Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O.C(N(CC)C(C)C)(C)C.Cl.Cl.[CH2:32]([O:39][C:40](=[O:48])[CH2:41][C@@H:42]([NH2:47])[CH2:43][N:44]([CH3:46])[CH3:45])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C=O>[CH2:32]([O:39][C:40](=[O:48])[CH2:41][C@@H:42]([NH:47][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]1[CH:17]=[CH:18][C:19]([F:20])=[C:2]([F:1])[CH:3]=1)[CH2:43][N:44]([CH3:45])[CH3:46])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: O=C(O)CCCCCCCOCc1ccc(F)c(F)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCOCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.9 %

Procedure:
A solution of 8-(3,4-difluoro-benzyloxy)-octanoic acid (153 mg, 0.53 mmol), N,N-diisopropylethylamine (414 mg, 3.21 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexaflurophophate (244 mg, 0.64 mmol) in N,N-dimethylformamide was stirred for 1 h at room temperature, then a solution of (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride (198 mg, 0.64 mmol) in N,N-dimethylformamide (1 mL) was added. The reaction mixture was stirred for 16 h at room temperature, then evaporated. Chromatography (SiO2, dichloromethane-[dichloromethane/methanol/25% aq. ammonia solution 110:10:1] gradient) produced (R)-3-[8-(3,4-difluoro-benzyloxy)-octanoylamino]-4-dimethylamino-butyric acid benzyl ester (136 mg, 50%). Light yellow oil, m/e=505.4 ([M+H]+).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].N1C=CC=CC=1.[C:14]([O:17][C:18]1[CH:35]=[CH:34][C:33]2[C@@H:32]3[C@H:23]([C@H:24]4[C@@:28]([CH2:30][CH2:31]3)([CH3:29])[C:27](=[O:36])[CH2:26][CH2:25]4)[CH2:22][C@@H:21]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:20]=2[CH:19]=1)(=[O:16])[CH3:15].C(OC(C)=C)(=O)C>C(Cl)Cl>[C:14]([O:17][C:18]1[CH:35]=[CH:34][C:33]2[C@@H:32]3[C@H:23]([C@H:24]4[C@@:28]([CH2:30][CH2:31]3)([CH3:29])[C:27]([O:36][C:1](=[O:3])[CH3:2])=[CH:26][CH2:25]4)[CH2:22][C@@H:21]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:20]=2[CH:19]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)c2ccc(OC(C)=O)cc21
Agent: C=C(C)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(OC(C)=O)=CC[C@@H]23)c2ccc(OC(C)=O)cc21

Procedure:
10.0 g. of 3-hydroxy-6β-ethoxycarbonylmethyl-1,3,5(10)-estratrien-17-one -- produced in accordance with A2 -- is acetylated with 20 ml. of acetic anhydride in 20 ml. of pyridine for 20 hours at room temperature. After precipitation into ice water, filtration, and taking up the precipitate in methylene chloride, the reaction product is dried and evaporated, thus obtaining 11.8 g. of 3-acetoxy-6β-ethoxycarbonylmethyl-1,3,5(10) estratrien-17-one, which is heated to the boiling point with 140 ml. of isopropenyl acetate in the presence of 1.4 g. of p-toluenesulfonic acid and then subjected to a slow distillation. The cooled reaction product is diluted with methylene chloride and washed with sodium bicarbonate solution and water, dried, and evaporated, thus resulting in 13.3 g. of a crude product. After chromatography on silica gel, pure 3,17-diacetoxy-6β-ethoxycarbonylmethyl-1,3,5(10),16-estratetraene is obtained as an almost colorless oil.
Reaction SMILES: [C:1]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:31][CH:32]([CH3:34])[CH3:33])[CH2:11][N:10]([C:12](=[O:26])[C@@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([CH3:17])([CH3:16])[CH3:15])[C@H:9]([C:27]([O:29]C)=[O:28])[CH2:8]2)=[CH:3][CH:2]=1.O.[OH-].[Li+]>C1COCC1.CO.O>[C:1]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:31][CH:32]([CH3:33])[CH3:34])[CH2:11][N:10]([C:12](=[O:26])[C@@H:13]([NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C:14]([CH3:15])([CH3:16])[CH3:17])[C@H:9]([C:27]([OH:29])=[O:28])[CH2:8]2)=[CH:3][CH:2]=1
Reactant: COC(=O)[C@@H]1C[C@@](SC(C)C)(c2ccc(-c3ccccc3)cc2)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)S[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)O)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of (2S,4R)-methyl 4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(isopropylthio)pyrrolidine-2-carboxylate (208 mg, 0.366 mmol) in THF (2 mL) and MeOH (2.000 mL) was added pre-made solution of Lithium hydroxide monohydrate (30.7 mg, 0.731 mmol) in water (2 mL). The resulting cloudy solution was stirred at room temperature overnight. Quenched with 5% citric acid, extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, evaporated, to afford the desired product (2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(isopropylthio)pyrrolidine-2-carboxylic acid (202 mg, 0.328 mmol, 90% yield) as a white foam. LC-MS (retention time: 3.39 min, method B), MS m/z 555 (M+H).
Reaction SMILES: [CH2:1]([CH:8]1[O:12][C:11](=[O:13])[CH:10]=[C:9]1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:32][CH2:33][N:34]([CH3:38])[C:35](=[O:37])[CH3:36])=[CH:24]1>>[CH2:1]([CH:8]1[O:12][C:11](=[O:13])[C:10]([CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:24]2[NH:23][C:31]3[C:26]([C:25]=2[CH2:32][CH2:33][N:34]([CH3:38])[C:35](=[O:37])[CH3:36])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[C:9]1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=C(O)C(Cc2ccccc2)O1
Reactant: CC(=O)N(C)CCc1c[nH]c2ccccc12
Reactant: O=Cc1ccccc1
Product: CC(=O)N(C)CCc1c(C(C2=C(O)C(Cc3ccccc3)OC2=O)c2ccccc2)[nH]c2ccccc12

Procedure:
Using general procedure C, 5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) was reacted with benzaldehyde and N-[2-(1H-indol-3-yl)-ethyl]-N-methyl-acetamide (Lit. 4) to give the title compound as pale yellow solid. MS: 493.3 ([M−H]−).
Reaction SMILES: [OH:1][CH:2]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O.[CH2:22](N)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].C(N)C[NH2:43]>>[CH2:39]([CH:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([OH:1])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:13]([NH2:43])=[O:15])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: CCCCCCC(O)CCCCCCCCCCC(=O)O
Reactant: NCCN
Product: CCCCCCCCCCCCCCCCCCC(CCCCCCCCCC(O)CCCCCC)C(N)=O

Procedure:
Heating 100 parts (0.33 equivalents) 12-hydroxystearic acid with 64.1 parts (0.23 equivalents) stearylamine and 3.0 parts ethylenediamine (0.1 equivalents) to 220° C. yielded an extended stearyl 12-hydroxystearamide as a hard, opaque wax having an acid number of 7. Treatment of the extended stearyl 12-hydroxystearamde with 36.0 parts (0.33 equivalents) isophorone diisocyanate at 150° C. provided isophorone diisocyanate-modified stearyl 12-hydroxystearamide as a translucent, hard, light-tan solid having a melting point of 87° C. and a melt viscosity of 154 cP at 130° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[N:2]1.O[N:14]=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.N>>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:12][N:22]=[C:15]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:14]=3)=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccc2snnc2c1
Agent: N
Product: c1cncc(-c2noc(-c3ccc4snnc4c3)n2)c1

Procedure:
The title compound was prepared according to Method C using benzo[d][1,2,3]thiadiazole-5-carboxylic acid (Maybridge) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 7.69 (ddd, J=8.0, 4.9, 0.7 Hz, 1H), 8.51 (dt, J=8.2, 1.9, 1.7 Hz, 1H), 8.57 (dd, J=8.5, 1.7 Hz, 1H), 8.73 (d, J=7.8 Hz, 1H), 8.85 (dd, J=4.9, 1.5 Hz, 1H), 9.32 (dd, J=2.4, 1.0 Hz, 1H), 9.51 (dd, J=1.7, 0.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 282 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:28][NH2:29])=[O:27])=[CH:21][CH:20]=2)=[O:17])=[CH:4][CH:3]=1.[C:30](OCC)(OCC)(OCC)[CH3:31].CS(O)(=O)=O.O1CCCC1>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][C:26]3[O:27][C:30]([CH3:31])=[N:29][N:28]=3)=[CH:23][CH:24]=2)=[O:17])=[CH:4][CH:3]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: Cn1ncc(/C=C/C(=O)Nc2ccc(CC(=O)NN)cc2)c1-c1ccc(F)cc1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nnc(Cc2ccc(NC(=O)/C=C/c3cnn(C)c3-c3ccc(F)cc3)cc2)o1
Yield: 47.1 %

Procedure:
A mixture of (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-N-[4-(2-hydrazino-2-oxoethyl)phenyl]acrylamide (0.50 g), triethyl orthoacetate (0.63 g), methanesulfonic acid (0.025 g), and tetrahydrofuran (10 mL) was heated under reflux for 1 hr. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-N-{4-[(5-methyl-1,3,4-oxadiazol-2-yl) methyl]phenyl}acrylamide as pale-yellow crystals (0.25 g, yield 46%) from a fraction eluted with ethyl acetate-methanol (100:0-20:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 151-152° C.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](Cl)(=[O:20])[C:17](Cl)=[O:18].[CH2:22]([OH:24])[CH3:23]>C(OCC)C>[C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16](=[O:20])[C:17]([O:24][CH2:22][CH3:23])=[O:18])=[CH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCO
Reactant: c1ccc(-n2ccc3ccccc32)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1cn(-c2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
An ice-cooled solution of 10 g (51.8 mmol) of 1-phenylindole in 100 ml of anhydrous diethyl ether was treated dropwise during 5 minutes with a solution of 6 ml (68.8 mmol) of oxalyl chloride in 20 ml of anhydrous diethyl ether. The mixture was stirred for 3 hours while cooling with ice and then treated with 25 ml of ethanol in one portion. After stirring for 10 minutes, the solvent was removed under reduced pressure and the residual solid was crystallized from 60 ml of ethanol to give 12.38 g of ethyl 1-phenylindole-3-glyoxylate as a pale yellow solid of melting point 109°-110° C.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[CH2:4].[C:11]1([S:17]([O-:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+].O.CCCCC>CN(C=O)C>[C:5]1([C:3](=[CH2:4])[CH2:2][S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:19])=[O:18])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=S([O-])c1ccccc1
Reactant: C=C(CCl)c1ccccc1
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Solvent: O
Product: C=C(CS(=O)(=O)c1ccccc1)c1ccccc1
Temperature: 70 °C
Yield: 76 %

Procedure:
This mixture (17 g, 0.05 molar as 1-chloro-2-phenyl-2-propene) is dissolved in DMF (100 cc). Sodium benzenesulphinate (8.2 g, 0.05 mole) is added and the mixture is heated to 70° C. for 2 h. The reaction mixture is poured into water and ice (350 g). It is stirred energetically with pentane (150 cc) to extract the 1-chloro-2-phenyl-1-propene and the 1-chloro-2-phenyl-2-propanol which have not reacted, for 15 to 30 min until crystallization is complete. The crystals formed are filtered off, are washed with pentane (50 cc) and with diisopropyl ether (50 cc) and are thoroughly drained and dried. 2-Phenyl-1-phenylsulphonyl-2-propene (9.8 g, 76%) is obtained. Mp=105° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].Cl[C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[CH2:23])[CH:17]=2)[C:12]([Cl:24])=[CH:11][N:10]=1.[CH:25]([C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30])=[CH2:26]>COCCO.Cl.C(O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:24][C:12]1[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[CH2:23])[CH:17]=2)=[N:14][C:9]([NH:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:27]([CH:25]=[CH2:26])[CH:28]=2)=[N:10][CH:11]=1.[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4]
Reactant: C=Cc1cccc(Nc2nc(Cl)ncc2Cl)c1
Reactant: C=Cc1cccc(N)c1
Agent: Cl
Solvent: COCCO
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: C=Cc1cccc(Nc2ncc(Cl)c(Nc3cccc(C=C)c3)n2)c1
Product: O=C([O-])C(F)(F)F
Temperature: 150 °C
Yield: 474 %

Procedure:
A solution of 2,5-dichloro-N-(3-vinylphenyl)pyrimidin-4-amine trifluoroacetate (150 mg, 0.56 mmol) and 3-vinylaniline (200 mg, 1.0 mmol) in 2-methoxyethanol (3.8 mL) and 3 N hydrogen chloride in ethanol (0.56 mL) were mixed and heated to 150° C. for 30 minutes in a microwave. Purification by preparative LCMS (pH 2) gave the desired product as a trifluoroacetate salt (150 mg, 60%). LCMS for C20H17ClN4 (M+H)+: m/z=349.1.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[N:19][CH:20]=1)[CH3:14].[CH2:22]=[O:23]>C1COCC1.CCOC(C)=O>[CH2:13]([C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][OH:23])=[N:19][CH:20]=1)[CH3:14]
Reactant: C=O
Reactant: CCc1ccc(C)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: CCc1ccc(CCO)nc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a cooled solution (−10° C.) of diisopropylamine (2.31 mL, 16.5 mL) in THF (45 mL) is added dropwise (2.5M) n-butyllithium (6.6 mL, 16.5 mmol), let stir 10 min. then cooled to −78° C. To this mixture is added dropwise a solution of 5-ethyl-2-methylpyridine (1.98 mL, 15 mmol) in THF (3 mL) and let stir for 10 min at −78° C. To the reaction mixture is added paraformaldehyde (1.13 g, 37.5 mmol), the cold bath removed and stirring continued for 1 hr. Quenched reaction with H2O, diluted with EtOAc and the organic layer washed with brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 0.5% ammonia/5% methanol/dichloromethane) to give the title compound as a pale yellow oil. MS (EI) 151 (M)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=O)[CH3:18].Cl.[NH2:21][OH:22]>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[N:21][OH:22])[CH3:18]
Reactant: NO
Reactant: CC(=O)c1ccccc1Nc1c(Cl)ccc(C)c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(=NO)c1ccccc1Nc1c(Cl)ccc(C)c1Cl

Procedure:
1-[2-[(2,6-Dichloro-3-methylphenyl)amino]phenyl]ethanone (0.8 g, 2.7 mmol) and hydroxylamine hydrochloride (0.8 g, 10.8 mmol) are dissolved in 15 ml of pyridine under argon at room temperature for 12 hours. The pyridine is evaporated, and the residue partitioned between methylene chloride and water. The organic layer is washed twice with 100 ml of water and dried over magnesium sulfate. The solution is concentrated on the rotovap and passed through a silica gel pad which is then eluted with methylene chloride. The solvent is evaporated and 1-[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]ethanone oxime is recrystallized from H2O/MeOH. Yield 0.2 g (24%); mp 116°-118° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11]Cl)[C:4]=2[O:3]1.[OH:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[CH:17][CH:16]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][O:14][C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[CH:19][CH:20]=3)[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cccc(CCl)c2O1
Reactant: CN(C)C(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)Nc1ccc(OCc2cccc3c2OC(C)(C)C3)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
3.0 g of 2,3-dihydro-2,2-dimethyl-7-benzofuranylmethyl chloride and 3.0 g of 1-(4-hydroxyphenyl)-3,3-dimethylurea were dissolved into 20 ml of dried N,N-dimethylformamide, and 2.5 g of anhydrous potassium carbonate was added thereto. After the mixture was stirred at 80° C. for 4 hours, the reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water, it was dried over anhydrous magnesium sulfate and ethyl acetate was distilled off. The residue was subjected to silica gel column chromatography using ethyl acetate/n-hexane (1/1) as a developer to obtain 4.0 g of Compound No. 7 shown in Table 1.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3(C=O)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[C:18]([F:30])[C:17]=2[F:31])=[C:12]([F:32])[C:11]=1[F:33])[CH3:8].O>C1COCC1>[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C@H:22]3[CH2:27][CH2:26][C@H:25](/[CH:17]=[CH:18]/[CH2:19][CH2:1][C:2]4[CH:5]=[CH:16][C:13]([CH2:12][CH2:11][CH3:10])=[CH:14][CH:3]=4)[CH2:24][CH2:23]3)=[C:18]([F:30])[C:17]=2[F:31])=[C:12]([F:32])[C:11]=1[F:33])[CH3:8]
Reactant: CCOc1ccc(-c2ccc(C3(C=O)CCCCC3)c(F)c2F)c(F)c1F
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1ccc(CC/C=C/[C@H]2CC[C@H](c3ccc(-c4ccc(OCC)c(F)c4F)c(F)c3F)CC2)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Well-dried compound (s5) (6.4 g) was mixed with THF (100 ml) under an atmosphere of nitrogen, and the solution was cooled to −10° C. Potassium t-butoxide (t-BuOK; 1.4 g) was added in the temperature range of −10° C. to −5° C. After 60 minutes of stirring at −10° C., the compound (s78) (4.0 g) dissolved in THF (30 ml) was added dropwise in the temperature range of −10 to −5° C. After 30 minutes of stirring at 0° C., the reaction mixture was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder. The purified product was mixed with sodium benzenesulfonate dihydrate (20.2 g) and Solmix A-11 (100 ml). Then, 6N-hydrochloric acid (16.8 ml) was added, and the mixture was heated to reflux for 2 hours. The reaction mixture was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder, and then by recrystallization from a mixed solvent of ethyl acetate and Solmix A-11 (ethyl acetate:Solmix=1:4 by volume) to give (E)-4-ethoxy-2,2′,3,3′-tetrafluoro-4′-(trans-4-(4-(4-propylphenyl)but-1-en-1-yl)cyclohexyl)-1,1′-biphenyl (No. 262) (3.6 g). The yield based on the compound (s78) was 65.3%.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][N:14]([CH2:18][CH3:19])[C:15]([NH2:17])=[S:16])[CH:8]=2)[N:3]=1.[CH:20]([CH:22](Cl)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=O>CN(C)C=O>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][N:14]([C:15]3[S:16][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][N:17]=3)[CH2:18][CH3:19])[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)C(Cl)C=O
Reactant: CCN(Cc1ccc2nc(C)[nH]c(=O)c2c1)C(N)=S
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(N(CC)Cc2ccc3nc(C)[nH]c(=O)c3c2)s1
Temperature: 100 °C
Yield: 21.8 %

Procedure:
A mixture of the thiourea (4.67 g), ethyl formylchloroacetate (Archiv der Pharmazie, 1953, 286, 494: 2.55 g) and dimethylformamide (25 ml) was stirred and heated to 100° C. for 1 hour. The mixture was cooled, filtered and the filtrate was evaporated. The residue was partitioned between methylene chloride and a saturated aqueous sodium bicarbonate solution. The organic solution was dried over sodium sulphate, filtered and evaporated. The residue was purified by trituration in ethyl acetate to give ethyl 2-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl) N-ethylamino]thiazole-5-carboxylate (1.37 g), m.p. 188°-192° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[F:27][C:28]1[CH:36]=[C:35]2[C:31]([C:32]([C:37]3[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=3)=[CH:33][NH:34]2)=[CH:30][CH:29]=1>CS(C)=O.C(OCC)(=O)C>[F:27][C:28]1[CH:36]=[C:35]2[C:31]([C:32]([C:37]3[CH2:38][CH2:39][N:40]([CH2:12][CH:13]4[O:14][C:15]5[C:16](=[CH:17][CH:18]=[C:19]6[N:20]=[C:21]([CH3:24])[O:22][C:23]6=5)[O:25][CH2:26]4)[CH2:41][CH:42]=3)=[CH:33][NH:34]2)=[CH:30][CH:29]=1
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1nc2ccc3c(c2o1)OC(CN1CC=C(c2c[nH]c4cc(F)ccc24)CC1)CO3
Temperature: 80 °C

Procedure:
[(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methyl 4-methylbenzenesulfonate (0.50 g, 1.31 mmole) and 6-fluoro-3-(1,2,3,6-tetrahydro4-pyridinyl)-1H-indole (1.0 g, 4.6 mmole) were combined in 10 mL of DMSO under nitrogen. This solution was heated at 80° C. under nitrogen. After completion, the reaction was cooled to room temperature and diluted with 400 mL of ethyl acetate. The organic phase was washed with 400 mL portions of saturated aqueous sodium bicarbonate, water and saturated brine and concentrated in vacuum. The crude residue was column chromatographed on silica gel using 1% methanol/methylene chloride to give 0.52 g of the (S)-enantiomer of the title compound, which was a yellow solid (m.p. 188-190° C.) after evaporation of the solvent.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=4)[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:46])C=1>ClCCl.CCOC(C)=O>[C:1]1([C:7]2[N:8]=[C:9]([C:18]34[O:46][CH:23]3[CH2:22][CH2:21][CH2:20][C@H:19]4[CH2:24][C:25]3[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=3)[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)COc1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)COc1cccc(C[C@@H]2CCCC3OC32c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Yield: 48.4 %

Procedure:
A solution of ethyl (S)-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}phenoxy}acetate (800 mg) and m-chloroperbenzoic acid (600 mg) in dichloromethane (20 ml) was stirred for 2 hours at room temperature. The mixture was diluted with EtOAc and washed with water and brine. Then, it was dried over MgSO4 and evaporated in vacuo. The residue was purified by chromatography on silica gel to give ethyl {3-{[(1S)-2-(4,5-diphenyloxazol-2-yl) -2,3-epoxy-1-cyclohexyl]methyl}phenoxy}-acetate (400 mg).