Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:20])([F:19])[S:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1)(=[O:7])=[O:6].Cl>O>[CH3:1][NH:2][S:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][S:5]([C:4]([F:20])([F:19])[F:3])(=[O:7])=[O:6])=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: O=S(=O)(Cl)c1ccc(NS(=O)(=O)C(F)(F)F)cc1
Reactant: CN
Agent: Cl
Solvent: O
Product: CNS(=O)(=O)c1ccc(NS(=O)(=O)C(F)(F)F)cc1
Reaction time: 8 h
Yield: 44.1 %

Procedure:
A mixture of a 40% aqueous solution of methylamine (0.7 g), 4-(trifluoromethanesulfonamido)benzenesulfonyl chloride (1.5 g) and water (20 ml) was allowed to stand overnight and made acidic with hydrochloric acid to precipitate crystals, which were then recrystallized from a mixture of water and ethanol to give 0.65 g of N-methyl-4-(trifluoromethanesulfonamido)benzenesulfonamide. M.P., 156°-157° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:32][NH:33][O:34][CH3:35]>C(#N)C.C(N(CC)CC)C>[CH3:32][N:33]([O:34][CH3:35])[C:7]([C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[CH:10]=1)=[O:8]
Reactant: CNOC
Reactant: O=C(O)c1cncc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CON(C)C(=O)c1cncc(Br)c1
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
To a suspension of 5-bromonicotinic acid (5.0 g) and N-hydroxysuccinimide (4.27 g) in acetonitrile (60 ml) was added 1-ethyl-3—(3′-dimethylaminopropyl)carbodiimide hydrochloride (7.12 g) at room temperature, and the mixture was stirred for 30 minutes. To the reaction mixture were added N,O-dimethyl-hydroxylamine hydrochloride (2.66 g) and triethylamine (10 ml), and the mixture was stirred for 64 hours and concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=2:1) to give N-methyl-N-methoxy-5-bromopyridine-3-carboxamide (3.71 g) as pale yellow oil.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]CCC)=[N+:2]=[N-:3].N([CH2:25][CH2:26]N)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7]([C:8]1[CH:9]=[CH:10][C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:26][CH:25]=1)=[O:21])=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: [N-]=[N+]=NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCCNC(=O)c1ccc(-c2ccccc2)cc1
Yield: 85.1 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, (0.283 g, 1.31 mmol) was reacted with 2-azidoethanamine (0.113 g, 1.31 mmol) and triethylamine (0.264 g, 2.61 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)biphenyl-4-carboxamide (0.297 g, 85%). 1H NMR (300 MHz, CDCl3) δ 7.88 (d, 2H), δ 7.67 (m, 4H), δ 7.44 (m, 3H), δ 6.63 (s, 1H), δ 3.67 (q, 2H), 6 (3.58 (t, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 167.8, 144.8, 140.1, 132.9, 129.2, 128.3, 127.8, 127.5, 127.4, 51.2, 39.7 ppm; HRMS (ESI) calcd for C15H14N4O (M+) 266.1168. Found 266.1162.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:3]=1[NH2:4].[C:12]([CH2:14][C:15](O)=[O:16])#[N:13].P(Cl)(Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[C:12]([CH2:14][C:15]([NH:4][C:3]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])=[O:16])#[N:13]
Reactant: N#CCC(=O)O
Reactant: Cc1cccc([N+](=O)[O-])c1N
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: Cc1cccc([N+](=O)[O-])c1NC(=O)CC#N
Temperature: 60 °C
Yield: 66.3 %

Procedure:
To a solution of 2-methyl-6-nitroaniline (25 g, 164.3 mmol) in benzene (200 ml) were added cyanoacetic acid (14.5 g, 170.46 mmol) and PCl5 (35 g, 168 mmol). The reaction mixture was heated at 60° C. for 7 h. After cooling to rt, the reaction mixture was filtered and the solid was washed with benzene and water. The solid was dried under reduced pressure to afford the title acetamide (24 g, 109 mmol) as a yellow solid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[CH:11]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C([BH3-])#N.[Na+].Cl>C(#N)C.C(O)(=O)C>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH2:1][NH:17][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: NC1CCCCC1
Reactant: COc1cccc(C=O)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1cccc(CNC2CCCCC2)c1
Reaction time: 16 h
Yield: 83.2 %

Procedure:
A solution of m-anisaldeyde (500 mg, 3.67 mmol) and cyclohexylamine (420 μL, 3.67 mmol) in acetonitrile (30 mL) was stirred for 4 h and slowly treated with sodium cyanoborohydride (227 mg, 4.4 mmol). Glacial acetic acid was added until pH˜6 (pH paper), and the solution was stirred for 16 h. Conc. HCl (0.5 mL) was added and acetonitrile was evaporated under reduced pressure. The crude residue was quenched with water (100 mL) and extracted with ethyl acetate. The aqueous phase was basified with 10% aqueous NaOH until pH>7 and extracted with dichloromethane (3×50 mL). The organic phase was dried over magnesium sulfate, filtered, and evaporated under reduced pressure without heating to provide 670 mg of N-(3-methoxybenzyl)-cyclohexylamine (83% yield) as a light oil. 1H NMR (300 MHz, acetone-d6) δ 1.05-1.30 (m, 5H), 1.58 (m, 1H), 1.72 (m, 2H), 1.89 (m, 2H), 2.45 (m, 1H), 3.77 (s, 2H), 3.79 (s, 3H), 6.77 (dd, J=2.1 and 8.2 Hz, 1H), 6.92 (d, J=7.5 Hz, 1H), 6.96 (s, 1H), 7.21 (t, J=7.8 Hz, 1H) ppm.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Li+].[OH-].Cl>CO.O>[F:31][C:28]1[CH:27]=[CH:26][C:25]([O:24][CH2:23][C:20]2[CH:19]=[CH:18][C:17]([CH2:16][O:15][C:13]([NH:12][CH:4]([CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:3]([OH:32])=[O:2])=[O:14])=[CH:22][CH:21]=2)=[CH:30][CH:29]=1
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)OCc1ccc(COc2ccc(F)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(NC(Cc1ccccc1)C(=O)O)OCc1ccc(COc2ccc(F)cc2)cc1
Reaction time: 2 h
Yield: 66.5 %

Procedure:
2-[4-(4-Fluoro-phenoxymethyl)benzyloxycarbonyl]amino-3-phenyl-propionic acid methyl ester 38 (115 mg) was dissolved in 10 ml methanol, then treated with 1.1 equiv LiOH in water. After 2 hrs at 60° C., the mixture was poured into water, acidified with HCl, and extracted The organic phase was dried, evaporated and recrystallized to yield about 74 mg of 2-[4-(4-fluorophenoxymethyl) benzyloxycarbonyl]amino-3-phenyl-propionic acid 40, mp. 111.8-113.4° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O.C(OCC)(=O)C>[CH2:16]([N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC1(C)NC(=O)N(Cc2ccccc2)C1=O
Temperature: 25 °C
Yield: 91.3 %

Procedure:
To the stirred solution of 5,5-dimethylhydantoin (7 g, 54.7 mmole) in dry acetone (150 mL) under nitrogen were added potassium carbonate (10.6 g, 76.8 mmole) and benzylbromide (11.2 g, 65.9 mmole) at room temperature. The reaction mixture was refluxed for 20 hr. The reaction mixture was cooled to room temperature and the solid was filtered off by suction filtration. The titrate was concentrated on a rotary evaporator to give a residue. The residue was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate and evaporated to give 10.9 g (yield=91.3 %) of 3-benzyl-5,5-dimethylhydantoin as a white solid, mp=101°-104° C. This intermediate was subjected to the next step without further purification.
Reaction SMILES: [CH:1]1([CH2:4]Br)[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:8]=[CH:9][C:10](=[O:13])[NH:11][N:12]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10](=[O:13])[N:11]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:12]=1
Reactant: BrCC1CC1
Reactant: O=c1ccc(Cl)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccc(Cl)nn1CC1CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Cyclopropylmethyl bromide (0.82 mL) was added to a mixture of 6-chloro-2H-pyridazin-3-one (1.0 g) and K2CO3 (2.10 g) in dimethylformamide (10 mL). The resulting mixture was stirred at 60° C. overnight. Then, water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine and dried (MgSO4). After removal of the solvent, the residue was purified by chromatography on silica gel (CH2Cl2/MeOH/NH4OH 99:1:0.1) to afford the title compound as an oil.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([OH:9])=[O:8])[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[N:21]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[C@@H:23](O)[CH2:22]2.O.N1(O)C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[S:1]1[CH:5]=[C:4]([CH:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([O:9][C@@H:23]2[CH:24]3[CH2:27][CH2:28][N:21]([CH2:26][CH2:25]3)[CH2:22]2)=[O:8])[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(Nc1ccccc1)c1csc2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 44.1 %

Procedure:
2-(Benzo[b]thiophen-3-yl)-2-(phenylamino)acetic acid (I18) (295 mg, 1.04 mmol), (R)-quinuclidin-3-ol (159 mg, 1.25 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (191 mg, 1.25 mmol), and DCC (258 mg, 1.25 mmol) were dissolved in dry THF and stirred at room temperature for 15 hours. The solvent was evaporated, and the crude product was dissolved in EtOAc and washed with NaHCO3, water and brine. The organic phase was dried with Na2SO4, filtered and evaporated under vacuum. The crude product was purified by flash chromatography (DCM/MeOH=9/1) to obtain (R)-quinuclidin-3-yl 2-(benzo[b]thiophen-3-yl)-2-(phenylamino)acetate (180 mg, 44% yield).
Reaction SMILES: [OH:1][CH:2]1[O:6][C:5](=[O:7])[CH:4]=[CH:3]1.[C:8]1([CH:15]=[CH:14][C:12](O)=[CH:11]C=1)O.C1CC=CC=1>C(Cl)(Cl)Cl>[OH:7][CH:5]1[CH:4]2[C:3](=[C:11]3[CH2:12][CH:14]2[CH2:15][CH2:8]3)[C:2](=[O:1])[O:6]1
Reactant: Oc1ccc(O)cc1
Reactant: O=C1C=CC(O)O1
Agent: C1=CCC=C1
Solvent: ClC(Cl)Cl
Product: O=C1OC(O)C2C1=C1CCC2C1
Temperature: 20 °C
Yield: 61756.5 %

Procedure:
A mixture of 30 g of 5-hydroxy-2(5H)-furanone, 150 ml of chloroform, 50 mg of hydroquinone and 35 ml of freshly distilled cyclopentadiene was stirred at 20° C. under an inert atmosphere and stirred for 17 hours at 20°-45° C. The mixture was evaporated to dryness under reduced pressure and the residue was crystallized from an isopropyl ether-petroleum ether mixture to obtain 46.6 g of 3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1-one melting at ≃103° C.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8](S(C)(=O)=O)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][C@H:22]([OH:26])[CH2:21]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[C:1]([NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][C@H:22]([OH:26])[CH2:21]2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N[C@@H]1CCC[C@H](O)C1
Reactant: CC(C)(C)Nc1nc(S(C)(=O)=O)ncc1C(N)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)Nc1nc(N[C@@H]2CCC[C@H](O)C2)ncc1C(N)=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a mixture of 4-(tert-butylamino)-2-(methylsulfonyl)pyrimidine-5-carboxamide (250 mg, 0.918 mmol; synthesis described herein) and (1S,3R)-3-aminocyclohexanol (138 mg, 1.2 mmol; prepared as described in Tetrahedron: Asymmetry 15:2051-2056 (2004)) in NMP (10 mL) was added DIEA (374 mg, 2.9 mmol). The resulting mixture was stirred at 100° C. overnight. The reaction mixture was purified by preparative HPLC to give the desired product (212.2 mg, 0.69 mmol, yield 75%). 1H NMR (400 MHz, CDCl3) δ ppm 8.86 (brs, 1H), 8.12 (s, 1H), 5.53 (brs, 3H), 3.93-3.91 (m, 1H), 3.88-3.82 (m, 1H), 2.27-2.25 (m, 1H), 1.92-1.85 (m, 3H), 1.47 (s, 9H), 1.42-1.25 (m, 4H); MS (ESI) m/z=308.2 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[CH:18][CH:19]([CH3:21])[CH3:20])[C:15]([OH:17])=O)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:22][C@@H:23]1[C:52](=[O:53])[N:25]2[C:26]([C:36]([O:38][CH:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])=[C:27]([CH2:30][O:31][C:32](=[O:35])[NH:33][CH3:34])[CH2:28][S:29][C@H:24]12.CN1CCOCC1.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[CH:18][CH:19]([CH3:21])[CH3:20])[C:15]([NH:22][C@@H:23]2[C:52](=[O:53])[N:25]3[C:26]([C:36]([O:38][CH:39]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)=[O:37])=[C:27]([CH2:30][O:31][C:32](=[O:35])[NH:33][CH3:34])[CH2:28][S:29][C@H:24]23)=[O:17])[N:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C=C(C(=O)O)c1csc(NC(=O)OC(C)(C)C)n1
Reactant: CNC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CNC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(=CC(C)C)c3csc(NC(=O)OC(C)(C)C)n3)[C@H]2SC1
Reaction time: 2 h
Yield: 60.8 %

Procedure:
To a mixture of 2-(2-tert-butoxycarbonylaminothiazol-4-yl)-4-methyl-2-pentenoic acid (1.56 g), diphenylmethyl 7β-amino-3-methylcarbamoyloxymethyl-3-cephem-4-carboxylate (2.27 g), and N-methylmorpholine (2.0 ml) in dichloromethane (50 ml) is added diphenylphosphoryl chloride (1.27 g) at -30° C. After 2 hours, the reaction mixture is neutralized with 10% citric acid, washed, dried, and purified by chromatography give diphenylmethyl 7β-[2-(2-tert-butoxycarbonylaminothiazol-4-yl)-4-methyl-2-pentenoylamino]-3-methylcarbamoyloxymethyl-3-cephem-4-carboxylate (2.27 g). Yield: 73%.
Reaction SMILES: O.Cl.[NH2:3][C:4]([CH3:9])([CH3:8])[C:5](=[O:7])[CH3:6].C1COCC1.[OH-].[Na+].[CH2:17]([O:24][C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:17]([O:24][C:25]([NH:3][C:4]([CH3:9])([CH3:8])[C:5](=[O:7])[CH3:6])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)C(C)(C)N
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)C(C)(C)NC(=O)OCc1ccccc1

Procedure:
3-Amino-3-methyl-2-butanone hydrochloride hydrate [J. Org. Chem. 49, 1209 (1984)] (10.6 g., 0.076 mol was dissolved in 700 ml. 1:1 THF:H2O and the pH adjusted to 6.8 with dilute NaOH. Benzylchloroformate (11.93 ml., 0.084 ml.) was added dropwise, maintaining pH 6.8-7.0 by the simultaneous dropwise addition of dilute NaOH. The pH was so maintained until it stabilized. The reaction mixture was extracted 4×100 ml. CHCl3. The organic extracts were combined, filtered and stripped to yield title product as an oil, 9.26.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH2:3][CH2:2]1.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[NH:23][C:24](=[O:27])[CH2:25]Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[C:9]([C:8]1[C:7]([CH:4]2[CH2:3][CH2:2][N:1]([CH2:25][C:24]([NH:23][C:17]3[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:16]=3[CH3:15])=[O:27])[CH2:6][CH2:5]2)=[N:14][CH:13]=[CH:12][CH:11]=1)#[N:10]
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: N#Cc1cccnc1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(C)c1NC(=O)CN1CCC(c2ncccc2C#N)CC1
Yield: 20.1 %

Procedure:
The product from Example 58D (trifluoroacetic acid salt, 30 mg, 0.1 mmol), N-(2,6-dimethylphenyl)-2-chloroacetamide (23 mg, 0.15 mmol, Aldrich) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure. The residue was purified by preparative HPLC to provide 7 mg (28%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ 1.82 (m, 2H), 2.05 (m, 2H), 2.12 (s, 6H), 2.35 (m, 2H), 3.05 (m, 3H), 3.15 (s, 2H), 7.05 (m, 3H), 7.45 (dd, J=6 Hz, 1H), 8.25 (d, J=6 Hz, 1H), 8.79 (dd, J=6 Hz, 1H), 9.21 (s, 1H); MS (ESI/APCI+) m/e 349 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([N:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[CH:28]=3)[N:17]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([N:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[CH:28]=3)[N:17]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NCc3cccc(N4CCCCC4)c3)ncc2[N+](=O)[O-])CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@H](CNc2nc(NCc3cccc(N4CCCCC4)c3)ncc2[N+](=O)[O-])CC1
Reaction time: 1 h
Yield: 90.3 %

Procedure:
(4-{[5-Nitro-2-(3-piperidin-1-yl-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamic acid tert-butyl ester (176 mg, 0.33 mmol) was dissolved in CH2Cl2 (6 mL). To this solution was added TFA (3 mL) and the reaction was stirred for 1 h. The volatiles were removed and the crude was re-dissolved in 90:9:1 (CH2Cl2:CH3OH:NH4OH), then concentrated again to afford a solid. The resultant solid was purified via flash chromatography (SiO2, 10-75% CH2Cl2-(90:9:1-CH2Cl2:CH3OH:NH4OH)) to afford 131 mg (91%) of the target compound , m/z 440.72 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:4]([CH3:16])=[N:3]1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](Cl)[N:19]=1>>[CH3:1][N:2]1[C:6]([O:7][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[N:19]=2)=[C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:4]([CH3:16])=[N:3]1
Reactant: Clc1cccc(Cl)n1
Reactant: Cc1nn(C)c(O)c1Sc1ccccc1Cl
Product: Cc1nn(C)c(Oc2cccc(Cl)n2)c1Sc1ccccc1Cl
Yield: 27.3 %

Procedure:
A mixture of 1.1 g (4 mmol) of 1,3-dimethyl-4-(2-chlorophenylthio)-5-hydroxypyrazole and 5.0 g (34 mmol) of 2,6-dichloropyridine was refluxed with heating for 20 hours. After completing the reaction, the reaction mixture was purified by means of silica gel column chromatography (developing solution: ethyl acetate-hexane (2:1 v/v)) to give 0.40 g of 1,3-dimethyl-4-(2-chlorophenylthio)-5-(6-chloropyridine-2-yloxy)pyrazole.
Reaction SMILES: C(OCC)C.C([Mg]Br)C.[C:10]1([S:16]([N:19]2[C:27]3[C:22](=[CH:23][C:24]([F:29])=[CH:25][C:26]=3[F:28])[C:21](I)=[CH:20]2)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:31]([N:38]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH:39]([CH3:42])[CH:40]=[O:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[CH2:43]([N:38]([CH:39]([CH3:42])[CH:40]([C:21]1[C:22]2[C:27](=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)[N:19]([S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])[CH:20]=1)[OH:41])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2cc(F)cc(F)c21
Reactant: CC(C=O)N(Cc1ccccc1)Cc1ccccc1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C(O)c1cn(S(=O)(=O)c2ccccc2)c2c(F)cc(F)cc12)N(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 76.8 %

Procedure:
A 3.0 M diethyl ether solution of ethylmagnesium bromide (7.3 ml, 21.8 mmol) is added under N2 at 0° C. to a 95 ml tetrahydrofuran solution of N-benzenesulfonyl-3-iodo-5,7-difluoro-indole (8.4 g, 20 mmol). The resulting mixture is stirred for 20 minutes at 0° C., allowed to warm to room temperature over 20 minutes, then recooled to 0° C. A 20 ml tetrahydrofuran solution of (S) N,N dibenzyl-2-aminopropanal (Syn. Lett., 1997,2, 223–224, 5.1 g, 22 mmol) is added to the reaction mixture and the resulting mixture is stirred 1 hour as it warmed to room temp. The reaction is quenched with aqueous NH4Cl, extracted with ethyl acetate, washed with brine, dried (Na2SO4), filtered, concentrated, and the residue is purified by flash chromatography (SiO2, ethyl acetate/hexane gradient) to yield 8.4 g of 2-(N,N-dibenzylamino)-1-(1-benzenesulfonyl-5,7-difluoro-1H-indol-3-yl)-propan-1-ol. (77%)
Reaction SMILES: COC1C=CC(C)=CC=1C(N[C@H]1CCC[C@@H]1NC1C=NC(C(F)(F)F)=CN=1)=O.Cl.[F:30][C:31]([F:46])([F:45])[C:32]1[N:33]=[CH:34][C:35]([NH:38][C@H:39]2[CH2:43][CH2:42][CH2:41][C@@H:40]2[NH2:44])=[N:36][CH:37]=1.[Cl:47][C:48]1[CH:49]=[CH:50][C:51]([N:57]2[CH:61]=[CH:60][CH:59]=[N:58]2)=[C:52]([CH:56]=1)[C:53](O)=[O:54]>>[Cl:47][C:48]1[CH:49]=[CH:50][C:51]([N:57]2[CH:61]=[CH:60][CH:59]=[N:58]2)=[C:52]([CH:56]=1)[C:53]([NH:44][C@H:40]1[CH2:41][CH2:42][CH2:43][C@@H:39]1[NH:38][C:35]1[CH:34]=[N:33][C:32]([C:31]([F:30])([F:45])[F:46])=[CH:37][N:36]=1)=[O:54]
Reactant: O=C(O)c1cc(Cl)ccc1-n1cccn1
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: COc1ccc(C)cc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1cc(Cl)ccc1-n1cccn1

Procedure:
Prepared according to the procedure for 2-methoxy-5-methyl-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 37) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 75 mg, 0.27 mmol) and 5-chloro-2-(1H-pyrazol-1-yl)benzoic acid (CAS number 1214622-57-7; 120 mg, 0.54 mmol) except this was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[F:29][C:30]([F:44])([F:43])[C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:34]Br>O1CCCC1>[F:29][C:30]([F:44])([F:43])[C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:34][N:8]([CH3:9])[C:6](=[O:7])[C:5]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:11][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CNC(=O)c1cnc(Cl)cc1-c1ccccc1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cc(Cl)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
To a solution of 10.0 g (38.4 mmol) 6-chloro-N-methyl-4-o-tolyl-nicotinamide in 190 ml tetrahydrofuran 46 ml of a 1 M solution (46 mmol) of potassium hexamethyldisilazide in tetrahydrofuran were added at 0° C. After 30 min, 8.5 ml (46 mmol) 3,5-bis(trifluoromethyl)benzyl bromide were added dropwise to the resulting suspension. After completed addition the ice-water cooling bath was removed and the reaction mixture was allowed to warm to room temperature. After 2 h the reaction was quenched with water. The mixture was adjusted to pH 3 with 1 M aqueous hydrochloric acid solution and stirred for 10 min. Basification with 1 M aqueous sodium hydroxide solution to pH 8 was followed by concentration to remove tetrahydrofuran. The aqueous residue was extracted with four portions of dichloromethane. The combined organic extracts were dried with sodium sulfate and concentrated to give 21.4 g of crude product. Column chromatography afforded 18.4 g (98.5%) of the title compound as a white solid.