Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:17]3[S:18][C:19]([C:23]([O-:25])=[O:24])=[C:20]([CH3:22])[N:21]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:5]=[CH:4][N:3]=[CH:2]1.O1CCCC1.CO.[OH-].[Na+].Cl>O>[N:1]1([C:6]2[CH:7]=[C:8]([C:17]3[S:18][C:19]([C:23]([OH:25])=[O:24])=[C:20]([CH3:22])[N:21]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1nc(-c2ccc(OCC(C)C)c(-n3ccnc3)c2)sc1C(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1nc(-c2ccc(OCC(C)C)c(-n3ccnc3)c2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A reaction mixture solution prepared by dissolving the crude product of 2-[3-(1H-imidazol-1-yl)-4-(2-methylpropoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylate obtained above in 1 mL of a mixed solution of tetrahydrofuran/methanol=1/1 followed by the addition of 0.2 mL of 2 M sodium hydroxide aqueous solution was stirred at room temperature for 4 hours. After the addition of 0.2 mL of 2 M hydrochloric acid to the reaction mixture solution under stirring, 3 mL of water was added and extraction was performed using 4 mL of ethyl acetate. The organic phase was concentrated, followed by purifying by a conventional method to obtain 2.50 mg of 2-[3-(1H-imidazol-1-yl)-4-(2-methylpropoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylic acid.
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH:7]=[CH:8][C:9]1=[N:10][CH2:11][CH2:12][NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]1=2.[N+:24]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1)([O-:26])=[O:25].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C(OCC)(=O)C.O>[ClH:3].[ClH:1].[Cl:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH:7]=[CH:8][C:9]1=[N:10][CH2:11][CH2:12][N:13]([CH2:31][C:30]2[CH:33]=[CH:34][C:27]([N+:24]([O-:26])=[O:25])=[CH:28][CH:29]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]1=2
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Clc1ccc(C=CC2=NCCNc3ccccc32)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(CN2CCN=C(C=Cc3ccc(Cl)c(Cl)c3)c3ccccc32)cc1
Yield: 15.2 %

Procedure:
A mixture of 117 mg (0.3 mmol) of (E)-5-(3,4-dichlorostyryl)-2,3-dihydro-1H-benzo-1,4-diazepine dihydrochloride, 70 mg (0.32 mmol) of 4-nitrobenzyl bromide and 127 mg (1.2 mmol) of sodium carbonate were heated at 70° C. in 3 ml of ethanol for 18 hours. The mixture was diluted with ethyl acetate and water and the organic phase dried over magnesium sulphate, filtered and evaporated to dryness. The residue was chromatographed three times on silica gel using ethyl acetate/petrol (3:1), dichloromethane/methanol (97:3) and ethyl acetate/petrol (9:1) for the elutions. The product was dissolved in a solution of hydrogen chloride in methanol, evaporated to dryness and the residue triturated with diethyl ether to give 12 mg of (E)-5-(3,4-dichlorostyryl)-2,3-dihydro-1-(4-nitrobenzyl)-1H-1,4-benzodiazepine dihydrochloride. MS: m/e 451.9 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([C:10]([OH:12])=[O:11])[NH:4][N:3]=1.S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([C:10]([O:12][CH2:18][CH3:19])=[O:11])[NH:4][N:3]=1
Reactant: Cc1n[nH]c(C(=O)O)c1[N+](=O)[O-]
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1[nH]nc(C)c1[N+](=O)[O-]

Procedure:
Esterification of 3-methyl-4-nitropyrazole-5-carboxylic acid was previously reported using ethanol and sulphuric acid at elevated temperatures. Attempts to repeat this procedure resulted in concomitant alkylation of the pyrazole nucleus. However, it was found that the desired ester could be obtained if this reaction was run at room temperature.
Reaction SMILES: [CH2:1]([N:8]([CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1>C1COCC1.O>[CH2:1]([N:8]([CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[N:20]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CBr)cc1
Reactant: CN(Cc1ccccc1)C(=O)C1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cn2c(C(=O)N3CCC(C(=O)N(C)Cc4ccccc4)CC3)cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-benzyl-1-(1H-indole-2-carbonyl)-N-methylpiperidine-4-carboxamide (100 mg, 0.266 mmol) was added to a suspension of sodium hydride (12.78 mg, 0.320 mmol) in THF (Volume: 1.5 mL). The reaction was stirred for 10 minutes before 1-(bromomethyl)-4-methoxybenzene (0.039 mL, 0.266 mmol) was added. The reaction was allowed to stir at room temperature overnight. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution. It was dried over magnesium sulfate, filtered and concentrated. The crude material was purified using 50%-100% ethyl acetate in hexanes to obtain white solid as a product. (Yield: 42 mg, white solid) 1H-NMR (400 MHz, DMSO-d6) 7.64-7.58, 7.41-7.15, 7.10-7.05, 6.85-6.81, 6.70-6.64, 5.48-5.38, 4.64, 4.56-4.45, 3.70-3.66, 3.01-2.92, 2.78, 1.54
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:8][C:4]=1[C:5]([OH:7])=O.CC(C)=O.ClC(OCC)=O.[CH:28]1([CH2:35][N:36]2[CH2:40][CH2:39][CH2:38][CH:37]2[CH2:41][NH2:42])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C(N(CC)CC)C.O>[CH:28]1([CH2:35][N:36]2[CH2:40][CH2:39][CH2:38][CH:37]2[CH2:41][NH:42][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([S:14](=[O:17])(=[O:16])[NH2:15])[CH:10]=[C:11]([O:12][CH3:13])[C:3]=2[O:2][CH3:1])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: COc1cc(S(N)(=O)=O)cc(C(=O)O)c1OC
Reactant: NCC1CCCN1CC1CCCCCC1
Agent: CCOC(=O)Cl
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(S(N)(=O)=O)cc(C(=O)NCC2CCCN2CC2CCCCCC2)c1OC
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
13 g of 2,3-dimethoxy-5-sulphamoyl benzoic acid, 150 ml of acetone, 28 ml of water and 7 ml of triethylamine (density 0.726) are placed in a 250 ml flask fitted with an agitator, a thermometer, a condenser and a dropping funnel. The resultant solution is cooled from 0° to +5° C. 5.4 g of ethyl chloroformate is added drop by drop and the reaction medium is agitated for 45 minutes at room temperature and cooled to 0° C. again. 13.7 g of 1-cycloheptylmethyl-2-aminomethylpyrrolidine is added drop by drop. The medium is agitated for 1 hour at room temperature then left to stand. The crystals formed are drained, washed with water and dried in an oven at 30° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH2:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:16][O:17][CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][O:17][CH3:16])=[N:6][CH:7]=1
Reactant: NCc1ccc(Br)cn1
Reactant: COCCCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COCCCC(=O)NCc1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 9.35 g of C-(5-bromopyridin-2-yl)methylamine [17399-23-0] in 200 ml of ethyl acetate is admixed with 300 ml of saturated aqueous sodium carbonate solution. The reaction mixture is cooled to 0° C. in an ice bath and subsequently admixed dropwise with a solution of 4-methoxybutanoyl chloride [61882-39-1] in 100 ml of ethyl acetate. The reaction mixture is stirred at 0° C. over 1 hour. The phases are separated and the aqueous phase is extracted with 300 ml of ethyl acetate (2×). The combined organic phases are washed with 300 ml of brine, dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]([CH3:19])([CH3:18])[CH2:10]2)[C:5]([F:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][CH:27]2[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]2)=[C:24]([C:42]([F:45])([F:44])[F:43])[CH:23]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CC(O)C.CCOC(C)=O>[CH3:18][C:11]1([CH3:19])[CH2:10][C@H:9]([NH:8][C:6]2[C:5]([F:20])=[CH:4][N:3]=[C:2]([NH:21][C:22]3[CH:41]=[CH:40][C:25]([O:26][CH:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]4)=[C:24]([C:42]([F:45])([F:43])[F:44])[CH:23]=3)[N:7]=2)[CH2:17][C@H:16]2[N:12]1[CH2:13][CH2:14][CH2:15]2
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2C(F)(F)F)CC1
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2F)C[C@@H]2CCCN21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC1(C)C[C@H](Nc2nc(Nc3ccc(OC4CCNCC4)c(C(F)(F)F)c3)ncc2F)C[C@@H]2CCCN21
Temperature: 110 °C
Yield: 36 %

Procedure:
A mixture of (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-5,5-dimethyloctahydroindolizin-7-amine (0.2 g, 0.95 eq, 0.7 mmol), tert-butyl 4-(4-amino-2-(trifluoromethyl)phenoxy)piperidine-1-carboxylate (0.25 g, 1.0 eq, 0.7 mmol) and PTSA (0.24 g, 1.8 eq, 1.3 mmol) was taken in iPrOH (50 mL) and heated at 110° C. overnight. After 18 hours of heating, reaction mixture was cooled to room temperature and PTSA (1.0 eq) was added to complete the deprotection of the Boc group. Next, the reaction mixture was heated at 110° C. for 2 hours while stifling and cooled to room temperature. The volatiles were removed under vacuum to leave a crude solid. The crude mixture was dissolved in EtOAc (100 mL) and partitioned with 1N aqueous NaOH solution (50 mL). Organic layers were separated and the aqueous layer was washed with EtOAc (50 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to leave a crude solid. The solid was purified by column chromatography on silica gel (ISCO System) using 2M NH3 in MeOH/CH2Cl2 (gradient system from 0:1 to 2:8) as eluent to give the product as a solid in 36% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][NH:16][C:17](=[O:39])[C:18]3[C:23]([F:24])=[C:22]([S:25][C:26]4[S:30][C:29]([NH:31][C:32]5[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][N:33]=5)=[N:28][CH:27]=4)[CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:41]([O:43][CH3:44])=[O:42]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][NH:16][C:17](=[O:39])[C:18]3[C:23]([F:24])=[C:22]([S:25][C:26]4[S:30][C:29]([NH:31][C:32]5[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][N:33]=5)=[N:28][CH:27]=4)[CH:21]=[CH:20][N:19]=3)[CH2:10][CH2:11][N:12]([C:41]([O:43][CH3:44])=[O:42])[CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccc(Cl)c(Cl)c5)CCNCC4)c3F)s2)c1
Reactant: COC(=O)Cl
Product: COC(=O)N1CCC(CNC(=O)c2nccc(Sc3cnc(Nc4cc(C)ccn4)s3)c2F)(c2ccc(Cl)c(Cl)c2)CC1

Procedure:
Following the procedure given for example 81, N-((4-(3,4-dichlorophenyl)piperidin-4-yl)methyl)-3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinamide (compound example 48) was reacted with methyl chloroformate to give the title compound. LC/MS (M+H)+: 661. Ret. time: 2.09 min. (Condition I); analytical HPLC Ret. time: 10.35 min (Condition H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@@H:15]([N:17]2[CH2:22][CH2:21][C@H:20]([OH:23])[C@@H:19]([CH3:24])[CH2:18]2)[CH3:16])[CH2:10][CH2:9]1)(C)(C)C.[ClH:26].O1CCOCC1.Cl.Cl.Cl.CC1CCN(CCN2CCC(N)CC2)CC1>>[ClH:26].[ClH:26].[ClH:26].[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@@H:15]([N:17]2[CH2:22][CH2:21][C@H:20]([OH:23])[C@@H:19]([CH3:24])[CH2:18]2)[CH3:16])[CH2:10][CH2:9]1
Reactant: C[C@H]1CN([C@@H](C)CN2CCC(NC(=O)OC(C)(C)C)CC2)CC[C@@H]1O
Agent: CC1CCN(CCN2CCC(N)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1CN([C@@H](C)CN2CCC(N)CC2)CC[C@@H]1O

Procedure:
It is prepared by BOC-cleavage of tert-butyl ester 59 (0.666 g, 1.95 mmol) with 4M-HCl in dioxane (2.93 ml, 11.72 mmol) as described for amine 7.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]([CH3:27])=[N:17][O:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:23]3[CH:24]=[CH:25][C:20]([C:19]4[O:18][N:17]=[C:16]([CH3:27])[C:15]=4[NH:14][CH:11]4[CH2:12][CH2:13][N:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH2:9][CH2:10]4)=[CH:21][CH:22]=3)=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:32])[CH3:29]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC4CCN(Cc5ccccc5)CC4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using (1-benzyl-piperidin-4-yl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][S:2]([N:5]([CH3:9])[C:6](Cl)=[O:7])(=[O:4])=[O:3].C(N(CC)CC)C.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[Cl:25])[NH2:21]>O1CCCC1>[CH3:9][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[C:6]([NH:21][C:20]1[CH:22]=[CH:23][C:24]([Cl:25])=[C:18]([Cl:17])[CH:19]=1)=[O:7]
Reactant: CN(C(=O)Cl)S(C)(=O)=O
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)Nc1ccc(Cl)c(Cl)c1)S(C)(=O)=O
Reaction time: 3 h
Yield: 58.2 %

Procedure:
A solution of 16 g of N-methylsulfonyl-N-methyl-carbamoyl chloride in 100 ml of tetrahydrofuran was slowly added at less than 10° C. to a mixture of 150 ml of tetrahydrofuran, 9.4 g of triethylamine and 15 g of 3,4-dichloroaniline and after stirring for 3 hours, the insolubles were removed by filtration, and the filtrate was concentrated to dryness under reduced pressure to obtain 16 g of N-methyl-N-methylsulfonyl-N'-(3,4-dichlorophenyl)-urea melting at 140° C. Crystallization from ethanol gave an unchanged melting point.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17](Cl)=[N:18][OH:19])=[CH:12][CH:11]=2)[CH:3]=1.[C:21]([C:23]1[C:24]([NH2:30])=[N:25][C:26]([NH2:29])=[CH:27][CH:28]=1)#[CH:22].C(N(CC)CC)C>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]3[CH:22]=[C:21]([C:23]4[C:24]([NH2:30])=[N:25][C:26]([NH2:29])=[CH:27][CH:28]=4)[O:19][N:18]=3)=[CH:12][CH:11]=2)[CH:3]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(COc2cc(F)ccn2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(COc4cc(F)ccn4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.7 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-(4-fluoro-pyridin-2-yloxymethyl)-phenyl)-acetohydroximoyl chloride (200 mg, 0.679 mmol) described in Manufacturing Example 59-1-5 and 3-ethynyl-pyridin-2,6-diamine (57.7 mg, 0.433 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (237 μL, 1.7 mmol). This mixture was stirred for 4 hours at room temperature. This mixture was partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1˜ethyl acetate) to obtain the title compound (113 mg, 43%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[Cl:11].[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:14]3[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[CH3:12])[CH2:21][CH2:22]2)=[O:8])=[CH:4][C:3]=1[Cl:11]
Reactant: O=C(O)c1ccc(Br)c(Cl)c1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)c(Cl)c3)CC2)c(C)c1
Yield: 100.7 %

Procedure:
Using 4-bromo-3-chlorobenzoic acid (2.4 g) and 1-(2,4-dimethylphenyl)piperazine (1.9 g) and by the reaction and treatment in the same manner as in Preparation Example 109, the title compound (4.1 g) was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=[C:12]([F:15])[C:13]=1F>C(#N)C>[F:7][C:8]1[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=[C:12]([F:15])[C:13]=1[N:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1
Reactant: C1CSCCN1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Solvent: CC#N
Product: O=[N+]([O-])c1cc(F)c(N2CCSCC2)c(F)c1
Yield: 88.6 %

Procedure:
Thiomorpholine (728 mg, 7.06 mmol) was added to a stirring solution of 3,4,5-trifluoronitro benzene (500 mg, 2.82 mmol) in acetonitrile (15 mL) and the reaction mixture was refluxed for 5 h. Evaporation of the solvent in a rotavapor under reduced pressure left a pasty mass which was dissolved in ethyl acetate (50 mL). Ethyl acetate portion was washed with water (30 mL×2) followed by brine (30 mL) and dried over sodium sulfate. Removal of volatiles yielded the title compound as yellow solid (650 mg, 85%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8][CH2:9][CH2:10][C:11]([CH3:14])([OH:13])[CH3:12])=[CH:6][C:5]([Br:15])=[CH:4][N:3]=1.CC(C)=[O:18].O.S([O-])(O[O-])(=O)=O.[K+].[K+]>CO>[NH2:1][C:2]1[C:7]([S:8]([CH2:9][CH2:10][C:11]([CH3:12])([OH:13])[CH3:14])=[O:18])=[CH:6][C:5]([Br:15])=[CH:4][N:3]=1
Reactant: CC(C)=O
Reactant: CC(C)(O)CCSc1cc(Br)cnc1N
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(O)CCS(=O)c1cc(Br)cnc1N
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 60 %

Procedure:
To a solution of 4-[(2-amino-5-bromopyridin-3-yl)thio]-2-methylbutan-2-ol (83 mg, 0.28 mmol) in a mixture of methanol (750 μL), acetone (750 μL) and water (450 μL) was added potassium peroxymonosulfate (131 mg, 0.21 mmol) and the reaction mixture was stirred for 90 minutes at 0° C. The reaction mixture was partitioned between water (20 mL) and ethyl acetate (50 mL). The organic layer was separated and washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography (35% to 80% ethyl acetate in hexane) gave 4-[(2-amino-5-bromopyridin-3-yl)sulfinyl]-2-methylbutan-2-ol (52 mg, 60%); MS (EI) for C10H15BrN2O2S: 308 (MH+).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:9]([F:10])=[C:8]([CH:11]2[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][CH2:12]2)[CH:7]=[CH:6][C:5]=1[CH:22]1[CH2:27][CH2:26][CH:25]([CH:28]2[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]2)[CH2:24][CH2:23]1.[H][H].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[F:3][C:4]1[C:9]([F:10])=[C:8]([CH:11]2[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][CH2:12]2)[CH:7]=[CH:6][C:5]=1[CH:22]1[CH2:27][CH2:26][CH:25]([CH:28]2[CH2:29][CH2:30][CH:31]([OH:34])[CH2:32][CH2:33]2)[CH2:24][CH2:23]1
Reactant: [H][H]
Reactant: CCCCCC1CCC(c2ccc(C3CCC(C4CCC(=O)CC4)CC3)c(F)c2F)CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCC1CCC(c2ccc(C3CCC(C4CCC(O)CC4)CC3)c(F)c2F)CC1
Temperature: 0 °C
Yield: 78.1 %

Procedure:
Sodium borohydride (1.37 g) and THF (60 ml) were put in a reaction vessel under a nitrogen atmosphere, and cooled to 0° C. The compound (47) (15.3 g) dissolved in a THF (60 ml) was added dropwise thereto, with caution in the evolution of hydrogen gas, and the mixture was stirred for 3 hours. A saturated aqueous solution of ammonium chloride (300 ml) and ethyl acetate (300 ml) were added and mixed thereto. The mixture was then allowed to stand until it had separated into organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase was fractionated, and washed with brine, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=5:1 by volume) as an eluent and silica gel as a stationary phase powder, and further purified by means of recrystallization from a mixed solvent of heptane and Solmix (heptane:Solmix=1:1 by volume), and dried, giving 12.0 g of 4′-(2,3-difluoro-4-(4-pentylcyclohexyl)phenyl)bi(cyclohexane)-4-ol (48). The yield based on the compound (47) was 78.3%.
Reaction SMILES: [OH:1][CH:2]1[C:6](=[O:7])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH2:3]1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.N1C=CC=CC=1>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:1][CH:2]1[C:6](=[O:7])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH2:3]1
Reactant: COC(=O)CCCCCCC1=CCC(O)C1=O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CCCCCCC1=CCC(OC2CCCCO2)C1=O
Reaction time: 1 h

Procedure:
A solution of p-toluenesulphonic acid (20 mg) in dry dichloromethane (5 ml) was added, dropwise, to a stirred mixture of methyl (±)-7-[4-hydroxy-5-oxocyclopent-1-enyl]-hepatanoate (1.2 g; prepared as described in Example 3) and 2,3-dihydropyran in dry dichloromethane (20 ml), with cooling to maintain the temperature below 30° C. After one hour, a further quantity of 2,3-dihydropyran (0.3 g) was added dropwise, and the mixture was stirred for one hour further. Pyridine (100 mg) was added, and the mixture was washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate, and evaporated in vacuo, finally at 0.1 mm Hg and 50° C. for 4 hours, to give methyl (±)-7-[4-(2-tetrahydropyranyloxy)-5-oxocyclopent-1-enyl]heptanoate (1.9 g), in the form of a brown oil, pure enough for use in the next stage without further purification.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:30]=[CH:31][C:32]=2[O:33][CH3:34])[N:10]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[C:20]([C:27]([OH:29])=[O:28])[CH:19]=2)[CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>CCOC(C)=O.O=[Pt]=O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:30]=[CH:31][C:32]=2[O:33][CH3:34])[N:10]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:35](=[O:37])[CH3:36])=[C:20]([C:27]([OH:29])=[O:28])[CH:19]=2)[CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(N(Cc2cccnc2)c2ccc([N+](=O)[O-])c(C(=O)O)c2)cc1OC1CCCC1
Reactant: CC(=O)OC(C)=O
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: COc1ccc(N(Cc2cccnc2)c2ccc(NC(C)=O)c(C(=O)O)c2)cc1OC1CCCC1
Reaction time: 16 h
Yield: 51.3 %

Procedure:
A solution of 3-cyclopentyloxy-4-methoxy-N-(3-carboxy-4-nitrophenyl)-N-(3-pyridylmethyl)aniline (200 mg, 0.43 mmol) in 35 mL of EtOAc and 0.1 mL (1.08 mmol) of acetic anhydride was hydrogenated at atmospheric pressure over 20 mg of PtO2 with stirring for 16 hours. The catalyst was removed by filtration and the solution concentrated. The residue was partitioned between 50 mL of DCM and 100 mL of brine. The organic layer was separated, dried (Na2SO4), and concentrated. The residue was chromatographed over SiO2 using MeOH/DCM (1/20) as eluant to give 105 mg (51% yield) of the target compound.