Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:39])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].F[C:42]1[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=1>>[C:1]([O:5][C:6](=[O:40])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:39])[C:16]2[CH:21]=[C:20]([O:22][C:42]3[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=3)[CH:19]=[C:18]([O:23][C:24]3[CH:25]=[CH:26][C:27]([CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:28][CH:29]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Oc2cc(O)cc(C(=O)NC3CCC(NC(=O)OC(C)(C)C)CC3)c2)cc1
Reactant: N#Cc1ccc(F)cc1
Product: CC(C)(C)OC(=O)NCc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)NC3CCC(NC(=O)OC(C)(C)C)CC3)c2)cc1
Yield: 92.8 %

Procedure:
Using 1.4 g (2.51 mmol) of {4-[3-[4-tert-Butoxycarbonylaminomethylphenoxy]-5-hydroxybenzoylamino]-cyclohexyl}carbamic acid tert-butyl ester and 4-fluoro-benzonitrile (0.76 g, 6.27 mmol) and following the procedure of Example 42(b) afforded 1.53 g of the required product. 1H NMR (DMSO-d6): δ 1.3 (4H, m), 1.4 (18H, s), 1.8 (4H, m), 3.2 (1H, m), 3.7 (1H, m), 4.15 (2H, d), 6.72 (1H, d), 7.20 (1H, s), 7.06 (2H, d), 7.18 (2H, d), 7.28 (2H, d), 7.38 (3H, d), 7.86 (2H, s), 8.3 (1H, d).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+].O>CC(C)=O>[C:17]([NH:11][C:9]1[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)c1cc(NC(=O)c2ccccc2)cc(C(C)(C)C)c1O
Reaction time: 1 h
Yield: 90.6 %

Procedure:
11.05 g (0.05 mole) 2,6-di-t-butyl-4-aminophenol is dissolved in 25 ml acetone and 7.03 g (0.05 mole) benzoyl chloride is added thereto. The reaction is exothermic. The mixture is shaken and 10 ml of 5 N sodium hydroxide is added thereto, portionwise, accompanied by agitation. A solid material separates and is allowed to stand for one hour, cooled and there is then added thereto 50 ml water. The mixture is filtered, washed with 50 ml water and then four times each time with 50 ml portions of petroleum ether to remove the red color. The solid material is air dried and there is obtained 14.72 g (a yield of 90.6%) of the 4-benzamido-2,6-di-t-butylphenol product. The solid material is dissolved in 100 ml of 90% ethanol, contacted with a charcoal adsorbent (Darco G-60) and then crystallized. The crystalline material is cooled, filtered, washed with 30 ml cold 90% ethanol and then dried in vacuo over phosphorus pentoxide. The pure product is characterized by a melting point of 209°-210° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[O:13])[N:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>C(OC(C)C)(C)C>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][OH:13])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(CCC=O)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Product: CC(=O)Nc1nc(CCCO)cs1
Reaction time: 1 h
Yield: 67.6 %

Procedure:
To a solution of 2-acetylamino-4-(2-formylethyl)thiazole (2.49 g) in diisopropyl ether (170 ml) was added sodium borohydride (120 mg) under ice-cooling and stirred for 1 hour at the same temperature. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (20:1 V/V) to give 2-acetylamino-4-(3-hydroxypropyl)thiazole (1.70 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[N:11]1([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23]([CH:28]=O)=[CH:22]3)[CH2:15][CH2:14][CH2:13][CH2:12]1.N1CCCCC1>C(O)C>[N:11]1([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23]([CH:28]=[C:3]2[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][C:2]2=[O:10])=[CH:22]3)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccccc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Temperature: 100 °C
Yield: 81.7 %

Procedure:
A mixture of oxindole (26.6 mg, 0.2 mmol), 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde (52 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 61 mg (81%) of the title compound.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([CH3:14])=[CH:9][C:8]=1[C:15]1[CH:19]=[C:18]([O:20][CH:21]([F:23])[F:22])[N:17]([CH3:24])[N:16]=1>ClC(Cl)(Cl)Cl>[Cl:4][C:19]1[C:15]([C:8]2[CH:9]=[C:10]([CH3:14])[C:11]([Cl:13])=[CH:12][C:7]=2[Cl:6])=[N:16][N:17]([CH3:24])[C:18]=1[O:20][CH:21]([F:22])[F:23]
Reactant: Cc1cc(-c2cc(OC(F)F)n(C)n2)c(Cl)cc1Cl
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(-c2nn(C)c(OC(F)F)c2Cl)c(Cl)cc1Cl
Reaction time: 2 h

Procedure:
16.9 g (125 mmol) of sulfuryl chloride were added dropwise to a solution of 35 g (114 mmol) of 3-(2,4-dichloro-5-methylphenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole in 120 ml of tetrachloromethane. After the reaction mixture had been stirred for 2 hours, it was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and then dried over magnesium sulfate, filtered and concentrated. Yield: 30.8 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([F:16])[C:11]([F:15])=[CH:12][CH:13]=3)[O:8][C:7](=[O:17])[C:6]=2[CH:18]=1.II>CC(C)=O>[F:16][C:10]1[C:11]([F:15])=[CH:12][CH:13]=[C:14]2[C:9]=1[O:8][C:7](=[O:17])[C:6]1[C:5]2=[CH:4][CH:3]=[C:2]2[C:18]=1[C:3]([CH3:2])=[CH:4][C:5]([CH3:14])([CH3:6])[NH:1]2
Reactant: Nc1ccc2c(c1)c(=O)oc1c(F)c(F)ccc12
Agent: II
Solvent: CC(C)=O
Product: CC1=CC(C)(C)Nc2ccc3c(c21)c(=O)oc1c(F)c(F)ccc13
Temperature: 110 °C
Reaction time: 120 h
Yield: 62.7 %

Procedure:
In a pressure tube, 8-amino-3,4-difluorobenzo[c]chromen-6-one (Reference Compound No. 1-2-(4), 2.30 g, 9.26 mmol) was dissolved in acetone (60 mL), then iodine (939 mg, 3.70 mmol) was added thereto, then the pressure tube was sealed, and then the reaction mixture was stirred at 110° C. for 5 days. After cooling down, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to give the titled reference compound (0.95 g) as a yellow solid. (Yield 31%)
Reaction SMILES: [NH3:1].Cl[C:3]1([C:14]2[C:15]([O:20][CH2:21][CH3:22])=[N:16][CH:17]=[CH:18][CH:19]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[NH:5][C:4]1=[O:13].O>ClCCl>[NH2:1][C:3]1([C:14]2[C:15]([O:20][CH2:21][CH3:22])=[N:16][CH:17]=[CH:18][CH:19]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[NH:5][C:4]1=[O:13]
Reactant: CCOc1ncccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: N
Solvent: ClCCl
Solvent: O
Product: CCOc1ncccc1C1(N)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
104 ml (728 mmol) of a 7N methanolic ammonia solution were added dropwise to a cooled solution of 47 g (145 mmol) of 3,5-dichloro-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one in 250 ml of dichloromethane under a nitrogen atmosphere, and the reaction mixture was then stirred at room temperature overnight. 250 ml of water and 250 ml of dichloromethane were added to the reaction mixture. After stirring for 5 min, a white solid was precipitated and filtered off and washed with water and dichloromethane. Drying in a vacuum drying oven resulted in 26 g of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[C:12]([C:20]([F:23])([F:22])[F:21])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].O[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[C@H:30]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:29][CH2:28]2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[C@H:30]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:29][CH2:28]4)[C:12]([C:20]([F:21])([F:23])[F:22])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Reactant: CCc1ccc(-c2ccc(C(F)(F)F)c(NCCCO)n2)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3nc(-c4ccc(CC)cc4)ccc3C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.6 %

Procedure:
To a solution of 3-{[6-(4-ethylphenyl)-3-(trifluoromethyl)-2-pyridinyl]amino}-1-propanol (Example 316) (0.34 g, 1.05 mmol) and ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 0.18 g, 0.84 mmol) in THF (8.50 mL) was added PPh3 (0.29 g, 1.09 mmol) and ADDP (0.28 g, 1.09 mmol) under argon. The golden yellow mixture was stirred at rt for 18 h, and then concentrated under reduced pressure. The product (0.33 g, 74%) was isolated after silica gel flash chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD2Cl2) δ 7.99 (d, 2H), 7.72 (d, 1H), 7.25 (d, 2H), 7.12 (d, 1H), 7.01 (d, 1H), 6.76 (d, 1H), 6.68 (dd, 1H), 4.15 (q, 2H), 4.08 (t, 2H), 3.82 (t, 2H), 3.45 (qt, 1H), 2.90-2.68 (m, 5H), 2.42-2.28 (m, 2H), 2.16 (qt, 2H), 1.78-1.68 (m, 1H), 1.30-1.24 (m, 6H).
Reaction SMILES: [H-].[Na+].[CH:3]1([C:8]2[NH:9][C:10]3[C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=[C:13]([O:21][CH3:22])[C:11]=3[N:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.I[CH3:24]>CN(C)C=O.C(OCC)C>[CH:3]1([C:8]2[N:12]([CH3:24])[C:11]3[C:13]([O:21][CH3:22])=[CH:14][CH:15]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[C:10]=3[N:9]=2)[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CI
Reactant: COC(=O)c1ccc(OC)c2nc(C3CCCC3)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1ccc(OC)c2c1nc(C1CCCC1)n2C
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A suspension of sodium hydride (0.55 g, 60% dispersion in mineral oil) in dimethylformamide (1 ml), cooled to 0° C., was treated with a solution of methyl 2-cyclopentyl-7-methoxy-3H-benzimidazole-4-carboxylate [3.61 g, Reference Example 3(t)]) in dimethylformamide (34 ml). The resulting mixture was stirred for 40 minutes then treated with iodomethane (0.82 ml). The reaction mixture was allowed to stand at 4° C. for 2 days then diluted with diethyl ether, then washed with brine, then dried over magnesium sulphate and then evaporated. The residue was subjected to flash chromatography on silica to give methyl 2-cyclopentyl-7-methoxy-1-methyl-1H-benzimidazole-4-carboxylate (3.18 g), [NMR (CDCl3): δ 1.70 (m,2H), 1.90(m,2H), 2.16(m,4H), 3.25(m,1H), 3.95(s,6H), 4.00(s,3H), 6.64(d,J=8 Hz,1H), 7.89(d,J=8 Hz,1H)]; and methyl 2-(cyclopentyl)-7-methoxy-3-methyl-3H-benzimidazole-4-carboxylate (0.37 g), [M+288, NMR (CDCl3): δ 1.70(m,2H), 1.90(m,2H), 2.14(m,4H), 3.25(m,1H), 3.92(s,6H), 4.02(s,3H), 6.64(d,J=8 Hz,1H), 7.75(d,J=8 Hz,1H)].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([N:12]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:13][C@H:14]([OH:23])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][OH:11])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>ClCCl>[CH2:24]([N:12]([C@H:9]([CH2:10][OH:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:37](=[O:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:3][CH:4]=1)[CH2:13][C@H:14]([OH:23])[CH2:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nc1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccccc2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccccc2)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
To an ice-cooled mixture of (2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-1-propanol (63 mg) and pyridine (25 μl) in dichloromethane (0.6 ml) was added dropwise benzoyl chloride (22 μl), and the mixture was stirred at room temperature for more than 2 hours. The mixture was partitioned between chloroform-methanol and water. The organic layer was separated, washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, chloroform/methanol) to give N-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]phenyl]benzamide (80 mg) as a white amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[S:9]1[CH:13]=[CH:12][C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:10]1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:11]2[CH:12]=[CH:13][S:9][CH:10]=2)=[CH:4][N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccsc1
Reactant: Clc1ncc(Br)cn1
Product: Clc1ncc(-c2ccsc2)cn1

Procedure:
2-Chloro-5-bromopyrimidine and 3-thienyltributyltin are treated in the same manner as in Example 190 to give 2-chloro-5-(3-thienyl)pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:22][CH:23]2[CH2:27][CH2:26][C:25](=O)[CH2:24]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].Cl.[CH3:30][O:31][NH2:32]>CO.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:22][CH:23]2[CH2:27][CH2:26][C:25](=[N:32][O:31][CH3:30])[CH2:24]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)C2)C(=O)Nc2cnccn2)cc1Cl
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CON=C1CCC(CC(C(=O)Nc2cnccn2)c2ccc(S(C)(=O)=O)c(Cl)c2)C1
Temperature: 25 °C
Yield: 79.8 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-N-pyrazin-2-yl-propionamide (prepared as in Example 45, 73.5 mg, 0.17 mmol) and methoxyamine hydrochloride (21.8 mg, 0.26 mmol) in methanol (512 μL) and pyridine (512 μL) was heated under reflux for 5 h. The reaction mixture was allowed to cool to 25° C. and was then concentrated in vacuo. The resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layers were washed with a saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 70% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-methoxyimino-cyclopentyl)-N-pyrazin-2-yl-propionamide (61.2 mg, 78%) as a white foam: mp 85–87° C.; (ES)+-HRMS m/e calcd for C20H23ClN4O4S (M+H)+ 451.1202 found 451.1207.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([NH:11][NH:12][C:13]([C:15]2[S:16][C:17]([CH2:26][CH3:27])=[C:18]3[CH2:23][C:22]([CH3:25])([CH3:24])[CH2:21][CH2:20][C:19]=23)=O)=[O:10])[CH:6]=[C:5]([CH3:28])[N:4]=1)[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1.CC(=O)OCC>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[O:10][C:13]([C:15]3[S:16][C:17]([CH2:26][CH3:27])=[C:18]4[CH2:23][C:22]([CH3:25])([CH3:24])[CH2:21][CH2:20][C:19]=34)=[N:12][N:11]=2)[CH:6]=[C:5]([CH3:28])[N:4]=1)[CH3:2]
Reactant: CCc1cc(C(=O)NNC(=O)c2sc(CC)c3c2CCC(C)(C)C3)cc(C)n1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cc(-c2nnc(-c3sc(CC)c4c3CCC(C)(C)C4)o2)cc(C)n1
Temperature: 110 °C
Yield: 28.9 %

Procedure:
A mixture of crude 3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid N′-(2-ethyl-6-methyl-pyridine-4-carbonyl)-hydrazide (289 mg, ca. 0.48 mmol) and Burgess Reagent (367 mg, 1.6 mmol) in THF (5 mL) is heated at 110° C. for 3 min in a microwave oven. The mixture is diluted with EA (50 mL) and extracted with 1M aq. NaOH (2×10 mL). The organic phase is dried (MgSO4), filtered and evaporated. The residue is purified by HPLC to give 2-ethyl-4-[5-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-[1,3,4]oxadiazol-2-yl]-6-methyl-pyridine (53 mg); LC-MS: tR=0.96 min, [M+1]=382.26.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:25])([F:24])[F:23])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([CH:19]=O)=[C:16]([CH3:21])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:26]([NH2:30])(=[O:29])[CH2:27][CH3:28].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C1(C)C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:22]([F:24])([F:25])[F:23])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([CH2:19][NH:30][C:26](=[O:29])[CH2:27][CH3:28])=[C:16]([CH3:21])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCC(N)=O
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1C=O
Agent: CC[SiH](CC)CC
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)NCc1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Yield: 49.7 %

Procedure:
A mixture of 5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carbaldehyde (120 mg), propionamide (66 mg), trifluoroacetic acid (68 μl) and triethylsilane (144 μl) in toluene (2 ml) is refluxed overnight. After 20 hours the reaction mixture is concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield N-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophen-2-ylmethyl}-propionamide (68 mg, compound 1.5 in Table 1) as a white foam. MS (HPLC/MS): 465 (MH+). Retention time: 1.98 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[C:6]([F:15])[CH:5]=[CH:4][C:3]=1[C@H:16]([O:18][C:19]1[CH:23]=[C:22]([N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:33]4[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=4)=[CH:32][C:27]=3[N:26]=[CH:25]2)[S:21][C:20]=1[C:39]([NH2:41])=[O:40])[CH3:17].[CH:42]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH2:43]>>[Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:43][CH2:42][S:44]([CH3:47])(=[O:46])=[O:45])[CH2:11][CH2:10]2)=[C:6]([F:15])[CH:5]=[CH:4][C:3]=1[C@H:16]([O:18][C:19]1[CH:23]=[C:22]([N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:33]4[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=4)=[CH:32][C:27]=3[N:26]=[CH:25]2)[S:21][C:20]=1[C:39]([NH2:41])=[O:40])[CH3:17]
Reactant: C=CS(C)(=O)=O
Reactant: C[C@@H](Oc1cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)sc1C(N)=O)c1ccc(F)c(OC2CCNCC2)c1Cl
Product: C[C@@H](Oc1cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)sc1C(N)=O)c1ccc(F)c(OC2CCN(CCS(C)(=O)=O)CC2)c1Cl
Yield: 79 %

Procedure:
3-({(1R)-1-[2-chloro-4-fluoro-3-(4-piperidinyloxy)phenyl]ethyl}oxy)-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxamide (Example 33, Step A, 80 mg, 0.13 mmol) and methyl vinyl sulfone (13 μL, 0.15 mmol) were coupled using a procedure analogous to Example 23 to give 72 mg of the title compound (79%). 1H NMR (400 MHz, d6-DMSO) δ 8.52 (s, 1H), 8.17 (s, 1H), 7.95 (s, 1H), 7.91 (s, 1H), 7.79 (br s, 1H), 7.56 (m, 2H), 7.45-7.35 (m, 2H), 7.13 (s, 1H), 7.08 (br s, 1H), 5.94 (m, 1H), 4.13 (m, 1H), 3.85 (s, 3H), 3.17 (t, J=6.2 Hz, 2H), 2.97 (s, 3H), 2.69-2.58 (m, 4H), 2.07 (m, 2H), 1.81-1.66 (m, 7H). HRMS calculated [M+H]+ C32H35ClFN6O5S2 701.17774, found 701.17740.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[CH:12][C:11]=2[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:6][CH:5]=1.S(=O)(=O)(O)O.[CH3:27]O>>[F:21][C:2]([F:1])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[CH:12][C:11]=2[CH2:15][CH2:16][C:17]([O:19][CH3:27])=[O:18])=[CH:6][CH:5]=1
Reactant: O=C(O)CCc1cnoc1-c1ccc(OC(F)(F)F)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc(OC(F)(F)F)cc1
Yield: 81 %

Procedure:
A mixture of 3-[5-(4-trifluoromethoxyphenyl)-4-isoxazolyl]propionic acid (3.30 g), conc. sulfuric acid (0.2 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[5-(4-trifluoromethoxyphenyl)-4-isoxazolyl]propionate (2.80 g, yield 81%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). NMR (CDCl3) δ: 2.66 (2H, t, J=7.4 Hz), 2.99 (2H, q, J=7.4 Hz), 3.69 (3H, s), 7.35 (2H, dd, J=1.0, 9.2 Hz), 7.76 (2H, d, J=9.2 Hz), 8.24 (1H, s).
Reaction SMILES: Cl.Cl.[CH:3]([N:16]1[CH2:21][C@@H:20]2[CH2:22][C@H:17]1[CH2:18][NH:19]2)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CS([C:27]1[N:32]=[CH:31][C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][N:28]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[CH:3]([N:16]1[CH2:21][C@@H:20]2[CH2:22][C@H:17]1[CH2:18][N:19]2[C:27]1[N:28]=[CH:29][C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][N:32]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1
Reactant: c1ccc(C(c2ccccc2)N2C[C@@H]3C[C@H]2CN3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCOC(=O)c1cnc(N2C[C@@H]3C[C@H]2CN3C(c2ccccc2)c2ccccc2)nc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
Title compound 201 (0.250 g, 0.741 mmol), ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate (0.122 g, 0.529 mmol), potassium carbonate (0.280 g, 2.645 mmol) and DME (5 mL) were combined. The reaction mixture was stirred at 50° C. for 2 hours. The mixture was cooled down and quench with water. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography eluting with 0% to 30% ethyl acetate in hexanes to afford title compound 202 (0.141 g, 64%). LRMS (ESI): (calc) 414.21. (found) 415.0 (MH)+.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3].CCN(C(C)C)C(C)C.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[NH4+].[Cl-]>C(Cl)Cl>[O:31]1[CH2:32][CH2:33][N:28]([S:2]([C:5]2[CH:6]=[C:7]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=2)[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3])[CH2:29][CH2:30]1
Reactant: C1COCCN1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1.3 h

Procedure:
To a solution of methyl 3-(chlorosulfonyl)-5-(trifluoromethyl)benzoate (0.3 g, 991 μmol, Buttpark Ltd.) in CH2Cl2 (1.0 mL) were added DIPEA (192 mg, 260 μL, 1.49 mmol) and morpholine (86.4 mg, 86.4 μL, 991 μmol). The clear light yellow solution was stirred at room temperature for 1.3 hours and then poured on saturated aqueous NH4Cl solution and CH2Cl2. The layers were separated and the aqueous layer was extracted twice with CH2Cl2. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. Light brown solid (0.357 g; 91%). MS (EI): m/z=353 [M].