Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH:10]=[CH:11][C:12](O)=[O:13]>>[CH3:5][O:6][C:7]1[CH:8]=[C:9](/[CH:10]=[CH:11]/[C:12]([Cl:3])=[O:13])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: O=S(Cl)Cl
Product: COc1ccc(/C=C/C(=O)Cl)cc1OC

Procedure:
To 5 mL of dried thionyl chloride (SOCl2) contained in a reaction vessel was slowly added 4 g (19 mmol) of 3,4-dimethoxy cinnamic acid (140) and 50 μl of dried N′N′-dimethylformamide. The contents of the reaction vessel were mixed continuously at room temperature for 10-15 minutes, and the resulting product was dried in vacuo at 30-40° C. to yield (E)-3-(3,4-dimethoxyphenyl)acryloyl chloride (180).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:5]([CH3:16])=[N:6][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]=1[NH2:9].[NH3:17]>O.C(O)C>[NH2:9][C:8]1[N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=[C:5]([CH3:16])[C:4]=1[N:3]=[C:4]1[C:8](=[NH:7])[NH:9][N:17]=[C:5]1[CH3:16]
Reactant: Cc1nn(-c2ccccc2)c(N)c1N
Reactant: N
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC1=NNC(=N)C1=Nc1c(C)nn(-c2ccccc2)c1N
Reaction time: 17 h

Procedure:
2.6 g 4,5-diamino-3-methyl-1-phenyl-1H-pyrazole dihydrochloride were dissolved in a mixture of 30 ml water and 30 ml ethanol. The pH of the resulting solution was then adjusted to 9 with concentrated ammonia. Subsequently the reaction mixture was stirred for 17 hours with a gasifying stirrer. The precipitated dye compounds was separated by filtration, washed with water and dried. The yield amounted to 1.2 g.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]2[O:22][CH2:23][CH2:24][N:25]=2)[CH:18]=[C:17]([Cl:26])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([CH2:15][OH:16])[CH:11]=1.[H-].[Na+].[H][H].[CH3:31]I>O1CCCC1.CCOCC>[Cl:26][C:17]1[CH:18]=[C:19]([C:21]2[O:22][CH2:23][CH2:24][N:25]=2)[CH:20]=[C:2]([Cl:1])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([CH2:15][O:16][CH3:31])[CH:11]=1
Reactant: CI
Reactant: [H][H]
Reactant: OCc1cc(CCCCCOc2c(Cl)cc(C3=NCCO3)cc2Cl)on1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCc1cc(CCCCCOc2c(Cl)cc(C3=NCCO3)cc2Cl)on1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 6.8 g of 5-{5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-isoxazolemethanol (Example 116) in 100 ml of dry tetrahydrofuran was added 0.45 g of sodium hydride. After hydrogen evolution had ceased, the solution was cooled in an ice-bath and 1.1 ml of methyl iodide was added. The reaction mixture was stirred at room temperature for 48 hrs, then diluted with ether and washed well with water. Evaporation of the solvent and chromatography provided 3.1 g of the product as a viscous yellow oil.
Reaction SMILES: CO[C:3]1[CH:4]([CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)[CH2:5][CH2:6][CH2:7][CH2:8][N:9]=1.[Cl-:16].[NH4+:17]>CO>[ClH:16].[O:12]1[CH2:13][CH2:14][CH2:15][CH:11]1[CH2:10][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:3]1=[NH:17]
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: COC1=NCCCCC1CC1CCCO1
Solvent: CO
Product: Cl
Product: N=C1NCCCCC1CC1CCCO1

Procedure:
The title product of Example 42 in MeOH is reacted with ammonium chloride by the method of Example 5 to generate the title material.
Reaction SMILES: [C:1]([C:3]1[O:7][C:6]2[C:8]([O:14]C(=O)C)=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:5]=2[C:4]=1[C:18](=[O:31])[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=1)#[N:2].[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C=O)C>[OH:14][C:8]1[C:6]2[O:7][C:3]([C:1]3[N:2]=[N:32][NH:33][N:34]=3)=[C:4]([C:18](=[O:31])[C:19]3[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=3)[C:5]=2[CH:11]=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(C(=O)c2c(C#N)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)c2c(-c3nn[nH]n3)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Temperature: 110 °C
Reaction time: 4 h

Procedure:
Mixture of 2-cyano-7-acetoxy-6-methoxy-3-(3,4,5-trimethoxybenzoyl)-benzo[b]furan (15 mg, 0.04 mmol) ammonium chloride (11 mg, 0.2 mmol) and sodium azide (13 mg, 0.2 mmol) in dry DMF (400 μL) was stirred at 110° C. for 4 hours. More sodium azide (15 mg, 0.23 mmol) was added and stirring was continued for 1 hour (tlc), quenched with saturated ammonium chloride solution and extracted with ethyl-acetate (10 mL×2). The organic layer was dried over magnesium sulfate and solvent was distilled and the crude was purified by silica gel plate to afford the title compound as creamy solid; (3.5 mg, 21%; 1H NMR (300 MHz, CDCl3) δ: 7.85(1H, NH), 7.26(d, J=8.54 Hz, 1H), 7.02(s, 2H, benzoyl Hs), 6.95(d, J=8.54 Hz, 1H), 5.74(b, 1H, OH), 3.97(s, 3H, OMe), 3.88(s, 3H, OMe), 3.82(s, 6H, 2×OMe).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Br:13]Br>C(O)(=O)C>[Br:13][C:10]1[CH:11]=[C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH:7]=[CH:8][C:9]=1[OH:12]
Reactant: CCCCCc1ccc(O)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: CCCCCc1ccc(O)c(Br)c1
Yield: 89.4 %

Procedure:
24.6 g (0.15 mol) of p-n-pentylphenol was reacted with 24.5 g (0.153 mol) bromine in glacial acetic acid to yield 32.6 g of 2-bromo-4-n-pentylphenol by vacuum distillation or a yield of 89.5%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8](=O)[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[C:10]([CH3:17])[NH:11]2.C([O-])(=O)C.[Na+].P(Cl)(Cl)([Cl:35])=O>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([Cl:35])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:10]([CH3:17])=[N:11]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)COc1ccc(Cl)c2[nH]c(C)c(Cc3ccc(Cl)cc3)c(=O)c12
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(Cl)cc3)c(Cl)c12

Procedure:
A solution of [8-chloro-3-(4-chlorobenzyl)-2-methyl-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.13 g) in phosphorus oxychloride (5.0 mL) was heated at 180° C. in a microwave reactor for 15 minutes. The mixture was poured into ice and the pH of the solution adjusted to 3 by the addition of sodium acetate. The mixture was extracted with ethyl acetate and the combined extracts washed with saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. The solvent removed under reduced pressure to afford title compound as a beige solid, 0.12 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH:15]([NH:18][S:19](=[O:24])(=[O:23])[N:20]([CH3:22])[CH3:21])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:25][C:26]1[NH:27][C:28]2[C:33]([CH:34]=1)=[CH:32][C:31]([NH2:35])=[CH:30][CH:29]=2>>[CH3:25][C:26]1[NH:27][C:28]2[C:33]([CH:34]=1)=[CH:32][C:31]([NH:35][C:2]1[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]([N:13]4[CH2:17][CH2:16][CH:15]([NH:18][S:19](=[O:24])(=[O:23])[N:20]([CH3:22])[CH3:21])[CH2:14]4)=[O:12])[S:10][C:3]=13)=[CH:30][CH:29]=2
Reactant: CN(C)S(=O)(=O)NC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CCC(NS(=O)(=O)N(C)C)C5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from (+/−)-dimethylsulfamic acid {1-[7-chloro-thieno[3,2-b]pyridine-2-carbonyl]-pyrrolidin-3-yl}-amide and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C. MS: 499 (MH+); HPLC Rf: 4.04 min.; HPLC purity 96%.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([CH3:8])[CH3:7])=[O:4].[OH:9][C:10]1[CH:21]=[CH:20][C:13]2[NH:14]C(=O)[O:16][C:17](=O)[C:12]=2[CH:11]=1>C(#N)C.ClCCl>[NH2:14][C:13]1[CH:20]=[CH:21][C:10]([OH:9])=[CH:11][C:12]=1[C:17]([NH:1][CH2:2][C:3](=[O:4])[NH:5][CH:6]([CH3:8])[CH3:7])=[O:16]
Reactant: CC(C)NC(=O)CN
Reactant: O=c1[nH]c2ccc(O)cc2c(=O)o1
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)NC(=O)CNC(=O)c1cc(O)ccc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.6 %

Procedure:
To a solution of 2-amino-N-isopropylacetamide (INTERMEDIATE I.1) (4.77 g, 41.1 mmol) in acetonitrile (50 mL) was added 6-hydroxy-1H-benzo[d][1,3]oxazine-2,4-dione (6.13 g, 34.2 mmol). The mixture was stirred for 16 h at room temperature during which time a very thick precipitate formed. The mixture was diluted with dichloromethane (100 mL) and the solid collected by filtration and washed with dichloromethane (2×20 mL) to afford 2-amino-5-hydroxy-N-(isopropylcarbamoylmethyl)benzamide (INTERMEDIATE II.1) (6.75 g, 32.0 mmol, 78%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:25]=[CH:24][C:13]2[C@:14]3([CH3:23])[C@@H:19]([CH2:20][CH2:21][C:12]=2[CH:11]=1)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]3.[C:26](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:26][N:18]1[C@H:19]2[C@@:14]([CH3:23])([C:13]3[CH:24]=[CH:25][C:10]([C:3]4[CH:4]=[C:5]([F:9])[CH:6]=[C:7]([F:8])[C:2]=4[F:1])=[CH:11][C:12]=3[CH2:21][CH2:20]2)[CH2:15][CH2:16][C:17]1=[O:22]
Reactant: CC(C)(C)O
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3cc(F)cc(F)c3F)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cc(F)cc(F)c4F)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(2,3,5-trifluorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (35 mg, 0.10 mmol), 0.3 mL of t-butanol, and potassium t-butoxide (34 mg, 0.30 mmol). Methyl iodide (0.019 mL, 0.30 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 30 mg (83%) of the title compound as a foam. FDMS: m/e=359.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([OH:13])=O)[S:10][C:3]=12.[CH3:14][NH:15][CH3:16].C1COCC1.CCN(CC)CC>>[CH3:14][N:15]([CH3:16])[C:11]([C:9]1[S:10][C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:8]=1)=[O:13]
Reactant: CNC
Reactant: O=C(O)c1cc2nccc(Cl)c2s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc2nccc(Cl)c2s1
Yield: 84 %

Procedure:
was prepared by the reaction of 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid (0.57 g, 2.67 mmol) with 2.0 M N,N-dimethylamine in THF (1.60 mL, 3.20 mmol) and Et3N (0.447 mL, 3.20 mmol) in a manner as described in Method A to give the desired amide as brown solid (0.54 g, 84%). 1H NMR (300 MHz, CDCl3) δ 8.63 (d, 1H, J=4.85 Hz), 7.74 (s, 1H), 7.35 (d, 1H, J=5.02 Hz), 3.28 (s, 3H), 3.22 (s, 3H); ESIMS (MH+): 240.95.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.C([N:21]([CH2:24][CH3:25])CC)C.Cl.N[C@H:28]1CC[O:30][CH2:29]1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:21][CH:24]3[CH2:25][CH2:28][CH2:29][O:30]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: N[C@H]1CCOC1
Reactant: CCN(CC)CC
Reactant: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Agent: Cl
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2cc(NC3CCCO3)ncn2)cc1

Procedure:
To a solution of 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (prepared as in Example 59: 0.12 mmol) in 2 mL of ethanol is added 50 L of triethylamine and (s)-3-aminotetrahydrofuran hydrochloride salt (14 mg, 0.12 mmol). The mixture is microwaved at 120 degrees until formation of the desired compound. The reaction mixture can then be filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: COC[C:4]1([CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH2:7]1)C=O.Cl.[OH2:17].C[C:19](C)=[O:20]>>[OH:17][C:4]1[CH:7]=[C:8]([C:12]([F:13])([F:14])[F:15])[CH:9]=[CH:10][C:11]=1[CH:19]=[O:20]
Reactant: COCC1(C=O)C=CC=C(C(F)(F)F)C1
Reactant: O
Reactant: CC(C)=O
Agent: Cl
Product: O=Cc1ccc(C(F)(F)F)cc1O

Procedure:
5.0 g of 1-(methoxymethyl)-3-(trifluoromethyl)benzaldehyde was dissolved in 25 ml acetone, and 22 ml of 6 N hydrochloric acid was added. The mixture was reacted at room temperature for 3 hours, and water was added thereto, followed by extracting with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evapaorated, to give 4.5 g of 2-hydroxy-4-(trifluoromethyl)benzaldehyde as a pale reddish orange oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9]1)=[O:7])([CH3:4])(C)C.Cl.[OH-].[Na+].ClC(OC[C:23]1[CH:28]=[CH:27]C=[CH:25][CH:24]=1)=O>CO.O1CCOCC1>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12]([OH:14])=[O:13])[CH2:11]1)=[O:7])[C:4]1[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.9 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (3.00 g, 14.9 mmol) in MeOH (12.5 mL) was added 4M HCl in 1,4-dioxane (12.5 mL). The reaction was stirred at rt for 16 h. The mixture was evaporated to dryness. To a cooled (0° C.) solution of the residue in 1,4-dioxane (15 mL) and 2N aqueous NaOH (75 mL) was added benzyl chloroformate (2.67 g, 15.7 mmol), dropwise. The reaction was warmed to rt and was allowed to stir for 4 h. The mixture was washed with ethyl acetate (75 mL) and the aqueous layer was acidified (pH 5) with the addition of conc HCl. The mixture was extracted with ethyl acetate (3×75 mL) and the combined organic layers were washed with brine, dried (Na2SO4) and evaporated to give 2.10 g (60%) of the desired product. ES-MS m/z 235.90 [M+H]+, HPLC RT (min) 2.53.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:12]=[CH:11][C:10]2[C:6](=[CH:7][N:8]([CH3:13])[N:9]=2)[C:5]=1[C@H:14]1[CH2:16][C@@H:15]1[CH2:17][NH2:18].C(N(CC)CC)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>O1CCCC1.C(=O)([O-])O.[Na+]>[F:3][C:4]1[CH:12]=[CH:11][C:10]2[C:6](=[CH:7][N:8]([CH3:13])[N:9]=2)[C:5]=1[C@H:14]1[CH2:16][C@@H:15]1[CH2:17][NH:18][C:26](=[O:28])[CH3:27]
Reactant: Cn1cc2c([C@H]3C[C@@H]3CN)c(F)ccc2n1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1C[C@@H]1c1c(F)ccc2nn(C)cc12
Yield: 103.6 %

Procedure:
A solution of 1-[(1S,2S)-2-(5-fluoro-2-methyl-2H-indazol-4-yl)cyclopropyl]methanamine dihydrochloride (230 mg, 0.787 mmol) and triethylamine (549 μL, 3.936 mmol) in tetrahydrofuran (8 mL) was stirred at room temperature for 20 min. To the reaction solution was added acetic anhydride (112 μL, 1.181 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 15 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate=0/100→5/95) to give the title compound (213 mg, yield 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:5]=[CH:6][C:7]=1C=O.[CH2:29]([O:31][C:32](=[O:36])[CH:33]=[CH:34]O)[CH3:30].[Na].[C:38](O)(=O)C>>[CH2:29]([O:31][C:32]([C:33]1[CH:38]=[N:1][C:2]2[C:7]([CH:34]=1)=[CH:6][CH:5]=[C:4]([NH:10][C:11]([C:13]1[C:14]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:21][CH:20]=3)=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:12])[CH:3]=2)=[O:36])[CH3:30]
Reactant: CC(=O)O
Reactant: CCOC(=O)C=CO
Reactant: Nc1cc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)ccc1C=O
Agent: [Na]
Product: CCOC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1

Procedure:
A solution of 4′-trifluoromethyl-biphenyl-2-carboxylic acid (3-amino-4-formyl-phenyl)-amide (7 g, 18.2 mmol, 1 equiv) and 3-hydroxy-acrylic acid ethyl ester, sodium salt (2.52 g, 18.2 mmol, 1 equiv) in glacial acetic acid (70 mL, 10 volumes) was heated at 80° C. for 2 hours. Additional 3-hydroxy-acrylic acid ethyl ester, sodium salt (2.52 g, 18.2 mmol, 1 equiv) was added and the solution heated for 15 hours. Again, additional 3-hydroxy-acrylic acid ethyl ester, sodium salt (1.26 g, 9.1 mmol, 0.5 equiv) was added and the solution heated for another 4 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc (300 mL) and the organic layer was washed with a saturated aqueous sodium carbonate solution (2×200 mL) and 1 N NaOH solution (200 mL). The combined aqueous layers were back extracted with ethyl acetate (200 mL). The combined organic layers were dried over sodium sulfate and treated with Darco G-60® (7 g). The solids were removed by filtration and the filtrate was concentrated to afford crude 7-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid ethyl ester, which was used in the next step without further purification.