Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([NH:7][C:8]([C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])[N:6]=1.Br[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])[N:6]=1
Reactant: Brc1cccnc1
Reactant: Cc1ccc(N)c(C(=O)Nc2csc(C)n2)n1
Product: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2csc(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (2-methyl-thiazol-4-yl)-amide and 3-Bromopyridine in accordance with the general method of example 20 to yield the final compound as a yellow crystalline solid, MS (ISP): m/e=326.0 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH:11]=[C:10]([CH3:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:23]([NH:27][S:28]([C:31]1[S:32][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:35]=1)(=[O:30])=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([NH:27][S:28]([C:31]1[S:32][C:33]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([CH3:22])[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=4)[N:13]=3)[CH:3]=2)=[CH:34][CH:35]=1)(=[O:29])=[O:30])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1

Procedure:
N-tert-Butyl-5-{3-[6-(3,4-dichloro-phenyl)-4-methyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-4-(3,4-dichloro-phenyl)-6-methyl-pyrimidine (example E.62) (0.39 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.45 g, 1.3 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.39 g), which was subsequently deprotected.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[CH:11][C:12]2[NH:13][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:20]=2[CH2:21][CH2:22][C:23](O)=[O:24])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.O>CN(C)C=O>[N:38]1([C:23](=[O:24])[CH2:22][CH2:21][C:20]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[NH:13][C:12]=2[CH:11]=[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]2=[O:1])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: O=C(O)CCc1c(C=C2C(=O)Nc3ccccc32)[nH]c2c1CCCC2
Reactant: C1COCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2ccccc2C1=Cc1[nH]c2c(c1CCC(=O)N1CCOCC1)CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
3-[2-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid (10 g) was dissolved in 100 mL of dimethylformamide. Carbonyldiimidazole (6.3 g) was added and the mixture stirred at ambient temperature for 1 hour. Morpholine (5.2 g) in 30 mL of dimethylformamide was added and the stirring continued overnight. Fifty mL of water was added to the mixture and stirring was continued for 10 minutes. The precipitate was collected by vacuum filtration, washed with 20 mL of water and then 20 mL of ethanol. The solid that formed was slurry-washed with 30 mL of refluxing ethanol for 5 minutes and cooled to room temperature. The solid was collected by vacuum filtration, washed with 20 mL of ethanol and vacuum dried to give 9.6 g (80%) of 3-[3-(3-morpholin-4-yl-3-oxopropyl)-4,5,6,7-tetrahydro-1H-indol-2-ylmethylene]-1,3-dihydroindol-2-one as an orange solid.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[CH:20]=[CH:19][C:9]([CH2:10][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+].O>ClCCl>[N:5]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][P:11](=[O:18])([O:12][CH2:13][CH3:14])[O:15][CH2:16][CH3:17])=[CH:19][CH:20]=1)=[C:1]=[S:2]
Reactant: S=C(Cl)Cl
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOP(=O)(Cc1ccc(N=C=S)cc1)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thiophosgene (4.1 mL, 54 mmol) was added al at once to a mixture of diethyl 4-aminobenzylphosphonate (12.04 g, 50 mmol), sodium bicarbonate (8.33 g, 99 mmol), water (100 mL), and dichloromethane (250 mL), and the mixture was stirred at room temperature for about 2 hours. The organic and aqueous layers were separated, the organic layer dried over magnesium sulfate, filtered, and concentrated to give the product isothiocyanate as a brown oil. This was used directly in the next step.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]([CH3:13])=[C:3]1[C:14](=[O:18])[CH2:15][C:16]#[N:17].[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]([CH3:13])=[C:3]1[C:14](=[O:18])[CH:15]([C:26](=[O:27])[NH:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16]#[N:17]
Reactant: O=C=Nc1ccccc1
Reactant: CCOC(=O)c1c(C)c(C(=O)CC#N)n(C)c1C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)c(C(=O)C(C#N)C(=O)Nc2ccccc2)n(C)c1C

Procedure:
To the solution of 1.6 g of 1,3,5-trimethyl-4-ethoxycarbonyl-β-oxo-2-pyrrolpropionitrile in 30 ml of dry toluene and 0.8 g of anhydrous triethylamine, 0.8 g of phenylisocyanate are added while stirring. The mixture is allowed to stand 10 minues at the steam cone and at room temperature overnight. It is evaporated, the residue taken up in methanol and the solution treated with 2 ml of 5 N hydrochloric acid and 200 ml of water. The crystals formed are collected, washed with water, triturated with methanol-ethanol and recrystallized from methanol, to yield the 1,3,5-trimethyl-4-ethoxycarbonyl-β-oxo-α-phenylcarbamoyl-2-pyrrolpropionitrile melting at 164°-166°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[S:29]([C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][C:40]=1[F:41])[N:37](CC1C=CC=C3C=1CN(C(OC(C)(C)C)=O)CC3)[N:36]=[CH:35]2)(=[O:31])=[O:30]>C1COCC1>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:11][N:10]=[CH:9][N:8]=1)[S:29]([C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][C:40]=1[F:41])[NH:37][N:36]=[CH:35]2)(=[O:30])=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(Cn3ncc4cc(S(=O)(=O)Cl)c(F)cc43)c2C1
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3cn[nH]c3cc2F)c(OC)c1
Reaction time: 0.5 h

Procedure:
To a solution of N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (1.6 g, 6.39 mmol, 1.5 equiv) in THF (32.0 mL) at −78° C. was added LHMDS (10.65 mL, 10.65 mmol, 2.5 equiv) and the system was stirred for 30 min followed by the slow addition of 6-fluoro-1H-indazole-5-sulfonyl chloride (1-4, 1.0 g, 4.26 mmol, 1.0 equiv) in THF (10.65 mL) and stirred overnight as the system approached ambient temperature. The reaction was quenched with ammonium chloride and extracted with EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated and the residue was purified by normal phase chromatography and used directly in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8][CH2:7]1)[CH3:2].Cl[C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1.C(N(CC)CC)C>C(O)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C@H:6]1[CH2:7][CH2:8][C@H:9]([NH:12][C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:11]1)[CH3:2]
Reactant: Clc1ncccn1
Reactant: CCOC(=O)C[C@H]1CC[C@H](N)CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@H]1CC[C@H](Nc2ncccn2)CC1

Procedure:
A solution of trans-(4-Amino-cyclohexyl)-acetic acid ethyl ester (Karapavicius K., Palaima A. I., Knunyants I. L., Izv. Akad. Nauk SSSR, Ser. Khim., 1980;10;2374-9) (3.46 g, 18.7 mmol), 2-chloropyrimidine (2.14 g, 18.7 mmol) and triethylamine (5.21 mL) is refluxed in ethanol (EtOH) (10 mL) for 48 hours. The reaction is cooled, and the solvents are removed under reduced pressure. The residue is partitioned between chloroform and 2N aqueous sodium carbonate solution. The organic layer is separated, dried over sodium sulfate, and the solvents are removed under reduced pressure. The residue is chromatographed over silica gel using a mixture of chloroform and methanol to give trans-[4-(pyrimidin-2-ylamino)-cyclohexyl]-acetic acid ethyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:18][CH:19]=[CH2:20])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][C:4]=1[C:21]([F:24])([F:23])[F:22])#[N:2].[CH3:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32](Br)=[CH:31][CH:30]=1)=[O:27]>>[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:20][CH2:19][CH2:18][N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:21]([F:23])([F:22])[F:24])[CH:5]=2)[CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])=[CH:31][CH:30]=1)(=[O:27])[CH3:25]
Reactant: C=CCN(CC(=O)OC(C)(C)C)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: CC(=O)Nc1ccc(Br)cc1
Product: CC(=O)Nc1ccc(CCCN(CC(=O)OC(C)(C)C)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized according to Example 84B from 1,1-dimethylethyl N-[4-cyano-3-(trifluoromethyl)phenyl]-N-2-propen-1-ylglycinate and 4-bromoacetanilide: MS (APCI) m/z 498 ([M+Na]+), 420 ({[M+H]—C4H8}+).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[S:15][C:16]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[CH:17][N:18]=3)[CH:5]=[CH:4][C:3]1=2.[OH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=O>>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[S:15][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][OH:26])[CH2:21][CH2:20]4)=[CH:17][N:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: O=CCCCCO
Reactant: CC1(C)CCC(C)(C)c2cc(-c3ncc(C4CCNCC4)s3)ccc21
Product: CC1(C)CCC(C)(C)c2cc(-c3ncc(C4CCN(CCCCCO)CC4)s3)ccc21

Procedure:
The preparation was carried out as already described via a reductive amination starting from 70 mg (0.20 mmol) of 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-5-yl]piperidine and 40 mg (0.40 mmol) of 5-hydroxypentanal. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:4][N:3]=1.[OH-].[Na+]>CN1CCCC1=O>[C:6]1([C@H:5]([NH:4][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[N:4][N:3]=2)[CH3:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Clc1nnc(C2CCCCC2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: C[C@@H](Nc1nnc(C2CCCCC2)c2ccccc12)c1ccccc1
Temperature: 140 °C
Reaction time: 6 h
Yield: 142.1 %

Procedure:
1.1 g of 1-chloro-4-cyclohexylphthalazine and 1.6 g of D-α-phenylethylamine were dissolved in N-methylpyrrolidone, and the solution was stirred at 140° C. for 6 hours. After cooling the solution, an aqueous 5% NaOH solution was added to the solution, and the resultant solution was extracted with chloroform. The organic layer was dried, concentrated, purified by silica gel chromatography (eluent: hexane, chloroform, ethyl acetate), and recrystallized from ether to obtain 1.05 g of (R)-1-(α-phenylethylamino)-4-cyclohexylphthalazine.
Reaction SMILES: [CH2:1]([N:4]([CH2:27][CH2:28][CH3:29])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:18][NH:19][CH2:20][C:21]3[NH:22][CH:23]=[CH:24][N:25]=3)[CH:15]=2)[C:10]1=[O:26])[CH2:2][CH3:3].[CH3:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]=O.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[CH2:27]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:18][N:19]([CH2:20][C:21]3[NH:22][CH:23]=[CH:24][N:25]=3)[CH2:36][C:32]3[N:31]([CH3:30])[CH:35]=[CH:34][N:33]=3)[CH:15]=2)[C:10]1=[O:26])[CH2:28][CH3:29]
Reactant: CCCN(CCC)CCCCN1Cc2cc(CNCc3ncc[nH]3)ccc2C1=O
Reactant: Cn1ccnc1C=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCN1Cc2cc(CN(Cc3ncc[nH]3)Cc3nccn3C)ccc2C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.6 %

Procedure:
The compound (20.3 mg) obtained in Example 7-7 was dissolved in methanol (2.0 ml). The solution was added with 1-methyl-2-imidazole carboxaldehyde (6.8 mg) and sodium cyanoborohydride (6.4 mg). The solution was adjusted to pH 4 by addition of acetic acid, followed by stirring at room temperature for 6 hours. Then, the solution was added with a saturated aqueous sodium hydrogen carbonate solution to stop the reaction and then subjected to extraction with chloroform. After that, the organic layer was washed with water and a saturated saline solution and then dried with anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining a hydrochloride (24.0 mg) of the subject compound as a pale-yellow solid.
Reaction SMILES: C([Li])CCC.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=[O:13])[CH:7]=1.[CH:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:15]1([CH:14]2[C:9]3[CH:10]=[CH:11][N:6]=[CH:7][C:8]=3[CH:12]([OH:13])[O:21]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1cccnc1
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1OC(c2ccccc2)c2ccncc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
N,N,N′-trimethylethane (1.55 ml, 12 mmol) was dissolved in THF (30 mL) and cooled to −78° C. 2.5 M n-butyllithium (4.4 mL) was then added to the reaction mixture, which was then stirred for 15 min, before addition of pyridine-3-carbaldehyde (0.94 mL, 10 mmol). The reaction mixture was maintained at −78° C. for 15 min, then n-butyllithium (8 mL) was added slowly so that the temperature was always below −42° C. The reaction mixture was stirred for 1 hour at −42° C., then cooled to −78° C. Benzaldehyde (3 mL) was then added slowly into the reaction mixture, which was then stirred for 15 min. The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 1-phenyl-1,3-dihydro-furo[3,4-c]pyridin-3-ol as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: FC(F)(F)c1cccc(CCl)c1
Product: O=[N+]([O-])c1cc(OCc2cccc(C(F)(F)F)c2)ccc1Cl

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 1-chloromethyl-3-trifluoromethyl-benzene using the conditions described in Example 10C to provide 1-chloro-2-nitro-4-(3-trifluoromethyl-benzyloxy)-benzene which was treated sequentially using the procedures from Examples 10D and 10E to provide 4-[2-Amino-4-(3-trifluoromethyl-benzyloxy)-phenylsulfanyl]-phenol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([CH2:25][CH2:26][OH:27])[N:21]=1)=[CH:16][CH:15]=3.I[CH3:34]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([CH2:25][CH2:26][O:27][CH3:34])[N:21]=1)=[CH:16][CH:15]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn(CCO)n4)ccc3n(C)c21
Reactant: CI
Product: COCCn1ccc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as in Example 10 above, using 3-(2,4-dichlorophenyl)-6-[1-(2-hydroxyethyl)-1H-pyrazol-3-yl]-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one from Example 51 and iodomethane.
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[C:25]=[O:26].[NH4+].[Cl-]>C(Cl)(Cl)Cl>[C:27]1([NH:24][C:25]([N:10]2[CH2:9][CH2:8][CH:7]([CH2:6][NH:5][C@@H:13]3[CH2:15][C@H:14]3[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)=[O:26])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Reactant: O=C=Nc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccccc1)N1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To the solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (60 mg, 0.184 mmol) (Example 11b) in chloroform (2 mL) was added isocyanatobenzene (0.030 mL, 0.276 mmol) The reaction mixture was stirred at room temperature for 1 hr. The saturated solution of NH4Cl was added, and layers were separated. The organic layer was evaporated and the oil dissolved in ethanol (2 mL) and 0.5 mL of 1 M NaOH was added. The reaction mixture was stirred for 1 hour at room temperature and then it was evaporated. The oil was purified on preparative HPLC (5 to 70% AcCN: H2O gradient with 0.1% formic acid modifier). The fractions were collected. The combined fractions were neutralized with aq. NH4OH, concentrated and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and evaporated. N-phenyl-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxamide (54 mg, 0.147 mmol, 80% yield) was isolated as yellow oil. 1H NMR (400 MHz, METHANOL-d4) δ 7.32-7.38 (m, 2H), 7.20-7.31 (m, 4H), 7.10-7.17 (m, 1H), 7.05-7.10 (m, 2H), 6.98-7.05 (m, 1H), 4.20 (d, J=12.63 Hz, 2H), 2.79-3.01 (m, 2H), 2.65 (d, J=6.57 Hz, 2H), 2.28-2.45 (m, 1H), 1.95 (ddd, J=3.16, 5.94, 9.35 Hz, 1H), 1.70-1.90 (m, 3H), 1.14-1.31 (m, 2H), 1.10 (dt, J=4.86, 9.47 Hz, 1H), 1.03 (dt, 1H); LC-MS Rt=0.56 min; MS (ESI): 350.3 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[O:10][CH2:9][O:8][C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH3:2].O.[CH3:18]O>S(=O)(=O)(O)O>[CH2:1]([C:3]1[C:11]2[O:10][CH2:9][O:8][C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:12][CH2:13][C:14]([O:16][CH3:18])=[O:15])[CH3:2]
Reactant: CO
Reactant: CCc1c(CCC(=O)O)ccc2c1OCO2
Agent: O=S(=O)(O)O
Solvent: O
Product: CCc1c(CCC(=O)OC)ccc2c1OCO2

Procedure:
A solution of the product from Stage (i) (20 g) in methanol (400 ml) and concentrated sulphuric acid (40 ml) was heated on a steam bath for 20 min, cooled and poured onto a mixture of ice and water. The mixture was extracted with ether and the extracts were dried and evaporated. The residue was purified by FCC using hexane/ether (7:3) as eluent to give the title compound (19.2 g), m.p. 44°-46°.
Reaction SMILES: [CH2:1]([S:3][C:4]1[NH:5][C:6](=[O:23])[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]=1[C:9]#[N:10])[CH3:2].[H-].[Na+].[Br:26][CH2:27][CH2:28][CH2:29]Br>O1CCOCC1>[Br:26][CH2:27][CH2:28][CH2:29][N:5]1[C:6](=[O:23])[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([C:9]#[N:10])=[C:4]1[S:3][CH2:1][CH3:2]
Reactant: CCSC1=C(C#N)C(c2ccccc2)(c2ccccc2)C(=O)N1
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCSC1=C(C#N)C(c2ccccc2)(c2ccccc2)C(=O)N1CCCBr
Reaction time: 48 h
Yield: 67.8 %

Procedure:
One dissolves 15.0 g 2-ethylthio-5-oxo-4,4-diphenyl-2-pyrroline-3-carbonitrile in 500 ml abs. dioxan, adds 1.4 g sodium hydride (80%) in white oil) thereto and boils under reflux for one hour. One allows to cool somewhat, adds 100.0 g 1,3-dibromopropane thereto and further boils for 48 hours. Thereafter, the reaction mixture is filtered, the solvent and the excess dibromopropane are distilled off under water pump vacuum and the residue is triturated with diisopropyl ether. One obtains 14.0 g 1-(3-bromopropyl)-2-ethylthio-5-oxo-4,4-diphenyl-2-pyrroline-3-carbonitrile of mp 97° C.
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C([O-])([O-])=O.[K+].[K+].[CH2:21](I)[CH3:22].O>CN(C=O)C>[C:8]([NH:1][C@H:2]([C:5]([O:7][CH2:21][CH3:22])=[O:6])[CH2:3][OH:4])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
To a solution of Boc-Ser-OH (0.3 g, 1.46 mmol, 1 eq) in dry DMF (4 ml) at 0° C., dry K2CO3 (0.22 g, 1.6 mmol, 1.1 eq) was added. The resulting white suspension was stirred for 15 minute and ethyl iodide (0.68 g, 0.35 ml, 4.38 mmol, 3 eq) was dropwise added. The cooling was removed and reaction mixture was stirred at room temperature under N2 for 24 h. To the formed white emulsion H2O was added, and the mixture extracted by EtOAc. The combined organic layer was washed by H2O and then brine, and dried over MgSO4. The solvent was evaporated and the obtained oil was dried overnight in high vacuum. Yield of the pure F—0.27 g (79%).
Reaction SMILES: [CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:17]=[C:18]([CH:35](C(OCC)=O)[CH3:36])[N:19]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:20]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:42])(=[O:6])=[O:5])([CH3:3])[CH3:2].Cl.[OH-:44].[Na+]>C(O)C.O>[CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:17]=[C:18]([CH2:35][CH2:36][C:27]([O:28][CH2:29][CH3:30])=[O:44])[N:19]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:34])[CH3:33])[C:20]=3[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:42])(=[O:6])=[O:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C)c1nc(-c2ccc3nc(N)n(S(=O)(=O)C(C)C)c3c2)c(-c2ccccc2)n1COCC[Si](C)(C)C
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCc1nc(-c2ccc3nc(N)n(S(=O)(=O)C(C)C)c3c2)c(-c2ccccc2)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 16 %

Procedure:
To a solution of 1-isopropylsulfonyl-2-amino-6-(1-(trimethylsilylethoxymethyl)-2-(1-(ethoxycarbonyl)ethyl)-5-(phenyl)-imidazol-4-yl)-benzimidazole (91 mg, 0.14 mmol) in ethanol (3 mL) add HCl (37%, 3 mL) and stir at room temperature for 24 hours. Then, dilute the mixture with water (10 mL) and add a solution of NaOH (15%) until pH=6-7. Extract the mixture with EtOAc (3×30 mL) and dry (MgSO4) the combined organic layers and concentrate int vacuo. Purify the residue by HPLC to give 1-isopropylsulfonyl-2-amino-6-(1-(trimethylsilylethoxymethyl)-2-(ethoxycarbonylethyl)-5-(phenyl)-imidazol-4-yl)-benzimidazole as a white solid, 11 mg, 16% yield. FIA MS(ES+): m/z=482 (M+H)+. 1-Isopropylsulfonyl-6-(2-(2-carboxyethyl)-5-(phenyl)-imidazol-4-yl)-benzimidazole as a white solid is also obtained, 3 mg, 5% yield. MS (ES+): m/z=454 (M+H)+
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[O:5][N:4]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([O:1][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[O:5][N:4]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cc(-c2ncccn2)on1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc(-c2ncccn2)on1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-(3-hydroxymethyl-isoxazol-5-yl)-pyrimidine (14 gm) and triethylamine (22 ml) in dichloromethane (400 ml), was added methanesulfonyl chloride (7.2 ml) at 0° C. The reaction mixture was stirred at 0° C. over a period of 0.5 h. The reaction was quenched by addition of water and layers were separated. Organic layer was evaporated under vacuum to provide title compound in 19.7 gm quantity (97.7%) as a yellow solid. This was used as such for the next reaction.