Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6][O:7][C:8]1[CH:33]=[CH:32][C:11]([CH2:12][NH:13][C:14]2[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]([NH:23][C:24]3[N:25]=[CH:26][C:27]([C:30]#[N:31])=[N:28][CH:29]=3)[CH:15]=2)=[CH:10][CH:9]=1>CCO>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][NH:13][C:14]2[C:19]([NH2:20])=[CH:18][N:17]=[C:16]([NH:23][C:24]3[N:25]=[CH:26][C:27]([C:30]#[N:31])=[N:28][CH:29]=3)[CH:15]=2)=[CH:32][CH:33]=1
Reactant: COc1ccc(CNc2cc(Nc3cnc(C#N)cn3)ncc2[N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(CNc2cc(Nc3cnc(C#N)cn3)ncc2N)cc1
Temperature: 70 °C
Yield: 84.7 %

Procedure:
Tin(II)chloride dihydrate (1.59 g, 7.04 mmol) was added portionwise to 5-(4-(4-methoxybenzylamino)-5-nitropyridin-2-ylamino)pyrazine-2-carbonitrile (531 mg, 1.41 mmol) in absolute EtOH (10 mL) at room temperature. The mixture was heated at 70° C. for 2 hours before being concentrated in vacuo. The residue was suspended in a mixture of ethyl acetate and saturated sodium bicarbonate solution, then filtered to remove insoluble material. The solids were then washed with EtOAc. The aqueous phase was re-extracted with ethyl acetate and the combined organic extracts were washed with brine, dried (Na2SO4) and concentrated to give crude title compound (415 mg) as a brown solid. The product was 50% pure by LCMS analysis and was used without further purification. LCMS (2) Rt=1.73 min; m/z (ESI−) 346 (M−H); (ESI+) 348 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][N:4]([CH3:9])[N:3]=1.[H-].[Na+].Cl[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21].O>O1CCCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([NH:1][C:2]2[C:6]([C:7]#[N:8])=[CH:5][N:4]([CH3:9])[N:3]=2)=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: Cn1cc(C#N)c(N)n1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(C#N)c(Nc2ccc(Cl)cc2[N+](=O)[O-])n1
Reaction time: 0.17 h

Procedure:
3-Amino-1-methylpyrazole-4-carbonitrile (Helv. Chim. Acta (1959) 42 763) (3.66 g) was stirred in dry tetrahydrofuran (40 ml). Sodium hydride (50% oil dispersion, 2.28 g) was added and the mixture was stirred for 10 minutes. 2,5-Dichloronitrobenzene (5.76 g) was added and the solution stirred under nitrogen for 20 hours. Water was added dropwise to destroy any excess sodium hydride, then the solution was poured on to a mixture of ice and dilute hydrochloric acid. After standing for 1 hour the brick-red precipitate was filtered, washed with water and dried. Crystallisation from ethanol-ethyl acetate afforded the product m.p. 205° C.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][C:36]([CH3:43])([CH3:42])[C:37]([O:39]CC)=[O:38])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:44][CH2:45][NH:46][S:47]([CH2:50][C:51]1[CH:56]=[CH:55][C:54]([Cl:57])=[C:53]([Cl:58])[CH:52]=1)(=[O:49])=[O:48])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>CO>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][C:36]([CH3:43])([CH3:42])[C:37]([OH:39])=[O:38])=[CH:31][CH:30]=2)(=[O:27])=[O:28])=[C:15]1[CH2:44][CH2:45][NH:46][S:47]([CH2:50][C:51]1[CH:56]=[CH:55][C:54]([Cl:57])=[C:53]([Cl:58])[CH:52]=1)(=[O:49])=[O:48])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(C)(C)Cc1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(Cc1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1)C(=O)O
Yield: 93.9 %

Procedure:
Ethyl 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino)-ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]-2,2-dimethylpropanoate (0.04 g, 0.05 mmol), THF (0.5 mL), MeOH (0.5 mL), and 1N NaOH (0.5 mL) were stirred together overnight. Solvents were removed and the resulting residue was taken up in water. The solution was acidified with 1N HCl and extracted with ethyl acetate. The extract was dried over sodium sulfate, and evaporated. The resulting residue was triturated with a mixture of ether and hexanes to give 0.04 g of 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)-sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]-2,2-dimethylpropanoic acid as a white solid; mp 207-208° C.; MS (ESI) m/z 849.1 (M−H); HRMS: calcd for C43H41Cl3N2O6S2, 850.1472; found (ESI+), 851.1545.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[NH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35].C[O-].[Na+]>>[OH:30][C:6]1[C:5]([C:3]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:4])=[N:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:10](=[O:23])[N:11]2[C@H:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:16]
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2[C@@H](C)c2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: C[C@@H](c1ccccc1)n1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)NCCC(=O)O)ncc21
Temperature: 25 °C
Yield: 75.8 %

Procedure:
A mixture of (S)-5-hydroxy-2-oxo-3-phenyl-1-(1-phenyl-ethyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.075 mmol), β-alanine (535 mg, 6.0 mmol) and NaOMe solution (9 mL, 4.5 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 26 mg of the title compound. MS: (+) m/z 458.36 (M+1).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([CH3:11])[CH2:9][N:8]([C:12]2[C:17]([NH2:18])=[CH:16][N:15]=[C:14]3[CH:19]([O:22]C(=O)C)[CH2:20][CH2:21][C:13]=23)[CH2:7][C@H:6]1[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=O)C.[C:34]([O:38][C:39]([NH:41][C:42]1[S:46][C:45]([C:47]2[C:52]([F:53])=[CH:51][CH:50]=[CH:49][C:48]=2[F:54])=[N:44][C:43]=1[C:55](O)=[O:56])=[O:40])([CH3:37])([CH3:36])[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.[OH-].[Na+].CO>[C:34]([O:38][C:39]([NH:41][C:42]1[S:46][C:45]([C:47]2[C:52]([F:53])=[CH:51][CH:50]=[CH:49][C:48]=2[F:54])=[N:44][C:43]=1[C:55]([NH:18][C:17]1[C:12]([N:8]2[CH2:9][C@H:10]([CH3:11])[C@@H:5]([OH:4])[C@H:6]([NH:26][C:27](=[O:28])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH2:7]2)=[C:13]2[CH2:21][CH2:20][CH:19]([OH:22])[C:14]2=[N:15][CH:16]=1)=[O:56])=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)[C@@H](OC(C)=O)[C@H](NC(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)cnc3c2CCC3O)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (3R,4R,5S)-1-[7-(acetyloxy)-3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-4-yl acetate (11.0 mg, 0.024 mmol), 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (12 mg, 0.032 mmol), HATU (33 mg, 0.09 mmol) in DMF (0.09 mL) and DIPEA (23 mg, 0.18 mmol) was stirred at room temperature for 16 h. The reaction mixture was diluted with 1 M NaOH solution (0.5 mL) and MeOH (0.5 mL). The reaction mixture was stirred at room temperature for 1 h, and was then concentrated under reduced pressure. The resulting aqueous layer was extracted with DCM three times. The combined organic layers were dried, filtered and concentrated under reduced pressure to give the crude product, which was purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a white powder. LCMS calc. for C34H43F2N6O7S (M+H)+: m/z=717.3. Found: 717.3.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1.[C:23](O)(=[O:26])[CH:24]=[CH2:25].C1(C=CC(O)=CC=1)O>C1C=CC=CC=1>[C:23]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:21][CH:22]=1)(=[O:26])[CH:24]=[CH2:25]
Reactant: O=C(O)c1ccc(OCCCCCCCCCCCO)cc1
Reactant: C=CC(=O)O
Agent: Oc1ccc(O)cc1
Solvent: c1ccccc1
Product: C=CC(=O)OCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Yield: 38.6 %

Procedure:
6.4 g of 4-(11-hydroxyundecanyloxy)benzoic acid and 5.8 g of acrylic acid were heat-refluxed in the pressure of hydroquinone in benzene for 80 hours. After distilling off the solvent, the product was purified by column chromatography to obtain 2.9 g of the objective product (yield: 38%).
Reaction SMILES: CS[C:3]([S:9][CH3:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6].[C:11]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>CCO>[C:11]([C:15]1[CH:16]=[CH:17][C:18]([NH:19][C:3](=[C:4]([C:7]#[N:8])[C:5]#[N:6])[S:9][CH3:10])=[CH:20][CH:21]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CSC(SC)=C(C#N)C#N
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: CCO
Product: CSC(Nc1ccc(C(C)(C)C)cc1)=C(C#N)C#N
Temperature: 25 °C
Yield: 53.4 %

Procedure:
A mixture of 2-(di(methylthio)methylene)malononitrile 1-7 (300 mg, 1.76 mmol) and 4-tert-butylaniline (263 mg, 1.76 mmol) in EtOH (5 mL) was refluxed for 3 days. After the reaction mixture was allowed to cool to room temperature, the resulting solid was filtered, washed with minimal EtOH, and dried to give compound 5 (255 mg, 53.5% yield, 98.9% purity) as a white powder.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]([C:19]2[CH:41]=[CH:40][C:22]([CH2:23][N:24]3[CH2:29][CH2:28][N:27](C(OCC4C=CC=CC=4)=O)[CH2:26][CH2:25]3)=[CH:21][CH:20]=2)[CH3:18])[N:11]=1)([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]([C:19]2[CH:41]=[CH:40][C:22]([CH2:23][N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:21][CH:20]=2)[CH3:18])[N:11]=1)([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(CN3CCN(C(=O)OCc4ccccc4)CC3)cc2)n1
Agent: [Pd]
Solvent: CCO
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(CN3CCNCC3)cc2)n1
Yield: 67.2 %

Procedure:
A mixture of benzyl 4-(4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzyl)piperazine-1-carboxylate (190 mg, 0.34 mmol) and 10% Pd—C(40 mg, 0.038 mmol) in ethanol (3.4 ml) is stirred under 1 atmosphere pressure of hydrogen for 3 h. The mixture is filtered and concentrated to give (S)-4-isopropyl-3-(2-(((S)-1-(4-(piperazin-1-ylmethyl)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a white solid (97 mg, 67.2% yield).
Reaction SMILES: [N:1]#[N:2].[CH3:3][CH:4]1[C:12]2[C:7](=[C:8]([N+:18]([O-:20])=[O:19])[C:9]([NH:14]C(=O)C)=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH:5]1[NH:21]C(=O)C.[ClH:25]>C(O)(=O)C>[N:1]#[N:2].[ClH:25].[CH3:3][CH:4]1[C:12]2[C:7](=[C:8]([N+:18]([O-:20])=[O:19])[C:9]([NH2:14])=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH:5]1[NH2:21]
Reactant: CC(=O)Nc1c(Br)cc2c(c1[N+](=O)[O-])CC(NC(C)=O)C2C
Agent: Cl
Agent: N#N
Solvent: CC(=O)O
Product: CC1c2cc(Br)c(N)c([N+](=O)[O-])c2CC1N
Temperature: 100 °C

Procedure:
A mixture of N2 -methyl-2,5-diacetamido-6-bromo-4-nitroindane (22.5 g, 61 mmol) in 3N HCl (150 mL) and acetic acid (50 mL) was heated at 100° C. for 24 h. The mixture was cooled in an ice bath and the orange precipitate was collected by filtration and dried (17.2 g).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl>C(OCC)(=O)C.CO.O1CCOCC1>[CH:1]1([N:5]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOC(C)=O
Product: C1CC(N2CCNCC2)C1
Temperature: 25 °C
Reaction time: 40 h
Yield: 84.7 %

Procedure:
A solution of tert-butyl 4-cyclobutylpiperazine-1-carboxylate (1.1553 g, 4.81 mmol) in ethyl acetate (10 mL) and methanol (10.00 mL) was treated with a 4M-solution hydrogen chloride in dioxane (1.669 mL, 48.07 mmol) was stirred at room temperature for 40 h under nitrogen. The reaction was incomplete so f 4M-solution hydrogen chloride in dioxane (10 mL) was added and the solution was stirred at room temperature for a further 2 h. The reaction mixture was evaporated to dryness to afford a solid. The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 3.5M NH3/MeOH and pure fractions were evaporated to dryness to afford 1-cyclobutylpiperazine (0.571 g, 85%) as a yellow oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH2:6])=[O:5])[CH3:2].Cl[CH:8]([C:14]([C:16]([F:19])([F:18])[F:17])=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10]>C(Cl)Cl>[CH2:1]([NH:3][C:4]1[O:5][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:14]([C:16]([F:17])([F:19])[F:18])[N:6]=1)[CH3:2]
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Reactant: CCNC(N)=O
Solvent: ClCCl
Product: CCNc1nc(C(F)(F)F)c(C(=O)OCC)o1
Yield: 63.4 %

Procedure:
By the procedures of Example 4, 5.3 g (60 mmol) of ethyl urea was reacted with 10.9 g (50 mmol) of ethyl 2-chloro-4,4,4-trifluoroacetoacetate at 140°-150° C. for 24 hours. The product mixture was treated with methylene chloride, washed with water, dried and concentrated. The residue was recrystallized from methylcyclohexane to yield 8.0 g of crystal product (m.p.=89°-90° C.) identified in Table I.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN(C1CCCCC1)C1CCCCC1.I[C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31](=[O:40])[N:32]([CH3:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:26][CH:25]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:1]([C:24]1[CH:25]=[CH:26][C:27]([O:30][C:31](=[O:40])[N:32]([CH3:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:28][CH:29]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: CN(C(=O)Oc1ccc(I)cc1)c1ccccc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Pd]
Agent: CN(C1CCCCC1)C1CCCCC1
Product: CN(C(=O)Oc1ccc(C=Cc2ccccc2)cc1)c1ccccc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
Styrene (1.2 mmol), N-methyldicyclohexylamine (1.2 mmol), Pd2(dba)3 (0.03 mmol), Pd(P(t-Bu)3)2 (0.06 mmol) and methyl-phenyl-carbamic acid 4-iodo-phenyl ester (1.0 mmol) were added to a Schlenk tube under nitrogen. The Schlenk tube was evacuated and refilled with nitrogen five times. Then dioxane (2 mL) was added and the reaction mixture was stirred at 70° C. for 8 h. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) giving the title compound in 17% yield as colorless crystals.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([C:6]([OH:8])=[O:7])[CH2:2]1.C(N(CC)C(C)C)(C)C.CO.[C:20]([CH:24]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:32]=[CH:33][C:34]3[S:38][C:37]([CH:39]=O)=[N:36][C:35]=3[CH:41]=2)[CH2:26][CH2:25]1)([CH3:23])([CH3:22])[CH3:21].C([BH3-])#N.[Na+]>>[C:20]([CH:24]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:32]=[CH:33][C:34]3[S:38][C:37]([CH2:39][N:1]4[CH2:5][CH2:4][C@@H:3]([C:6]([OH:8])=[O:7])[CH2:2]4)=[N:36][C:35]=3[CH:41]=2)[CH2:26][CH2:25]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C(O)[C@@H]1CCNC1
Reactant: CC(C)(C)C1CCC(Oc2ccc3sc(C=O)nc3c2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C1CCC(Oc2ccc3sc(CN4CC[C@@H](C(=O)O)C4)nc3c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(R)-Pyrrolidine-3-carboxylic acid (100 mg, 0.9 mmol) (HCl salt) was combined with N,N-Diisopropylethylamine (300 uL, 2 mmol) in Methanol (4.0 mL, 98 mmol) and stirred for 15 min. 5-(4-tert-Butyl-cyclohexyloxy)-benzothiazole-2-carbaldehyde (1.0E2 mg, 0.33 mmol) was then added and the mixture was stirred at RT for 30 minutes. After 30 minutes the reaction was cooled to 0° C. and Sodium cyanoborohydride (100 mg, 2 mmol) was added in two portions. The reaction was then allowed to warm to RT while stirring overnight. The reaction was then purified directly on the Gilson (10-90% CH3CN/H2O (0.1% TFA), 19×150 cm C18, RT=8.6 min) The product was then dried on the highvac to give the title compound as a white solid. 1H NMR (400 MHz, MeOD) Shift=8.00-7.78 (m, 1H), 7.69-7.51 (m, 1H), 7.27-7.05 (m, 1H), 5.09-4.93 (m, 3H), 4.39-4.21 (m, 1H), 4.01-3.39 (m, 4H), 2.65-2.18 (m, 3H), 2.01-1.80 (m, 2H), 1.53-1.04 (m, 6H), 0.92 (s, 9H). MS (ESI, M+1): 417.30.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[Cl:28][CH:29]1[CH2:32][CH:31]([C:33](O)=[O:34])[CH2:30]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33]([CH:31]5[CH2:32][CH:29]([Cl:28])[CH2:30]5)=[O:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: O=C(O)C1CC(Cl)C1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)C1CC(Cl)C1

Procedure:
The title compound, white solid (13 mg, 35.6%), MS (ISP) m/z=448.2 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and 3-chlorocyclobutanecarboxylic acid.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([O:22][CH3:23])=[CH:20][C:19]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH3:31])[CH:25]=3)=[C:18]([F:32])[CH:17]=2)=[C:11]([N+:33]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>[Zn]>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]([NH2:33])[C:12]([NH:15][C:16]2[C:21]([O:22][CH3:23])=[CH:20][C:19]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH3:31])[CH:25]=3)=[C:18]([F:32])[CH:17]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2ccc(Cl)c(C)c2)c(F)cc1Nc1ccc(SCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1cc(-c2ccc(Cl)c(C)c2)c(F)cc1Nc1ccc(SCc2ccccc2)cc1N
Temperature: 70 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a vial was added N-(4-(benzylthio)-2-nitrophenyl)-4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-amine (2.56 g, 5.03 mmol), acetic acid (25.9 mL, 453 mmol) and zinc powder (0.463 mL, 50.3 mmol). The cloudy maroon reaction mixture was capped and stirred for 60 min at 70° C. The reaction mixture was filtered through Celite and washed with MeOH. The residual filtrate was concentrated in vacuo, then partitioned between EtOAc (2×300 ml) and saturated aqueous NaHCO3 (350 ml). The combined organic layers were dried over Na2SO4 and concentrated. Reaction was purified using Biotage and eluted with 0-50% EtOAc/Heptane. Collected fractions and removed solvent in vaccuo, affording the title compound, 4-(benzylthio)-N-(4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)benzene-1,2-diamine (1.87 g, 3.90 mmol, 78% yield). m/z (ESI) 480.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.[CH2:19]([O:21][C:22]([CH3:31])([CH3:30])[C:23]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)=[O:24])[CH3:20]>>[CH2:19]([O:21][C:22]([CH3:30])([CH3:31])[C:23]([C:25]1[S:26][C:27]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:3]=2)=[CH:28][CH:29]=1)=[O:24])[CH3:20]
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: CCOC(C)(C)C(=O)c1cccs1
Product: CCOC(C)(C)C(=O)c1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1

Procedure:
The title compound was prepared analogous to Method C, starting from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 2-ethoxy-2-methyl-1-thiophen-2-yl-propan-1-one.
Reaction SMILES: Cl.[CH2:2]([S:4]([CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][C@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1)(=[O:6])=[O:5])[CH3:3].C(N(CC)CC)C.[CH2:31]1[O:34][C@H:32]1[CH3:33].O>CO>[CH2:2]([S:4]([CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][C@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH2:31][C@@H:32]([OH:34])[CH3:33])(=[O:6])=[O:5])[CH3:3]
Reactant: CCS(=O)(=O)CCc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Reactant: C[C@H]1CO1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: CCS(=O)(=O)CCc1ccc2[nH]cc(C[C@H]3CCCN3C[C@H](C)O)c2c1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 22.6 %

Procedure:
To a stirred solution of 5-(2-ethylsulphonylethyl)-3-(2(R)-pyrrolidinylmethyl)-1H-indole hydrochloride (Preparation 5; 200 mg, 0.56 mmol) in methanol (2 ml) at room temperature under nitrogen was added triethylamine (0.09 ml). After 10 minutes, (S)-(-)-propylene oxide (0.05 ml, 0.71 mmol) and then water (12 ml) were added and the reaction mixture was warmed at 50° C. for 18 hours. The cool reaction mixture was evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The organic phase was separated, washed with water, dried (Na2SO4) and evaporated under reduced pressure to give an oil. Purification by column chromatography on silica gel, eluting with a gradient of ethanol in dichloromethane (0 to 10% ethanol), afforded the title compound as a gum (48 mg). Rf 0.50 (SS 4). [α]D25 +58° (c=0.1, CH3OH). Found: C,57.44; H,7.58; N,6.39. C20H30N2O3S; 0.50 H2O; 0.50 CH2Cl2 requires C,57.26; H,7.50; N,6.52%. δ(CDCl3): 1.15(3H,d), 1.38(3H,t), 1.50-1.90(4H,m), 2.20-2.38(2H,m), 2.60-2.75(2H,m), 2.85-2.95(3H,m), 3.10(1H,m), 3.20-3.38(5H,m), 3.60-3.90(2H,m), 5.30(1H,s,CH2Cl2), 7.02(1H,d), 7.05(1H,s), 7.32(1H,d), 7.40(1H,s), 8.10(1H,br s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:27](=[O:29])[CH3:28])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]2[NH:18][C:17]3[CH:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:21]=[CH:22][C:16]=3[N:15]=2)[CH2:10][CH2:9]1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]([OH:29])[CH3:28])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([C:14]2[NH:18][C:17]3[CH:19]=[C:20]([C:23]([F:25])([F:26])[F:24])[CH:21]=[CH:22][C:16]=3[N:15]=2)[CH2:12][CH2:13]1
Reactant: CC(=O)c1cnc(N2CCN(c3nc4ccc(C(F)(F)F)cc4[nH]3)CC2)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cnc(N2CCN(c3nc4ccc(C(F)(F)F)cc4[nH]3)CC2)c(Cl)c1
Temperature: 0 °C

Procedure:
To a solution of 1-{5-chloro-6-[4-(6-trifluoromethyl-1H-benzoimidazol-2-yl)-piperazin-1-yl]-pyridin-3-yl}-ethanone (0.3 g, 0.71 mmol, Example 97e) in MeOH (20 mL) was added portionwise NaBH4 (0.037 g, 1.0 mmol, Aldrich) with stirring at 0° C. The reaction mixture was stirred at 0° C. for 30 min, quenched with 20 mL of satd. aq. NaHCO3, and diluted with EtOAc (50 mL). The organic phase was separated, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was recrystallized from 1:1 EtOAc/hexane mixture to give the title compound as a white foam. MS (ESI, pos. ion) m/z: 426 (M+1).