Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][C:17]([OH:19])=O)[CH2:11]2)=[O:8])=[CH:4][CH:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:23][CH2:22]1>>[CH3:20][N:21]1[CH2:22][CH2:23][CH:24]([N:27]2[CH2:32][CH2:31][N:30]([C:17](=[O:19])[CH2:16][N:12]3[CH2:13][CH2:14][CH2:15][CH:10]([NH:9][C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:8])[CH2:11]3)[CH2:29][CH2:28]2)[CH2:25][CH2:26]1
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: O=C(O)CN1CCCC(NC(=O)c2ccc(Cl)s2)C1
Product: CN1CCC(N2CCN(C(=O)CN3CCCC(NC(=O)c4ccc(Cl)s4)C3)CC2)CC1

Procedure:
Using general procedure D {3-[(5-chloro-thiophene-2-carbonyl)-amino]-piperidin-1-yl}-acetic acid (containing 2 mol equivalents of sodium chloride) was coupled with 1-(N-methyl-4-piperidyl)-piperazine to give 5-chloro-thiophene-2-carboxylic acid (1-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-piperidin-3-yl)-amide. Off-white solid. 468.5 ([M+H]+)
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]([CH2:9][C-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)[CH3:8].[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[Fe+2:20].I[CH2:22][N:23]([CH3:25])[CH3:24]>C(OCC)C>[CH3:6][N:7]([CH2:9][C-:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:22][N:23]([CH3:25])[CH3:24])[CH3:8].[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[Fe+2:20]
Reactant: CN(C)C[c-]1cccc1
Reactant: CN(C)CI
Agent: [Fe+2]
Agent: [Li]CCCC
Agent: c1cc[cH-]c1
Solvent: CCOCC
Product: CN(C)Cc1ccc[c-]1CN(C)C
Temperature: -70 °C
Reaction time: 4 h

Procedure:
n-Butyllithium (Aldrich, 2.5 molar in hexane, 24 ml, 54 mmol) is added to a solution of (dimethylaminomethyl)ferrocene (Aldrich, 13.13 g, 10.69 ml, 48.97 mmol) in diethyl ether (80 ml) under nitrogen at a temperature of 25° C. and the reaction mixture stirred for 4 hours. The resulting red solution is then cooled to approximately −70° C. in a dry ice/acetone bath and Eschenmosers salt (ICH2NMe2)(Aldrich, 10 g, 54 mmol) is added. The reaction is allowed to warm to room temperature and stirred overnight.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[C:8]([OH:16])[CH:7]=2)[CH2:3][CH2:2]1.[C:17](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.Cl>CC(=O)CC>[CH:1]1([CH2:4][O:5][C:6]2[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[C:8]([O:16][CH3:17])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OCC2CC2)cc1O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CCC(C)=O
Product: COc1cc(OCC2CC2)ccc1C(=O)O
Reaction time: 12 h

Procedure:
A 3.00 g portion of methyl 4-cyclopropylmethyloxy-2-hydroxybenzoate was dissolved in 70 ml of 2-butanone, and 2.80 g of potassium carbonate and 1.9 ml of dimethyl sulfate were added, followed by 12 hours of heating under reflux. After completion of the reaction, the solvent was evaporated, the resulting residue was suspended in chloroform, and insoluble matter was removed by celite filtration. The solvent was again evaporated, and then the thus obtained residue was dissolved in 20 ml of tetrahydrofuran, mixed with 30 ml of 2N sodium hydroxide aqueous solution and subjected to 3 hours of heating under reflux. After completion of the reaction, the reaction solution was poured into 1N hydrochloric acid aqueous solution, and the thus precipitated product of interest was collected by filtration, washed with water and then dried under a reduced pressure to give 2.74 g of 4-cyclopropylmethyloxy-2-methoxybenzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16](F)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:20]#[N:21])[CH:5]=[CH:6][CH:7]=1.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][O-:26].[Na+]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([O:26][CH2:25][CH2:24][N:23]([CH3:27])[CH3:22])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:20]#[N:21])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CC[O-]
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1cccc(Br)c1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCOc1cc2c(Nc3cccc(Br)c3)c(C#N)cnc2cn1

Procedure:
To 100 mg of 4-(3-bromo-phenylamino)-6-fluoro-[1.7]naphthyridine-3-carbonitrile under an inert atmosphere was added 3 mL of 1 M sodium (2-dimethylamino-ethoxide) in tetrahydrofuran. After refluxing for 3 hours, the reaction was diluted with water and the product extracted five times with chloroform. The crude product was purified by flash chromatography with 1% triethyl amine and 10% methanol/chloroform followed by recrystallized from chloroform/ether to give 100 mg of 4-(3-bromo-phenylamino)-6-(2-dimethylamino-ethoxy)-[1.7]naphthyridine-3-carbonitrile as a yellow solid: melting point 138-139° C.; mass spectrum (m/e): M+H 411.9, 413.9.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:12]3=[N:13][CH:14]=[C:15]([N:17]([CH3:19])[CH3:18])[N:16]=[C:11]3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:22].[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=1[N:34]=[C:35]=[O:36]>>[CH3:19][N:17]([CH3:18])[C:15]1[N:16]=[C:11]2[N:10]=[CH:9][CH:8]=[C:7]([O:6][C:5]3[CH:20]=[CH:21][C:2]([NH:1][C:35]([NH:34][C:25]4[CH:26]=[C:27]([C:30]([F:31])([F:33])[F:32])[CH:28]=[CH:29][C:24]=4[F:23])=[O:36])=[C:3]([F:22])[CH:4]=3)[C:12]2=[N:13][CH:14]=1
Reactant: CN(C)c1cnc2c(Oc3ccc(N)c(F)c3)ccnc2n1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Product: CN(C)c1cnc2c(Oc3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)ccnc2n1

Procedure:
Method F2 was used with 8-(4-amino-3-fluorophenoxy)-N,N-dimethylpyrido[3,2-b]pyrazin-3-amine and 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene to afford the title compound as a white solid. Yield: 40 mg (66%).
Reaction SMILES: CC([O-])(C)C.[K+].F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[Cl:17][CH2:18][CH2:19][CH2:20][OH:21]>CS(C)=O>[Cl:17][CH2:18][CH2:19][CH2:20][O:21][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OCCCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(OCCCCl)cc1
Reaction time: 3 h
Yield: 34.6 %

Procedure:
To a cooled (5°-10° C.) suspension of KOtBu (1.34 g, 11.96 mmol) in DMSO (5 mL) was added a solution of 4-fluoronitrobenzene (1.61 g, 11.39 mmol) and 3-chloro-1-propanol (1.13 g, 11.96 mmol) in DMSO (5 mL). The cooling bath was removed and stirring was continued for 3 hours. The mixture was diluted with water (100 mL) and extracted with ether. The combined extracts were washed with brine, dried (MgSO4), and concentrated to give a brown oil. Purification by flash chromatography (10% EtOAc/hexane) gave 850 mg (35%) of product as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:26]=[CH:25][C:24](B4OC(C)(C)C(C)(C)O4)=[CH:23][C:8]=3[N:9]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[CH2:10][C@@H:11]([CH3:12])[C:5]2=[N:4][N:3]=1.Br[C:37]1[N:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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][C:2]1[N:6]2[C:7]3[CH:26]=[CH:25][C:24]([C:37]4[N:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=4)=[CH:23][C:8]=3[N:9]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=3)[CH2:10][C@@H:11]([CH3:12])[C:5]2=[N:4][N:3]=1
Reactant: Nc1cnc(Br)cn1
Reactant: Cc1nnc2n1-c1ccc(B3OC(C)(C)C(C)(C)O3)cc1N(c1ccc(S(C)(=O)=O)cc1)C[C@H]2C
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nnc2n1-c1ccc(-c3cnc(N)cn3)cc1N(c1ccc(S(C)(=O)=O)cc1)C[C@H]2C
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 24.9 %

Procedure:
To a solution of (R)-1,4-dimethyl-6-(4-(methylsulfonyl)phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (0.34 mmol) in 1,4-dioxane and H2O (10:1, 5 mL) was added 5-bromopyrazin-2-amine (63.2 mg, 0.36 mmol), Cs2CO3 (197.3 mg, 0.61 mmol) and Tetrakis(triphenylphosphine)palladium(0) (21.9 mg, 0.03 mmol). The mixture was purged with N2 and stirred in the microwave at 130° C. for 20 min. The reaction solution was concentrated and purified by prep-TLC (elute: DCM:CH3OH=15:1) to give (R)-5-(1,4-dimethyl-6-(4-(methylsulfonyl)phenyl)-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)pyrazin-2-amine (39 mg, 28%).
Reaction SMILES: Cl[C:2]1(C(O)=O)[C:4]2([CH2:9][CH2:8][C:7]([C:25]#[N:26])([C:10]3[C:18]4[C:17]5[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=5[O:15][C:14]=4[C:13]([O:23][CH3:24])=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[O:3]1.[OH2:30]>CS(C)=O>[C:25]([C:7]1([C:10]2[C:18]3[C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:23][CH3:24])=[CH:12][CH:11]=2)[CH2:8][CH2:9][CH:4]([C:2]([OH:3])=[O:30])[CH2:5][CH2:6]1)#[N:26]
Reactant: COc1ccc(C2(C#N)CCC3(CC2)OC3(Cl)C(=O)O)c2c1oc1ccccc12
Reactant: O
Solvent: CS(C)=O
Product: COc1ccc(C2(C#N)CCC(C(=O)O)CC2)c2c1oc1ccccc12
Temperature: 100 °C

Procedure:
At room temperature, to a solution of the epoxy acid (0.380 g, 0.0009 mol) (as formed in step 2) in DMSO (8 ml)/Water (0.8 ml) sodium chloride (0.055 g, 0.000.9 mol) was charged and the reaction mass was heated to 100° C. for 7 hrs. Once the product has formed, the reaction mass was quenched with water and extracted with ethyl acetate. The organic layer was dried with sodium sulfate and concentrated under vacuum. 4-cyano-4-(4-methoxy-dibenzofuran-1-yl)-cyclohexane carboxylic acid was isolated by column chromatography. Yield 0.035 g, (10.8%)
Reaction SMILES: C(#N)C.[N:4]1[NH:5][N:6]=[N:7][C:8]=1[CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12][CH2:11]1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>C(N(CC)CC)C>[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:6]2[N:5]=[N:4][C:8]([CH2:9][C@H:10]3[CH2:15][CH2:14][C@H:13]([O:16][C:17](=[O:24])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:12][CH2:11]3)=[N:7]2)=[CH:29][CH:28]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C(O[C@H]1CC[C@H](Cc2nn[nH]n2)CC1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(Cn2nnc(C[C@H]3CC[C@H](OC(=O)c4ccccc4)CC3)n2)cc1
Temperature: 25 °C

Procedure:
To an acetonitrile (20 mL) suspension of trans-benzoic acid 4-(2H-tetrazol-5-ylmethyl)-cyclohexyl ester (1.34 g) obtained in Example (44b), triethylamine (0.68 mL) and 4-methoxybenzyl chloride (0.70 mL) were added at room temperature. The reaction mixture was heated to reflux for 2 hours, cooled to room temperature, concentrated, then diluted with ethyl acetate, and filtered. The filtrate was washed with 1 N hydrochloric acid, then dried over sodium sulfate, and then concentrated. The residue was purified by column chromatography (hexane/ethyl acetate) to obtain the title compound (610 mg, 32%) as a colorless oil.
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2>>[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])/[C:28]/2=[CH:14]\[C:11]1[NH:10][C:7]2[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:5](=[O:16])[C:6]=2[C:12]=1[CH3:13]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Product: Cc1c(/C=C2\C(=O)Nc3ccc(Cl)cc32)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Yield: 85 %

Procedure:
The title compound was prepared under the same conditions as described in step 6 of Example 5 with (S)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 5f obtained from step 5 of Example 5 and 5-chloro-1,3-dihydro-indol-2-one as starting materials to give (S,Z)-2-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 6 (87 mg, yield 85%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]12[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:14]C(=O)O[C:10]2=O>>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:10]1[C:9]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:14]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Nc1ccccc1S
Product: Nc1ccccc1-c1nc2ccccc2s1
Temperature: 140 °C
Reaction time: 2.5 h
Yield: 80.4 %

Procedure:
2-Aminothiophenol (137.7 g) was heated to 110° C., and isatoic anhydride (C8H5NO3, 203.9 g) was added portionwise over a 1 h period while taking care to avoid foaming. Thereafter the temperature was raised to 140° C., and heating was continued for about 2 to 4 h until the starting material 2-aminothiophenol was consumed. The melt was poured into an enamel cuvette and after cooling, the cold material was crushed, then boiled in aqueous NaOH solution (12 g of NaOH solved in 3.5 L of water) for 2 to 3 h. The precipitate was filtered off and the filter cake was washed with cold water until the pale blue fluorescence disappeared in the washings. The precipitate was dried at 80° C. to afford 2-(benzo[d]thiazol-2-yl)phenylamine (200 g). The product was used without further purification in the next stage of preparation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[N:36]1([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.[C:45]1([C:51]2([C:57]([OH:59])=[O:58])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[N:36]1([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:54]3[CH2:53][CH2:52][C:51]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)([C:57]([OH:59])=[O:58])[CH2:56][CH2:55]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Agent: NC(=O)N1CCCCC1
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 4-phenylpiperidine-4-carboxylic acid piperidine-amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [Cl-].[NH4+].[Br:3][C:4]1[CH:5]=[C:6]([O:13][CH3:14])[C:7]([N+:10]([O-])=O)=[N:8][CH:9]=1.[CH2:15]([OH:17])C>O.[Fe]>[Br:3][C:4]1[CH:5]=[C:6]([O:13][CH3:14])[C:7]([NH:10][CH:15]=[O:17])=[N:8][CH:9]=1
Reactant: CCO
Reactant: COc1cc(Br)cnc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: COc1cc(Br)cnc1NC=O
Temperature: 85 °C
Reaction time: 1 h

Procedure:
Iron (67.3 g) and ammonium chloride (129 g) were added to a solution of 5-bromo-3-methoxy-2-nitropyridine (56.0 g, CAS: 152684-26-9) in ethanol (500 mL) and water (200 mL). The reaction solution was stirred at 80 to 90° C. for one hour and then left to cool to room temperature. The reaction solution was filtered through celite and washed with ethanol. Then, the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate and water, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was diluted with THF (84 mL). The THF solution was added dropwise to a mixed solution of formic acid (78.1 mL) and acetic anhydride (78.3 mL) at room temperature. Then, the reaction solution was stirred for one hour. Ice water (500 mL) was added to the reaction solution, and the precipitated crystals were collected by filtration. The crystals were washed with water and then air-dried. The crystals were recrystallized from toluene to obtain 34.1 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1.[CH:34](=O)[CH3:35].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:34][CH3:35])[CH2:23][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCNCc2cccs2)CC1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1cccs1

Procedure:
4-Amino-5-chloro-2-methoxy-N-((1-(6-(2-thienylmethylamino)hexyl)-piperidin-4-yl)methyl)benzamide (0.8 g) as starting compound, acetaldehyde (0.12 ml) and sodium cyanoborohydride (0.26 g) were reacted and treated in the same manner as in Example 136 to give 0.8 g of 4-amino-5-chloro-N-((1-(6-(N-ethyl-N-(2-thienylmethyl)amino)hexyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13](O)=[O:14])[C:7](=[CH:11][CH:12]=1)[C:8](O)=[O:9])([O-:3])=[O:2].CO>O1CCCC1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][OH:9])=[C:6]([CH2:13][OH:14])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CO)c(CO)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Nitrophthalic acid (40 g, 189.5 mmol) in tetrahydrofuran (500 mL) was added dropwise over 1.5 h to a solution of borane-THF complex (1 M, 490 mL, 490 mmol), keeping the reaction temperature between 0° C. and 5° C. After the addition, the reaction was allowed to warm slowly to ambient temperature and stirred for 18 h. Methanol (100 mL) was added carefully and the precipitated solid dissolved. The mixture was concentrated in vacuo to about 500 mL, cooled to 0° C., and 10 N sodium hydroxide was added to adjust the pH to 10-11. This mixture was extracted with EtOAc (3×600 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=207 (M−OH+CH3CN).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:19]=[CH:18][C:17]2[O:16][C:15]3[C:10](=[CH:11][C:12]([C:20](=[O:24])[CH2:21][CH2:22]Cl)=[CH:13][CH:14]=3)[CH2:9][C:8]=2[CH:7]=1)=[O:5].[F:25][C:26]([F:40])([F:39])[C:27]1[CH:28]=[C:29]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1>>[F:40][C:26]([F:25])([F:39])[C:27]1[CH:28]=[C:29]([N:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][C:4]([C:6]3[CH:19]=[CH:18][C:17]4[O:16][C:15]5[C:10](=[CH:11][C:12]([C:20](=[O:24])[CH2:21][CH2:22][N:36]6[CH2:35][CH2:34][N:33]([C:29]7[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:39])([F:40])[F:25])[CH:28]=7)[CH2:38][CH2:37]6)=[CH:13][CH:14]=5)[CH2:9][C:8]=4[CH:7]=3)=[O:5])[CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: O=C(CCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCl)ccc1O2
Product: O=C(CCN1CCN(c2cccc(C(F)(F)F)c2)CC1)c1ccc2c(c1)Cc1cc(C(=O)CCN3CCN(c4cccc(C(F)(F)F)c4)CC3)ccc1O2

Procedure:
Prepared from compound 17 and 4-(3-trifluoromethyl-phenyl)-piperazine according to General Procedure C to give a solid. Mp 155-157° C. 1H NMR (CDCl3, 400 MHz) δ7.92-7.88 (m, 4H), 7.39 (t, J=8.8 Hz, 2H), 7.17-7.13 (m, 6H), 7.07 (dd, J=8.8, 2.0 Hz, 2H), 4.17 (s, 2H), 3.53-3.04 (m, 24H). Anal. (C41H40F6N4O3).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH3:26])=[C:5]([C:10]2[NH:11][C:12](=[O:25])[N:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:14]=2)[C:6]([CH3:9])=[CH:7][CH:8]=1.CN(C=O)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[O:54]1[CH2:58][CH2:57][CH2:56][C@@H:55]1[C:59](O)=[O:60]>C1COCC1>[CH3:26][C:4]1[C:5]([C:10]2[NH:11][C:12](=[O:25])[N:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=3)[N:14]=2)=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][C:59]([C@H:55]1[CH2:56][CH2:57][CH2:58][O:54]1)=[O:60]
Reactant: O=C(O)[C@H]1CCCO1
Reactant: Cc1ccc(CN)c(C)c1-c1nn(-c2ccc(C(F)(F)F)cc2)c(=O)[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(CNC(=O)[C@H]2CCCO2)c(C)c1-c1nn(-c2ccc(C(F)(F)F)cc2)c(=O)[nH]1
Reaction time: 1 h
Yield: 26.8 %

Procedure:
To a solution of 5-(3-(aminomethyl)-2,6-dimethylphenyl)-2-(4-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-66, 0.050 g, 0.138 mmol) in dry THF:DMF (4 mL:1 mL), TBTU (0.132 g, 0.414 mmol) and TEA (1.0 mL) were added and the reaction mass was stirred for 1 h under nitrogen atmosphere. To the reaction mass, (R)-(−)-tetrahydrofuran-2-carboxylic acid (0.024 g, 0.207 mmol) was added and stirred for 18 h at room temperature. After completion of the reaction, the reaction mass was quenched in water, extracted with ethyl acetate and concentrated to afford crude product which was purified by column chromatography by eluting with solution of 2% ammonia in 10% MeOH:DCM to afford 0.017 g of the title product. 1H NMR (400 MHz, DMSO d6): δ 1.79 (m, 3H), 1.87 (m, 3H), 2.20 (s, 6H), 3.74-3.79 (m, 1H), 3.88-3.92 (m, 1H), 4.25 (d, J=4.5 Hz, 2H), 7.16 (d, J=6.0 Hz, 1H), 7.25 (d, J=6.0 Hz, 1H), 7.82 (d, J=6.6 Hz, 1H), 8.17 (d, J=6.3 Hz, 2H), 8.24 (t, J=4.8 Hz, 2H), 12.30 (br s, 1H); MS (m/z): 461.14 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH:13]([NH2:16])([CH3:15])[CH3:14]>O>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH:16][CH:13]([CH3:15])[CH3:14])(=[O:11])=[O:10])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: CC(C)N
Reactant: O=S(=O)(Cl)c1cc(Br)cc(Br)c1
Solvent: O
Product: CC(C)NS(=O)(=O)c1cc(Br)cc(Br)c1
Reaction time: 2 h

Procedure:
3.0 G. of 3,5-dibromobenzenesulfonylchloride is added to a solution of 17.7 g. of isopropylamine in 25 ml. of water at room temperature. A complete solution results which is stirred for 2 hours and poured onto 250 ml. of water. The precipitate is filtered, washed with water, and dried affording 3,5-dibromo-N-isopropylbenzenesulfonamide, m.p. 105° to 107° C.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C[O:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=1>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:26][C:23]3[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][C:17]([OH:28])=[O:16])=[CH:21][C:22]=3[F:27])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COC(=O)CCc1ccc(O)c(F)c1
Reactant: ClCc1cccnc1SC1CCCC1
Product: O=C(O)CCc1ccc(OCc2cccnc2SC2CCCC2)c(F)c1
Yield: 85.6 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (0.032 g, 0.14 mmol) obtained in Step C of Preparation Example 8 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid methyl ester (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.045 g, 84%).