]Pan, Guojun; Yang, Ke; Ma, Yantao; Zhao, Xia; Lu, Kui; Yu, Peng [Bulletin of the Korean Chemical Society, 2015, vol. 36, # 5, p. 1460 - 1466]

53
[ 117-39-5 ]
[ 75-36-5 ]
[ 1064-06-8 ]

Yield	Reaction Conditions	Operation in experiment
84%	With pyridine at 20℃; for 24h; Inert atmosphere;	General procedure for acylation of flavonoids General procedure: To a stirred solution of flavonoid (1 mmol) in pyridine (2 mL)was added acyl chloride (6 mmol) or n-butyl isocyanate (6 mmol)in nitrogen atmosphere. The mixture was stirred for 24 h at roomtemperature. The reaction solution was poured into 100 mL ofwater with ice. Solid was filtered, washed with water and dried.The residue was purified by column chromatography or crystallizationfrom mixture of methanol and acetone
74.7%	With dmap; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 24h;	Example of synthesis of 2-(3,4-bis(palmitoyloxy)phenyl)-4-oxo-4/-/-chromene-3,5,7- triyl acetate: 10a. Acetyl chloride (0.850 ml; 0.012 mol), DIPEA (3.09 ml; 0.018 mol) and DMAP (0.36 g; 0.003 mol) were added sequentially to a solution of 3,3',4',5,7-pentahydroxy flavone 9 (0.56 g; 0.0016 mol) in anhydrous DCM (50 ml). The reaction mixture was stirred at room temperature. Upon completion (after 24 hours), a white precipitate forms. The reaction mixture was partitioned between H2O and DCM and the combined organic phases were dried over anhydrous Na2S04, filtered, and the solvent was removed under reduced pressure. The solid residue was recrystallized from MTBE (fe/f-butyl methyl ether) from which a yellow solid product corresponding to 10a (74.7 %) is obtained.

Reference： [1]Hoang, T. Kim-Dung; Huynh, T. Kim-Chi; Nguyen, Thanh-Danh [Bioorganic Chemistry, 2015, vol. 63, p. 45 - 52]
[2]Current Patent Assignee: VERA SALUS RICERCA - WO2019/8537, 2019, A1 Location in patent: Page/Page column 42

54
[ 117-39-5 ]
[ 74-88-4 ]
[ 572-32-7 ]

Yield	Reaction Conditions	Operation in experiment
44%	Stage #1: quercetol With potassium hydroxide In dimethyl sulfoxide for 0.5h; Stage #2: methyl iodide In dimethyl sulfoxide for 4h;	Methylation of Q by CH3I (1:7) in DMF Methylation of Q by CH3I (1:7) in DMF was carried out in the same manner as above. The obtained yellowishgreenprecipitate was filtered off, rinsed with H2O, dried, and chromatographed over a column of SG with elution byC6H6-EtOH (200:1, 100:1, 100:2, 100:3, v/v). The principal fraction was isolated and identified as tri-O-methyl ether 4(0.15 g, 44% yield). The other fractions contained inseparable product mixtures.
42%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere;
39%	With sodium hydride In N,N-dimethyl-formamide at 20℃;	Reaction with MeI/NaH/DMF (run 4 in Table 1) According to the reported conditions [4]a mixture of 2 (0.149 g, 4.9 × 10-4 mol), NaH (0.052 g, 22 × 10-4 mol), and MeI (0.5 mL, 80 ×10-4 mol) in DMF (10 mL) was stirred at rt for 21 h. After quenched with H2O the mixture wasextracted. Purification of the residue (0.166 g) by preparative TLC (CHCl3 : EtOAc = 8 : 1,v/v) afforded 3 (Rf = 0.34-0.65, 0.068 g, 39%) as a main product

Reference： [1]Karimova; Baltina; Spirikhin; Kondratenko; Farkhutdinov; Petrova [Chemistry of Natural Compounds, 2015, vol. 51, # 5, p. 851 - 855][Khim. Prir. Soedin., 2015, vol. 51, # 5, p. 851 - 855]
[2]Kristufek, Samantha L.; Yang, Guozhen; Link, Lauren A.; Rohde, Brian J.; Robertson, Megan L.; Wooley, Karen L. [ChemSusChem, 2016, vol. 9, # 16, p. 2135 - 2142]
[3]Tatsuzaki, Jin; Ohwada, Tomohiko; Otani, Yuko; Inagi, Reiko; Ishikawa, Tsutomu [Beilstein Journal of Organic Chemistry, 2018, vol. 14, p. 3112 - 3121]

55
[ 117-39-5 ]
[ 13157-90-9 ]

Yield	Reaction Conditions	Operation in experiment
57%	With potassium carbonate In N,N-dimethyl-formamide at 0℃; for 0.25h; Inert atmosphere;	3.1 To a stirred of [1] (3.0 g, 9.9 mmol) in DMF was added K2CO3 (1.3 g, 49.5 mmol) at 0° C. under nitrogen atmosphere. After stirring at this temperature for 15 min, was added Benzyl bromide drop-wise. The temperature of reaction mixture was allowed to rise to room temperature and stirred it for overnight. TLC showed complete consumption of [10]. Reaction mixture was quenched with water (50 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layer was washed with water, brine and dried over sodium sulphate. The organic layer was rotary evaporated to afford light brown sticky material. This crude product was loaded on to silica gel column and eluted with 8% ethyl acetate/hexane to afford yellowish green powder [11] (3.2 g, 57%). Analytical Data: ESIMS: 753 [M++1]

Reference： [1]Current Patent Assignee: EPIRIUM BIO - US2015/368223, 2015, A1 Location in patent: Paragraph 0138; 0139; 0140; 0141

56
[ 117-39-5 ]
[ 18162-48-6 ]
3,7,3',4'-tetra-O-(tert-butyldimethylsilyl)quercetin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	4.2 Step 2: 3,7,3 ', 4'-tetracarboxylic -O- tert-butyldimethylsilyl Quercetin Under nitrogen, the quercetin (2g, 6.6mmol) and TBSCl (5g, 33mmol) dissolved in dry DMF (5mL), and room temperature, TLC track to complete the reaction. The reaction system was extracted with DCM, washed with water, then washed with a saturated brine, dried over anhydrous sodium sulfate. The resulting filtrate was concentrated under reduced pressure column chromatography to obtain the objective product (4.3g, 85%).
	Multi-step reaction with 2 steps 1: 1,8-diazabicyclo[5.4.0]undec-7-ene / dichloromethane / 5 h / 20 °C 2: iodine; water / dichloromethane / 3 h / Reflux

Reference： [1]Current Patent Assignee: JIANGXI NORMAL UNIVERSITY - CN105273028, 2016, A Location in patent: Paragraph 0073; 0074; 0075
[2]Liao, Jin-Xi; Fan, Nai-Li; Liu, Hui; Tu, Yuan-Hong; Sun, Jian-Song [Organic and Biomolecular Chemistry, 2016, vol. 14, # 4, p. 1221 - 1225]

57
[ 117-39-5 ]
[ 106-89-8 ]
7,4'-diglycidyloxy-3,5,3'-trihydroxyflavone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	Stage #1: quercetol; epichlorohydrin With N-pentadecyl-N,N-dimethyl N-benzyl ammonium chloride In dimethyl sulfoxide at 80℃; for 0.5h; Inert atmosphere; Stage #2: With sodium hydroxide In water; dimethyl sulfoxide at 80℃; for 4h; Inert atmosphere;	Synthesis of diglycidyl quercetin (I) Mixture of quercetin (2.00 g, 6.6 mmol), epichlorohydrin (1.034 mL, 13.2 mmol), N-pentadecyl-N-benzyl-N,N-dimethylammonium chloride (0.50 g, 2.19 mmol) and DMSO was heated at 80 °C for 30 min in argon atmosphere. Then, solution of sodium hydroxide (2.65 g, 66.2 mmol) in water (9.0 mL) was added, and the mixture was heated at 80 °C for 4 h. After that, it was concentrated and cooled, and the obtained precipitation was re-crystallized from acetone. Finally, glycidyl ether of quercetin was purified by column chromatography (silica gel; chloroform/acetone = 10:1 v/v). Yield was 65 %. Elemental Analysis: Calc. (wt%): C-60.87; H-4.38; O-34.75. Found (wt%): C-59.70; H-4.55; O-35.75.

Reference： [1]Mishurov, Dmitry A.; Voronkin, Andrey A.; Roshal, Alexander D. [Structural Chemistry, 2016, vol. 27, # 1, p. 285 - 294]

58
[ 117-39-5 ]
[ 106-89-8 ]
7,3',4'-triglycidyloxy-3,5-dihydroxyflavone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	Stage #1: quercetol; epichlorohydrin With N-pentadecyl-N,N-dimethyl N-benzyl ammonium chloride In dimethyl sulfoxide at 80℃; for 0.5h; Inert atmosphere; Stage #2: With sodium hydroxide In water; dimethyl sulfoxide at 80℃; for 4h; Inert atmosphere;	Synthesis of diglycidyl quercetin (I) General procedure: Mixture of quercetin (2.00 g, 6.6 mmol), epichlorohydrin (1.034 mL, 13.2 mmol), N-pentadecyl-N-benzyl-N,N-dimethylammonium chloride (0.50 g, 2.19 mmol) and DMSO was heated at 80 °C for 30 min in argon atmosphere. Then, solution of sodium hydroxide (2.65 g, 66.2 mmol) in water (9.0 mL) was added, and the mixture was heated at 80 °C for 4 h. After that, it was concentrated and cooled, and the obtained precipitation was re-crystallized from acetone. Finally, glycidyl ether of quercetin was purified by column chromatography (silica gel; chloroform/acetone = 10:1 v/v). Yield was 65 %.

Reference： [1]Mishurov, Dmitry A.; Voronkin, Andrey A.; Roshal, Alexander D. [Structural Chemistry, 2016, vol. 27, # 1, p. 285 - 294]

59
[ 117-39-5 ]
[ 106-89-8 ]
3,7,3',4'-tetraglycidyloxy-5-hydroxyflavone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	Stage #1: quercetol; epichlorohydrin With N-pentadecyl-N,N-dimethyl N-benzyl ammonium chloride In dimethyl sulfoxide at 80℃; for 0.5h; Inert atmosphere; Stage #2: With sodium hydroxide In water; dimethyl sulfoxide at 80℃; for 4h; Inert atmosphere;	Synthesis of diglycidyl quercetin (I) General procedure: Mixture of quercetin (2.00 g, 6.6 mmol), epichlorohydrin (1.034 mL, 13.2 mmol), N-pentadecyl-N-benzyl-N,N-dimethylammonium chloride (0.50 g, 2.19 mmol) and DMSO was heated at 80 °C for 30 min in argon atmosphere. Then, solution of sodium hydroxide (2.65 g, 66.2 mmol) in water (9.0 mL) was added, and the mixture was heated at 80 °C for 4 h. After that, it was concentrated and cooled, and the obtained precipitation was re-crystallized from acetone. Finally, glycidyl ether of quercetin was purified by column chromatography (silica gel; chloroform/acetone = 10:1 v/v). Yield was 65 %.

Reference： [1]Mishurov, Dmitry A.; Voronkin, Andrey A.; Roshal, Alexander D. [Structural Chemistry, 2016, vol. 27, # 1, p. 285 - 294]

60
[ 117-39-5 ]
[ 79-03-8 ]
3,3',4',7-tetra-O-propionylatedquercetin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With pyridine In dichloromethane at 0 - 20℃;	2.1 1) 3.02 g of quercetin was dissolved in 5 mL of pyridine, and 20 mL of dichloromethane was added thereto. Cool in an ice-water bath with stirring0 & lt; 0 & gt; C, 3.5 mL of propionyl chloride was slowly added dropwise, slowly warmed to room temperature and the reaction monitored by TLC. After completion of the reaction, the reaction solution was pouredIn 50 mL of 1 N HC1, extracted three times with 20 mL of ethyl acetate, washed three times with 20 mL of 1N HCl, and washed with 60 mL of distilled waterTwice, 60 mL of saturated brine, dried over anhydrous sodium sulfate overnight, suction filtered, and the filtrate was dried to give 3,3 ', 4', 7-tetra-O-propionylated quercetin crude. This was recrystallized from a petroleum ether / methylene chloride system to give 3,3 ', 4', 7-tetra-O-propionylatedQuercetin 3.78 g, yield 72%.

Reference： [1]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY - CN105693677, 2016, A Location in patent: Paragraph 0021

61
[ 117-39-5 ]
[ 75-36-5 ]
[ 7251-37-8 ]

Yield	Reaction Conditions	Operation in experiment
82%	With pyridine In dichloromethane at 0 - 20℃;	1.1 (1) the 3.02g quercetin dissolved in 5 ml pyridine, by adding 20 ml dichloromethane. Stirring in the ice-water cooling to 0 °C, slowly dropping 2.84 ml acetyl chloride, slowly to the room temperature and for monitoring TLC the reaction. To be after the reaction is complete, the reaction is poured into the fluid leans 50mL1NHCl in, in order to 20 ml ethyl acetate extraction three times, 20mL1NHCl washing three times, 60 ml wash once distilled water, 60 ml saturated salt water washing two times, overnight drying by anhydrous sodium sulfate, filtered, the filtrate is obtained turns on lathe does 3,3 the [...], the 4 [...], 7-tetra-O-acetylated quercetin crude product. The petroleum ether/dichloromethane system for re-crystallization, to obtain 3,3 the [...], the 4 [...], 7-tetra-O-acetylated quercetin 3.86g, yield 82%.

Reference： [1]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY - CN105693677, 2016, A Location in patent: Paragraph 0017

62
[ 15604-36-1 ]
[ 117-39-5 ]
cis-[Pt(PPh₃)₂(que)] [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With potassium hydroxide; In ethanol; dichloromethane; at 40℃;	A solution of KOH (2.90 mmol, 162.7 mg) in ethanol (7.0 mL) kept at 40 C was added dropwise to a clear yellow solution of cis-[PtCl2(PPh3)2] (1.45 mmol, 1.149 g) and quercetin (1.45 mmol, 0.439 g) in CH2C12 (80 mL) at room temperature under stirring. After overnight stirring at room temperature, the resulting dark orange reaction mixture was filtered (in order to remove KCl) and dried under reduced pressure. The red orange residue was dissolved in CH2Cl2 (10 mL) and added of n-hexane (30 mL), which caused the formation of a red-orange precipitate. This solid was filtered after overnight cooling at 4 C, washed with n-hexane (3 * 10 mL) and dried under vacuum. Yield: 1.073 g, 72%. Mp = 212.5 C (dec). Relevant 1H and 13C{1H} NMR features are reported in Tables 3 and 2, respectively, except those belonging to PPh3 groups. PPh3 region: 1H NMR (400 MHz, dmso-d6, 25 C) δ = 7.45 ppm (m, 12H, Hortho), 7.42 ppm (m, 6H, Hpara), 7.29 ppm (m, 12H, Hmeta); 13C{1H} NMR (100 MHz dmso-d6, 25 C) δ = 134.7 ppm (s, Cortho), 131.6 (s, Cpara), 128.8 (s, Cipso), 128.6 (s, Cmeta). 31P{1H} NMR (121.5 MHz, dmso-d6, 25 C): δ = 9.6 ppm (d, 2JPP = 23 Hz, 1JPtP = 3565 Hz); 8.3 ppm (d, 2JPP = 23 Hz, 1JPtP = 3600 Hz). 195Pt{1H} NMR (85.99 MHz, dmso-d6, 25 C): δ = - 4062 ppm (dd, 1JPtP = 3565 Hz, 1JPtP = 3600 Hz). IR (KBr, cm- 1): 3372-3633 (b, m, O-H), 3058 (m, C-H), 1650 (s, C=O), 1617 (s, C=C), 1515 (s, C=C), 1491 (s, C=C), 1426 (s, C=C), 1354 (m, O-H), 1270 (s, C-O-C), 1162 (m, O-H), 1099 (m, C-H), 997 (m, C-O-C), 741 (m, C-H), 530 (m, Pt-O). HRMS (ESI, acetonitrile, positive ion mode) m/z: calcd. for C51H38O7P2Pt [M]+ 1019.1740; found 1019.1681. HRMS (ESI, acetonitrile, negative ion mode) m/z: calcd. for C51H37O7P2Pt [M-H]- 1018.1672; found 1018.1678.

Reference： [1]Journal of Inorganic Biochemistry,2016,vol. 163,p. 346 - 361

63
[ 117-39-5 ]
[ 108-24-7 ]
[ 7251-37-8 ]
[ 1064-06-8 ]

Yield	Reaction Conditions	Operation in experiment
55%	With triethylamine In N,N-dimethyl-formamide at 20℃; for 5h;	1 Compound 2b: Quercetin 1 (300 mg, 1.00 mmol) was dissolved in 10 mL DMF and acetic anhydride (0.37 mL,4.00 mmol), triethylamine (0.83 mL, 6.00 mmol), the reaction system was reacted for 5 h at room temperature, and the TLC reaction was completely eliminated.Lost. The reaction solution was poured into ice water, a white solid precipitated, ethyl acetate extraction, the organic phase was saturated with sodium bicarbonate solution, satietyAfter washing with saline, dry over anhydrous sodium sulfate. After spin-drying the solution, a mixture of compounds 2a and 2b was obtained. Column chromatography (PE:EtOAc = 2.5:1) to give compound 2b in 55% yield.
1: 50 mg 2: 20 mg	With pyridine at 80℃; for 120h;

Reference： [1]Current Patent Assignee: NANJING HUITELAI PHARMACEUTICAL - CN104557891, 2017, B Location in patent: Paragraph 0025
[2]Guimarães, Giovana C.; Piva, Hemily R.M.; Araújo, Gabriela C.; Lima, Caroline S.; Regasini, Luis O.; de Melo, Fernando A.; Fossey, Marcelo A.; Caruso, Ícaro P.; Souza, Fátima P. [International Journal of Biological Macromolecules, 2018, vol. 111, p. 33 - 38]

64
[ 22393-36-8 ]
[ 117-39-5 ]
[(2,2'-bipyridine)Cu(Quercetin)Cl].3H₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With triethylamine In ethanol; water at 20℃; for 0.166667h; Inert atmosphere;	2.2. Synthesis General procedure: General method: To a solution of (N^N)MCl2 (0.591 mmol) in10 mL degassed H2O was added 20 mL degassed ethanol solutioncontaining quercetin (0.200 g, 0.591 mmol) and NEt3 (0.16 mL,1.182 mmol). The product formed instantly as a red precipitate inthe case of Cu(II) complexes and orange solid in the case of Zn(II)complexes and was filtrated out, washed repeatedly with waterand ethanol and dried under vacuum.Complex 1, [bpyCuQCl]3H2O: 0.302 g (84%). Anal. Calc. for C25-H23ClCuN2O10 (610.46 gmol1): C, 49.19; H, 3.80; N, 4.59. Found:C, 49.25; H, 3.91; N, 4.79. AAS: Cu% calcd.: 10.41, found: 10.72.IR (KBr, cm-1): 3435.2, 3078.7 (νO-H), 1640.3 (νC=O), 1602.7 (νCC+ νNC), 1572.5 (νCC + νNC + δCCH), 1479.5 (νCOH), 1447.1 (νCC + νNC +δNCH), 1264.7 (νCOC), 1163.8 (νCC + δCCH), 764.4, 727.5 (ΓNCCH +ΓCCCH). TGA: (66.1 °C - onset peak) experimental mass loss 9.17%corresponds to 3H2O molecules (calcd. 8.85%); residue CuO: experimental13.55% (calcd. 13.03%).

Reference： [1]Andelescu, Adelina A.; Cretu, Carmen; Sasca, Viorel; Marinescu, Sorin; Cseh, Liliana; Costisor, Otilia; Szerb, Elisabeta I. [Polyhedron, 2018, vol. 147, p. 120 - 125]

65
[ 14491-36-2 ]
[ 117-39-5 ]
[(2,2'-bipyridine)Zn(Quercetin)Cl].3H₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With triethylamine In ethanol; water at 20℃; for 0.166667h; Inert atmosphere;	2.2. Synthesis General procedure: General method: To a solution of (N^N)MCl2 (0.591 mmol) in10 mL degassed H2O was added 20 mL degassed ethanol solutioncontaining quercetin (0.200 g, 0.591 mmol) and NEt3 (0.16 mL,1.182 mmol). The product formed instantly as a red precipitate inthe case of Cu(II) complexes and orange solid in the case of Zn(II)complexes and was filtrated out, washed repeatedly with waterand ethanol and dried under vacuum.

Reference： [1]Andelescu, Adelina A.; Cretu, Carmen; Sasca, Viorel; Marinescu, Sorin; Cseh, Liliana; Costisor, Otilia; Szerb, Elisabeta I. [Polyhedron, 2018, vol. 147, p. 120 - 125]

66
[ 14783-09-6 ]
[ 117-39-5 ]
[(1,10-phenanthroline)Cu(Quercetin)Cl].3H₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With triethylamine; In ethanol; water; at 20℃; for 0.166667h;Inert atmosphere;	General procedure: General method: To a solution of (N^N)MCl2 (0.591 mmol) in10 mL degassed H2O was added 20 mL degassed ethanol solutioncontaining quercetin (0.200 g, 0.591 mmol) and NEt3 (0.16 mL,1.182 mmol). The product formed instantly as a red precipitate inthe case of Cu(II) complexes and orange solid in the case of Zn(II)complexes and was filtrated out, washed repeatedly with waterand ethanol and dried under vacuum.

Reference： [1]Polyhedron,2018,vol. 147,p. 120 - 125

67
[ 14049-94-6 ]
[ 117-39-5 ]
[(1,10-phenanthroline)Zn(Quercetin)Cl].3H₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With triethylamine In ethanol; water at 20℃; for 0.166667h; Inert atmosphere;	2.2. Synthesis General procedure: General method: To a solution of (N^N)MCl2 (0.591 mmol) in10 mL degassed H2O was added 20 mL degassed ethanol solutioncontaining quercetin (0.200 g, 0.591 mmol) and NEt3 (0.16 mL,1.182 mmol). The product formed instantly as a red precipitate inthe case of Cu(II) complexes and orange solid in the case of Zn(II)complexes and was filtrated out, washed repeatedly with waterand ethanol and dried under vacuum.

Reference： [1]Andelescu, Adelina A.; Cretu, Carmen; Sasca, Viorel; Marinescu, Sorin; Cseh, Liliana; Costisor, Otilia; Szerb, Elisabeta I. [Polyhedron, 2018, vol. 147, p. 120 - 125]

68
[ 117-39-5 ]
[ 108-24-7 ]
[ 7622-90-4 ]

Yield	Reaction Conditions	Operation in experiment
98%	With magnesium In neat (no solvent) at 25℃; for 3.5h;	Quercetin-3’,4’,5,7-tetraacetate (2j) A mixture of quercetin (1j, 302.2 mg, 1 mmol), acetic anhydride (1.2 mL, 12 mmol) and magnesium metal powder (3.1 mg, 0.125 mmol) were stirred at 25 °C for 3.5 h (or at 50 °C for 3.5 h in another experiment). After completion of the reaction, the mixture was diluted with EtOAc (60 mL). The reaction mixture was washed with saturated NaHCO3 (30 mL × 2) and brine (30 mL), dried over Na2SO4, filtered, concentrated, and finally vacuum dried. The product quercetin-3’,4’,5,7-tetraacetate (2j) was directly obtained in a chromatographically pure form with the yield of 459.6 mg, 98% (the yield of the product 2j at 50 °C reaction condition was 446.0 mg, 95%). TLC Rf = 0.77 (silica gel, hexane/ethyl acetate, 1:3). DART-MS m/z = 470.27 (calcd for C23H18O11 = 470.0849). 1H NMR (CDCl3, 400 MHz) δ ppm: 12.11 (s, 1H), 7.76-7.73 (m, 2H), 7.37 (dd, J = 0.8, 8 Hz, 1H), 6.85 (d, J = 2.4 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 2.37 (s, 3H), 2.34 (s, 3H), 2.34 (s, 3H), 2.33 (s, 3H) (Figure S1). 13C-NMR (CDCl3, 100 MHz) δ ppm: 176.35, 168.29, 167.91, 167.84, 161.79, 156.43, 156.02, 155.65, 144.73, 142.33, 132.28, 127.62, 126.64, 124.11, 108.89, 105.63, 101.27, 21.28, 20.77, 20.50 (Figure S2). Anal. calcd for C23H18O11 (470.3860): C, 58.73; H, 3.86. Found: C, 58.58; H, 3.87.

Reference： [1]Bajracharya, Gan B.; Shrestha, Suryaman Sama [Synthetic Communications, 2018, vol. 48, # 13, p. 1688 - 1693]

69
[ 117-39-5 ]
[ 528-48-3 ]

Reference： [1]Bioscience, Biotechnology and Biochemistry,2018,vol. 82,p. 1316 - 1322

70
[ 117-39-5 ]
[ 79074-45-6 ]
2-(3,4-dihydroxyphenyl)-3,5,7-tris((3,5,6-trimethylpyrazin-2-yl)methoxy)-4H-chromen-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With potassium carbonate In tetrahydrofuran; N,N-dimethyl-formamide; acetone for 2h; Inert atmosphere;	2-(3,4-Dihydroxyphenyl)-3,5,7-tris((3,5,6-trimethylpyrazin-2-yl)methoxy)-4H-chromen-4-one (21). TMP-Br(7.09 mmol) and quercetin (1.66 mmol) were dissolved in dry DMF (30 mL), then K2CO3 (10.87 mmol)was added in portions. The mixture was refluxed and kept at 75 °C for 2 h under a nitrogenatmosphere; the brown solution was filtered and concentrated under vacuum. The product wasseparated by flash chromatography with dichloromethane-acetone (15:1) as eluent and recrystallizedfrom dichloromethane. Yellow powder, m.p.: 121.2-122.3 °C, yield 65%. 1H-NMR (CDCl3) (ppm) δ 12.63 (s, 1H), 7.48 (s, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.05 (d, J = 8.5 Hz, 1H), 6.53 (d, J = 1.6 Hz, 1H), 6.45(d, J = 1.5 Hz, 1H), 5.21 (s, 2H), 5.19 (s, 2H), 5.18 (s, 2H), 2.58 (s, 3H), 2.57 (s, 3H), 2.56 (s, 3H), 2.52 (s,9H), 2.51 (s, 3H), 2.42 (s, 3H), 2.40 (s, 3H) ; 13C-NMR (CDCl3) (ppm) δ 178.92, 164.45, 162.18, 156.94,156.85, 151.92, 151.87, 151.13, 150.03, 149.95, 149.49, 149.02, 148.82, 148.64, 148.35, 148.24, 145.45, 145.13,144.73, 137.59, 126.04, 121.31, 117.19, 116.91, 106.50, 98.73, 93.23, 73.15, 72.00, 70.38, 21.85, 21.68, 21.55,21.37, 21.06, 20.71, 20.59, 20.34. MS (ESI) m/z: [M + H]+ 705.3043, calcd. for C39H40N6O7 704.2958.
65%	With potassium carbonate In N,N-dimethyl-formamide at 75℃; for 2h; Inert atmosphere;	13 Example 13 Preparation of Derivatives of Ligustrazine and Quercetin (CH-12) Weigh 0.50g of quercetin in a 100mL round-bottom flask, put TMP-Br in a molar ratio of 1: 3, add an appropriate amount of anhydrous DMF to the reaction flask and stir to dissolve, then add an appropriate amount of K2CO3, under nitrogen protection, the reaction bottle was placed in an oil bath at 75 ° C and heated for 2h (TLC followed the reaction). After the reaction is complete, cool and filter. The filtrate was heated in a water bath at 55 ° C, and DMF was removed using a rotary evaporator. After reconstituting with dichloromethane, adding silica gel to mix samples, silica gel column separation and purification, eluent dichloromethane / acetone = 10: 1-2: 1 elution, improved color development of potassium bismuth iodide, TLC detection,Obtained light yellow granular target, compound CH-12. M.p .: 121.2-122.3 ° C, yield 65%.

Reference： [1]Wang, Hui; Zhang, Wenxi; Cheng, Yatao; Zhang, Xinyu; Xue, Nannan; Wu, Gaorong; Chen, Meng; Fang, Kang; Guo, Wenbo; Zhou, Fei; Cui, Herong; Ma, Tao; Wang, Penglong; Lei, Haimin [Molecules, 2018, vol. 23, # 9]
[2]Current Patent Assignee: XINHUOZHIYAO BEIJING TECH - CN110857295, 2020, A Location in patent: Paragraph 0128; 0129

71
[ 117-39-5 ]
[ 79074-45-6 ]
2-(3,4-bis((3,5,6-trimethylpyrazin-2-yl)methoxy)phenyl)-3,5,7-tris((3,5,6-trimethylpyrazin-2-yl)-methoxy)-4H-chromen-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With potassium carbonate In tetrahydrofuran; N,N-dimethyl-formamide; acetone for 2h; Inert atmosphere;	2-(3,4-bis((3,5,6-Trimethylpyrazin-2-yl)methoxy)phenyl)-3,5,7-tris((3,5,6-trimethylpyrazin-2-yl)-methoxy)-4Hchromen-4-one (22). TMP-Br (11.83 mmol) and quercetin (1.66 mmol) were dissolved in dry DMF(30 mL), then K2CO3 (10.87 mmol) was added in portions. The mixture was refluxed and kept at75 °C for 2 h under a nitrogen atmosphere; the brown solution was filtered and concentrated undervacuum. The product was separated by flash chromatography with dichloromethane-acetone (15:1)as eluent and recrystallized from dichloromethane. White powder, m.p.: 179.4-180.1 °C, yield 67%.1H-NMR (CDCl3) (ppm) δ 7.75 (s, 1H), 7.63 (dd, J = 8.6, 1.7 Hz, 1H), 7.08 (d, J = 8.7 Hz, 1H), 6.74 (s,1H), 6.70 (d, J = 1.8 Hz, 1H), 5.37 (s, 2H), 5.27 (s, 2H), 5.24 (s, 2H), 5.22 (s, 2H), 5.01 (s, 2H), 2.74 (s, 3H),2.65 (s, 3H), 2.61 (s, 3H), 2.55 (s, 9H), 2.53 (s, 4H), 2.52 (s, 15H), 2.50 (s, 3H), 2.39 (s, 3H), 2.32 (s, 3H);13C-NMR (CDCl3) (ppm) δ 173.50, 162.49, 159.57, 158.53, 153.02, 151.84, 151.31, 151.18, 151.12, 150.77,150.29, 150.18, 150.07, 149.98, 148.88, 148.49, 148.11, 148.02, 145.98, 145.54, 145.35, 145.19, 144.61, 139.67,123.86, 122.56, 114.44, 113.34, 110.02, 98.20, 94.63, 72.83, 71.24, 71.05, 70.91, 70.32, 21.78, 21.71, 21.68,21.52, 21.47, 21.39, 21.37, 21.29, 20.86, 20.73, 20.63, 20.57. MS (ESI) m/z: [M + H]+ 973.4751, calcd. forC55H60N10O7 972.4646.
67%	With potassium carbonate In N,N-dimethyl-formamide at 75℃; for 2h; Inert atmosphere;	14 Example 14 Preparation of Derivatives of Ligustrazine and Quercetin (CH-13) Weigh 0.50g of quercetin in a 100mL round-bottom flask, put TMP-Br at a molar ratio of 1: 5, add an appropriate amount of anhydrous DMF to the reaction flask and stir to dissolve, then add an appropriate amount of K2CO3, under nitrogen protection, the reaction bottle was placed in an oil bath at 75 ° C and heated for 2h (TLC followed the reaction). After the reaction is complete, cool and filter. The filtrate was heated in a water bath at 55 ° C, and DMF was removed using a rotary evaporator. After reconstituting with dichloromethane, adding silica gel to mix samples, silica gel column separation and purification, eluent dichloromethane / acetone = 10: 1-2: 1 elution, improved color development of potassium bismuth iodide, TLC detection,The target compound was obtained as a white powder, namely compound CH-13. M.p .: 179.4-180.1 , yield 67%.

Reference： [1]Wang, Hui; Zhang, Wenxi; Cheng, Yatao; Zhang, Xinyu; Xue, Nannan; Wu, Gaorong; Chen, Meng; Fang, Kang; Guo, Wenbo; Zhou, Fei; Cui, Herong; Ma, Tao; Wang, Penglong; Lei, Haimin [Molecules, 2018, vol. 23, # 9]
[2]Current Patent Assignee: XINHUOZHIYAO BEIJING TECH - CN110857295, 2020, A Location in patent: Paragraph 0130; 0131

72
[ 117-39-5 ]
[ 142-61-0 ]
3,5,7,3',4'-penta-O-hexanoyl-quercetin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With dmap; triethylamine In N,N-dimethyl-formamide at 20℃; for 4.5h; Cooling with ice;	General procedure for the synthesis of perhexanoylated flavonoid (1a-7a) General procedure: Flavonoid (1 (5.40 g, 0.02 mol), 2 (5.72 g, 0.02 mmol), 3 (5.45 g, 0.02 mmol), 4 (5.69 g, 0.02 mmol), 5 (5.08 g, 0.02 mmol), 6 (5.40 g, 0.02 mmol), or 7 (6.04 g, 0.02 mmol)) was dissolved in DMF (50 mL); Et3N (for 4, 5, 6.9 mL, 0.05 mol; for 1, 3, 6, 9.7 mL, 0.07 mol; for 2, 12.4 mL, 0.09 mol; for 7, 15.3 mL, 0.11 mol) and DMAP (240 mg, 2 mmol) were added. The mixture was then cooled in an ice-bath, and hexanoyl chloride (for 4, 5, 6.9 mL, 0.05 mol; for 1, 3, 6, 9.7 mL, 0.07 mol; for 2, 12.4 mL, 0.09 mol; for 7, 15.3 mL, 0.109 mol) was added and the reaction was allowed to slowly rise to room temperature in 30 min and stirred for an additional 4 h. After complete consumption of the flavonoid starting material as shown by TLC, the reaction mixture was diluted with CH2Cl2 (100 mL) and washed with 1 M HCl aqueous solution (100 mL), saturated aqueous NaHCO3 (100 mL * 2), brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the crude product (oil/solid), which was further purified by crystallization (methanol). Compound 1a-3a (1a, 9.8 g, 87%, Ref. [30]; 2a, 11.5 g, 85%; 3a, 10.4 g, 92%) were obtained as a light yellow solid and 4a-7a (4a, 8.4 g, 87%; 5a, 8.6 g, 95%, Ref. [28]; 6a, 9.1 g, 81%, Ref. [43]; 7a, 13.1 g, 83%) as a white solid. Analytical data and NMR spectra see Supporting Information.

Reference： [1]Zheng, Zhiwei; Han, Ziyi; Cai, Li; Zhou, Dandan; Chavis, Bryson R.; Li, Changsheng; Sui, Qiang; Jiang, Kaiyuan; Gao, Qi [Tetrahedron Letters, 2018, vol. 59, # 50, p. 4442 - 4447]

73
[ 7431-83-6 ]
[ 117-39-5 ]
[ 554-91-6 ]

Reference： [1]Chemistry of Natural Compounds,2016,vol. 52,p. 1093 - 1094
Khim. Prir. Soedin.,2016,p. 941 - 942,2

74
[ 609-99-4 ]
[ 117-39-5 ]
C₁₅H₁₀O₇*3C₇H₄N₂O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol at 20℃; for 3h;	2.5. Synthesis and separation of solid Qc/DSA, Qc/PA and Qc/ochloranilsolid charge transfer (CT) complexes The stable solid CT-complexes of Qc with DSA, PA, and ochloranilwere prepared by addition of 1M quantity of Qc with 3Mof DSA, PA and o-chloranil with 10 ml methanol individually. Thesolutions were stirred for about 3hr on a magnetic stirrer at roomtemperature and resulted in the precipitation of the yellow colouredprecipitation of stable CT-complexes. The formed solidcomplex was filtered off with Whatman 42 grade filter paper andwas washed twice with a minimum volume of solvent. Solid CTcomplexesthus collected dried under vacuum over anhydrouscalcium chloride for 48 h.

Reference： [1]Karmakar, Animesh; Singh, Bula [Journal of Molecular Structure, 2019, vol. 1180, p. 698 - 707]

75
[ 117-39-5 ]
[ 141-75-3 ]
[ 82546-97-2 ]

Yield	Reaction Conditions	Operation in experiment
52%	With triethylamine In tetrahydrofuran at 25 - 55℃; for 12h;	75 Example 75: [2-butanoyloxy-4-[3,5,7-tri(butanoyloxy)-4-oxo-chromen-2-yl]phenyl]butanoate To a mixture of 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-chromen-4-one (1 g) and butanoylchloride (3.53 g) in THE (40 mL) was added triethylamine (3.35 g) at 25°C, then the mixture was stirred at55°C for 12 h. The reaction mixture was concentrated in vacuum and purified by reverse phase prepH PLC (Cl 8, water(0.05%HCI)-aceton itri le gradient) to give [2-butanoyloxy-4-[3 ,5,7-tri(butanoyloxy)-4-oxo- chromen-2-yl]phenyl]butanoate (1.13 g, 52% yield) as a colorless solid. LCMS: 653.3 (M÷Hj 1H NMR (400 MHz, 0D013): O 7.666 - 7.608 (m, 2H), 7.292 - 7.210 (m, 2H), 6.880 (s, 1 H), 2.542 (t, 2H), 2.535 -2.484 (m, 8H), 1.753 (m, 1OH), 1.020 - 0.997 (m, 12H), 0.949 (t, 3H) ppm
52%	With triethylamine In tetrahydrofuran at 25 - 55℃; for 12h;	1 Compound 5: [2-butanoyloxy-4-[3,5,7-tri(butanoyloxy)-4-oxo-chromen-2-yl]phenyl] butanoate To a mixture of 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-chromen-4-one (1 g) and butanoyl chloride (3.53 g) in THF (40 ml_) was added TEA (3.35 g) at 25°C, then the mixture was stirred at 55 °C for 12 h. The reaction mixture was concentrated in vacuum and purified by reverse phase prep-HPLC (C18, water (0.05%HCI)-ACN gradient) to give compound 5 (1 .13 g, 52% yield) as a colorless solid. (0463) LCMS: 653.3 (M+H+) 1 H NMR (400 MHz, CDC ). 7.666 - 7.608 (m, 2H), 7.292 - 7.210 (m, 2H), 6.880 (s, 1 H), 2.542 (t, 2H), 2.535 - 2.484 (m, 8H), 1 .753 (m, 10H), 1 .020 - 0.997 (m, 12H), 0.949 (t, 3H).
52%	With triethylamine In tetrahydrofuran at 25 - 55℃; for 12h;	1 Compound 1 5: [2-butanoyloxy-4-[3,5,7-tri(butanoyloxy)-4-oxo-chromen-2-yl]phenyl] butanoate To a mixture of 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-chromen-4-one (1 g) and butanoyl chloride (3.53 g) in THF (40 mL) was added TEA (3.35 g) at 25°C, then the mixture was stirred at 55 °C for 12 h. The reaction mixture was concentrated in vacuum and purified by reverse phase prep-HPLC (C18, water(0.05%HCI)-ACN gradient) to give compound 15 (1 .13 g, 52% yield) as a colorless solid. LCMS: 653.3 (M+H+) 1H NMR (400 MHz, CDCb). d 7.666 - 7.608 (m, 2H), 7.292 - 7.210 (m, 2H),6.880 (s,1 H), 2.542 (t, 2H), 2.535 - 2.484 (m, 8H),1 .753 (m,10H),1 .020 - 0.997 (m,12H), 0.949 (t,3H).

52%

With triethylamine In tetrahydrofuran at 55℃; for 12h;

Compound 5: [2-butanoyloxy-4-[3,5,7-tri(butanoyloxy)-4-oxo-chromen-2-yl]phenyl]butanoate To a mixture of 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-chromen-4-one (1 g) and butanoyl chloride (3.53 g) in THF (40 ml_) was added TEA (3.35 g) at 25C, then the mixture was stirred at 55C for 12 h. The reaction mixture was concentrated in vacuum and purified by reverse phase prep-HPLC (C18, water (0.05%HCI)-ACN gradient) to give compound 5 (1 .13 g, 52% yield) as a colorless solid. LCMS: 653.3 (M+H+) 1H NMR (400 MHz, CDCI3). 7.666 - 7.608 (m, 2H), 7.292 - 7.210 (m, 2H), 6.880 (s, 1H), 2.542 (t, 2H), 2.535 -2.484 (m, 8H), 1 .753 (m, 10H), 1 .020 - 0.997 (m, 12H), 0.949 (t, 3H).

Reference： [1]Current Patent Assignee: FLAGSHIP PIONEERING INC - WO2018/226732, 2018, A1 Location in patent: Page/Page column 107
[2]Current Patent Assignee: FLAGSHIP PIONEERING INC - WO2019/236765, 2019, A1 Location in patent: Page/Page column 43
[3]Current Patent Assignee: FLAGSHIP PIONEERING INC - WO2019/236775, 2019, A1 Location in patent: Page/Page column 67; 73
[4]Current Patent Assignee: FLAGSHIP PIONEERING INC - WO2019/236772, 2019, A1 Location in patent: Page/Page column 55; 137

76
[ 117-39-5 ]
[ 111-64-8 ]
[2-octanoyloxy-4-[3,5,7-tri(octanoyloxy)-4-oxo-chromen-2-yl] phenyl] octanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%	With triethylamine In tetrahydrofuran at 25 - 55℃; for 12h;	76 Example 76: [2-octanoyloxy-4-[3,5,7-tri(octanoyloxy)-4-oxo-chromen-2-yl] phenyl] octanoate To a mixture of 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-chromen-4-one (0.32 g) and octanoylchloride (1 .72 g) in THE (20 mL) was added triethylamine (1 .07 g) at 25°C. Then the mixture was stirredat 55 °C for 12 h. A portion of the solvent was removed in vacuum and the precipitate was collected byfiltration to give [2-octanoyloxy-4-[3,5,7-tri(octanoyloxy)-4-oxo-chromen-2-yl] phenyl] octanoate (0.20 g,20%) as a white solid. 1H NMR (400 MHz, CDCI3): O 7.709 - 7.655 (m, 2H), 7.329 - 7.301 (m, 2H), 6.837(s, 1H), 2.723(t, 2H), 2.612-2.539(m, 8H), 1.751 (m, 10H), 1.412-1.309 (m, 40H), 0.896 (m, 15H)ppm
20%	With triethylamine In tetrahydrofuran at 25 - 55℃; for 12h;	1 Compound 6: [2-octanoyloxy-4-[3,5,7-tri(octanoyloxy)-4-oxo-chromen-2-yl] phenyl] octanoate To a mixture of 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-chromen-4-one (0.32 g) and octanoyl chloride (1 .72 g) in THF (20 mL) was added TEA (1 .07 g) at 25 °C. Then the mixture was stirred at 55 °C for 12 h. A portion of the solvent was removed in vacuum and the precipitate was collected by filtration to give compound 6 (0.20 g, 20%) as a white solid. 1 H NMR (400 MHz, CDCb). 7.709 - 7.655 (m, 2H), 7.329 - 7.301 (m, 2H), 6.837 (s, 1 H), 2.723 (t, 2H), 2.612 - 2.539 (m, 8H), 1 .751 (m, 10H), 1 .412 - 1 .309 (0467) (m, 40H), 0.896 (m, 15H).
20%	With triethylamine In tetrahydrofuran at 25 - 55℃; for 12h;	1 Compound 1 6: [2-octanoyloxy-4-[3,5,7-tri(octanoyloxy)-4-oxo-chromen-2-yl] phenyl] octanoate To a mixture of 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-chromen-4-one (0.32 g) and octanoyl chloride (1 .72 g) in THF (20 mL) was added TEA (1 .07 g) at 25°C. Then the mixture was stirred at 55 °C for 12 h. A portion of the solvent was removed in vacuum and the precipitate was collected by filtration to give compound 16 (0.20 g, 20%) as a white solid. 1H NMR (400 MHz, CDCI3). d 7.709 - 7.655 (m, 2H), 7.329 - 7.301 (m, 2H),6.837 (s,1 H), 2.723 (t, 2H), 2.612 - 2.539 (m, 8H),1 .751 (m,10H),1 .412 - 1 .309 (0782) (m,40H), 0.896 (m,15H).

20%

With triethylamine In tetrahydrofuran at 55℃; for 12h;

Compound 6: [2-octanoyloxy-4-[3,5,7-tri(octanoyloxy)-4-oxo-chromen-2-yl]phenyl]octanoate To a mixture of 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-chromen-4-one (0.32 g) and octanoyl chloride (1 .72 g) in THF (20 ml_) was added TEA (1 .07 g) at 25C. Then the mixture was stirred at 55 C for 12 h. A portion of the solvent was removed in vacuum and the precipitate was collected by filtration to give compound 6 (0.20 g, 20%) as a white solid. 1H NMR (400 MHz, CDCI3). 7.709 - 7.655 (m, 2H), 7.329 - 7.301 (m, 2H), 6.837 (s, 1H), 2.723 (t, 2H), 2.612 -2.539 (m, 8H), 1 .751 (m, 10H), 1 .412 - 1 .309 (m, 40H), 0.896 (m, 15H).

Reference： [1]Current Patent Assignee: FLAGSHIP PIONEERING INC - WO2018/226732, 2018, A1 Location in patent: Page/Page column 108
[2]Current Patent Assignee: FLAGSHIP PIONEERING INC - WO2019/236765, 2019, A1 Location in patent: Page/Page column 43
[3]Current Patent Assignee: FLAGSHIP PIONEERING INC - WO2019/236775, 2019, A1 Location in patent: Page/Page column 67; 73-74
[4]Current Patent Assignee: FLAGSHIP PIONEERING INC - WO2019/236772, 2019, A1 Location in patent: Page/Page column 56; 137

77
[ 117-39-5 ]
[ 112-13-0 ]
[2-decanoyloxy-4-[3,5,7-tris(decanoyloxy)-4-oxo-chromen-2-yl] phenyl] decanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With triethylamine In tetrahydrofuran at 25 - 55℃; for 12h;	77 Example 77: [2-decanoyloxy-4-[3,5,7-tris(decanoyloxy)-4-oxo-chromen-2-yl] phenyl] decanoate To a mixture of 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-chromen-4-one (1 g) and decanoylchloride (6.31 g) in THE (50 mL) was added triethylamine (3.35 g) at 25 00 then the mixture was stirredat 55°C for 12 h. A portion of the solvent was removed in vacuum and the precipitate was collected byfiltration to give [2-decanoyloxy-4-[3,5,7-tris(decanoyloxy)-4-oxo-chromen-2-yl] phenyl] decanoate (2.47 g,69%) as a white solid. 1H NMR (400 MHz, CDCI3): O 7.772 - 7.669 (m, 2H), 7.343 - 7.321 (m, 2H), 6.685(s, 1 H), 2.736 (t, 2H), 2.610 - 2.551 (m, 8H), 1.762 (m, 1 OH), 1 .557 - 1.295 (m, 50H), 0.899 (m, 1 5H)ppm
69%	With triethylamine In tetrahydrofuran at 25 - 55℃; for 12h;	1 Compound 7: [2-decanoyloxy-4-[3,5,7-tris(decanoyloxy)-4-oxo-chromen-2-yl] phenyl] decanoate To a mixture of 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-chromen-4-one (1 g) and decanoyl chloride (6.31 g) in THF (50 ml_) was added TEA (3.35 g) at 25 °C, then the mixture was stirred at 55 °C for 12 h. A portion of the solvent was removed in vacuum and the precipitate was collected by filtration to give compound 7 (2.47 g, 69%) as a white solid. 1 H NMR (400 MHz, CDCI3). 7.772 - 7.669 (m, 2H), 7.343 - 7.321 (m, 2H), 6.685 (s, 1 H), 2.736 (t, 2H), 2.610 - 2.551 (m, 8H), 1 .762 (m, 10H), 1 .557 - 1 .295 (m, 50H), 0.899 (m, 15H).
69%	With triethylamine In tetrahydrofuran at 25 - 55℃; for 12h;	1 Compound 1 7: [2-decanoyloxy-4-[3,5,7-tris(decanoyloxy)-4-oxo-chromen-2-yl] phenyl] decanoate To a mixture of 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-chromen-4-one (1 g) and decanoyl chloride (6.31 g) in THF (50 mL) was added TEA (3.35 g) at 25 °C, then the mixture was stirred at 55°C for 12 h. A portion of the solvent was removed in vacuum and the precipitate was collected by filtration to give compound 17 (2.47 g,69%) as a white solid. 1H NMR (400 MHz, CDCI3). d 7.772 - 7.669 (m, 2H), 7.343 - 7.321 (m, 2H),6.685 (s,1 H), 2.736 (t, 2H), 2.610 - 2.551 (m, 8H),1 .762 (m,10H),1 .557 - 1 .295 (m, 50H), 0.899 (m,15H).

69%

With triethylamine In tetrahydrofuran at 55℃; for 12h;

Compound 7: [2-decanoyloxy-4-[3,5,7-tris(decanoyloxy)-4-oxo-chromen-2-yl]phenyldecanoate To a mixture of 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-chromen-4-one (1 g) and decanoyl chloride (6.31 g) in THF (50 ml_) was added TEA (3.35 g) at 25 C, then the mixture was stirred at 55C for 12 h. A portion of the solvent was removed in vacuum and the precipitate was collected by filtration to give compound 7 (2.47 g, 69%) as a white solid. 1H NMR (400 MHz, CDCI3). 7.772 - 7.669 (m, 2H), 7.343 - 7.321 (m, 2H), 6.685 (s, 1H), 2.736 (t, 2H), 2.610 -2.551 (m, 8H), 1 .762 (m, 10H), 1 .557 - 1 .295 (m, 50H), 0.899 (m, 15H).

Reference： [1]Current Patent Assignee: FLAGSHIP PIONEERING INC - WO2018/226732, 2018, A1 Location in patent: Page/Page column 108
[2]Current Patent Assignee: FLAGSHIP PIONEERING INC - WO2019/236765, 2019, A1 Location in patent: Page/Page column 44
[3]Current Patent Assignee: FLAGSHIP PIONEERING INC - WO2019/236775, 2019, A1 Location in patent: Page/Page column 67; 74
[4]Current Patent Assignee: FLAGSHIP PIONEERING INC - WO2019/236772, 2019, A1 Location in patent: Page/Page column 56; 136-137

78
[ 69256-15-1 ]
[ 13306-05-3 ]
[ 117-39-5 ]
2R,4R-flavan-3,3,4-triol [ No CAS ]
[ 480-18-2 ]
[ 480-18-2 ]

Reference： [1]Journal of Agricultural and Food Chemistry,2019,vol. 67,p. 3595 - 3604

79
[ 117-39-5 ]
[ 529-44-2 ]
C₂₉H₁₆O₁₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With polyphenol oxidase; In aq. phosphate buffer; at 30℃; for 1.2h;	Weigh 75g of <strong>[529-44-2]myricetin</strong> and quercetin, respectively, dissolved in 15L of citric acid-dibasic sodium phosphate buffer with a pH of 4.0, and add a certain amount of pear polyphenol oxidase (addition amount is 1.5g/L).The aeration rate was 30 L/min, and the reaction was carried out at 30 C for 1.2 hours.Heating rapidly increased the temperature to 100 C to inactivate the polyphenol oxidase for 5 minutes.The obtained reaction liquid was subjected to column chromatography on a polyamide resin, and the column torus diameter ratio was 1:10, the volume ratio of the sample to the bed was 1:4, and the loading flow rate was 2 BV/h, followed by water,Elution with 5% aqueous ethanol solution and 95% aqueous ethanol solution.The 95% ethanol eluting site was collected, concentrated and dried under reduced pressure at 40 C to obtain a crude extract.Further separation and purification using BUCHI medium pressure preparation, column chromatography specification: 15mm * 310mm, filler C18, flow rate 3mL / min, the crude extract was dissolved in 35% ethanol aqueous solution (concentration of 80mg /mL) as a sample solution, the elution gradient was eluted with 15%-35% ethanol aqueous solution for 3h, 35% ethanol aqueous solution for 2h, 35%-60% ethanol aqueous solution eluted for 3h, 60%-95% ethanol aqueous solution for 2h, collected 35% ethanol water elution solution, 45 C minusThe mixture was concentrated to a non-alcoholic taste and lyophilized to give Compound 3 (HPLC purity ? 98%).

Reference： [1]Patent: CN109422786,2019,A .Location in patent: Paragraph 0060; 0061; 0062; 0063; 0064; 0065; 0066; 0067

80
[ 112-16-3 ]
[ 117-39-5 ]
2-hydroxy-4-(3,5,7-trihydroxy-4-oxo-4H-benzopyran-2-yl)phenyl dodecanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With sodium carbonate; triethylamine In tetrahydrofuran at 20℃; for 10h; Inert atmosphere;	1-4 Example 3: A method for synthesizing a quercetin derivative, the synthetic route is a target compound obtained by directly reacting with a quercetin and a dodecanoyl chloride under the action of a catalyst, and the method specifically comprises the following steps:S1, 10 mL of anhydrous THF was added to a 100 mL three-necked flask, then 151 mg of quercetin was added, and 136.25 mg of dodecanoyl chloride was dissolved in 10 mL of anhydrous THF, and slowly added dropwise to the reaction solution, and 25 mg of sodium carbonate and 15.18 mg of triethyl were added. Amine, vacuumed with a diaphragm vacuum pump, nitrogen protection throughout the whole process, ice water bath to room temperature shading reaction, rotation speed 650 rpm / min, reaction 10h;S2, adding 0.1 mol/L HCL at the end of the reaction, adjusting the pH to 6-7, adding 30 mL of ethyl acetate and 10 ml of purified water, extracting, separating, and the aqueous layer is further extracted twice with 30 mL of ethyl acetate;S3. After combining the organic layer obtained each time, anhydrous magnesium sulfate is added thereto and left overnight, and then the reaction liquid is sequentially suction-filtered, spin-dried by a rotary evaporator, and then subjected to 200-300 mesh silica gel column chromatography and liquid phase purification. That is, a quercetin derivative is obtained.The obtained product is 2-hydroxy-4-(3,5,7-trihydroxy-4-oxo-4H-benzopyran-2-yl)phenyldodecanoate, the yield is 80%, the purity is up to 96%, Rf=0.382.

Reference： [1]Current Patent Assignee: ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN110128385, 2019, A Location in patent: Paragraph 0031-0054

81
[ 117-39-5 ]
[ 120221-14-9 ]
[ 482-35-9 ]

Reference： [1]Journal of Organic Chemistry,2019,vol. 84,p. 11482 - 11492

82
[ 117-39-5 ]
sodium salt of 3,5,7-trihydroxy-2-(3,4-dihydroxy-5-sulfophenyl)-4(4H)-chromenone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	Stage #1: quercetol With sulfuric acid In water at 80℃; for 2h; Stage #2: With sodium hydroxide In water	Chemical synthesis of II and III General procedure: The synthesis of quercetin-5′-sulfonic acid (HQSA) and its sodiumsalt was described for the first time in 1914 [29]. We have proposed amodified and more efficient synthesis procedure. The compounds wereprepared in a two-stage process: the first stage consisted in synthesis ofquercetin-5′-sulfonic acid and the second one involved neutralization ofthe obtained acid. Quercetin (0.033 mol; 10 g) was mixed with 40 cm3of sulfuric(VI) acid with the density of 1.84 g·cm-3. The mixture washeated in a bath at 80 °C for 2 h with stirring. After the mixture wascooled down, 50 cm3 of purified water was added with continuousstirring. The orange-red precipitate of quercetin-5′-sulfonic acid wasfiltrated and double crystalized from the saturated aqueous solutionobtained at 80 °C. Then, it was neutralized to pH≈ 3.30 using 20% and10% NaOH/KOH solutions. The yellow precipitates were filtrated anddouble crystalized from the saturated water solutions. After air-dryingand triturating, yellow microcrystalline products were obtained. Theyields of synthesis were 74% and 68% for II and III, respectively.The stoichiometry of the obtained complexes was determined basedon elemental, XRF, and TG analyses as follows: C15H9O10SNa·4H2O.Anal. Data Calc.: C 37.82; H 3.60; S 6.73; Na 4.83; H2O 15.13%, found:C 37.55; H 3.63; S 6.32; Na 4,67; H2O 15.21%.C15H9O10SK·2H2O Anal. Data Calc.: C 39.47; H 2.87; S 7.02; K 8.57;H2O 7.89%, found: C 39.27; H 2,91; S 6.90; K 8,92; H2O 8.13%.The molecular structure of the compounds (Fig. 1) was characterizedby XPS and 1H/13C NMR spectroscopy, respectively.

Reference： [1]Czerwonka, Arkadiusz; Kałafut, Joanna; Kuźniar, Anna; Maciołek, Urszula; Mendyk, Ewaryst; Rzeski, Wojciech [Bioorganic Chemistry, 2019]

83
[ 117-39-5 ]
quercetin-5'-sulfonic acid, potassium salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	Stage #1: quercetol With sulfuric acid In water at 80℃; for 2h; Stage #2: With potassium hydroxide In water	Chemical synthesis of II and III General procedure: The synthesis of quercetin-5′-sulfonic acid (HQSA) and its sodiumsalt was described for the first time in 1914 [29]. We have proposed amodified and more efficient synthesis procedure. The compounds wereprepared in a two-stage process: the first stage consisted in synthesis ofquercetin-5′-sulfonic acid and the second one involved neutralization ofthe obtained acid. Quercetin (0.033 mol; 10 g) was mixed with 40 cm3of sulfuric(VI) acid with the density of 1.84 g·cm-3. The mixture washeated in a bath at 80 °C for 2 h with stirring. After the mixture wascooled down, 50 cm3 of purified water was added with continuousstirring. The orange-red precipitate of quercetin-5′-sulfonic acid wasfiltrated and double crystalized from the saturated aqueous solutionobtained at 80 °C. Then, it was neutralized to pH≈ 3.30 using 20% and10% NaOH/KOH solutions. The yellow precipitates were filtrated anddouble crystalized from the saturated water solutions. After air-dryingand triturating, yellow microcrystalline products were obtained. Theyields of synthesis were 74% and 68% for II and III, respectively.The stoichiometry of the obtained complexes was determined basedon elemental, XRF, and TG analyses as follows: C15H9O10SNa·4H2O.Anal. Data Calc.: C 37.82; H 3.60; S 6.73; Na 4.83; H2O 15.13%, found:C 37.55; H 3.63; S 6.32; Na 4,67; H2O 15.21%.C15H9O10SK·2H2O Anal. Data Calc.: C 39.47; H 2.87; S 7.02; K 8.57;H2O 7.89%, found: C 39.27; H 2,91; S 6.90; K 8,92; H2O 8.13%.The molecular structure of the compounds (Fig. 1) was characterizedby XPS and 1H/13C NMR spectroscopy, respectively.

Reference： [1]Czerwonka, Arkadiusz; Kałafut, Joanna; Kuźniar, Anna; Maciołek, Urszula; Mendyk, Ewaryst; Rzeski, Wojciech [Bioorganic Chemistry, 2019]

84
[ 366-18-7 ]
copper(II) chloride hydrate [ No CAS ]
[ 117-39-5 ]
C₂₇H₁₇ClCuN₂O₇*2.5H₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	Stage #1: copper(II) chloride hydrate; quercetol With sodium hydroxide In methanol at 20℃; for 1h; Stage #2: [2,2]bipyridinyl In methanol for 4h; Reflux;	General procedure for the synthesis of Complexes1-4 General procedure: Complexes 1-4 were synthesized by the following method.A solution of metal(II) chloride x-hydrate (0.5 mmol) in room temperature to a mixture of quercetin (0.5 mmol)and sodium hydroxide (0.5 mmol) in methanol (30 mL).The reaction mixture was stirred at room temperature for1 h and then a solution of 1,10-phenanthroline (phen)/2,2′-bipyiridine (bpy) in methanol (10 mL) was added. Theresulting mixture was refluxed for about 4 h. After 4 h, themixture was cooled to room temperature, the precipitatedsolid was filtered, wash and dried at room temperature(Scheme 1).

Reference： [1]Ari, Ferda; Erkisa, Merve; Sahin, Saliha; Ulukaya, Engin; Alper, Pınar; Mutlu Gençkal, Hasene [Journal of Biological Inorganic Chemistry, 2020, vol. 25, # 1, p. 161 - 177]

85
[ 117-39-5 ]
[ 106-96-7 ]
C₁₈H₁₂O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With potassium carbonate In N,N-dimethyl-formamide at 50 - 60℃; for 5h;	1 Add 3.0 g (10 mmol) quercetin and 1.68 g (10 mmol) K2CO3 to a reactor containing 20 mL of anhydrous DMF. Slowly add 1.18 g (10 mmol) bromopropyne under vigorous stirring and react at 50-60 5h. After the reaction was completed, the solvent was distilled off under reduced pressure. The residue was added with 20 mL of water, filtered, and the filter cake was washed with water and dried.Column chromatography purification,7-propargyloxyquercetin (II) was obtained with a yield of 67%.

Reference： [1]Current Patent Assignee: SHIJIAZHUANG UNIVERSITY - CN108047271, 2020, B Location in patent: Paragraph 0017-0019

86
[ 117-39-5 ]
[ 2106-10-7 ]
quercetin 7-α-O-glucoside [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With α-glucosidase from sulfolobus solfataricus; In dimethyl sulfoxide; at 45℃; for 2h;pH 9.0;Enzymatic reaction;	General procedure: A mixture of donor sugar (1, 0.12mmol) and acceptor (0.1mmol) in Tris-HCl buffer (5mL; 0.2M; pH 9.0) containing 30% DMSO was treated with MalA-D416A (1mg), and the mixture was incubated for 2h at 45C. The flavonoid glucosides were purified on a C18 SEP PAK cartridge (Waters) to remove unreacted sugar, DMSO, proteins and salts. After the solvent was evaporated under reduced pressure, transfer products were isolated by flash silica gel chromatography by solvent gradient elution (ethyl acetate/methanol/water, 17:2:1 to 7:2:1). The structures of purified product were characterized by LC-MS, 1D (1H and 13C) and 2D (COSY, HSQC, HMBC, and NOESY) NMR spectra, successively. The isolation yield of each transfer product was calculated using the weight of the isolated product based on the subjected flavonoid as the substrate.

Reference： [1]Bioorganic Chemistry,2021,vol. 107

87
[ 117-39-5 ]
[ 107-30-2 ]
2-(3,4-bis(methoxymethoxy)phenyl)-3,5,7-tris(methoxymethoxy)-4H-chromen-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 2.5h;	2.5.3. 2-(3,4-Bis(methoxymethoxy)phenyl)-3,5,7-tris(methoxymethoxy)-4H-chromen-4-one (6) A mixture of quercetin (4 g,13.23 mmol), NaH (4.23 g, 105.75 mmol) and MOMCl (10.6 g131.7 mmol) in DMF (50 mL) was stirred for 30 min at 0 °C. The reaction mixture was warm to room temperature and stirred for 2 h. The reaction solution was poured into ice water (200 mL). A solid was precipitated, filtration, collection and dried. Compound 6 was obtained as a white solid (5.87 g, 85%). 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 2.0 Hz, 1H), 7.71 (dd, J = 8.6, 2.0 Hz, 1H), 7.27 (d, J = 8.6Hz, 1H), 6.79 (d, J = 2.2 Hz, 1H), 6.73 (d, J = 2.2 Hz, 1H), 5.35 (s, 2H), 5.31 (s, 2H), 5.30 (s, 2H), 5.25 (s, 2H), 5.21 (s, 2H), 3.56 (s, 3H), 3.55 (s,3H), 3.54 (s,3H), 3.51 (s, 3H), 3.24 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 173.7, 161.2, 158.4, 158.2, 153.5, 149.2, 146.6, 137.8, 124.9, 123.7, 117.7, 115.7, 110.7, 101.5, 97.7, 96.9, 95.7, 95.5, 95.1, 94.4, 57.6, 56.6, 56.5, 56.4, 56.3.
85%	With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 2.5h;	2.5.3. 2-(3,4-Bis(methoxymethoxy)phenyl)-3,5,7-tris(methoxymethoxy)-4H-chromen-4-one (6) A mixture of quercetin (4 g,13.23 mmol), NaH (4.23 g, 105.75 mmol) and MOMCl (10.6 g131.7 mmol) in DMF (50 mL) was stirred for 30 min at 0 °C. The reaction mixture was warm to room temperature and stirred for 2 h. The reaction solution was poured into ice water (200 mL). A solid was precipitated, filtration, collection and dried. Compound 6 was obtained as a white solid (5.87 g, 85%). 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 2.0 Hz, 1H), 7.71 (dd, J = 8.6, 2.0 Hz, 1H), 7.27 (d, J = 8.6Hz, 1H), 6.79 (d, J = 2.2 Hz, 1H), 6.73 (d, J = 2.2 Hz, 1H), 5.35 (s, 2H), 5.31 (s, 2H), 5.30 (s, 2H), 5.25 (s, 2H), 5.21 (s, 2H), 3.56 (s, 3H), 3.55 (s,3H), 3.54 (s,3H), 3.51 (s, 3H), 3.24 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 173.7, 161.2, 158.4, 158.2, 153.5, 149.2, 146.6, 137.8, 124.9, 123.7, 117.7, 115.7, 110.7, 101.5, 97.7, 96.9, 95.7, 95.5, 95.1, 94.4, 57.6, 56.6, 56.5, 56.4, 56.3.

Reference： [1]Zhang, Yinan; Zhang, Xiaoting; Xiao, Zhiyi; Zhang, Xinying; Sun, Hua [Fitoterapia, 2022, vol. 156]
[2]Zhang, Yinan; Zhang, Xiaoting; Xiao, Zhiyi; Zhang, Xinying; Sun, Hua [Fitoterapia, 2022, vol. 156]

88
[ 2051-90-3 ]
[ 117-39-5 ]
C₄₁H₂₆O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	at 90℃; for 12h;	1-3 Example 1 Add quercetin (1g) to a 10ml glass reaction vial and dichlorodiphenylmethane (3.94mL), After adding a magnetic stirrer, place the reaction flask on a small modular heating magnetic stirrer, heat to 90°C, stir for 12h, cool to room temperature, Neutralized with aqueous sodium bicarbonate solution, extracted with ethyl acetate, After drying and concentration, 5 g of a red oily crude product containing 3',4',6,7-diphenylmethane protected quercetin marigold was obtained, with a yield of 85% and a purity of 34.51%.

Reference： [1]Current Patent Assignee: ZHEJIANG UNIVERSITY; CHENGUANG BIOTECH GROUP COMPANY LIMITED - CN113845504, 2021, A Location in patent: Paragraph 0009; 0032-0033; 0040-0041; 0044-0045

Type	HazMat fee for 500 gram (Estimated)
Excepted Quantity	USD 0.00
Limited Quantity	USD 15-60
Inaccessible (Haz class 6.1), Domestic	USD 80+
Inaccessible (Haz class 6.1), International	USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic	USD 100+
Accessible (Haz class 3, 4, 5 or 8), International	USD 200+

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
{[ item.p_purity ]}	{[ item.pr_size ]}	{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]}	{[ getRatePrice(item.pr_usd, 1,1) ]}	Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]}	{[ item.pr_usastock ]}	Inquiry -	{[ item.pr_chinastock ]}	Inquiry -

CAS No. :	117-39-5	MDL No. :	MFCD00006828
Formula :	C₁₅H₁₀O₇	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	REFJWTPEDVJJIY-UHFFFAOYSA-N
M.W :	302.24	Pubchem ID :	5280343
Synonyms :	Sophoretin;C.I. 75720;Xanthaurine.;Quertine;Quercetol;Quercetine;NSC 9219;NCI-C60106;Meletin;Kvercetin;NSC 9221	Chemical Name :	2-(3,4-Dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one

Num. heavy atoms :	22
Num. arom. heavy atoms :	16
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	7.0
Num. H-bond donors :	5.0
Molar Refractivity :	78.04
TPSA :	131.36 Å²

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-7.05 cm/s

[ CAS No. 117-39-5 ] {[proInfo.proName]}

Quality Control of [ 117-39-5 ]

Related Doc. of [ 117-39-5 ]

Product Details of [ 117-39-5 ]

Calculated chemistry of [ 117-39-5 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 117-39-5 ]

Application In Synthesis of [ 117-39-5 ]

[ 117-39-5 ] Synthesis Path-Upstream 1~4

[ 117-39-5 ] Synthesis Path-Downstream 1~88

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Log Po/w (iLOGP) :	1.63
Log Po/w (XLOGP3) :	1.54
Log Po/w (WLOGP) :	1.99
Log Po/w (MLOGP) :	-0.56
Log Po/w (SILICOS-IT) :	1.54
Consensus Log Po/w :	1.23

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Log S (ESOL) :	-3.16
Solubility :	0.211 mg/ml ; 0.000698 mol/l
Class :	Soluble
Log S (Ali) :	-3.91
Solubility :	0.0374 mg/ml ; 0.000124 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.24
Solubility :	0.173 mg/ml ; 0.000573 mol/l
Class :	Soluble

PAINS :	1.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	3.23

Signal Word:	Danger	Class:	6.1
Precautionary Statements:	P264-P270-P301+P310+P330-P405-P501	UN#:	2811
Hazard Statements:	H301	Packing Group:	Ⅲ
GHS Pictogram:

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P378
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P391	Collect spillage. Hazardous to the aquatic environment
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