Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([CH2:38][CH:39]1[CH2:41][CH2:40]1)[CH2:35][CH2:36][CH3:37])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][N:9]=1)#[N:2].[OH-].[Na+].C(OCC)(=O)C>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:46])[F:47])[CH:44]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([CH2:38][CH:39]1[CH2:40][CH2:41]1)[CH2:35][CH2:36][CH3:37])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1)#[N:2]
Reactant: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C#N)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C#N)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
Ethyl 4-(2-{(3-cyano-5-trifluoromethyl-benzyl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (240 mg) is dissolved in tetrahydrofuran (2.6 ml), and thereto is added 1N-aqueous sodium hydroxide solution (2.6 ml) and the mixture is stirred at 40° C. for additional 30 minutes and warmed to 50° C. and stirred for 3 hours. Thereto is added a 2N-aqueous sodium hydroxide solution (650 μl) and the mixture is stirred at 60° C. for 20 minutes. The reaction solution is cooled to room temperature and thereto are added ethyl acetate and a 1N-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=19:1) to give 4-(2-{(3-cyano-5-trifluoromethyl-benzyl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (189 mg). MS (m/z): 650 [M+H]+
Reaction SMILES: [Li]CCCC.[C:6]1([S:12][CH3:13])[CH:11]=[CH:10]C=C[CH:7]=1.Cl[Si:15]([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[S:12]1[CH:13]=[CH:10][CH:11]=[C:6]1[CH2:7][Si:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: C[Si](C)(C)Cl
Reactant: CSc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)Cc1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
To a stirred solution of 143 mL of 1.4 M n-BuLi (0.20 mol) in 55 mL of dry THF, was added dropwise at room temperature under a nitrogen atmosphere 24.8 g (0.20 mol) of thioanisole. Upon completion of the addition, the yellow mixture began to reflux spontaneously. The mixture was stirred at room temperature for 3 hours. Upon addition of 21.84 g (0.20 mol) of chlorotrimethylsilane, the mixture again began to reflux spontaneously. After stirring at room temperature overnight, the mixture was quenched with 100 mL of 5% of HC1. The aqueous layer was separated, and the organic layer was dried over MgSO4, filtered, and the solvent removed in vacuo from a water bath at 45° C. The crude product was distilled to give 19.22 g (49%) of the colorless sulfide, bp 84-°86° C./0.3 Torr; 1H NMR (CDCL3) δ 0.17 (s, 9H, Si(CH3)3), 2.13 (s, 2H, CH2S), 7.0-7.42 (m, 5H, phenyl).
Reaction SMILES: [CH2:1]([N:7]([CH2:19][C:20]1[CH:39]=[CH:38][C:23]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36]C)=[O:35])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.Cl>CO.O1CCCC1.[OH-].[Na+]>[CH2:1]([N:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:28][CH:27]=2)=[CH:38][CH:39]=1)[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN(Cc1ccc(COc2ccc(CCC(=O)OC)cc2)cc1)c1nc(-c2ccccc2)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCN(Cc1ccc(COc2ccc(CCC(=O)O)cc2)cc1)c1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
Methyl 3-{4-[(4-{[hexyl(4-phenyl-1,3-thiazol-2-yl)amino]methyl}benzyl)oxy]phenyl}propanoate (250 mg) was dissolved in a mixed solvent of methanol (2 mL) and tetrahydrofuran (2 mL), and 2N aqueous sodium hydroxide solution (2 mL) was added. The mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, acidified with 1N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried using Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.) and concentrated to give the title compound (220 mg, yield 90%) as pale-yellow crystals.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:18]([O:20]CC)=O)=[N:5][O:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)#[N:2].[CH:23]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24]1>C(O)C>[C:1]([C:3]1[C:4]([C:18]([NH:28][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:20])=[N:5][O:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][CH:9]=1)#[N:2]
Reactant: CCOC(=O)c1noc(-c2ccc(C(F)(F)F)cc2)c1C#N
Reactant: NC1CCCC1
Solvent: CCO
Product: N#Cc1c(C(=O)NC2CCCC2)noc1-c1ccc(C(F)(F)F)cc1
Temperature: 82 °C

Procedure:
A mixture of ethyl 4-cyano-5-(4-(trifluoromethyl)phenyl)isoxazole-3-carboxylate (150 mg, 0.48 mmol) and cyclopentylamine (0.24 mL, 2.4 mmol) in ethanol (5 mL) was heated to 82° C. for 16 hours. The volatiles were removed in vacuo and the residue was purified by silica gel chromatography, eluting with 5% methanol in dichloromethane to afford the title compound: (130 mg, 0.37 mmol). 1H NMR (300 MHz, CDCl3) δ 8.27 (m, 2H), 7.86 (m, 2H), 6.68 (br. d, 1H), 4.43 (m, 1H), 2.11 (m, 2H), 1.85-1.45 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:20])=[C:4]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.C1C(=O)N([Br:28])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>>[Br:1][C:2]1[C:3]([Cl:20])=[C:4]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:5]([F:9])=[C:6]([CH2:8][Br:28])[CH:7]=1
Reactant: Cc1cc(Br)c(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: N#Cc1cc(Cl)cc(Oc2c(F)c(CBr)cc(Br)c2Cl)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 21.9 %

Procedure:
To a solution of 3-[(3-bromo-2-chloro-6-fluoro-5-methylphenyl)oxy]-5-chlorobenzonitrile (2.74 g, 7.31 mmol) and NBS (1.300 g, 7.31 mmol) in carbon tertrachloride (200 ml) was added AIBN (0.060 g, 0.365 mmol) and the reaction mixture was stirred at 80° C. overnight. The solvent was removed and the crude material was purified via silica gel chromatography to give the title compound 3-{[3-bromo-5-(bromomethyl)-2-chloro-6-fluorophenyl]oxy}-5-chlorobenzonitrile (1.04 g, 1.604 mmol, 22% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.01 (d, 1H), 7.79 (s, 1H), 7.58 (s, 2H), 4.68 (s, 2H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([O:16][CH3:17])[C:12]([NH2:15])=[N:13][CH:14]=1.[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[S:26](Cl)(=[O:28])=[O:27]>>[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[S:26]([NH:15][C:12]1[C:11]([O:16][CH3:17])=[N:10][C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:14][N:13]=1)(=[O:28])=[O:27]
Reactant: COc1nc(-c2ccc(F)cc2F)cnc1N
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Product: COc1nc(-c2ccc(F)cc2F)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 1 using 5-(2,4-difluorophenyl)-3-methoxy-2-pyrazinamine (0.2 g) and 2,3-dichlorobenzenesulphonyl chloride (0.2 g). Yield 0.06 g.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1(C)C=CC=CC=1>[CH3:21][S:22]([O:13][C@@H:10]1[CH2:11][CH2:12][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9]1)(=[O:24])=[O:23]
Reactant: O[C@@H]1CCN(Cc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1CCN(Cc2ccccc2)C1

Procedure:
10 g of (R)-1-(phenylmethyl)-3-pyrrolidinol were dissolved in 160 ml of anhydrous toluene. The solution was stirred under a stream of nitrogen, cooled in an ice/ethanol bath and 8.7 ml of triethylamine were added. At a temperature of −5° C. 4,9 ml of a solution of methanesulfonylchloride in 110 ml of anhydrous toluene were added dropwise over 1,5 hours and the reaction mixture was stirred for 1 hour at 0° C. The solid was filtered and washed with ethyl acetate. The filtrate was washed with water, dried and evaporated in vacuo to give 13,9 g of (R)-3-methanesulfonyloxy-1-(phenylmethyl)-pyrrolidine as an almost colourless oil. M.S. (C.I.) (M/Z): 256 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:10]1[O:14][CH:13]=[N:12][CH:11]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[Cl:15][S:16](O)(=[O:18])=[O:17]>>[CH3:3][C:2]([C:4]1[CH:9]=[CH:8][C:7]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:6][CH:5]=1)([C:10]1[O:14][CH:13]=[N:12][CH:11]=1)[CH3:1]
Reactant: CC(C)(c1ccccc1)c1cnco1
Reactant: O=S(=O)(O)Cl
Product: CC(C)(c1ccc(S(=O)(=O)Cl)cc1)c1cnco1
Temperature: 60 °C
Yield: 63 %

Procedure:
A solution of 5-(1-Methyl-1-phenylethyl)oxazole (3.87 mmol, 1.0 eq.) in CDCl3 (0.3 mL) was stirred at 0° C. and chlorosulfonic acid (11.7 mmol, 3.0 eq.)was slowly added in. The mixture was heated to 60° C. for 3 h and cooled to room temperature. The solution was further mixed with crushed ice (15 g) and extracted with EtOAc (3×15 mL). The extracts were combined, washed by saturated aqueous NaCl solution, dried by MgSO4, filtered and concentrated in vacuo to afford the title compound as a pale yellow oil (697 mg, 63%) which was used as it was. 1H NMR: δ (400 MHz, CDCl3) 7.97 (d, 2H), 7.83 (s, 1H), 7.47 (d, 2H), 6.96 (s, 1H), 1.74 (s, 6H). MS (M+H+): 286.0
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:30])[CH2:20][C:21]4[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=4[C:23]([OH:25])=O)[CH:15]=[CH:16][CH:17]=3)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(OP(Cl)(OCC)=O)C.[CH2:40]([N:42](CC)[CH2:43]C)C.Cl.CNC>O1CCCC1>[CH:1]1([C:5]2[N:6]=[C:7](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:30])[CH2:20][C:21]4[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=4[C:23]([N:42]([CH3:43])[CH3:40])=[O:25])[CH:15]=[CH:16][CH:17]=3)[S:8][CH:9]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCN(CC)CC
Reactant: O=C(Cc1ccccc1C(=O)O)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Agent: CCOP(=O)(Cl)OCC
Agent: CNC
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccccc1CC(=O)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Reaction time: 20 h

Procedure:
A mixture of 0.836 g of (E)-2-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid, 0.38 g of diethylchlorophosphate, 2.2 g of triethylamine, 1.8 g of dimethylamine hydrochloride and 25 ml of tetrahydrofuran was stored at room temperature for 20 hr. The solvent was removed in vacuo and the residual materials were taken up in 100 ml of methylene chloride and then washed with water (3×30 ml), dried (MgSO4) and the solvent removed in vacuo. The residual materials were crystallized from ethanol to yield (E)-2-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]-N,N-dimethylbenzamide as an off-white colored solid, m.p. 125°-127° C.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18](OC)=[O:19])=[C:14]([F:22])[CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].[NH3:25].CO>>[C:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH2:25])=[O:19])=[C:14]([F:22])[CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2c(C)c(Cl)cc(C(C)=O)c2OC)cc1F
Reactant: N
Solvent: CO
Product: COc1c(C(C)=O)cc(Cl)c(C)c1-c1ccc(C(N)=O)c(F)c1
Temperature: 90 °C

Procedure:
A mixture of methyl 3′-acetyl-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-carboxylate (25 mg, 0.071 mmol) and 7.0 M ammonia in methanol (2.0 mL, 14 mmol) was heated at 90° C. in a sealed tube overnight. After evaporating the mixture to dryness, the residue was used directly in next step.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19]C)=[O:18])[CH:8]=2)[N:3]=1.[NH:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[CH:22]1.C(O[K])(C)=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:21]1([C:2]2[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:17]([OH:19])=[O:18])[CH:8]=3)[N:3]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[CH:22]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)O[K]
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-n1cnc2ccccc21
Temperature: 170 °C
Reaction time: 3 h
Yield: 7.3 %

Procedure:
The mixture of methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (200 mg, 0.68 mmol), 1H-benzo[d]imidazole (500 mg, 4.24 mmol), AcOK (200 mg, 2.05 mmol) and Pd(PPh3)4 (39 mg, 0.03 mmol) was stirred for 3 h at 170° C. and then purified by silica gel chromatography eluting with 2%-5% methanol in dichloromethane to afford 2-(1H-benzo[d]imidazol-1-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a yellow solid (18.0 mg, 7%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][C:5]=1[C:21]([F:24])([F:23])[F:22])([O-])=O>[C].[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][C:5]=1[C:21]([F:22])([F:23])[F:24]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc(N)c(C(F)(F)F)c1

Procedure:
10% palladium carbon (0.1 g) was added in the ethyl acetate (20 mL) solution of diethyl 2-(4-nitro-3-trifluoromethyl-phenyl)-malonate (1.1 g, 3.15 mmol) which had been obtained in 1), and the solution was hydrogenated. After the catalyst was removed by filtration, the solvent was concentrated under reduced pressure and yellow oily diethyl 2-(4-amino-3-trifluoromethyl-phenyl)-malonate (1.38 g (the content of 0.39%), 68%) was obtained, and the product was used in the next reaction without purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[O:18]([C:25]1[CH:30]=[CH:29][C:28](OB(O)O)=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.CCOC(C)=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:28]1[CH:29]=[CH:30][C:25]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:26][CH:27]=1)[CH:9]=2)=[O:4]
Reactant: OB(O)Oc1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2oc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1c(O)c2ccc(-c3ccc(Oc4ccccc4)cc3)cc2oc1=O
Yield: 68.7 %

Procedure:
A mixture of 7-bromo-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester (256 mg, 0.855 mmol), 4-phenoxyphenylboric acid (211 mg, 0.984 mmol), Pd(PPh3)4 (99 mg, 0.086 mmol) and aqueous sodium carbonate solution (1.1 mL, 2 M) in 1,2-dimethoxyethane (5 mL) was refluxed for 2.5 h. Then cooled, the slurry was diluted with EtOAc and water, solids were filtered off over Celite; EtOAc phase was separated from aqueous, washed with sat. NaCl solution, dried over sodium sulfate, filtered, and concentrated; the crude material was crystallized from dichloromethane and methanol to give the desired product as white micro crystals (228 mg). 1H NMR (200 MHz, CDCl3): δ (ppm)=14.58 (s, 1H), 8.04 (d, 1H, J=8.4 Hz), 7.61-7.04 (m, 11H), 4.04 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9].[Mg].II.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25]=[O:26]>O1CCCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][CH3:9])=[C:2]([CH:25]([C:21]3[O:20][CH:24]=[CH:23][CH:22]=3)[OH:26])[CH:3]=2)=[CH:11][CH:12]=1
Reactant: O=Cc1ccco1
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1Br
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C(O)c1ccco1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Approximately 10 ml of a solution of 3-bromo-4′-chloro-4-ethylbiphenyl (40.0 g, 135.3 mmol) in tetrahydrofuran (200 ml) is added to magnesium turnings in a dry flask, followed by a crystal of iodine. The mixture is allowed to stand without stirring for 30 minutes, then stirred once and warmed until the orange coloured mixture becomes colourless. The remainder of the 3-bromo-4′-chloro-4-ethylbiphenyl solution is added dropwise over 30 minutes with external heating applied as necessary to maintain a gentle reflux. Once the addition is complete, the mixture is heated to reflux for 2-3 hours, until only trace residues of magnesium remain. The mixture is cooled to room temperature, and then cooled further in an ice-bath. A solution of 2-furaldehyde (13.05 g, 135.8 mmol) in tetrahydrofuran (80 ml) is added dropwise over 35 minutes, and the mixture is stirred at room temperature overnight.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:13]([NH:15][CH3:16])=[O:14].CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:13]([NH:15][CH3:16])=[O:14])[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CNC(=O)c1ccc(C)c(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(C)c(Nc2cc(Cl)ncn2)c1
Yield: 43.1 %

Procedure:
To a solution of 4,6-dichloropyrimidine (2.0 g, 13.4 mmol) in p-dioxane (50 mL), 3-amino-4,N-dimethyl-benzamide (3.0 g, 18.3 mmol) and DIEA (2.3 mL) were added. The resulting mixture was heated to reflux for 4 days. The solvent was removed in vacuo, the residue was taken in water and ethyl acetate, and the ethyl acetate layer was separated and concentrated. The product was purified by silica gel column chromatography using ethyl acetate:hexane (1:1) as eluent to afford the pale white solid product (1.6 g, yield 43%). MS (m/z): 277 (M+H).
Reaction SMILES: [NH2:1][C:2](=[O:33])[CH:3]([N:16]([C@@H:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26])[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:4][C:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([F:15])=[CH:10][CH:11]=2)[CH:6]=1>CCO.[OH-].[OH-].[Pd+2]>[NH2:1][C:2](=[O:33])[CH:3]([N:16]([C@@H:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26])[C:17](=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([F:15])=[CH:10][CH:11]=2)[CH2:6]1
Reactant: C[C@H](c1ccccc1)N(C(=O)c1ccccc1)C(CC1=Cc2cc(F)ccc2CC1)C(N)=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](c1ccccc1)N(C(=O)c1ccccc1)C(CC1CCc2ccc(F)cc2C1)C(N)=O
Reaction time: 12 h

Procedure:
A suspension of 2.70 g (6.10 mmol) of the compound obtained in Step 2 and 1 g of Pd(OH)2 in 120 ml of EtOH is hydrogenated under one atmosphere for 12 hours. After filtering off the catalyst, the solvent is evaporated off in vacuo. The residue obtained is chromatographed on SiO2, eluting with a solution of cyclohexane/EtOAc=40/60, to yield the title compound in the form of 2 diastereoisomers.
Reaction SMILES: [C:1](Cl)(=O)[CH3:2].[CH2:5]([O:7][C:8]1[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=[O:15])[O:10][N:9]=1)[CH3:6].C([O-])(O)=O.[Na+]>CCO>[CH2:5]([O:7][C:8]1[C:12]([CH3:13])=[C:11]([C:14]([O:16][CH2:1][CH3:2])=[O:15])[O:10][N:9]=1)[CH3:6]
Reactant: CC(=O)Cl
Reactant: CCOc1noc(C(=O)O)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1onc(OCC)c1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90.4 %

Procedure:
Acetyl chloride (25 mL, 0.35 mol) was added to EtOH (250 mL) at 0° C. and the solution was stirred at 0° C. for 20 min. A solution of 3-ethoxy-4-methylisoxazole-5-carboxylic acid (WO95/12587,A1) (18 g, 0.10 mol) in EtOH (20 ml) was added and the resulting mixture was boiled under reflux for 4 h. The mixture was cooled, added NaHCO3 (200 mL) and extracted with diethylether (3×300 mL). The organic extracts were dried (MgSO4) and concentrated in vacuo to afford crude title compound (18 g, 86%).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[S:18][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][CH:15]=1)[CH3:7].[CH3:24][C:25]([NH2:38])([CH3:37])[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1.Cl([O-])(=O)(=O)=O.[Li+]>C1(C)C=CC=CC=1>[OH:1][C@H:2]([CH2:3][NH:38][C:25]([CH3:37])([CH3:24])[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)[CH2:4][O:5][CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[S:18][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][CH:15]=1)[CH3:7]
Reactant: CC(C)(N)Cc1ccc2ccccc2c1
Reactant: CCOC(=O)c1ccc(-c2ccccc2C(C)OC[C@H]2CO2)s1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2ccccc2C(C)OC[C@H](O)CNC(C)(C)Cc2ccc3ccccc3c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
Ethyl 5-[2-[1-(((2R)-oxiranyl)methoxy)ethyl]phenyl]thiophene-2-carboxylate (499 mg) obtained in Step 4 was dissolved in toluene, [2-methyl-1-(naphthalen-2-yl)propan-2-yl]amine (299 mg) and lithium perchlorate (160 mg) were successively added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=30:1) to give the title compound (770 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][O:18][C:3]1[C:2]([Cl:1])=[CH:17][C:6]2[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])=[N:8][O:9][C:5]=2[CH:4]=1)[CH3:27]
Reactant: Oc1cc2onc(-c3ccccc3F)c2cc1Cl
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2onc(-c3ccccc3F)c2cc1Cl
Temperature: 25 °C

Procedure:
A solution of 5-chloro-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole (14.8 g) in DMF (40 ml) is added dropwise at room temperature to a suspension of sodium hydride (3.0 g) in DMF (40 ml) and the mixture is stirred at room temperature for one half hour. A solution of ethyl bromoacetate (10.31 g) in DMF (40 ml) is then added dropwise and the mixture stirred 18 hours at room temperature. An additional 0.3 g of NaH suspended in DMF is added, followed by 1 g of ethyl bromoacetate. The mixture is warmed to 50° C. for 1 and one half hours, cooled and poured over ice/water and extracted with ether. The ether extracts are washed with water, saturated sodium chloride, dried over sodium sulfate and the solvent is removed to give a solid. Trituration with ether-petroleum ether (1:1) gives ethyl{[5-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate, mp 114°-115° C.