Name: 3943-97-3|Methyl 3-(4-hydroxyphenyl)acrylate|98%
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SKU: A225252
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1
[ 67-56-1 ]
[ 7400-08-0 ]
[ 3943-97-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sulfuric acid for 24h; Reflux;	General procedure for the synthesis of compounds 9-12 and 21-29 General procedure: After dissolving the carboxylic acid in the alcohol, three drops of H2SO4 95% were added to the solution and the mixture was refluxed for 24 h. The solvent was evaporated under reduced pressure and water was added to the crude mixture. The pH of the aqueous layer was adjusted to 7 adding drops of a saturated solution of NaHCO3 and brine was added in the mixture. The aqueous layer was extracted three times with ethyl acetate; the organic layer was dried over Na2SO4 and the solvent was evaporated under reduced pressure yielding the final compound. Further purification step was made when it was necessary.
99%	With sulfuric acid for 7h; Heating;
99%	With sulfuric acid for 24h; Reflux;

99%	With sulfuric acid for 21h; Reflux;	15 (E)-Methyl 3-(4-hydroxyphenyl)acrylate (E)-Methyl 3-(4-hydroxyphenyl)acrylate (0403) (0404) p-Coumaric acid (3.0 g, 18.3 mmol) was suspended in MeOH (12 mL) and treated with 3 drops of conc. H2SO4. The mixture was refluxed for 21 h. The resulting clear solution was cooled to rt and concentrated under vacuum to yield a white solid that was dissolved in EtOAc and successively washed with sat. NaHCO3 solution (3×) and brine (3×). The organic layer was dried over anhydrous MgSO4 and evaporated to dryness under vacuum to afford 3.22 g (18.1 mmol, 99% yield) of a white solid identified by NMR as (E)-methyl 3-(4-hydroxyphenyl)acrylate. (0405) 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J=16.0 Hz, 1H), 7.43 (ddd, J=8.8, 2.8, 2.0 Hz, 2H), 6.86 (ddd, J=8.8, 2.8, 2.0 Hz, 2H), 6.30 (d, J=16.0 Hz, 1H), 5.47 (br s, 1H), 3.80 (s, 3H).
98%	Heating / reflux;	27.27a Step 27a. (E)-Methyl 3-(4-hydroxyphenyl)acrylate (Compound 0501-66) A mixture of 4-hydroxycinnamic acid (8.2 g, 50 mmol) and a drop of H2SO4 in methanol (30 mL) was heated to reflux overnight. Then the solvent was evaporated, the residue was dissolved in ethyl acetate, washed with saturated NaHCO3 solution twice, brine, dried over MgSO4, concentrated to give the title compound 0501-66 as white solid (8.7 g, 98%): LCMS: 179 [M+1]+.
98%	With sulfuric acid Heating / reflux;	27.a Example 27Preparation of (E)-3-(4-(2-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)ethoxy)phenyl)-N-hydroxyacrylamide (Compound 66)Step 27a. (E)-Methyl 3-(4-hydroxyphenyl)acrylate (Compound 0501-66); A mixture of 4-hydroxycinnamic acid (8.2 g, 50 mmol) and a drop of H2SO4 in methanol (30 mL) was heated to reflux overnight. Then the solvent was evaporated, the residue was dissolved in ethyl acetate, washed with saturated NaHCO3 solution twice, brine, dried over MgSO4, concentrated to give the title compound 0501-66 as white solid (8.7 g, 98%): LCMS: 179 [M+1]+.
97%	With Dowex 50 W (8200 4) Heating;
97%	With sulfuric acid for 12h; Reflux; Inert atmosphere;
96%	With sulfuric acid for 16h; Heating;
95%	With sulfuric acid for 24h; Molecular sieve; Reflux;
95%	With sulfuric acid for 24h; Molecular sieve;
95%	With acetyl chloride In methanol at 20℃; Inert atmosphere;	Preparation of methyl 4-hydroxycinnamate To a solution of anhydrous methanol (50 mL) in round bottom flask under N2 was added acetyl chloride (0.5 mL) followed by a solution of 4-hydroxycinnamic acid (1 g) in anhydrous methanol (10 mL). The mixture was stirred overnight at room temperature, added NaCl solution (20%, 100 mL) then extracted twice with ethyl acetate (150 mL). The organic layers were combined and washed with NaCl solution (20%, 50 mL), dried over MgSO2, then evaporated under reduced pressure. The product was purified by vacuum column chromatography on silica gel to give the title compound as white solid (1.04 g, yield 95%). 1H- and 13C-NMR spectrum were in good agreement with previously reported data[45].
95%	With sulfuric acid for 12h; Reflux;
94%	With sulfuric acid for 0.166667h; Irradiation;
93%	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 0.5h;
92%	With toluene-4-sulfonic acid for 24h; Reflux;
92%	With thionyl chloride
90%	With sulfuric acid for 24h; Heating;
89%	for 90h; Reflux; Inert atmosphere;	12 4.12. Methyl (E)-p-coumarate (24) To a solution of p-coumaric acid 22 (3.0 g, 18.3 mmol) in MeOH (40 mL) was added Dowex 50W-X8 (2.4 g) at room temperature and the resulting mixture was refluxed for 90 h. After the Dowex 50W-X8 was filtered, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography (30% AcOEt in hexane) to give a methyl ester with trace impurities. Recrystallization from CHCl3 gave 24 (2.91 g, 89%) as a white solid in a pure form. Mp: 130-132 °C; IR (KBr) 3384, 2952, 1689, 1634, 1602, 1517, 1435, 1284, 1200, 986, 834 cm-1; 1H NMR (600 MHz, CDCl3) δ 3.80 (s, 3H), 5.33 (s, 1H; OH), 6.30 (d, J=16.0 Hz, 1H), 6.85 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.5 Hz, 2H), 7.64 (d, J=16.0 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 51.7, 115.1, 115.9, 127.1, 130.0, 144.8, 157.8, 168.1; HRMS (FAB) calcd for C10H11O3 [M+H]+ 179.0708, found 179.0700.
88%	at 20℃; for 36h; Reflux;	1.7 (Example 1-7) Synthesis of intermediate 10 for glucose derivative () 3-(4-Hydroxyphenyl)methylacrylate (10) A mixed solution (amixture) of cinnamic acid (5 g, 30.48 mmol) was refluxed for 1.5 days in the presence of dry MeOH (300 mL) and concentrated (conc.) H2SO4 (1 drop). The solution was cooled to room temperature (r.t.) and then evaporated with 30% ammonia water under reduced pressure and neutralized. Finally, the solution was evaporated with EtOH, to thereby obtain a completely dried product. The dried residue was subj ected to silica gel column chromatography, to thereby obtain a colorless needle-like product 10 (4.8 g, 88%) from a fraction eluted with AcOEt-n-hexane (1:4, v/v). Melting point (m.p.) 122-123°C. Rf=0.23 (AcOEt:n-hexane, 1:8, v/v). IR (KBr) cm-1; 1600 (C=C), 1695 (C=O), 3380 (OH). 1H NMR (CDCl3, 300 MHz): δ 3.81 (s, 3H, O-Me), 5.92 [s, 1H, Ar-OH (exchangeable with D2O)], 6.32 (d, J=15.9 Hz, 1H, Ar-CH=CH-), 6.86 (d, 2H, J=8.4 Hz, Ar-H), 7.42 (d, 2H, J=8.4 Hz, Ar-H), 7.67 (d, J=15.9 Hz, 1H, Ar-CH=CH-).
87.98%	With sulfuric acid Reflux;	4.2. General Procedure for Preparation of Compounds 1-8 General procedure: p-Coumaric acid (0.1 g; 0.61 mmol) in alcohol (20 mL) was dissolved in the presence of H2SO4(0.2 mL) and refluxed for complete reaction (5-27 h), being observed using single spot thin-layerchromatography (TLC) [71], as published by Lopes et al. [44].
87%	With sulfuric acid for 24h; Reflux;	30 Example 30 (E) Synthesis of 3-(4-Hydroxyphenyl) Methyl Acrylate Add 4-hydroxycinnamic acid (1mmol, 164mg)Dissolved in anhydrous methanol (5mL),Add sulfuric acid (1 drop) under stirring at room temperature,The reaction was heated to reflux for 24 hours.Cool down the mixture,And the solvent was removed in vacuo.The residue was dissolved in ethyl acetate (30 mL),And use saturated sodium bicarbonate aqueous solution (20mL)Wash with saturated aqueous NaCl solution (2×20 mL).After filtering, dry with anhydrous Na2SO4,After the filtrate is concentrated,Separation and purification by column chromatography,The eluent is EtOAc:petroleum ether=1:5,A white solid compound is obtained,The yield was 87%.
85%	With thionyl chloride at 0℃; Reflux; Inert atmosphere;	5.2. General procedure for preparation of esters General procedure: Thionyl chloride (1.16 g, 1.5 equiv) was added drop-wise to a solution of acid (1.0 g, 1.0 equiv) in the corresponding alcohol (15 ml) at 0&d eg;C. The solution was refluxed under a nitrogen atmosphere until all starting material was consumed (TLC monitoring). Then the solvent was removed under vacuo and the residue was purified by silica gel column chromatography eluting with ethyl acetate/n-hexane to afford the corresponding carboxylic esters.
82%	With sulfuric acid for 5.5h; Heating;
82%	With sulfuric acid at 80℃; for 0.25h; Microwave irradiation;	4.1.3. General Procedure for the Synthesis of Compounds 14-17 General procedure: In a 30 mL glass pressure microwave tube, equipped with a magnetic stirrer bar, a fewdrops of concentrated sulphuric acid were added to a solution of hydroxycinnamic acid(p-coumaric acid or caffeic acid or ferulic acid) (1 eq) in methanol (for 14-16) or ethanol(for 17) (10 mL). The mixture was subjected to microwave irradiation (power: 150 W;temperature: 80 C for 14-16 and 98 C for 17) for 15 min, basified with aqueous sodiumbicarbonate (5% solution), and extracted with dichloromethane (3 5 mL). The collectedorganic phases were dried over anhydrous sodium sulphate and evaporated to dryness togive the pure ester. (E)-Methyl 3-(4-hydroxyphenyl)acrylate 14: white solid; 82%; mp 125-127 C ([58] 132-134 C); 1H-NMR 3.79 (s, 3H), 5.37 (bs, 1H), 6.28 (d, J = 16.0 Hz, 1H), 6.85 (m, Ar, 2H), 7.42(m, Ar, 2H), 7.63 (d, J = 16.0, 1H); 13C-NMR 51.75, 114.52, 115.91, 125.98, 129.89, 144.79,158.12, 167.65. Anal. Calcd. for C10H10O3 C, 67.41; H, 5.66; Found: C, 67.53; H, 5.56.
79%	With sulfuric acid at 60℃; for 72h;
78%	With sulfuric acid at 45℃; for 2h;
78%	With sulfuric acid for 24h; Heating;
77.8%	With sulfuric acid at 80℃; for 5h;	Prerjaration of reagent KR-28: Methyl (E)-3-(4-hydroxyrjhenyl)rjrorj-2-enoate A solution of the commercially available trans-4-hydroxycinnamic acid, 16, (5 g, 30.5 mmol) in MeOH (30 mL) was added H2504 (3 mL), then the mixture was stirred at 80 00 for 5 h. The resulting mixture was cooled to room temperature and concentrated under vacuo. The mixture was quenched into water, extracted with EA, dried with anhydrous Na2504, concentrated to givethe product KR-28 (4.2 g, 77.8%) as a pale yellow solid. ESI-MS (Mi-i): 179.1 calc. for 010H1003: 178.0.
75%	With sulfuric acid for 2h; Reflux;	Synthesis of (E)-methyl 3-(4-hydroxyphenyl)acrylate (13): A 5 gof trans-4-hydroxy cinnamic acid (12) (30.49 mmol, 1 equiv) was dissolved in 20 mL of methanol. A 0.33 mL of conc. H2SO4 (6.10 mmol, 0.2 equiv) was added. This reaction mixture was refluxed for 2 hr. Methanol was evaporated and the reaction mixture was washed with aq. NaHCO3 solution. Further it was extracted in ethyl acetate and concentrated to get desired compound. Light pale yellow liquid, Yield: 75%, Rf: 0.5 (2:8 EtOAc: hexane), IR (cm-1): 1595 (C=C), 1680 (C=O), 2357(C-H), 3281(O-H). 1H NMR (400 MHz, CDCl3): δ 3.71(s, 3H,CH3); 6.31 (d, 1H, J = 16 Hz, CH=CH); 6.79 (m, 2H); 7.44-7.47(m, 2H); 7.55 (d, 1H, J = 16 Hz, CH=CH); 9.85 (s, 1H, OH); 13C NMR (CDCl3): δ 50.00, 113.69, 115.66, 124.91, 129.85, 144.53, 159.76,166.87; MS-ESI (m/z):179.59 (M+1).
74.1%	With boron trifluoride diethyl etherate at 70℃; for 2h;	1 Boron trifluoride etherate (0.067 mol) is added to a solution of coumaric acid (0.034 mol) in methanol (50 ml) in a 250 ml round bottom flask and the mixture stirred at 70° C. for 2 hours and evaporated to dryness under reduced vacuum. The residual solid is taken up in CH2Cl2, washed with aqueous NaHCO3, dried over MgSO4 and filtered to provide, after evaporation of the CH2Cl2, the desired product as a pale yellow solid in 74.1% yield.
74%	With acetyl chloride at 20℃;
63%	With sulfuric acid Heating;
58%	With sulfuric acid for 2h; Reflux;
57%	With sulfuric acid for 3h;	2.3. Synthesis of the esters General procedure: The ester derivatives (b-f) were synthesized following classicFischer esterification [18] using 1 mmol of the corresponding acid,0.1 mL of concentrated sulfuric acid and the corresponding alcohol assolvent. The reaction proceeded for 3 h or until no more acid was observedin TLC. The reaction mixture was neutralized with aqueousNaHCO3 saturated solution, and the solvent excess was evaporatedunder reduced pressure. The residue was taken up in 10 mL ethylacetate and washed with 3x10 mL of saturated NaHCO3 solution and10 mL of water. The organic layer was dried with anhydrous Na2SO4.The desired compounds were further purified in a silica gel columnchromatography, using hexane:ethyl acetate as eluent.Methyl p-coumarate (1b). White solid (m.p. 134-136 °C); 57% yield.1H NMR (CDCl3) δ 7.65 (d, J = 16.0 Hz, 1H), 7.42 (d, J = 8.6 Hz, 2H),6.86 (d, J = 8.6 Hz, 2H), 6.30 (d, J = 16.0 Hz, 1H), 6.11 (s, 1H), 3.81(s, 3H).
56%	With sulfuric acid Reflux;	2.3. General procedure for the synthesis of the esters General procedure: The ester derivatives (p-coumarates 1a-c and cinnamates 2a-c) weresynthesized following classic Fischer esterification. In a flask, 1 mmol ofthe corresponding acid (1 or cinnamic acid 2) and 0.1 mL of concentratedsulfuric acid were added to an excess (10 mL) of correspondingalcohol (methanol, ethanol or isopropanol) as solvent. Thereaction mixture was stirred under reflux for 3-24 hours until no morestarting acid was present (monitored by thin layer chromatography,TLC). The acid was neutralized with saturated sodium bicarbonate solution,and the excess of alcohol was evaporated under reduced pressure.The residue was taken up in 15 mL ethyl acetate and washed threetimes with 15 mL saturated sodium bicarbonate solution and dried overanhydrous sodium sulfate. The solvent was removed and the crudeproduct was purified through open silica gel column chromatographyusing hexane:ethyl acetate as eluent. The yields are given after chromatographicpurification.
54.4%	With sulfuric acid Reflux;	3.1 General procedure for the synthesis of compounds General procedure: A mixture of organic acid (0.5 g) and methanol (100 ml) was heated under reflux in presence of sulphuric acid (0.8 ml) until the completion of the reaction which was checked by single spot TLC. Then, methanol was removed under reduced pressure a half and the solution was diluted with 20 ml of water. The product was extracted with ethyl acetate (30 ml). The organic phase was neutralized successively with NaHCO3 5%and water, dried over anhydrous Na2SO4, and filtered. The ethyl acetate phase was separated, which on evaporation yielded the ester derivatives
17%
	With sulfuric acid at 75 - 80℃; unter Druck;
	With sulfuric acid
	With hydrogenchloride for 5h;
	With hydrogenchloride for 6h; Heating;
	With Dowex 50W-8X cation-exhange resin for 3h;
	With Dowex 50 W x 8200-400 Heating;
	With sulfuric acid at 90℃; for 16h;
	With hydrogenchloride Heating;
	With thionyl chloride at 23℃; for 16h;
	With toluene-4-sulfonic acid for 5h; Heating;
	With sulfuric acid for 12h; Heating;
	at 20℃;
	With boron trichloride at 55℃; for 0.0833333h;
	With sulfuric acid for 16h; Heating;
	Stage #1: methanol With thionyl chloride at 0℃; for 0.5h; Stage #2: p-Coumaric Acid for 1.5h; Heating / reflux;	106 Thionyl chloride (1.75 mL) was dropwise added under stirring to methanol at 0°C. After 30 minutes 4-hydroxycinnamic acid (3.29 g) was added and the mixture was refluxed for 1.5 h. The solvent was evaporated in vacuo and the residue was crystalized from diisopropyl ether and hexane to give Compound (106) (2.41 g) as a white crystal. 1H-NMR (300 MHz, CDCL3, ) : 3.80 (3H, s), 5.44 (1H, s), 6.31 (1H, d, J=16 Hz), 6.85 (2xlH, d, J=8.5 Hz), 7.43 (2xlH, d, J=8.5 Hz), 7.64 (1H, d, J=16 Hz); MASS (ES-): m/e 177.
	Stage #1: methanol With thionyl chloride at 0℃; for 0.5h; Stage #2: p-Coumaric Acid In methanol for 1.5h; Heating / reflux;	106 Preparation 106 Thionyl chloride (1.75 mL) was dropwise added under stirring to methanol at 0° C. After 30 minutes 4-hydroxycinnamic acid (3.29 g) was added and the mixture was refluxed for 1.5 h. The solvent was evaporated in vacuo and the residue was crystalized from diisopropyl ether and hexane to give Compound (106) (2.41 g) as a white crystal. 1H-NMR (300 MHz, CDCl3, δ): 3.80 (3H, s), 5.44 (1H, s), 6.31 (1H, d, J=16 Hz), 6.85 (2×1H, d, J=8.5 Hz), 7.43 (2×1H, d, J=8.5 Hz), 7.64 (1H, d, J=16 Hz); MASS (ES-): m/e 177.
	With sulfuric acid for 2h; Reflux;	Synthesis of methyl p-coumarate (4), methyl caffeate (5), and methyl ferulate (6) The appropriate phenolic acid (100 mg) was dissolved in MeOH (50 ml) to which 3 drops of H2SO4 had been added. The solution was refluxed for 2 h, NaHCO3 (100 mg) was added, and the solvent was evaporated in vacuo at 40 °C. The residue was partitioned between Et2O (15 mL) and H2O (15 mL), the organic layer separated, dried (Na2SO4), and the solvent was evaporated in vacuo to afford the desired ester, as a white solid. The esters were used in the oxidation reaction without further purification.
	With sulfuric acid at 80℃; for 16h;	11.A [00324] Method A: A mixture of cinnamic acid (25 mmol) and concentrated H2S04 (0.1 ml_) in anhydrous MeOH (25 mL) was refluxed at 80¾ (bath temperature) for 16 h. After the excess MeOH was removed by a rotary evaporator, the residue was treated with H20 (50 mL), and the resulting mixture was extracted with EtOAc (3^50 mL). The combined extracts were washed with H20 (50 mL) and brine (50 mL), and dried (anhydrous Na2S04). The solvent was evaporated to dryness, and the crude products were purified by flash silica gel chromatography (eluting with 10-60% hexane in EtOAc) to afford methyl cinnamate. To an ice-cold solution of methyl cinnamate described above (8 mmol) dissolved in anhydrous MeOH (10 mL) and THF (10 mL) was added hydroxylamine hydrochloride (1.67g, 24 mmol, 3 equiv) followed by 25% sodium methoxide in methanol solution (8.4 mL, 36 mmol, 4.5 equiv). The reaction mixture was stirred under argon and at 0 for 2 h, then allowed to warm to ambient temperature with the stirring was continued overnight (16 h). The resulting yellow suspension was condensed to dryness with a rotary evaporator, and the residue was treated with 1 N HCI aqueous solution (30 mL). The mixture was extracted with EtOAc (3 <50 mL), and dried (anhydrous Na2S04). Evaporation of the solvent afforded the crude products (480 mg), which was purified by flash silica gel chromatography (eluting with 5-15% MeOH in DCM) to afford the hydroxamate.[00325] Using Method A, Compounds 103, 125, 129, 130, and 131 were synthesized. The carboxyl acid of PCA was converted to hydroxamite to synthesize compound 103 by reacting methyl ester 101 with hydroxylamine under basic conditions. Compound 103 was a light-brown solid, obtained at 25% yield (based on the methyl ester). The hydroxyl group of 103 was replaced by methoxy group, resulting in the hydroxamate 125. Compound 125 was light-brown solid, obtained at 67% yield. Compound 129 was light-brown solid, obtained at 21 % yield. Compound 130 was an off-white solid, obtained at 63% yield. Compound 131 was a grey solid, obtained at 25% yield. Identity of compounds was verified by H NMR (75 MHz, CD3OD).
	With acetyl chloride
280 g	With sulfuric acid for 5h; Reflux;	1 Example 1 First Step: (0174) trans-Coumaric acid (400 g) was added to methanol (1,200 ml) and concentrated sulfuric acid (10 g) was added dropwise, and the mixture was heated under reflux with stirring for 5 hours. After the reaction mixture had been cooled to room temperature, the methanol was distilled off under reduced pressure. The resulting residue was poured into ice-water (2,000 ml), and the mixture was extracted with ethyl acetate (2,000 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. The ethyl acetate was distilled off under reduced pressure, and the resulting residue was recrystallized from ethanol to give the compound (ex-1) (280 g).
15.6 g	With acetyl chloride at 0 - 75℃; for 5h;
	With sulfuric acid In methanol for 5h; Reflux;
	With sulfuric acid for 1h; Reflux;	Synthesis of cinnamic acid derivatives Zosteric acid was synthesized as already described in a previous work [16]. The cis isomer 38was obtained starting from cis 4-hydroxycinnamic acid 32 under microwave irradiation in thepresence of sulfur trioxide pyridine complex in acetonitrile (Fig 3). The final product was isolatedas sodium salt. Most of the substituted cinnamic acid derivatives were prepared in highyield (> 90%) by the Knoevenagel-Doebner procedure. In detail, compounds 2, 7, 8, 11 and 17were obtained through a one-pot reaction between the suitable substituted benzaldehyde andmalonic acid in refluxing pyridine to induce decarboxylation (Fig 4) [20]. The trans geometriesof the ethenyl π-bonds were confirmed by proton-proton coupling constants. Cis cinnamicacid 37 was synthesized from the commercially available ethyl phenylpropiolate. The subsequenthydrogenation of alkyne in the presence of the Lindlar catalyst and pyridine in methanolled to the corresponding cis-alkene 36. Then the ester group was hydrolyzed under alkaline conditions to provide the final compound 37 (Fig 5). Esters of cinnamic acid in cis (33) or intrans configuration (23, 24) were prepared by Fischer esterification of the carboxylic group[21]. The protection of the hydroxyl group as methyl ether in the presence of iodomethane indry N,N-dimethylformamide provided the compounds 35. The hydrolysis of the ester was performedin alkaline conditions to obtain compound 34 (Fig 3).
	With sulfuric acid for 12h; Reflux;	3.2. General Method for Synthesizing Compounds 5-12 General procedure: Ferulic acid (1) or trans-4-hydroxycinnamic acid (2) or isoferulic acid (3) or trans-3-hydroxycinnamic acid (4) and five drops of H2SO4 (95%) were refluxed in methanol or ethanol for 12 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed with a 5% aqueous NaHCO3 solution and water. After drying over anhydrous Na2SO4,the ethyl acetate was removed in vacuo. The residue was purified by column chromatography on silica gel using ethyl acetate/petroleum ether mixtures as eluents to afford compounds 5-12.
	With hydrogenchloride In water at 65℃;
280 g	With sulfuric acid for 5h; Reflux;	1.2 400 g of trans-p-coumaric acid was added to 1200 ml of methanol, 10 g of concentrated sulfuric acid was added dropwise, and the mixture was stirred under reflux for 5 hours. After cooling to room temperature, methanol was distilled off under reduced pressure. The obtained residue was poured into 2000 ml of ice water, 2000 ml of ethyl acetate And the organic layer was separated. The obtained organic layer was washed with saturated aqueous sodium bicarbonate and water, And dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, The resulting residue was recrystallized from ethanol to obtain 280 g of Compound (ex-2).
	With sulfuric acid for 24h; Reflux;
	With thionyl chloride at 0 - 20℃; for 1h;	3.5.2. Preparation of M2 (methyl (E)-3-(4-((3,5,6-trimethylpyrazin-2-yl)methoxy)phenyl)acrylate)) To verify the accuracy of the proposed structure, we synthesized one of the metabolites, M2. Hydroxycinnamic acid (10.14 mmol) was added to anhydrous methanol (30 mL). After complete dissolution, thionyl chloride was slowly added dropwise under ice-cooling, while being stirred at 0 °C for 0.5 h, and then the temperature was slowly raised to room temperature. Then, the reaction solution was evaporated under reduced pressure. The reaction product was placed in a one-necked flask with potassium carbonate and N,N-dimethylformamide was added; the mixture was stirred at 65 °C for 3 h under nitrogen. Water was added to the reaction solution for dispersion before extraction with methylene chloride. After being evaporated, the residue was eluted with silica gel, and metabolite M2 was obtained. M2: m.p.: 124.0-124.4 °C. 1H-NMR (500 MHz, CDCl3) δ 7.64-7.61 (d, J = 7.6Hz, 1H, Ar-H), 7.46-7.44 (d, J = 7.4 Hz, 1H, Ar-H), 7.01-6.99 (d, J = 7.3 Hz, 1H, Ar-H), 6.31-6.28 (d, J = 6.3 Hz, 1H, Ar-H), 5.16 (s, 2H, -CH2), 3.78, 2.63 (s, 3H, -CH3), 2.57 (s, 3H, -CH3), 2.51 (s, 3H, -CH3) 13C-NMR (150 MHz, CDCl3) δ 167.92, 160.58, 151.73, 150.20, 148.92, 145.45, 144.61, 129.93, 127.80, 115.78, 115.64, 115.43, 70.22 (-CH2), 51.81 (-OCH3), 21.94 (-CH3), 21.65 (-CH3), 20.85 (-CH3), HR-MS (ESI) m/z: 313.16403 [M + H]+, calcd. for C18H20N2O3.
	With sulfuric acid for 24h; Reflux;
	With sulfuric acid for 48h; Reflux;	(E)-Methyl 3-(4-hydroxyphenyl)acrylate (13) Acid 12 (1.06 g 6.46 mmol) was dissolved in dry methanol. 2-3drops of conc. sulfuric acid were added and solution obtained was refluxedfor a two days until disappearing of starting material (controlledby TLC, CH2Cl2-acetic acid 100:1). After completion of the reactionmethanol was evaporated under vacuum. A residue was re-dissolved inethyl acetate (30 mL) and washed with water (10 mL), brine (10 mL)and dried over magnesium sulfate. Solvent was evaporated and theresidue was used in following step without further purification.White-off powder, 92% yield. 1H NMR (400 MHz, CDCl3) δ 3.81 (s,3H), 6.30 (d, J=16.0 Hz, 1H), 6.53 (br.s, 1H), 6.82-6.91 (m, 2H), 7.41(d, J = 8.6 Hz, 2H), 7.64 (d, J = 16.0 Hz, 1H).
	With acetyl chloride at 20℃; for 51h;

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2
[ 7400-08-0 ]
[ 3943-97-3 ]

Yield	Reaction Conditions	Operation in experiment
98%	With sulfuric acid In methanol Heating / reflux;	27.27a A mixture of 4-hydroxycinnamic acid (8.2 g, 50 mmol) and a drop OfH2SO4 in methanol (30 mL) was heated to reflux overnight. Then the solvent was evaporated, the residue was dissolved in ethyl acetate, washed with saturated NaHCO3 solution twice, brine, dried over MgSO4, concentrated to give the title compound 0501-66 as white solid (8.7 g, 98%): LCMS: 179 [M+l]+.
61%	With sulfuric acid In methanol; ethanol; water	1 4-Hydroxycinnamic Acid Methyl Ester (Compound 2a) Example 1 4-Hydroxycinnamic Acid Methyl Ester (Compound 2a) A solution of 4-hydroxycinnamic acid (compound 1a, 20.0 g, 0.12 mol) and 5 drops of concentrated sulfuric acid in 500 mL of reagent grade methanol was stirred for four days at 55° C., while monitored by TLC. The solvent was then removed from the reaction mixture on the rotovap and the solid residue was recrystallized from a mixture of 200 mL of ethanol and 200 mL of water to give 13.3 g of product in 61% yield: 13C NMR (75.4 MHz, CDCl3) δ 168.18, 157.88, 144.85, 129.95, 126.91, 115.86, 114.87, 51.81.
	With methanol; sulfuric acid

	Multi-step reaction with 4 steps 1: K₂CO₃ / dimethylformamide / Heating 2: aq. NaOH / methanol / 70 °C 3: K₂CO₃ / acetone / Heating 4: aq. HCl; AcOH / 70 °C
	With sulfuric acid In methanol; water	6.1 Synthesis of Compound (1c) 1) 25 g (0.152 mol) of p-hydroxycinnamic acid was dissolved in 100 ml of methanol, to which 1 g of concentrated sulfuric acid was added and refluxed for 8 hours. After allowing the system to cool down to room temperature, twice the amount of water was added thereto. The pellet was collected by filtration, washed with water, and dried. 25 g of a yellowish white solid was obtained. The solid was recrystallized from toluene. As a result, 21 g of methyl para-hydroxycinnamate was obtained as a yellowish white solid.
	Multi-step reaction with 2 steps 1: thionyl chloride / dichloromethane / 2 h / 20 °C / Reflux 2: dichloromethane / 3 h / Reflux
	Multi-step reaction with 2 steps 1: thionyl chloride / 2 h / 85 °C 2: triethylamine / 2 h / 20 °C

Reference： [1]Current Patent Assignee: CURIS INC - WO2008/33747, 2008, A2 Location in patent: Page/Page column 134
[2]Current Patent Assignee: BELROSE PHARMA INC - US2009/17004, 2009, A1
[3]Schmid; Karrer [Helvetica Chimica Acta, 1945, vol. 28, p. 722,738]
[4]Silva, A. M. S.; Alkorta, I.; Elguero, J.; Silva, V. L. M. [Journal of Molecular Structure, 2001, vol. 595, # 1-3, p. 1 - 6]
[5]Current Patent Assignee: KAO CORPORATION - US5505936, 1996, A
[6]Zhang, Zhenghua; Liu, Jinbing; Wu, Fengyan; Zhao, Liangzhong [Letters in drug design and discovery, 2013, vol. 10, # 6, p. 529 - 534]
[7]Lei, Tao; Zhou, Chao; Huang, Mao-Yong; Zhao, Lei-Min; Yang, Bing; Ye, Chen; Xiao, Hongyan; Meng, Qing-Yuan; Ramamurthy, Vaidhyanathan; Tung, Chen-Ho; Wu, Li-Zhu [Angewandte Chemie - International Edition, 2017, vol. 56, # 48, p. 15407 - 15410][Angew. Chem., 2017, vol. 48, # 129, p. 15609 - 15612,4]

3
[ 3943-97-3 ]
[ 108-24-7 ]
methyl (2E)-3-[4-(acetyloxy)phenyl]-2-propenoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With pyridine at 20℃; for 26h;	5 Reference Example 5; methyl (2E)-3-[4-(acetyloxy)phenyl]acrylate; [Show Image] To a solution of methyl (2E)-3-(4-hydroxyphenyl)acrylate (5.35 g, 30.0 mmol) in acetic anhydride (45.0 mL, 476 mmol) was added pyridine (4.85 mL, 60.0 mmol), and the mixture was stirred at room temperature for 26 hr. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals were washed with ethyl acetate-hexane to give the title compound (6.15 g, yield 93%) as colorless crystals. MS m/z 221 (MH+) .
	With pyridine
	With pyridine; dmap In dichloromethane

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1916234, 2008, A1 Location in patent: Page/Page column 28
[2]Freudenberg; Gehrke [Chemische Berichte, 1951, vol. 84, p. 443,450]
[3]Snider, Barry B.; Grabowski, James F. [Tetrahedron Letters, 2005, vol. 46, # 5, p. 823 - 825]

4
[ 3943-97-3 ]
[ 100-39-0 ]
[ 84184-51-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate In acetone at 23℃; for 4h; Reflux; Inert atmosphere;
87%	With sodium hydride In N,N-dimethyl-formamide at 20℃; for 14h;
82%	With sodium hydroxide In ethanol

81%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 4h;	1.8.a 3-(4-Benzyloxy or 4-Ethoxyphenyl)methylacrylate (11a-b) 3-(4-Hydroxyphenyl)methylacrylate (9) (0.18g, 1 mmol) was mixed with anhydrous K2CO3 (1.5 mmol) and dry DMF (5 mL). Then, an appropriate alkyl halide (1.5 mmol) was added, and the mixture was stirred well at room temperature (r.t.) for 4 hours. The reaction mixture was added to cold water (10 mL), and extraction was carried out with ethyl acetate (2*20 mL). The organic layer was dried over anhydrous MgSO4 and evaporated to thereby obtain a white solid. The residue was crystallized from a mixed solution (amixture) of AcOEt and n-hexane, to thereby obtain compounds 11a-b as colorless crystalline powder. a) 3-(4-Benzyloxyphenyl)methylacrylate (11a) Yield 0.17 g (81%). Melting point (m.p.) 132-133°C. Rf=0.18 (AcOEt:n-hexane, 1:14, v/v). IR (KBr) cm-1; 1605 (C=C), 1710 (C=O). 1H NMR (CDCl3, 300 MHz) δ 3.79 (s, 3H, O-Me), 5.10 (s, 2H, -CH2-O-), 6.34 (d, J=15.9 Hz, 1H, Ar-CH=CH-), 6.96-6.98 (d, J=8.7 Hz, 2H, Ar-H), 7.33-7.49 (m, 8H, Ar-H), 7.67 (d, J=15.9 Hz, 1H, Ar-CH=CH-).
	With potassium hydroxide
	Stage #1: methyl 4-hydroxycinnamate With potassium carbonate In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere;	9 Preparation of methyl (E)-3-(4-(benzyloxy)phenyl)acrylate (E207). To methyl (E)-3-(4- hydroxyphenyl)acrylate in DMF at 0 C was added K2C03 and the solution stirred at 0 C for 30 minutes. Then benzyl bromide was added and the reaction was warmed to room temperature and stirred overnight under N2. The mixture was poured into HCI (1 N) and EtOAc and extracted with EtOAc, dried (Na2S04), filtered and evaporated. Column chromatography over silica gel eluting with 0-70% EtOAc-Hexanes gave pure (E)-3-(4-(benzyloxy)phenyl)acrylate (E207).

Reference： [1]Martin, Maria Jesus; Rodriguez-Acebes, Raquel; Garcia-Ramos, Yésica; Martinez, Valentin; Murcia, Carmen; Digon, Isabel; Marco, Isabel; Pelay-Gimeno, Marta; Fernández, Rogelio; Reyes, Fernando; Francesch, Andrés M.; Munt, Simon; Tulla-Puche, Judit; Albericio, Fernando; Cuevas, Carmen [Journal of the American Chemical Society, 2014, vol. 136, # 18, p. 6754 - 6762]
[2]Sajiki, Hironao; Hirota, Kosaku [Tetrahedron, 1998, vol. 54, # 46, p. 13981 - 13996]
[3]Krawczyk, Andrzej R.; Lipkowska, Ewa; Wrobel, Jerzy T. [Bulletin of the Polish Academy of Sciences: Chemistry, 1986, vol. 34, # 3-4, p. 115 - 122]
[4]Current Patent Assignee: OKAYAMA UNIVERSITY - EP2460810, 2012, A1 Location in patent: Page/Page column 15
[5]Stoermer; Wodarg [Chemische Berichte, 1928, vol. 61, p. 2328]
[6]Current Patent Assignee: AERIE PHARMACEUTICALS INC - WO2018/183911, 2018, A1 Location in patent: Page/Page column 103

5
[ 3943-97-3 ]
[ 870-63-3 ]
[ 81053-49-8 ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium carbonate; potassium iodide In acetone for 20h; Reflux;
86%	With potassium carbonate; potassium iodide In acetone for 20h; Reflux;
26%	With sodium methylate at 20℃; for 3h; Inert atmosphere;	Preparation of methyl (E)-4-(3'-methylbut-2-enyloxy)cinnamate (20) To a solution of anhydrous methanol (10 mL) in round bottom flask under N2 was added sodium metal (0.12 g). The mixture was stirred at room temperature to form sodium methoxide. A solution of 4-hydroxycinnamate methyl ester (0.8 g) in methanol (30 mL) was added followed by dimethylallyl bromide (0.66 mL). The mixture was stirred at room temperature for 3 hours, added NaCl solution (20%, 50 mL) then extracted twice with ethyl acetate (50 mL). The organic layers were combined and washed with NaCl solution (20%, 50 mL), dried over MgSO4, and evaporated under reduced pressure. The product was purified by vacuum column chromatography on silica gel to give crude product that was subjected to vacuum column chromatography on silica gel using a stepwise gradient system of hexane/ethyl acetate (0:1-2:3) to afford 20 as white solid (0.26 g, yield approximately 26%). 1H- and 13C-NMR spectrum were in good agreement with previously reported data[46].

	With sodium methylate In methanol
	With potassium carbonate; potassium iodide 1.) acetone, 30 min, reflux; 2.) 4 h, reflux; Yield given. Multistep reaction;
	With potassium carbonate In acetone at 50℃; for 12h;	4.1.5. General Procedure for the Synthesis of Compounds 4, 6, 7, and 9 General procedure: Compound 14 or 15 or 16 (1 eq) was dissolved in dry acetone (15 mL) and thenanhydrous potassium carbonate (1 eq) and appropriated alkenyl bromide (1 eq) wereadded. The resulting mixture was stirred at 50 C for 12 h, then sodium hydroxide 2 N(15 mL) was added and the reaction mixture was stirred at 90 C for an additional 3 h.The cooled solution was acidified to pH 2 with hydrochloridric acid (10% solution) andextracted with dichloromethane (3 50 mL). The collected organic phases were dried overanhydrous sodium sulphate and evaporated to dryness to give the pure ether.

Reference： [1]Location in patent: experimental part De, Prithwiraj; Baltas, Michel; Lamoral-Theys, Delphine; Bruyère, Céline; Kiss, Robert; Bedos-Belval, Florence; Saffon, Nathalie [Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 7, p. 2537 - 2548]
[2]Location in patent: experimental part De, Prithwiraj; Koumba Yoya, Georges; Constant, Patricia; Bedos-Belval, Florence; Duran, Hubert; Saffon, Nathalie; Daffé, Mamadou; Baltas, Michel [Journal of Medicinal Chemistry, 2011, vol. 54, # 5, p. 1449 - 1461]
[3]Koolaji, Nooshin; Abu-Mellal, Abdallah; Tran, Van H.; Duke, Rujee K.; Duke, Colin C. [European Journal of Medicinal Chemistry, 2013, vol. 63, p. 415 - 422]
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[6]Balmas, Virgilio; Carta, Paola; Casalini, Stefano; Chtioui, Wiem; Delogu, Giovanna; Dettori, Maria A.; Fabbri, Davide; Migheli, Quirico; Oufensou, Safa [Molecules, 2021, vol. 26, # 3]

6
[ 31772-06-2 ]
[ 3943-97-3 ]
[ 34062-00-5 ]

Reference： [1]Bulletin of the Chemical Society of Japan,1971,vol. 44,p. 1909 - 1914

7
[ 106-41-2 ]
[ 292638-85-8 ]
[ 3943-97-3 ]

Yield	Reaction Conditions	Operation in experiment
90%	With palladium diacetate; triethylamine; tris-(o-tolyl)phosphine at 90℃; for 21h; Inert atmosphere;
88%	With C₂₅H₁₆O₆C₄H₁₁NH₂O; tetrabutylammomium bromide; palladium diacetate; potassium carbonate In water at 90℃;	Mizoroki-Heckcross-coupling reactions General procedure: A mixture of aryl halide (1.0 mmol), alkenes (1.5 mmol), K2CO3 (2.0 mmol), novel ligand (0.3 mol %), Pd(OAc)2 (0.3 mol %) and TBAB (0.6 mmol) was heated in water (5 ml) at 90 °C temperature. The progress of the reaction is monitor by TLC. After the completion of the reaction, ethyl acetate (10 ml) was added to the reaction mixture and extracted with ethyl acetate (3 x 10 ml). The combined organic layer was dried with anhyd. Na2SO4 and the solvent were concentrated in vacuum to obtain a solid. The residue was purified by silicagel column chromatography (5-10% EtOAc in hexane) to afford the corresponding pure products.
83%	With C₅₁H₈₀N₂O₃₈Pd; potassium carbonate In water; N,N-dimethyl-formamide at 80℃; for 12h; Schlenk technique; Green chemistry;	4.5. General procedure for Mizoroki-Heck cross-coupling reactionsof aryl halides with olefin using PdLnβ-CD (3a-3u) General procedure: A Schlenk flask equipped with asepta and a magnetic stir bar wasfilled with aryl halide (3.0 mmol), alkene (3.2 mmol), K2CO3(3.5 mmol) and PdLn-β-CD 3 mol% catalyst in water (5 mL pure orplain). The reaction was refluxed for the appropriate time underaerobic conditions. After completion of the reaction was confirmedby TLC, the reaction mixturewas cooled to room temperature.The solvent was removed by rotary evaporator and extraction of theproduct was carried out using ethyl acetate. The ethyl acetate fractionwas separated and dried over anhydrous sodium sulphate. Theresulting crude product was purified using flash column chromatographyof silica gel 60-120mesh with n-hexane/ethyl acetate (8:2ratio) as the eluent and afforded the pure desired product. After extractionof product, catalyst was simply reprecipitated from theaqueous layer by the addition of 10 mL of acetone. The recoveredcatalyst was filtered, washed with acetone (3 × 5 mL) and dried ina vacuum at 70 °C for 5 h and reused.

80%	With potassium phosphate; 2-hydroxy-3-(p-tolyl)-2,3-dihydroindan-1-one; palladium diacetate In 1,4-dioxane at 80℃;	General Procedure for Mizoroki-Heck Cross-Coupling Reactions (25-33) General procedure: A mixture of aryl halides/tosylates (1.0 mmol), alkenes (1.5 mmol), K3PO4 (2.0 mmol), ligand (0.3 mol%) and Pd(OAc)2 (0.3 mol%) was heated in dioxane (5 mL) at 80 °C. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the mixture was cooled to r.t., and solvent was removed under reduced pressure. Water (10 mL) was added to the mixture, and extracted with EtOAc (3 × 10mL). The combined organic layer was dried with anhydrous Na2SO4 and the solvent was concentrated in vacuum to obtain a solid. The residue was purified by silica gel column chromatography (EtOAc-hexane, 5-10%) to afford the corresponding pure products.
77%	With [PdBr₂(PPh₃)2]; potassium carbonate In N,N-dimethyl-formamide at 20 - 100℃; for 8h; Inert atmosphere; stereoselective reaction;	Typical procedure for the Mizoroki-Heck reaction of aryl bromides with terminal olefins General procedure: In an oven-dried round bottom flask under an atmosphere of nitrogen at room temperature were placed complex 1 (0.0005 mmol) and DMF (3 mL). After stirring for 5 min, the aryl bromide (5 mmol), olefinic substrate (10 mmol) and K2CO3 (6 mmol) were introduced into the reaction flask. The reaction mixture was heated at 100 °C for the required reaction time under an atmosphere of nitrogen. At the end of the reaction, the reaction mixture was cooled to room temperature, diluted with EtOAc (20 mL), washed dil. HCl and water. The combined organic layer was dried over anhydrous Na2SO4 and stripped off the solvent under reduced pressure. The residue was subjected to column chromatography on silica gel using ethyl acetate and hexane mixtures to afford the Mizoroki-Heck product in high purity. The products were characterized by 1H NMR analysis
75%	With C₂₁H₂₁ClN₄Pd; triethylamine In 1-methyl-pyrrolidin-2-one at 140℃; for 8h; Sealed tube;
62%	With potassium carbonate In N,N-dimethyl-formamide at 130℃; for 6h; Inert atmosphere;
	With triethylamine; tris-(o-tolyl)phosphine

Reference： [1]Quitschau, Melanie; Schuhmann, Tim; Piel, Joern; Von Zezschwitz, Paultheo; Grond, Stephanie [European Journal of Organic Chemistry, 2008, # 30, p. 5117 - 5124]
[2]Waheed, Mohammed; Ahmed, Naseem [Tetrahedron Letters, 2016, vol. 57, # 33, p. 3785 - 3789]
[3]Dindulkar, Someshwar D.; Jeong, Daham; Kim, Hwanhee; Jung, Seunho [Carbohydrate Research, 2016, vol. 430, p. 85 - 94]
[4]Waheed, Mohammed; Ahmed, Naseem [Synthesis, 2017, vol. 49, # 18, p. 4372 - 4382]
[5]Prabhu, Rupesh Narayana; Ramesh, Rengan [Tetrahedron Letters, 2012, vol. 53, # 44, p. 5961 - 5965,5]
[6]Maji, Ankur; Singh, Ovender; Singh, Sain; Mohanty, Aurobinda; Maji, Pradip K.; Ghosh, Kaushik [European Journal of Inorganic Chemistry, 2020, vol. 2020, # 17, p. 1596 - 1611]
[7]Location in patent: experimental part Sanjaykumar; Mukri, Bhaskar Devu; Patil, Satish; Madras, Giridhar; Hegde [Journal of Chemical Sciences, 2011, vol. 123, # 1, p. 47 - 54]
[8]Ziegler,C.B.; Heck,R.F. [Journal of Organic Chemistry, 1978, vol. 43, p. 2941 - 2946]
[9]Pill, Michael F.; Holz, Katharina; Preußke, Nils; Berger, Florian; Clausen-Schaumann, Hauke; Lüning, Ulrich; Beyer, Martin K. [Chemistry - A European Journal, 2016, vol. 22, # 34, p. 12034 - 12039]

8
[ 3943-97-3 ]
[ 3101-60-8 ]
[ 70193-89-4 ]

Reference： [1]Patent: DE2735856,1979,
Chem.Abstr.,1979,vol. 91

9
[ 3943-97-3 ]
[ 3101-60-8 ]
[ 60377-18-6 ]

Reference： [1]Patent: DE2460689,1976,
Chem.Abstr.,1979,vol. 90

10
[ 67-56-1 ]
[ 78164-38-2 ]
[ 3943-97-3 ]
[ 1882-72-0 ]

Reference： [1]Tetrahedron Letters,1981,vol. 22,p. 2103 - 2106

11
[ 67-56-1 ]
genistein 7-O-(2"-p-coumaroyl-β-D-glucopyranoside) [ No CAS ]
[ 3943-97-3 ]
[ 529-59-9 ]

Reference： [1]Phytochemistry,1986,vol. 25,p. 2687 - 2688

12
[ 3943-97-3 ]
[ 5597-50-2 ]

Yield	Reaction Conditions	Operation in experiment
99%	With hydrogen In ethanol for 24h; Ambient temperature;
99%	In ethanol	16 Methyl 3-(4-hydroxyphenyl)propanoate Methyl 3-(4-hydroxyphenyl)propanoate To a solution of (E)-methyl 3-(4-hydroxyphenyl)acrylate (1.0 g, 5.6 mmol) in EtOH (20 mL), Pd/C (0.1g) was added. The reaction mixture was vigorously stirred under hydrogen atmosphere (1 bar) at room temperature for 21 h. The suspension was filtered through a Celite pad and evaporated to dryness under vacuum to afford 1.0 g (5.6 mmol, 99% yield) of an oil identified as methyl 3-(4-hydroxyphenyl)propanoate. 1H NMR (400 MHz, CDCl3) δ 7.07 (ddd, J = 8.8, 2.8, 2.0 Hz, 2H), 6.76 (ddd, J = 8.8, 2.8, 2.0 Hz, 2H), 4.72 (br s, 1H), 3.67 (s, 3H), 2.88 (t, J = 7.8 Hz, 2H), 2.60 (t, J = 7.8 Hz, 2H).
99%	With palladium on activated charcoal; hydrogen In ethanol at 20℃; for 21h;	16 Methyl 3-(4-hydroxyphenyl)propanoate Methyl 3-(4-hydroxyphenyl)propanoate (0413) (0414) To a solution of (E)-methyl 3-(4-hydroxyphenyl)acrylate (1.0 g, 5.6 mmol) in EtOH (20 mL), Pd/C (0.1 g) was added. The reaction mixture was vigorously stirred under hydrogen atmosphere (1 bar) at room temperature for 21 h. The suspension was filtered through a Celite pad and evaporated to dryness under vacuum to afford 1.0 g (5.6 mmol, 99% yield) of an oil identified as methyl 3-(4-hydroxyphenyl)propanoate. (0415) 1H NMR (400 MHz, CDCl3) δ 7.07 (ddd, J=8.8, 2.8, 2.0 Hz, 2H), 6.76 (ddd, J=8.8, 2.8, 2.0 Hz, 2H), 4.72 (br s, 1H), 3.67 (s, 3H), 2.88 (t, J=7.8 Hz, 2H), 2.60 (t, J=7.8 Hz, 2H).

82%	With 5%-palladium/activated carbon; hydrogen In ethyl acetate
80%	With sodium tetrahydroborate; nickel (II) chloride hexahydrate In methanol	Methyl 3-(4-hydroxyphenyl)propanoate (14) To an ice-bath cooled solution of 13 (0.845 g, 5.1 mmol) and nickeldichloride hexahydrate (0.12 g, 0.5 mmol) in dry methanol (10 mL) asodium borohydride (0.5 g, 13.2 mmol) was added in small portion.After completion of reaction (controlled by GC-MS), saturated ammoniumchloride solution (2.5 mL) was added and methanol was evaporatedunder reduced pressure. Water (5 mL) and aqueous ammonia(10 mL) were added to the residue, and the product was extracted withethyl acetate (3x15 ml). The extracts were combined, dried overNa2SO4, and evaporated. The crude product was purified by columnchromatography (hexane-ethyl acetate 7:3).White solid, 0.67 g 80%. 1H NMR (500 MHz, CDCl3) δ 2.60 (t,J = 7.70 Hz, 2H), 2.88 (t, J = 7.70 Hz, 2H), 3.67 (s, 3H), 5.55 (br.s,1H), 6.70-6.80 (m, 1H), 7.00-7.09 (m, 1H).
71%	With ferrous ammonium sulphate hexahydrate; isopropyl β-D-thiogalactopyranoside In aq. phosphate buffer at 37℃; for 48h;
	With hydrogen In methanol for 0.5h; Ambient temperature;
	With hydrogen In ethanol for 16h;
	With palladium 10% on activated carbon; hydrogen In ethyl acetate at 20℃; for 12h;
36 %Spectr.	With methanol; (4,4'-di-tert-butyl-2,2'-dipyridyl)-bis-(2-phenylpyridine(-1H))-iridium(III) hexafluorophosphate; diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate at 20℃; for 16h; Inert atmosphere; Irradiation; Sealed tube;

Reference： [1]Menon, Sanjay R.; Patel, Vishal K.; Mitscher, Lester A.; Shih, Peter; Pillai, Segaran P.; Shankel, Delbert M. [Journal of Natural Products, 1999, vol. 62, # 1, p. 102 - 106]
[2]Current Patent Assignee: PROUS INSTITUTE FOR BIOMEDICAL RES; PROUS INSTITUTE FOR BIOMEDICAL RESEARCH SA - EP2745876, 2014, A1 Location in patent: Page/Page column
[3]Current Patent Assignee: PROUS INSTITUTE FOR BIOMEDICAL RES; PROUS INSTITUTE FOR BIOMEDICAL RESEARCH SA - US2015/344408, 2015, A1 Location in patent: Paragraph 0413-0415
[4]Location in patent: experimental part Bisogno, Fabricio; Mascoti, Laura; Sanchez, Cecilia; Garibotto, Francisco; Giannini, Fernando; Kurina-Sanz, Marcela; Enriz, Ricardo [Journal of Agricultural and Food Chemistry, 2007, vol. 55, # 26, p. 10635 - 10640]
[5]Gureev, Maxim; Krasavin, Mikhail; Kuranov, Sergey O.; Luzina, Olga A.; Onopchenko, Oleksandra; Pishel, Iryna; Salakhutdinov, Nariman F.; Zozulya, Sergey [Bioorganic Chemistry, 2020, vol. 99]
[6]Sirasani, Gopal; Tong, Liuchuan; Balskus, Emily P. [Angewandte Chemie - International Edition, 2014, vol. 53, # 30, p. 7785 - 7788][Angew. Chem., 2014, vol. 53, # 30, p. 7919 - 7922,4]
[7]Lam, Thi Bach Tuyet; Iiyama, Kenji; Stone, Bruce A. [Phytochemistry, 1992, vol. 31, # 4, p. 1179 - 1184]
[8]Percec, Virgil; Peterca, Mihai; Sienkowska, Monika J.; Ilies, Marc A.; Aqad, Emad; Smidrkal, Jan; Heiney, Paul A. [Journal of the American Chemical Society, 2006, vol. 128, # 10, p. 3324 - 3334]
[9]Location in patent: experimental part Narsaiah, A. Venkat; Kumar, J. Kranthi [Synthetic Communications, 2011, vol. 41, # 11, p. 1603 - 1608]
[10]Larionova, Natalia A.; Ondozabal, Jun Miyatake; Cambeiro, Xacobe C. [Advanced Synthesis and Catalysis, 2021, vol. 363, # 2, p. 558 - 564]

13
[ 3943-97-3 ]
(±)-methyl trans-(E)-2-(4-hydroxyphenyl)-5-(-3-methoxy-3-oxoprop-1-en-1-yl)-2,3-dihydrobenzofuran-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With sodium carbonate; potassium hexacyanoferrate(III) In chloroform; water
36%	With silver(l) oxide In acetone; benzene at 20℃; for 20h; Darkness; Inert atmosphere;
23%	With phosphate buffer; dihydrogen peroxide horseradish peroxidase;

23%	With silver(l) oxide In acetone; benzene for 65h;
19%	With sodium hydrogencarbonate; potassium hexacyanoferrate(III) In dichloromethane; chloroform; water at 20℃; for 49h;	1 Example 1 Methyl (2R,3R)-2-(4-hydroxyphenyl)-5-((E)-3-methoxy-3-oxoprop-l-en-l-yl)-2,3- dihydrobenzofuran-3-carboxylate (compound 1 in Table 1) Methyl coumarate (20g, 112 mmol, 0.5 equiv) was dissolved in CH2CI2/CHCI3 mixture (56 + 504 mL; 1/9 (V/V); 0.21 to ester) and the resulting mixture was stirred at RT for 5 min. In separated reaction vessel was dissolved K3[Fe(CN)6] (87g, 270 mmol, 1.2 equiv) in saturated aqueous solution of NaHCCL (560 mL, 0.2M to ester). Resulted homogenous brown solution was placed to dropping funnel and the whole mixture was added at RT to methyl coumarate solution within a period of lh. Resulting mixture was stirred for additional 48h before the organic layer was removed in vacuo. Resulting aqueous layer was extracted with EtOAc (4x500 mL) and combined organic layers were washed with brine (500 mL). Resulting organic layer was filtered through Celite, filtrate was dried over Na2SC>4 and concentrated in vacuo. Residue (22.05 g) was purified on by flash column chromatography (S1O2; hexane:EtOAc = 4: 1 ->2: 1) and yielded 3.79 g (19%; purity 98+%).Pale yellow solid, chemical formula: C20H18O6, yield (%): 19, trans/cis = 21:1.HPLC-UV/VIS retention time, purity (min., %): 27.1, 98.6.ESI+-MS m/z (rel. int. %, ion): 355.5 (10, M+H]+), 295.1 (100, M-C02CH2]+). NMR (500 MHz, Chloroform-d) d (ppm): 3.80 (s, 3H), 3.82 (s, 3H), 4.27 (d, J = 7.5 Hz, 1H), 5.95 (broad s, 1H), 6.08 (d, J= 7.5 Hz, 1H), 6.31 (d, J = 15.9 Hz, 1H), 6.84 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.5 Hz, 1H), 7.24 (d, J= 9.2 Hz, 2H), 7.41 (dd, J= 8.5, 1.9 Hz, 1H), 7.54 (t, J= 1.5 Hz, 1H), 7.65 (d, J = 15.9 Hz, 1H).13C NMR (126 MHz, Chloroform-d) d (ppm): 51.9, 53.1, 55.1, 86.5, 110.4, 115.2, 115.8, 125.1, 125.2, 127.6, 127.8, 131.0, 131.9, 145.0, 156.4, 161.3, 168.2, 171.1.
10%	With dihydrogen peroxide; horseradish peroxidase In aq. phosphate buffer; acetone at 20℃; for 3h;	4.2.5. Oxidative coupling with HRP (general procedure E) General procedure: The procedure was carried out according to literature [16]. Thecorresponding cinnamate analogue (0.5 mmol) was dissolved inacetone (2.5 mL) and diluted under stirring with citrate-phosphatebuffer (19 mmol/L, pH 3.1, 22.5 mL). Horseradish peroxidase inbuffer (1.48 mg/mL, 707 mL, ~210 U) and 1 mol/L H2O2 (250 mL,0.25 mmol) were portion-wise added over a period of 20 min. Thereaction was stirred for 3 h at rt. Afterwards 5% NaCl (5 mL) wasadded and the organic solvent carefully removed. The residualmixture was extracted with EtOAc (3x) and the product purified asindicated.

Reference： [1]Wasserman; Brunner; Buyank; et al. [Journal of the American Chemical Society, 1985, vol. 107, # 2, p. 519 - 521]
[2]Medeiros, Talita C.T.; Dias, Herbert J.; Silva, Eliane O.; Fukui, Murilo J.; Soares, Ana Carolina F.; Kar, Tapas; Heleno, Vladimir C.G.; Donate, Paulo M.; Parreira, Renato L.T.; Crotti, Antônio E.M. [Journal of the Brazilian Chemical Society, 2016, vol. 27, # 1, p. 136 - 143]
[3]Yoshihara, Teruhiko; Yamaguchi, Katsuyoshi; Sakamura, Sadao [Agricultural and Biological Chemistry, 1983, vol. 47, # 2, p. 217 - 220]
[4]Pieters, Luc; Van Dyck, Stefaan; Gao, Mei; Bai, Ruoli; Hamel, Ernest; Vlietinck, Arnold; Lemière, Guy [Journal of Medicinal Chemistry, 1999, vol. 42, # 26, p. 5475 - 5481]
[5]Current Patent Assignee: PALACKY UNIVERSITY OLOMOUC - WO2021/110185, 2021, A1 Location in patent: Page/Page column 12
[6]Bernal, Freddy A.; Gerhards, Marcel; Kaiser, Marcel; Wünsch, Bernhard; Schmidt, Thomas J. [European Journal of Medicinal Chemistry, 2020, vol. 205]

14
[ 3943-97-3 ]
[ 59576-98-6 ]

Yield	Reaction Conditions	Operation in experiment
67%	With ammonium hydroxide; ammonia In methanol; water for 288h;
30%	With ammonia In methanol at 90℃; for 72h; Sealed tube;	11 Synthesis of preparing cinnamamide (102); [00329] PCA was converted into its methyl ester 101 by refluxing in methanol in the presence of sulfonic acid. Compound 101 was transformed to amide 102 by reacting with ammonia. A solution of methyl cinnamate (28 mmol) and 7 M ammonia in MeOH (30 mL) was sealed in a 100 mL thick-wall round bottom flashed, and heated at 90 with stirring for 72 h, resulting in a brown solution. After the solvent was removed by a rotary evaporator, the crude products were purified by flash silica gel chromatography (eluting with 2-10% MeOH in DCM) to afford cinnamamide. Compound 102 was a yellow solid, obtained at 30% yield. Identity was confirmed by 1H NMR (300 MHz, CD3OD).
	With ammonia In methanol at 90℃; for 72h;

With ammonia

Reference： [1]Sipilae, Julius; Nurmi, Harri; Kaukonen, Ann Marie; Hirvonen, Jouni; Taskinen, Jyrki; Yli-Kauhaluoma, Jari [European Journal of Pharmaceutical Sciences, 2005, vol. 25, # 4-5, p. 417 - 425]
[2]Current Patent Assignee: DUKE UNIVERSITY - WO2011/103189, 2011, A1 Location in patent: Page/Page column 76; 88
[3]Cevasco, Giorgio; Thea, Sergio [Journal of Organic Chemistry, 1994, vol. 59, # 21, p. 6274 - 6278]
[4]Nishioka, Tetsuo; Watanabe, Jun; Kawabata, Jun; Niki, Ryoya [Bioscience, Biotechnology and Biochemistry, 1997, vol. 61, # 7, p. 1138 - 1141]

15
[ 3943-97-3 ]
[ 107-30-2 ]
[ 84184-55-4 ]

Yield	Reaction Conditions	Operation in experiment
97%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 21h; Inert atmosphere;	14 4.14. Methyl (E)-4-O-methoxymethyl-p-coumarate (26) To a solution of methyl ester 24 (2.91 g, 16.3 mmol) and i-Pr2NEt (5.7 mL, 49.0 mmol) in CH2Cl2 (60 mL) was added MOMCl (3.7 mL, 49.0 mmol) at room temperature and the mixture was stirred for 21 h at this temperature. The reaction mixture was quenched with saturated aqueous NH4Cl. The crude products were extracted with AcOEt. The combined extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (10% AcOEt in hexane) to give 26 as a colorless oil (3.52 g, 97%). IR (neat) 2952, 2828, 1791, 1636, 1604, 1510, 1436, 1315, 1242, 1170, 1081, 992, 831 cm-1; 1H NMR (600 MHz, CDCl3) δ 3.45 (s, 3H), 3.79 (s, 3H), 5.20 (s, 2H), 6.32 (d, J=16.0 Hz, 1H), 7.04 (d, J=8.5 Hz, 2H), 7.47 (d, J=8.5 Hz, 2H), 7.65 (d, J=16.0 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 51.6, 56.1, 94.2, 115.8, 116.5, 128.2, 129.6, 144.4, 159.0, 167.7; HRMS (FAB) calcd for C12H15O4 [M+H]+ 223.0970, found 223.0978.
89%	Stage #1: methyl 4-hydroxycinnamate With potassium carbonate In acetone at 20℃; for 0.333333h; Stage #2: chloromethyl methyl ether In acetone at 20℃; for 12h;
21.446 g	With potassium carbonate In acetone for 0.5h; Ambient temperature;

Reference： [1]Oyama, Kin-Ichi; Watanabe, Noriyuki; Yamada, Tomomi; Suzuki, Masako; Sekiguchi, Yukiko; Kondo, Tadao; Yoshida, Kumi [Tetrahedron, 2015, vol. 71, # 20, p. 3120 - 3130]
[2]Ueda, Rie; Suzuki, Takayoshi; Mino, Koshiki; Tsumoto, Hiroki; Nakagawa, Hidehiko; Hasegawa, Makoto; Sasaki, Ryuzo; Mizukami, Tamio; Miyata, Naoki [Journal of the American Chemical Society, 2009, vol. 131, # 48, p. 17536 - 17537]
[3]Ishii, Hisashi; Ishikawa, Tsutomu; Tohojoh, Toshiaki; Murakami, Keiko; Kawanable, Eri; et al. [Journal of the Chemical Society. Perkin transactions I, 1982, # 9, p. 2051 - 2058]

16
[ 3943-97-3 ]
[ 92420-89-8 ]
[ 866417-47-2 ]

Reference： [1]Carbohydrate Research,2005,vol. 340,p. 2077 - 2085

17
[ 3943-97-3 ]
[ 20649-40-5 ]

Yield	Reaction Conditions	Operation in experiment
93%	With lithium aluminium tetrahydride In diethyl ether at 27℃; for 0.5h;
79%	With diisobutylaluminium hydride In dichloromethane at -78 - 20℃; for 1h; Inert atmosphere; stereoselective reaction;
57%	With diisobutylaluminium hydride In tetrahydrofuran at 0℃;

43%	Stage #1: methyl 4-hydroxycinnamate With aluminium hydride In diethyl ether at 20℃; for 1h; Stage #2: With hydrogenchloride In diethyl ether; water; ethyl acetate Cooling with ice;	11 [00328] Compound 101 was reduced with aluminium hydride to generate the 4- hydroxycinnamyl alcohol 104. A cold solution of Aici3 (1 -33 g, 10 mmol) in anhydrous diethyl ether (25 mL) was added dropwise to an ice-cold stirred suspension of LiAIH4 (1.33 g, 35 mmol) in anhydrous diethyl ether (25 mL). After completion of the addition, the mixture was allowed to warm to ambient temperature, with stirring for 30 min, resulting in a grey suspension. To this grey suspension was added dropwise a solution of methyl cinnamate (10 mmol) dissolved in anhydrous diethyl ether (25 mL) within 10 min, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was cooled with an ice bath, and carefully treated with EtOAc (50 mL) and 1 N HCI solution (100 mL). The resulting mixture was extracted with EtOAc (3x50 mL). The combined extracts were washed with H20 (50 mL) and brine (50 mL), and dried (anhydrous Na2S04). The solvent was evaporated to dryness, and the crude products were purified by flash silica gel chromatography (eluting with 20-50% hexane in EtOAc) to afford the cinnamyl alcohol. Compound 104 was a yellow solid, obtained at: 43% yield. Compound 126 was a white solid, obtained at 79% yield. Identity of compounds was verified by 1H NMR (75 MHz, CD3OD for 104; 400 MHz, CDCI3 for 126)
31.6%	With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 2h;	21 A solution of methyl 4-hydroxy cinnamate obtained in preparation 20 (1.5 g, 8.43 mmol) in THF (15 mL) was added drop wise to a suspension of LAH (416 mg) in dry THF (10 mL) at 0° C. and the reaction mixture was stirred at room temperature for 2 h. The excess LAH was quenched with satd. Na2SO4 solution. It was filtered through celite bed and the filtrate was dried (Na2SO4) and evaporated to dryness. The residue was purified by column chromatography using 20% EtOAc in pet ether to afford the title compound (0.4 g, 31.6%) as off white solid. [0276] Mp: 116-118° C. [0277] 1H NMR (200 MHz, CD3OD) δ: 4.17 (d, J=5.9 Hz, 2H); 6.15 (td, J=5.9 and 15.8 Hz, 1H); 6.50 (d, J=5.9 Hz, 1H); 6.71 (d, J=8.3 Hz, 2H); 7.23 (d, J=8.6 Hz, 2H) [0278] Mass m/z (CI): 151 [M+1]
	Multi-step reaction with 2 steps 1: pyridine 2: LiAlH₄; diethyl ether
	With diisobutylaluminium hydride In toluene at 0℃;
530 mg	With diisobutylaluminium hydride In tetrahydrofuran; toluene at 0 - 20℃; for 20h; Inert atmosphere;

Reference： [1]Kumar, N. S. Saleesh; Varghese, Shinto; Narayan, Gopinathan; Das, Suresh [Angewandte Chemie - International Edition, 2006, vol. 45, # 38, p. 6317 - 6321]
[2]Konrádová, Daniela; Kozubíková, Hana; Doležal, Karel; Pospíšil, Jiří [European Journal of Organic Chemistry, 2017, vol. 2017, # 35, p. 5204 - 5213]
[3]Location in patent: scheme or table Zhao, Huiping; Brandt, Gary E.; Galam, Lakshmi; Matts, Robert L.; Blagg, Brian S.J. [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 9, p. 2659 - 2664]
[4]Current Patent Assignee: DUKE UNIVERSITY - WO2011/103189, 2011, A1 Location in patent: Page/Page column 75; 87-88
[5]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - US2003/229083, 2003, A1 Location in patent: Page 25
[6]Freudenberg; Gehrke [Chemische Berichte, 1951, vol. 84, p. 443,450]
[7]Moon, Sun-Joo; Kwon, Mi; Choi, Donha; Won, Keehoon; Kim, Yong Hwan; Choi, In-Gyu; Choi, Joon Weon [Phytochemistry, 2012, vol. 82, p. 15 - 21]
[8]Kim, Stacie S.; Sattely, Elizabeth S. [Journal of the American Chemical Society, 2021, vol. 143, # 13, p. 5011 - 5021]

18
[ 3943-97-3 ]
[ 106-93-4 ]
[ 1012058-33-1 ]

Yield	Reaction Conditions	Operation in experiment
95.2%	With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 6h;	8.8a EXAMPLE 8: Preparation of 5-((Z)-(5-fluoro-2-oxomdolin-3-ylidene)methyl)-7V-(2-(4-((is)-3-(hydroxyainino)-3-oxoprop-l- enyl)phenoxy)ethyl)-2,4-dimethyl-lH-pyrrole-3-carboxamide(compound 14) Step 8a. (is)-Methyl 3-(4-(2-bromoethoxy)phenyl)acrylate (Compound 301)To a solution of (E)-methyl 3-(4-hydroxylphenyl)acrylate (2.0 g, 11.24 mmol) in DMF (2.5 mL) was added 1 ,2-Dibromoethane (40 ml), K2CO3 (4.66 g, 33.7 mmol). The mixture was stirred at 90 °C for 6 hour and filtered. The filtrate was evaporated to give product 301 as a white solid (3.05 g, 95.2%). LCMS: 286
95.2%	With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 6h;	8.8a To a solution of (E)-methyl 3-(4-hydroxylphenyl)acrylate (2.0 g, 11.24 mmol) in DMF (2.5 niL) was added 1,2-Dibromoethane (40 ml), K2CO3 (4.66 g, 33.7 mmol). The mixture was stirred at 90 °C for 6 hour and filtered. The filtrate was evaporated to give product 301 as a white solid (3.05 g, 95.2%). LCMS: 286 [M+l]+.
65%	With potassium carbonate In acetone at 65℃;

Stage #1: methyl 4-hydroxycinnamate With sodium hydride In diethyl ether; mineral oil at 20℃; for 6h; Inert atmosphere; Stage #2: ethylene dibromide In N,N-dimethyl acetamide; mineral oil at 130 - 160℃; for 26h;

Reference： [1]Current Patent Assignee: CURIS INC - WO2008/33743, 2008, A1 Location in patent: Page/Page column 54; 62
[2]Current Patent Assignee: CURIS INC - WO2008/33747, 2008, A2 Location in patent: Page/Page column 207
[3]Lin, Ping; Zeng, Jia-Cheng; Chen, Ji-Guang; Nie, Xu-Liang; Yuan, En; Wang, Xiao-Qiang; Peng, Da-Yong; Yin, Zhong-Ping [Journal of Enzyme Inhibition and Medicinal Chemistry, 2020, vol. 35, # 1, p. 1879 - 1890]
[4]Tercel, Moana; Lee, Ho H.; Mehta, Sunali Y.; Youte Tendoung, Jean-Jacques; Bai, Sally Y.; Liyanage, H. D. Sarath; Pruijn, Frederik B. [Journal of Medicinal Chemistry, 2017, vol. 60, # 13, p. 5834 - 5856]

19
[ 3943-97-3 ]
[ 540-51-2 ]
[ 156806-95-0 ]

Yield	Reaction Conditions	Operation in experiment
26%	With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 24h;	27.27b A mixture of compound 0501-66 (5.0 g, 28.0 mmol) and 2-bromoethanol (3.9 g, 62.0 mmol) and potassium carbonate in N, N- dimethylformamide was stirred at 8O0C for 24 hours. The reaction process was monitored by TLC. The mixture was filtrated. The filtrate was concentrated under reduce pressure. The residue was wash with diethyl ether and dried to give (E)-methyl 3-(4-(2-hydroxyethoxy)phenyl)- acrylate as yellow solid (1.6 g, 26.0%): LCMS: 223 [M+l]+.To a mixture of triethylamine (0.3 g, 3 mol) and dichloromethane (20 mL) was added tosyl chloride (285 mg, 1.5 mmol) batchwise and stirred for 0.5 hour.
26%	With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 24h;	27.27b Step 27b. (E)-Methyl 3-(4-(2-(tosyloxy)ethoxy)phenyl)acrylate (Compound 0502-66) A mixture of compound 0501-66 (5.0 g, 28.0 mmol) and 2-bromoethanol (3.9 g, 62.0 mmol) and potassium carbonate in N,N-dimethylformamide was stirred at 80° C. for 24 hours. The reaction process was monitored by TLC. The mixture was filtrated. The filtrate was concentrated under reduce pressure. The residue was wash with diethyl ether and dried to give (E)-methyl 3-(4-(2-hydroxyethoxy)phenyl)-acrylate as yellow solid (1.6 g, 26.0%): LCMS: 223 [M+1]+.
26%	With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 24h;	27.b Step 27b. (E)-Methyl 3-(4-(2-(tosyloxy)ethoxy)phenyl)acrylate (Compound 0502-66); A mixture of compound 0501-66 (5.0 g, 28.0 mmol) and 2-bromoethanol (3.9 g, 62.0 mmol) and potassium carbonate in N,N-dimethylformamide was stirred at 80° C. for 24 hours. The reaction process was monitored by TLC. The mixture was filtrated. The filtrate was concentrated under reduce pressure. The residue was wash with diethyl ether and dried to give (E)-methyl 3-(4-(2-hydroxyethoxy)phenyl)-acrylate as yellow solid (1.6 g, 26.0%): LCMS: 223 [M+1]+.To a mixture of triethylamine (0.3 g, 3 mol) and dichloromethane (20 mL) was added tosyl chloride (285 mg, 1.5 mmol) batchwise and stirred for 0.5 hour. Compound (E)-methyl 3-(4-(2-hydroxyethoxy)phenyl)acrylate (333 mg, 1.5 mmol) was added into above mixture and heated to reflux for 24 hours. The reaction mixture was added saturated ammonium chloride solution and the organic layer was separated and washed by brine, dried (MgSO4), evaporated to give compound 0502-66 as white solid (200 mg, 36%): LCMS: 377 [M+1]+.

31.9 g

With sodium hydroxide In N,N-dimethyl-formamide at 60 - 80℃; for 8h; Inert atmosphere;

4 Example 4 First Step: (0193) The compound (ex-1) (40 g) and sodium hydroxide (9.9 g) were added to N,N-dimethylformamide (DMF; 400 ml), and the mixture was heated at 60° C. with stirring under an atmosphere of nitrogen. 2-Bromoethanol (30.9 g) was added dropwise. After the addition, the stirring was continued at 80° C. for 8 hours. Precipitates were filtered off, and water (800 ml) was added to the filtrate, which was extracted with ethyl acetate (800 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. The ethyl acetate was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel, eluent: toluene/ethyl acetate=4/1 by volume) and then by recrystallization from toluene to give the compound (ex-2) (31.9 g).

Reference： [1]Current Patent Assignee: CURIS INC - WO2008/33747, 2008, A2 Location in patent: Page/Page column 134
[2]Current Patent Assignee: CURIS INC - US2009/76022, 2009, A1 Location in patent: Page/Page column 76
[3]Current Patent Assignee: CURIS INC - US2009/111772, 2009, A1 Location in patent: Page/Page column 75
[4]Current Patent Assignee: CHISSO CORPORATION - US8450517, 2013, B2 Location in patent: Page/Page column 32

20
[ 805250-51-5 ]
[ 3943-97-3 ]
methyl (2E)-3-(4-[4'-(2-ethoxyethoxy)-2',6'-dimethylbiphenyl-3-yl]methoxy}phenyl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine In toluene at 20℃; for 24h;	4 Reference Example 4; methyl (2E)-3-(4-[4'-(2-ethoxyethoxy)-2',6'-dimethylbiphenyl-3-yl]methoxy}phenyl)acrylate; [Show Image] A solution of methyl (2E)-3-(4-hydroxyphenyl)acrylate (0.713 g, 4.00 mmol), [4'-(2-ethoxyethoxy)-2',6'-dimethylbiphenyl-3-yl]methanol (1.20 g, 4.00 mmol) and tributylphosphine (1.29 g, 6.40 mmol) in toluene (65 mL) was stirred, 1,1'-(azodicarbonyl)dipiperidine (1.61 g, 6.40 mmol) was added in small portions, and the mixture was stirred at room temperature for 24 hr. Hexane (35 mL) was added to the reaction mixture. The precipitated insoluble material was filtrated, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane = 0:100 - 25:75), and recrystallized from ethyl acetate-hexane to give the title compound (1.58 g, yield 86%) as colorless crystals. melting point 69°C.

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1916234, 2008, A1 Location in patent: Page/Page column 28

21
[ 3943-97-3 ]
[ 2538-87-6 ]

Reference： [1]Angewandte Chemie - International Edition,2006,vol. 45,p. 6317 - 6321
[2]Journal of the Chemical Society. Perkin transactions I,1982,p. 2051 - 2058
[3]European Journal of Organic Chemistry,2017,vol. 2017,p. 5204 - 5213

22
[ 3943-97-3 ]
[ 24807-40-7 ]

Reference： [1]Tetrahedron,1998,vol. 54,p. 13981 - 13996

23
[ 3943-97-3 ]
[ 501-98-4 ]

Reference： [1]Journal of the American Chemical Society,1993,vol. 115,p. 7103 - 7110

24
[ 653307-48-3 ]
[ 3943-97-3 ]
[ 653307-55-2 ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium carbonate In 1-methyl-pyrrolidin-2-one at 80℃; for 4h;	4 3. 14 g (4.48 [MMOL)] 2,2-bis (4-nitrobenzyl)-1, 3 di (6-bromohexanoyl) propanediol and 1.60 g (8.98 [MMOL)] methyl 4-hydroxycinnamate were dissolved in 24 ml 1-methyl-2-pyrrolidon. 2.45 g (17.73 [MMOL)] potassium carbonate were added. The reaction suspension was then heated at [80 °C] for 4 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Chromatography of the residue yielded 3.72 g (88 %) 2,2-bis [(4-NITROBENZYL)-1,] 3 di [(6- {4- [ (1E)-3-METHOXY-3-OXOPROP-1-] enyl] phenoxy} hexanoyl) propanediol as yellowish powder.

Reference： [1]Current Patent Assignee: BASF SE - WO2004/13086, 2004, A1 Location in patent: Page 45-46

25
[ 2081-44-9 ]
[ 3943-97-3 ]
[ 871109-62-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 25h; Ultrasonification;	13.1 Example 13; Synthesis of a compound of Formula (I) where R R3, R6, and R8 are OMe, R2, k7, and RIO are Me, R4 and R5 are OH, R9 is H, R¹¹ is CN, Y is CH2, and R¹2 is 3-(4-tetrahydropyran-4- yloxyphenyl) acryloylamino (compound 43); Step 1; To a solution of PPh3 (1.14 g, 4.32 mmol) in THF (2 mL) was added DIAD (894 µL, 4.32 mmol). After 5 min of stirring at room temperature, the reaction mixture was treated with a solution of methyl 4-hydroxycinnamate (513 mg, 2.88 mmol), and tetrahydro-4H-pyran-4-ol (280 µL, 2.88 mmol) in THF (3 mL). The reaction mixture was agitated by means of ultrasonification for 5 min and stirred at room temperature for 25 hr. Then, the reaction mixture was concentrated in vacuo. Purification of the crude material by column chromatography (2:8 EtOAc/hexane) provided methyl 4-(tetrahydro-4H-pyran-4- yloxy) cinnamate (755 mg, 100%) as a white solid.

Reference： [1]Current Patent Assignee: QUEST DIAGNOSTICS INC - WO2005/118584, 2005, A2 Location in patent: Page/Page column 76

26
[ 5326-87-4 ]
[ 3943-97-3 ]
[ 1040113-52-7 ]

Yield	Reaction Conditions	Operation in experiment
91%	Stage #1: methyl 4-hydroxycinnamate With sodium hydride In N,N-dimethyl-formamide at 5℃; for 0.5h; Stage #2: N-(phenyl)bromoacetamide In N,N-dimethyl-formamide at 0 - 20℃; for 4h;	29.II To a suspension of sodium hydride (60% w/w, 0.43g, 18mmol) in DMF (5 mL) was added methyl-4-hydroxy cinnamate (2.3g, 13mmol) in DMF (6mL) at 5 0C and the reaction mixture was stirred for 30 minutes. A solution of 29a (2.72g, 13mmol) in DMF (5mL) was added drop wise to the above reaction mixture at 0 0C and it was allowed to warm up to room temperature and was stirred at room temperature for 4 hours. The reaction mixture was diluted with ice water (50OmL and the precipitated solid was filtered and washed with water (20OmL), dried under vacuum to afford the title compound (29b) as pale brown colored solid (3.6g, 91% yield).

Reference： [1]Current Patent Assignee: ORCHID PHARMA LTD - WO2008/87514, 2008, A2 Location in patent: Page/Page column 33

27
[ 3943-97-3 ]
[ 200112-75-0 ]
[ 1250397-40-0 ]

Yield	Reaction Conditions	Operation in experiment
77%	Stage #1: methyl 4-hydroxycinnamate With sodium hydroxide In dimethyl sulfoxide Inert atmosphere; Stage #2: 3-(perfluorooctyl)propyl iodide In dimethyl sulfoxide	Synthesis of Compound for reacting with a functional group: (E)-methyl 3-(4-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,ll,ll,ll-heptadecafluoroundecyloxy)phenyl) acrylate (E)-Methyl 3-(4-hydroxyphenyl)acrylate (166 mg, 0.93 mmol) was added to dry DMSO ( 10 mL) and stirred under nitrogen in a round bottom flask. Crushed sodium hydroxide (44 mg, 1.1 mmol) was added. After 30 minutes, 1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-heptadecafluoro-l l-iodoundecane (500 mg, 0.85 mmol) was added. The reaction was allowed to stir overnight. Washed with water and extracted with dichloromethane to yield an oil. This crude product was purified on a silica column using hexanes with increasing amounts of ethyl acetate as the eluent. A white solid was isolated (418 mg, 77 % yield). 1H NMR (400.14 MHz, CDCl3) δ 7.65 (d, J= 16.0 Hz), 7.48 (d, J= 8.75 Hz, 2H), 6.90 (d, J= 8.75 Hz, 2H), 6.32 (d, J= 16.0 Hz), 4.07 (t, J= 5.90 Hz, 2H), 3.80 (3H), 2.40 - 2.20 (m, 2H), 2.18 - 2.05 (m, 2H).
77%	With sodium hydroxide In dimethyl sulfoxide	Synthesis of Compound for Reacting with a Functional Group: (E)-methyl 3-(4-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluoroundecyloxy)phenyl)acrylate Synthesis of Compound for Reacting with a Functional Group: (E)-methyl 3-(4-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluoroundecyloxy)phenyl)acrylate (E)-Methyl 3-(4-hydroxyphenyl)acrylate (166 mg, 0.93 mmol) was added to dry DMSO (10 mL) and stirred under nitrogen in a round bottom flask. Crushed sodium hydroxide (44 mg, 1.1 mmol) was added. After 30 minutes, 1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-heptadecafluoro-11-iodoundecane (500 mg, 0.85 mmol) was added. The reaction was allowed to stir overnight. Washed with water and extracted with dichloromethane to yield an oil. This crude product was purified on a silica column using hexanes with increasing amounts of ethyl acetate as the eluent. A white solid was isolated (418 mg, 77% yield). 1H NMR (400.14 MHz, CDCl3) δ 7.65 (d, J=16.0 Hz), 7.48 (d, J=8.75 Hz, 2H), 6.90 (d, J=8.75 Hz, 2H), 6.32 (d, J=16.0 Hz), 4.07 (t, J=5.90 Hz, 2H), 3.80 (3H), 2.40-2.20 (m, 2H), 2.18-2.05 (m, 2H).
77%	Stage #1: methyl 4-hydroxycinnamate With sodium hydroxide In dimethyl sulfoxide for 0.5h; Inert atmosphere; Stage #2: 3-(perfluorooctyl)propyl iodide In dimethyl sulfoxide	Synthesis of Compound for Reacting with a Functional Group: (E)-methyl 3-(4-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluoroundecyloxy)phenyl)acrylate (E)-Methyl 3-(4-hydroxyphenyl)acrylate (166 mg, 0.93 mmol) was added to dry DMSO (10 mL) and stirred under nitrogen in a round bottom flask. Crushed sodium hydroxide (44 mg, 1.1 mmol) was added. After 30 minutes, 1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-heptadecafluoro-11-iodoundecane (500 mg, 0.85 mmol) was added. The reaction was allowed to stir overnight. Washed with water and extracted with dichloromethane to yield an oil. This crude product was purified on a silica column using hexanes with increasing amounts of ethyl acetate as the eluent. A white solid was isolated (418 mg, 77% yield).

Reference： [1]Current Patent Assignee: GEORGIA INSTITUTE OF TECHNOLOGY - WO2010/115854, 2010, A1 Location in patent: Page/Page column 34
[2]Current Patent Assignee: GEORGIA INSTITUTE OF TECHNOLOGY - US2011/114935, 2011, A1
[3]Current Patent Assignee: GEORGIA INSTITUTE OF TECHNOLOGY - JP5670329, 2015, B2 Location in patent: Paragraph 0075

28
[ 3943-97-3 ]
[ 934279-31-9 ]

Yield	Reaction Conditions	Operation in experiment
70%	With dihydrogen peroxide; calcium chloride In methanol at 20℃; for 0.5h; aq. buffer; Enzymatic reaction; regiospecific reaction;	Dimerization reaction of phenolic esters using crude onion POD A solution containing 2 mM of phenolic ester 4, 5 or 6 dissolved in MeOH, DMF or glycerol (1 mL) was added to a mixture containing crude onion POD extract (10% of the total volume) and 8ml H2O2 (3 mM in phosphate/citrate buffer, pH 5 containing 2 mM CaCl2) for 30 min at room temperature. The reaction was stopped by the addition of TCA (0.1 ml, 10% in EtOH) and then subjected to centrifugation at 5000g for 10 min. The mixture was extracted with EtOAc (3 × 20 mL) and the organic layer was dried over Na2SO4. After vacuum distillation of the solvent, the residue was redissolved in MeOH (1 mL), filtered through 0.45 μm syringe filters, and the filtrate was used for chromatographic analyses. The crude reaction products were purified using preparative silica gel TLC (developed with petroleum ether/EtOAc 7:3), followed by preparative normal phase HPLC using a CECIL 1100 Series liquid chromatography pump equipped with a GBC LC-1240 refractive index detector and a Supelcosil SPLC-Si (25 cm × 10 mm) column with cyclohexane/EtOAc (6:4) as eluent.

Reference： [1]Location in patent: experimental part Moussouni, Sonia; Saru, Maria-Liliana; Ioannou, Efstathia; Mansour, Mohamed; Detsi, Anastasia; Roussis, Vassilios; Kefalas, Panagiotis [Tetrahedron Letters, 2011, vol. 52, # 11, p. 1165 - 1168]

29
[ 123-08-0 ]
[ 21204-67-1 ]
[ 3943-97-3 ]

Yield	Reaction Conditions	Operation in experiment
97%	In toluene at 150℃; for 0.166667h; Inert atmosphere; Microwave irradiation; Sealed tube; stereoselective reaction;
92%	In dichloromethane at 20℃; for 6h;
92%	In water at 90℃; for 1h; Green chemistry;	3.1.2. General Method for the HWE Reaction in Water General procedure: A suspension of an appropriate aromatic aldehyde (1 eq.), and ylide I or II (1.3-1.5 eq.) inwater (4-10 mL) was stirred at 90 °C for 0.5-24 h. Next, the heterogeneous reaction mixturewas cooled to room temperature, and the aqueous phase was extracted with DCM (3 10 mL).The solvent was evaporated under diminished pressure. Column chromatography (hexane-ethylacetate, or chloroform-methanol) of the residue gave the E-alkene as the major product.

Reference： [1]Konrádová, Daniela; Kozubíková, Hana; Doležal, Karel; Pospíšil, Jiří [European Journal of Organic Chemistry, 2017, vol. 2017, # 35, p. 5204 - 5213]
[2]Location in patent: experimental part Narsaiah, A. Venkat; Kumar, J. Kranthi [Synthetic Communications, 2011, vol. 41, # 11, p. 1603 - 1608]
[3]Sidoryk, Katarzyna; Jaromin, Anna; Filipczak, Nina; Cmoch, Piotr; Cybulski, Marcin [Molecules, 2018, vol. 23, # 9]

30
[ 540-38-5 ]
[ 292638-85-8 ]
[ 3943-97-3 ]

Yield	Reaction Conditions	Operation in experiment
90%	With C₂₅H₁₆O₆C₄H₁₁NH₂O; tetrabutylammomium bromide; palladium diacetate; potassium carbonate In water at 90℃;	Mizoroki-Heckcross-coupling reactions General procedure: A mixture of aryl halide (1.0 mmol), alkenes (1.5 mmol), K2CO3 (2.0 mmol), novel ligand (0.3 mol %), Pd(OAc)2 (0.3 mol %) and TBAB (0.6 mmol) was heated in water (5 ml) at 90 °C temperature. The progress of the reaction is monitor by TLC. After the completion of the reaction, ethyl acetate (10 ml) was added to the reaction mixture and extracted with ethyl acetate (3 x 10 ml). The combined organic layer was dried with anhyd. Na2SO4 and the solvent were concentrated in vacuum to obtain a solid. The residue was purified by silicagel column chromatography (5-10% EtOAc in hexane) to afford the corresponding pure products.
88%	With C₅₁H₈₀N₂O₃₈Pd; potassium carbonate In water for 12h; Schlenk technique; Reflux; Green chemistry;	4.5. General procedure for Mizoroki-Heck cross-coupling reactionsof aryl halides with olefin using PdLnβ-CD (3a-3u) General procedure: A Schlenk flask equipped with asepta and a magnetic stir bar wasfilled with aryl halide (3.0 mmol), alkene (3.2 mmol), K2CO3(3.5 mmol) and PdLn-β-CD 3 mol% catalyst in water (5 mL pure orplain). The reaction was refluxed for the appropriate time underaerobic conditions. After completion of the reaction was confirmedby TLC, the reaction mixturewas cooled to room temperature.The solvent was removed by rotary evaporator and extraction of theproduct was carried out using ethyl acetate. The ethyl acetate fractionwas separated and dried over anhydrous sodium sulphate. Theresulting crude product was purified using flash column chromatographyof silica gel 60-120mesh with n-hexane/ethyl acetate (8:2ratio) as the eluent and afforded the pure desired product. After extractionof product, catalyst was simply reprecipitated from theaqueous layer by the addition of 10 mL of acetone. The recoveredcatalyst was filtered, washed with acetone (3 × 5 mL) and dried ina vacuum at 70 °C for 5 h and reused.
83%	With potassium phosphate; 2-hydroxy-3-(p-tolyl)-2,3-dihydroindan-1-one; palladium diacetate In 1,4-dioxane at 80℃;	General Procedure for Mizoroki-Heck Cross-Coupling Reactions (25-33) General procedure: A mixture of aryl halides/tosylates (1.0 mmol), alkenes (1.5 mmol), K3PO4 (2.0 mmol), ligand (0.3 mol%) and Pd(OAc)2 (0.3 mol%) was heated in dioxane (5 mL) at 80 °C. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the mixture was cooled to r.t., and solvent was removed under reduced pressure. Water (10 mL) was added to the mixture, and extracted with EtOAc (3 × 10mL). The combined organic layer was dried with anhydrous Na2SO4 and the solvent was concentrated in vacuum to obtain a solid. The residue was purified by silica gel column chromatography (EtOAc-hexane, 5-10%) to afford the corresponding pure products.

75%	With triethylamine In N,N-dimethyl-formamide at 130℃; for 2h;
	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; lithium chloride; potassium hydroxide In water at 85℃; for 3h;

Reference： [1]Waheed, Mohammed; Ahmed, Naseem [Tetrahedron Letters, 2016, vol. 57, # 33, p. 3785 - 3789]
[2]Dindulkar, Someshwar D.; Jeong, Daham; Kim, Hwanhee; Jung, Seunho [Carbohydrate Research, 2016, vol. 430, p. 85 - 94]
[3]Waheed, Mohammed; Ahmed, Naseem [Synthesis, 2017, vol. 49, # 18, p. 4372 - 4382]
[4]Mpungose, Philani P.; Sehloko, Neo I.; Dasireddy, Venkata D.B.C.; Mahadevaiah, Narayanappa; Maguire, Glenn E.; Friedrich, Holger B. [Molecular catalysis, 2017, vol. 443, p. 60 - 68]
[5]Shard, Amit; Sharma, Naina; Bharti, Richa; Dadhwal, Sumit; Kumar, Rajesh; Sinha, Arun K. [Angewandte Chemie - International Edition, 2012, vol. 51, # 49, p. 12250 - 12253][Angew. Chem., 2012, vol. 124, # 49, p. 12416 - 12419,4]

31
[ 3943-97-3 ]
[ 182133-00-2 ]
[ 1622308-93-3 ]

Yield	Reaction Conditions	Operation in experiment
97%	Stage #1: methyl 4-hydroxycinnamate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.166667h; Stage #2: 2-(4'-methoxyphenyl)-3-bromo-6-methoxybenzo[b]thiophene S-oxide In N,N-dimethyl-formamide; mineral oil at 80℃; for 18h;	(E)-methyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 71) (E)-methyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (compound 71) To a solution of (E)-methyl 3-(4-hydroxyphenyl)acrylate (190 mg, 1.07 mmol) in DMF (5 mL) was added sodium hydride (60% suspension in oil, 42.7 mg, 1.07 mmol). The resulting mixture was allowed to stir for 10 min at room temperature after which 3-bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene 1-oxide (300 mg, 0.82 mmol) was added, as a solid. The reaction was heated to 80° C. for 18 h and upon completion was cooled to room temperature, quenched with water and diluted with DCM. The organic phase was collected (phase separator) and concentrated in vacuo to afford the crude product which was purified by column chromatography (SiO2, 0-80% EtOAc/Heptane) to afford (E)-methyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (370 mg, 0.80 mmol, 97% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm=7.75 (d, J=9.09 Hz, 2H), 7.65 (d, J=15.66 Hz, 1H), 7.54 (d, J=2.02 Hz, 1H), 7.43-7.52 (m, J=9.09 Hz, 2H), 7.07-7.16 (m, J=8.59 Hz, 2H), 6.98-7.07 (m, 1H), 6.93 (d, J=9.09 Hz, 3H), 6.35 (d, J=16.17 Hz, 1H), 3.91 (s, 3H), 3.82 (d, J=1.52 Hz, 6H). LC/MS (m/z, MH+): 463.4.
97%	Stage #1: methyl 4-hydroxycinnamate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.166667h; Stage #2: 2-(4'-methoxyphenyl)-3-bromo-6-methoxybenzo[b]thiophene S-oxide In N,N-dimethyl-formamide; mineral oil at 80℃; for 18h;

Reference： [1]Current Patent Assignee: THOMSEN NEOEL MARIE FRANCE; Novartis (w/o Sandoz); NOVARTIS AG - US2014/235660, 2014, A1 Location in patent: Paragraph 0311; 0312
[2]Tria, George S.; Abrams, Tinya; Baird, Jason; Burks, Heather E.; Firestone, Brant; Gaither, L. Alex; Hamann, Lawrence G.; He, Guo; Kirby, Christina A.; Kim, Sunkyu; Lombardo, Franco; Macchi, Kaitlin J.; McDonnell, Donald P.; Mishina, Yuji; Norris, John D.; Nunez, Jill; Springer, Clayton; Sun, Yingchuan; Thomsen, Noel M.; Wang, Chunrong; Wang, Jianling; Yu, Bing; Tiong-Yip, Choi-Lai; Peukert, Stefan [Journal of Medicinal Chemistry, 2018, vol. 61, # 7, p. 2837 - 2864]

32
[ 3943-97-3 ]
[ 471-53-4 ]
trans-4-hydroxycinnamic acid methyl ester 3β-hydroxy-11-oxo-olean-12-en-30-oate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h;	3.4. General Method for Synthesizing Compouds 17-24 General procedure: GA (485 mg, 1 mmol) was dissolved in dry DCM (30 mL) and stirred at room temperature for 5 min. Then EDCI (230 mg, 1.2 mmol), DMAP (24 mg, 0.2 mmol) and compounds 5-12 (1 mmol) were added to the solution, and then the reaction mixture was stirred at room temperature for 12 h. The organic layer was washed with 1 M HCl solution and concentrated in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate/petroleum as eluent to yield pure compounds 17-24.

Reference： [1]Li, Yang; Feng, Ling; Song, Zhi-Fang; Li, Hai-Bei; Huai, Qi-Yong [Molecules, 2016, vol. 21, # 2]

33
[ 64-17-5 ]
[ 3943-97-3 ]
[ 2979-06-8 ]

Reference： [1]Chemical Biology and Drug Design,2016,vol. 88,p. 926 - 937

34
[ 3943-97-3 ]
[ 58479-61-1 ]
4-O-tert-butyldiphenylsilyl-(E)-p-coumaric acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With 1H-imidazole In N,N-dimethyl-formamide at 0℃; for 18h;	3.4.5. 4-O-tert-Butyldiphenylsilyl-(E)-p-coumaric acid methylester (20) A solution of (E)-p-coumaric acid methyl ester (19, 2.70 g,15.0 mmol) in dry DMF (150 mL) was treated with imidazole (1.20 g, 1.20 equiv) and TBDPSCl (14.1 mL, 1.05 equiv) at 0 C for 18 h. The reaction mixture was poured into H2O and extracted with EtOAc. Work-up of the EtOAc extract as described in Section 3.4.1. gave a residue, which was purified by normal-phase silica gel CC [200 g, n-hexane-EtOAc (40:1, v/v)] to give 20 (6.00 g, 96%); as acolorless oil.

Reference： [1]Manse, Yoshiaki; Ninomiya, Kiyofumi; Nishi, Ryosuke; Kamei, Iyori; Katsuyama, Yushi; Imagawa, Takahito; Chaipech, Saowanee; Muraoka, Osamu; Morikawa, Toshio [Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 23, p. 6215 - 6224]

35
[ 3943-97-3 ]
[ 106-95-6 ]
methyl (2E)-3-(4-allyloxyphenyl)-2-propenoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium carbonate In acetone at 50℃; for 12h;	4.1.5. General Procedure for the Synthesis of Compounds 4, 6, 7, and 9 General procedure: Compound 14 or 15 or 16 (1 eq) was dissolved in dry acetone (15 mL) and thenanhydrous potassium carbonate (1 eq) and appropriated alkenyl bromide (1 eq) wereadded. The resulting mixture was stirred at 50 C for 12 h, then sodium hydroxide 2 N(15 mL) was added and the reaction mixture was stirred at 90 C for an additional 3 h.The cooled solution was acidified to pH 2 with hydrochloridric acid (10% solution) andextracted with dichloromethane (3 50 mL). The collected organic phases were dried overanhydrous sodium sulphate and evaporated to dryness to give the pure ether.
2.57 g	With potassium carbonate In acetone at 70℃; for 12h;

Reference： [1]Balmas, Virgilio; Carta, Paola; Casalini, Stefano; Chtioui, Wiem; Delogu, Giovanna; Dettori, Maria A.; Fabbri, Davide; Migheli, Quirico; Oufensou, Safa [Molecules, 2021, vol. 26, # 3]
[2]Beňová, Eva; Zeleňák, Vladimír; Halamová, Dáša; Almáši, Miroslav; Petrul'ová, Veronika; Psotka, Miroslav; Zeleňáková, Adriána; Bačkor, Martin; Hornebecq, Virginie [Journal of Materials Chemistry B, 2017, vol. 5, # 4, p. 817 - 825]

36
[ 3943-97-3 ]
[ 645-31-8 ]
[ 106005-97-4 ]

Yield	Reaction Conditions	Operation in experiment
67%	With 1-methyl-pyrrolidin-2-one; sodium hydrogencarbonate; In N,N-dimethyl acetamide; at 160℃; for 12.0h;Inert atmosphere;	14.2g Dopamine hydrobromide, 9.0g methyl p-hydroxycinnamate, 5.1 g of sodium bicarbonate and 50 ml of N-methylpyrrolidone added into 100mL the four-necked round bottom flask, system using under nitrogen protection, and the internal temperature raised at 160 C for 12 hours, and the TLC test has been completed. Added 200mL water, add ethyl acetate 100mL X 3 extract. The organic phase has been washed with saturated brine 100mL X2, 1N dilute hydrochloric acid 100mL X2, dried over anhydrous sodium sulfate, filtered and concentrated then obtained 28.0 g of slurry. to this slurry added the 20mL of petroleum ether and 2mL of ethyl acetate, then heated to reflux for 30 minutes. Cooling, standing, pours out the upper layer solution, and added the 10mL absolute ethanol to the slurry, stirs for 30 minutes, filter, dry, then obtained the 10.2g white solid product. Identified by nuclear magnetic resonance, the obtained product is N-coumaroyl dopamine. By this method can achieve the design goal, no need to column purification in order to get pure product, yield increased up to 67%.

Reference： [1]Patent: CN105777573,2016,A .Location in patent: Paragraph 0010; 0015-0016

37
[ 3943-97-3 ]
[ 3188-13-4 ]
(E)-methyl 3-(4-(ethoxymethoxy)phenyl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	Stage #1: methyl 4-hydroxycinnamate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.166667h; Inert atmosphere; Stage #2: ethyl chloromethyl ether In tetrahydrofuran; mineral oil at 0 - 20℃; for 2h; Inert atmosphere;	General procedure for EOM-protection (GP1) General procedure: A solution of the desired methyl ester (1 equiv) in THF (1.5mL/mmol) was added dropwise to a suspension of NaH (60% in mineral oil) in THF (5mL/mmol) at 0°C under inert atmosphere. After 10min a solution of chloromethylethylether (EOMCl) in THF (2.2mL/mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature and monitored by TLC. After 2h the reaction was quenched with a saturated NaHCO3 solution until pH 10at 0°C and extracted with EtOAc (3×15mL). The organic extracts were dried over Na2SO4 and concentrated to obtain the desired EOM-protected compound (2c, 2d, 2f, 2g, 2i or 2j). The crude was purified by column chromatography only when specified.

Reference： [1]Giacomini, Daria; Musumeci, Rosario; Galletti, Paola; Martelli, Giulia; Assennato, Lorenzo; Sacchetti, Gianni; Guerrini, Alessandra; Calaresu, Enrico; Martinelli, Marianna; Cocuzza, Clementina [European Journal of Medicinal Chemistry, 2017, vol. 140, p. 604 - 614]

38
[ 3943-97-3 ]
[ 459-46-1 ]
(E)-methyl 3-(4-((4-fluorobenzyl)oxy)phenyl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16h;	Step-1: (E)-methyl 3-(4-((4-fluorobenzyl)oxy)phenyl)acrylate-XXXIII To a stirred solution of (E)-methyl 3-(4-hydroxyphenyl)acrylate (5.1 g, 28.6 mmol), in dry DMF (50 mL) was added l-(bromomethyl)-4-fluorobenzene (6.5 g, 34.3 mmol) and potassium carbonate (11.86 g, 85.9 mmol) at room temperature and the resulting mixture was stirred at room temperature for 16h. Ice water was added to it and then extracted with ethylacetate (3x 50 mL). The combined organic extract was washed with water, brine, dried over sodium sulphate and concentrated under reduced pressure to afford the product as off-white solid (XXXIII, 8 g, 97 %). LC-MS m/z calcd for C17H15FO3, 286.1; found 287.1 [M+H]+.

Reference： [1]Current Patent Assignee: JUBILANT PHARMOVA LTD - WO2017/195216, 2017, A1 Location in patent: Page/Page column 146-147

39
[ 3943-97-3 ]
[ 87227-41-6 ]
C₁₇H₂₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium carbonate In acetone at 64℃; for 24h;	27 100ml with cooling tubeMethyl 4-hydroxycinnamate (3.6 g, 20.0 mmol) was added to the eggplant flask.2-(4-bromo-1-butyl)-1,3-dioxolane 4.2 g (20.0 mmol),Potassium carbonate 5.5g (40mmol),And acetone 50ml to form a mixture,The reaction was carried out while stirring at a temperature of 64°C for 24 hours.After the reaction is over,The reaction solution was poured into 500 ml of pure water.A white solid 6.0g was obtained.The solid was measured by NMR.The result of the measurement is as follows.According to the result,It was confirmed that the white solid was the intermediate compound [MA42-1] (yield 98%).

Reference： [1]Current Patent Assignee: HYOGO PREFECTURE; NISSAN CHEMICAL CORPORATION; HYOGO UNIVERSITY - CN107473969, 2017, A Location in patent: Paragraph 0667; 0669-0671

40
[ 3943-97-3 ]
[ 14704-31-5 ]
C₂₃H₂₀O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 6h;Inert atmosphere;	General procedure: To a mixture of compound 2 (550?mg, 2.0?mmol), methyl-4-hydroxycinnamate (434?mg, 2.3?mmol) in DMF (10.0?mL) was added K2CO3 (1.38?g, 10.0?mmol) and the mixture was stirred for 6?h?at 50?C. After cooling, the resulting mixture was extracted with EtOAc and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc?=?15/1) to afford compound 7b (457?mg, 63.8%) as a white solid.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 158,p. 123 - 133

41
[ 51632-16-7 ]
[ 3943-97-3 ]
C₂₃H₂₀O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 6h;Inert atmosphere;	General procedure: To a mixture of compound 2 (550?mg, 2.0?mmol), methyl-4-hydroxycinnamate (434?mg, 2.3?mmol) in DMF (10.0?mL) was added K2CO3 (1.38?g, 10.0?mmol) and the mixture was stirred for 6?h?at 50?C. After cooling, the resulting mixture was extracted with EtOAc and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc?=?15/1) to afford compound 7b (457?mg, 63.8%) as a white solid.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 158,p. 123 - 133

42
[ 3943-97-3 ]
[ 1700-31-8 ]
C₂₄H₂₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 6h;Inert atmosphere;	General procedure: To a mixture of compound 2 (550?mg, 2.0?mmol), methyl-4-hydroxycinnamate (434?mg, 2.3?mmol) in DMF (10.0?mL) was added K2CO3 (1.38?g, 10.0?mmol) and the mixture was stirred for 6?h?at 50?°C. After cooling, the resulting mixture was extracted with EtOAc and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc?=?15/1) to afford compound 7b (457?mg, 63.8percent) as a white solid.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 158,p. 123 - 133

43
[ 3943-97-3 ]
[ 3101-60-8 ]
[ 60377-55-1 ]

Reference： [1]Patent: DE2460689,1976,
Chem.Abstr.,1979,vol. 90

44
[ 3943-97-3 ]
rac-1,2-dimethyl (1R,2R,3S,4S)-3,4-di-(p-methylphenyl)cyclobutane-1,2-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With tris[2-phenylpyridinato-C₂,N]iridium(III) In 1,4-dioxane at 25℃; for 36h; Inert atmosphere; Irradiation;	47 Example 47 A method for constructing a quaternary carbon ring by visible light catalysis [2+2] reaction, comprising the following steps: The ruthenium complex 1 was used as a visible light catalyst, and 1.3 mg of the catalyst and 0.2 mmol were added to 2 mL of 1,4-dioxane.(E)-methyl-3-p-hydroxyphenyl acrylate(corresponding R2 is p-hydroxyphenyl and R3 is methoxy), wherein the concentration of the visible light catalyst is 1.0 x 10-3 M. Argon gas was introduced for ten minutes, and then light-illuminated in an argon atmosphere at 25 ° C for 36 hours with Blue LEDs of 450 nm ± 10 nm. After the reaction was completed, the mixture was directly dried and separated by column.Nuclear magnetic resonance spectrum, carbon spectrum,And mass spectrometry identified products as racemic(1R, 2R, 3S, 4S)-dimethyl-3,4-di-p-methylphenylcyclobutane-1,2-dicarboxylate. The conversion of the starting material was 100% and the yield of the cyclobutane product was 93%.

Reference： [1]Current Patent Assignee: Technical Institute of Physics & Chemistry(in: CAS); CHINESE ACADEMY OF SCIENCES - CN108623425, 2018, A Location in patent: Paragraph 0217-0219

45
[ 141-82-2 ]
[ 3943-97-3 ]
[ 45101-66-4 ]
6-[4-[(E)-3-methoxy-3-oxo-prop-1-enyl]phenoxy]hexyl 2-methylprop-2-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: methyl 4-hydroxycinnamate; 2-methyl-acrylic acid 6-chloro-hexyl ester With 10H-phenothiazine; potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 90℃; for 6h; Inert atmosphere; Stage #2: malonic acid With morpholine In N,N-dimethyl-formamide at 85℃; for 8h;	8 Example 1: Preparation of (E)-3-[4-[6-(2-methylprop-2-enoyloxy)hexoxy]phenyl]prop-2-enoic acid General procedure: 100.0 g of 4-hydroxybenzaldehyde, 147.0 g of potassium carbonate (powder), 12.0 g of potassium iodide and 0.1 g of phenothiazine are suspended in 500.0 g of DMF. To this suspension is added 176.0 g of 6-chlorohexyl 2-methylprop-2-enoate. The resulting mixture is then heated up to 90 °C under Nitrogen atmosphere. After 6 hours at 90^ the reaction mixture is cooled down to 20 ^ and filtered on Hyflo. The remaining solid is washed with 100 g of DMF. The resulting DMF solution is transferred in a reactor. To this solution 14.3 g of morpholine and 0.1 g of phenothiazine are added. The reaction mixture is then heated up to 85^ and a solution of 170.7 g of malonic acid in 270 g of DMF is added dropwise over a period of 4 hours. After 4 more hours of stirring at this temperature the reaction mixture is cooled to 60 'C and 300 ml_ of water are added dropwise. After cooling down the mixture to 15^ the solid is filtered off to obtain 218 g of Compound 1 as a yellowish solid with an HPLC purity of >95%. 1 H NMR (300MHz) in DMSO-d6 of compound 1 : 12.05 (s, 1 H), 7.61 (d, 2H), 7.49 (d, 1 H), 6.94 (d, 2H), 6.35 (d, 1 H), 6.01 (t, 1 H), 5.65 (t, 1 H), 4.09 (t, 2H), 4.00 (t, 2H), 1 .87 (m, 3H), 1 .72 (m, 2H), 1 .63 (m, 2H), 1 .41 (m, 4H).

Reference： [1]Current Patent Assignee: BASF SE - WO2019/30294, 2019, A1 Location in patent: Page/Page column 25; 29

46
[ 3943-97-3 ]
[ 123-08-0 ]
[ 123064-80-2 ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 1657 - 1668

47
[ 3943-97-3 ]
7-bromo-N-(trityloxy)heptanamide [ No CAS ]
methyl (E)-3-(4-((7-oxo-7-((trityloxy)amino)heptyl)oxy)phenyl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 4h; Inert atmosphere;	27 4.1.27. Methyl (E)-3-(4-((7-oxo-7-((trityloxy)amino)heptyl)oxy)phenyl)acrylate (31) To a solution of compound 10 (480 mg, 1.0 mmol) and compound30 (100 mg, 0.51 mmol) in dry DMF 5 mL, K2CO3 (213 mg, 1.54 mmol)was added. The mixture was stirred at 40 °C for 4 h. The reaction wasquenched with saturated brine and extracted with EA (3×15 mL). Thecombined organic layers were washed with saturated brine, dried overNa2SO4, and concentrated to give an oily crude product, which waspurified on a silica gel column [PE/EA=2:1-1:1] to give compound 31as a yellow solid (269 mg, yield: 93%). 1H NMR (400 MHz, CDCl3) δ7.65 (d, J=15.9 Hz, 1H), 7.46 (d, J=8.1 Hz, 4H), 7.33 (s, 14H), 6.87(d, J=8.1 Hz, 2H), 6.30 (d, J=16.0 Hz, 1H), 3.93 (t, J=6.1 Hz, 2H),3.79 (s, 3H), 1.75-1.66 (m, 2H), 1.61 (s, 4H), 1.29 (s, 3H), 1.10 (s, 1H).13C NMR (100 MHz, CDCl3) δ 168.0, 161.1, 144.8, 129.9, 129.2, 128.3,127.1, 115.2, 115.0, 68.1, 51.7, 29.8, 29.8, 29.0, 28.9, 25.8. HRMS(ESI) calcd for C36H37NNaO5 [M+Na]+ 586.2564, found 586.2568.

Reference： [1]Ge, Weizhi; Liu, Zhongquan; Sun, Yu; Wang, Tianpeng; Guo, Hongyu; Chen, Xinyi; Li, Shengzu; Wang, Mengmeng; Chen, Yue; Ding, Yahui; Zhang, Quan [Bioorganic Chemistry, 2019, vol. 87, p. 699 - 713]

48
[ 3943-97-3 ]
[ 4584-46-7 ]
[ 245467-31-6 ]

Yield	Reaction Conditions	Operation in experiment
93.6%	With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 80℃; for 10h;	1-7 Example 4 Methyl p-hydroxycinnamic acid (4.12 g, 23.1 mmol), N, N-dimethylaminochloroethane hydrochloride (34.65 mmol), N, N-dimethylformamide 41.2 ml, potassium carbonate (184.8 mmol ), Potassium iodide (11.55 mmol) was added to the reaction flask, heated to 80 ° C. with stirring, and the reaction was held for 10 hours. After completion of the reaction, the reaction solution was added to water, extracted with ethyl acetate (50 ml × 2), and the layers were separated. The organic phase was washed with water, saturated brine, and dried with anhydrous sodium sulfate. Concentration under reduced pressure gave 4-dimethylaminoethoxycinnamic acid methyl ester as a white solid (yield: 93.6%, purity: 99.8%).

Reference： [1]Current Patent Assignee: LUNAN PHARMACEUTICAL GROUP CO LTD - CN110305024, 2019, A Location in patent: Paragraph 0029-0052

49
[ 1643-29-4 ]
[ 3943-97-3 ]
C₁₉H₁₈O₅ [ No CAS ]
C₁₉H₁₈O₅ [ No CAS ]

Reference： [1]Chemical Science,2020,vol. 11,p. 2130 - 2135

50
[ 3943-97-3 ]
[ 2523-42-4 ]
C₂₃H₁₈O₃ [ No CAS ]

Reference： [1]Chemical Science,2020,vol. 11,p. 2130 - 2135

51
[ 3943-97-3 ]
[ 17024-12-3 ]
C₂₄H₁₈O₃ [ No CAS ]

Reference： [1]Chemical Science,2020,vol. 11,p. 2130 - 2135

52
[ 13327-31-6 ]
[ 3943-97-3 ]
C₁₉H₁₅NO₃ [ No CAS ]
C₁₉H₁₅NO₃ [ No CAS ]

Reference： [1]Chemical Science,2020,vol. 11,p. 2130 - 2135

53
[ 3943-97-3 ]
[ 79-11-8 ]
[ 731845-75-3 ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium carbonate In N,N-dimethyl-formamide; acetone at 0 - 20℃; for 4h;	Synthesis of (E)-2-(4-(3-methoxy-3-oxoprop-1-en-1-yl)phenoxy)acetic acid (15): A 3 g of (E)-methyl 3-(4-hydroxyphenyl)acrylate (13) (16.84 mmol, 1 equiv) was dissolved in 50 mL of acetone. To this solution, 7 g of K2CO3 (50.52 mmol, 3 equiv) was mixed properly and thereafter a solution of 3.18 g of chloroacetic acid (14) (33.68 mmol, 2equiv) was added dropwise in 10 mL of acetone. Further, the stirring of the mixture was carried at room temperature for 4 hr and reaction progress was monitored by TLC. The mixture was acidified with dil. HCl and organic phase was extracted with ethyl acetate. The organic phase was dried with anhydrous Na2SO4 and filtered. The filtrate was dried toafford (E)-2-(4-(3-methoxy-3-oxoprop-1-en-1-yl)phenoxy)acetic acid(15). White solid mass; Yield: 80%, Rf: 0.5 (4:6 EtOAc: hexane), mp 90-110 °C; IR (cm-1): 1510 (C=C), 1600 (C=N), 1728 (C=O), 3421(O-H); 1H NMR (400 MHz, CDCl3): δ 3.72(s, 3H, CH3); 5.01 (s, 2H),6.30 (d, 1H, J = 16 Hz, CH=CH); 6.79 (d, 2H, J = 8 Hz); 7.45 (d, 2H,J=8 Hz); 7.55 (d, 1H, J=16 Hz, CH=CH); 9.83 (s, 1H, OH); 13C NMR(100 MHz, CDCl3) δ 50.95, 65.21, 78.94, 113.67, 115.66, 124.90,129.80, 144.51, 159.74, 166.86. MS (m/z): 236.58 (M + ).

Reference： [1]Bhat, Sana; Bhat, Zahid Rafiq; Gupta, Jeena; Kaur, Jaskiran; Kaur, Paranjeet; Khatik, Gopal L.; Khurana, Navneet; Kumar, Rajan; Kumar, Rakesh; Tikoo, Kulbhushan [Bioorganic Chemistry, 2020, vol. 100]

54
[ 3943-97-3 ]
(4-chloro-7-((2-(trimethylsilyl)ethoxy)methoxy)2H-chromen-3-yl)(m-tolyl)methanone [ No CAS ]
methyl (E)-3-(4-((3-(3-methylbenzoyl)-7-((2-(trimethylsilyl)ethoxy)methoxy)2H-chromen-4-yl)oxy)phenyl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With caesium carbonate In acetonitrile at 60℃; for 2h;	4.1.26 Synthesis of methyl (E)-3-(4-((3-(3-methylbenzoyl)-7-((2-(trimethylsilyl) ethoxy) methoxy)-2H-chromen-4-yl) oxy) phenyl) acrylate (16a) General procedure: Compound 15a (0.3g, 0.6mmol), methyl 4-hydroxycinnamate (0.15g, 0.66mmol) and cesium carbonate (0.39g, 1.2mmol) were dissolved in acetonitrile and the reaction mixture was stirred at 60 for 2h. After completion, the reaction mixture was cooled to room temperature and poured into water. The aqueous phase was extracted with ethyl acetate (10ml×2). The organic layer was combined, dried with anhydrous sodium sulfate and concentrated to in vacuo obtain crude product that was purified by column chromatography to get compound 16a as a yellow oil liquid (0.31g, 80%). 1H NMR (300MHz, CDCl3) δ 7.60 (d, J=16.0Hz, 1H), 7.42 (d, J=7.3Hz, 1H), 7.29 - 7.14 (m, 4H), 6.75 (d, J=2.3Hz, 1H), 6.65 - 6.52 (m, 3H), 6.31 (d, J=15.8Hz, 1H), 5.27 (s, 2H), 5.23 (s, 2H), 3.84 (s, 3H), 3.78 (d, J=8.4Hz, 2H), 2.24 (s, 3H), 1.01 (t, J=8.3Hz, 2H), 0.06 (d, J=1.8Hz, 9H).
80%	With caesium carbonate In acetonitrile at 60℃; for 2h;	25 Synthesis of (E)-3-(3-methylbenzoyl)-4-(4-methylacrylate-1-phenoxy)-7-((2-trimethylsilylethoxy)-methoxy)-2H-chromene (8a) Compound 7a (0.3g, 0.6mmol), p-hydroxycinnamic acid 78 (0.15g, 0.66mmol) and cesium carbonate (0.39g, 1.2mmol) were dissolved in acetonitrile and reacted at 60°C for 2h. Stop the reaction, cool to room temperature, pour the system into water, extract twice with ethyl acetate, combine the organic phases, extract once withsaturated brine, and dry with anhydrous sodium sulfate. Column chromatography gave a yellow oily liquid 8a (0.31g, 80%).

Reference： [1]Lu, Xiang; Teng, Yu; Lin, Xin; Xiao, Maoxu; Liu, Chenna; Chi, Xinglong; Zhang, Yulan; Luo, Guoshun; Xiang, Hua [Bioorganic Chemistry, 2021, vol. 109]
[2]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY - CN112898260, 2021, A Location in patent: Paragraph 0119-0121

55
[ 3943-97-3 ]
(4-chloro-7-((2-(trimethylsilyl)ethoxy)methoxy)2H-chromen-3-yl)(p-tolyl)methanone [ No CAS ]
methyl (E)-3-(4-((3-(4-methylbenzoyl)-7-((2-(trimethylsilyl)ethoxy)methoxy)2H-chromen-4-yl)oxy)phenyl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With caesium carbonate In acetonitrile at 60℃; for 2h;	4.1.26 Synthesis of methyl (E)-3-(4-((3-(3-methylbenzoyl)-7-((2-(trimethylsilyl) ethoxy) methoxy)-2H-chromen-4-yl) oxy) phenyl) acrylate (16a) General procedure: Compound 15a (0.3g, 0.6mmol), methyl 4-hydroxycinnamate (0.15g, 0.66mmol) and cesium carbonate (0.39g, 1.2mmol) were dissolved in acetonitrile and the reaction mixture was stirred at 60 for 2h. After completion, the reaction mixture was cooled to room temperature and poured into water. The aqueous phase was extracted with ethyl acetate (10ml×2). The organic layer was combined, dried with anhydrous sodium sulfate and concentrated to in vacuo obtain crude product that was purified by column chromatography to get compound 16a as a yellow oil liquid (0.31g, 80%). 1H NMR (300MHz, CDCl3) δ 7.60 (d, J=16.0Hz, 1H), 7.42 (d, J=7.3Hz, 1H), 7.29 - 7.14 (m, 4H), 6.75 (d, J=2.3Hz, 1H), 6.65 - 6.52 (m, 3H), 6.31 (d, J=15.8Hz, 1H), 5.27 (s, 2H), 5.23 (s, 2H), 3.84 (s, 3H), 3.78 (d, J=8.4Hz, 2H), 2.24 (s, 3H), 1.01 (t, J=8.3Hz, 2H), 0.06 (d, J=1.8Hz, 9H).