Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1.[CH3:14][S:15][CH2:16][CH2:17][C:18](O)=[O:19]>ClCCl>[N:5]1([C:18](=[O:19])[CH2:17][CH2:16][S:15][CH3:14])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1
Reactant: CSCCC(=O)O
Reactant: c1ccc2[nH]nnc2c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CSCCC(=O)n1nnc2ccccc21
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
Sulfurous dichloride (4.95 g, 41.6 mmol) was added to a stirred solution of 1H-benzo[d][1,2,3]triazole (19.83 g, 166 mmol) in anhydrous dichloromethane (300 mL) at room temperature under argon. The mixture was stirred for 30 min and 3-(methylthio)propanoic acid (5.0 g, 41.6 mmol) was added in one portion and stirring was continued for 2 h. The resulting suspension was filtered off and the filtrated was washed with 2 M NaOH (3×50 mL), dried over MgSO4, and purified by column chromatography to give the title compound as clear oil (5.12 g). LCMS m/z=222.1 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 2.21 (s, 3H), 3.05 (t, J=7.07 Hz, 2H), 3.74 (t, J=7.07 Hz, 2H), 7.42-7.54 (m, 1H), 7.56-7.69 (m, 1H), 8.08 (d, J=8.34 Hz, 1H), 8.24 (d, J=8.08 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29](=[O:36])(=[O:35])[NH:30]C(C)(C)C)=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3](=[O:37])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29](=[O:36])(=[O:35])[NH2:30])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:8]([Cl:14])=[CH:9][CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)NC(=O)c1c(Cl)cccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.4 %

Procedure:
N-(2,6-Dichlorobenzoyl)-4-[2-[N-(tert-butyl)sulfamoyl]phenyl]-L-phenylalanine methyl ester (130 mg) was dissolved in TFA (2 mL), to this solution was added anisole (20 μM) and the mixture was stirred at room temperature for 6 h. TFA was removed under reduced pressure to give 100 mg of N-(2,6-dichlorobenzoyl)-4-(2-sulfamoylphenyl)-L-phenylalanine methyl ester. ESMS: m/z 507 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[C:9]2[CH:14]=[CH:13][C:12]([S:15]C(Cl)(Cl)Cl)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:20])[C:9]2[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(SC(Cl)(Cl)Cl)cc1
Solvent: CO
Product: O=C(c1ccc(S)cc1)c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 98 %

Procedure:
16.5 g said 4′-chloro-4(trichloromethyl sulfenyl)benzophenone is added in a 100 ml three-neck flask, and then 30 g methanol is added. Under nitrogen protection, the solution is heated with stirring to reflux. After reacting for 3 hours, it is analyzed to find that 4′-chloro-4(trichloromethyl sulfenyl)benzophenone is completely consumed. Distilling to remove the methanol and all low-boiling-point substances, the residue has a mass of 11.0 g, and the yield is 98%. Said residue is recrystallized in a mixed solvent consisting of dichloroethane and petroleum ether in a weight ratio 1:3 to obtain 9.5 g white flake crystal with a purity of 99.0%, and the melting point is 157-161° C. 1H-NMR data (solvent CDCl3): δ3.656 ppm, s, 1H; δ7.320, 7.348 ppm, d, 2H; δ7.443, 7.471 ppm, d, 2H; δ7.644, 7.672 ppm, d, 2H; δ7.698, 7.726 ppm, d, 2H.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]Cl.[I-].[Na+].[CH3:19][NH:20][CH3:21]>CN(C)C=O>[CH3:19][N:20]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][C:3]1[CH:12]=[C:13]([Br:16])[CH:14]=[CH:15][C:2]=1[F:1])[CH3:21]
Reactant: Fc1ccc(Br)cc1COCCCCCCl
Reactant: CNC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCCCOCc1cc(Br)ccc1F
Temperature: -78 °C
Reaction time: 8 h

Procedure:
In a sealable tube, under a nitrogen atmosphere, 5-[2-fluoro-5-bromobenzyloxy]pentyl chloride (0.380 g, 1.23 mmol) was dissolved in N,N-dimethylformamide (5 ml). To this solution sodium iodide (55 mg, 0.368 mmol) was added and the resulting mixture was cooled to −78° C. To the reaction mixture dimethylamine (precondensed in anhydrous conditions) was added and the tube was sealed. The mixture was warmed to 85° C. and stirred for eight hours. The mixture was cooled to ambient temperature and stirred for another twelve hours. The mixture was bubbled with nitrogen gas for fifteen minutes to remove excess dimethylamine. The reaction mixture was partitioned between 1 M potassium carbonate and methylene chloride. The aqueous fraction was back-extracted with methylene chloride. The organic fractions were combined, dried over sodium sulfate, and the solvents were removed in vacuo. The title intermediate was further purified by silica gel.
Reaction SMILES: C([O:8][C:9]1[C:10]2[CH2:21][C@:20]3([CH3:34])[C@@H:22]([CH3:33])[CH2:23][CH2:24][C@H:25]4[C:26]([CH3:32])([CH3:31])[C@@H:27]([OH:30])[CH2:28][CH2:29][C@@:19]34[O:18][C:11]=2[C:12]2[CH2:13][NH:14][CH2:15][C:16]=2[CH:17]=1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[OH:8][C:9]1[C:10]2[CH2:21][C@:20]3([CH3:34])[C@@H:22]([CH3:33])[CH2:23][CH2:24][C@H:25]4[C:26]([CH3:32])([CH3:31])[C@@H:27]([OH:30])[CH2:28][CH2:29][C@@:19]34[O:18][C:11]=2[C:12]2[CH2:13][NH:14][CH2:15][C:16]=2[CH:17]=1
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)CC[C@]23Oc2c4c(cc(OCc5ccccc5)c2C[C@]13C)CNC4
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)CC[C@]23Oc2c(c(O)cc4c2CNC4)C[C@]13C
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
To Compound (33a) (40 mg, 0.087 mmol) dissolved in 4.0 ml of ethanol was added 12 mg of 10% palladium-carbon, and the mixture stirred at room temperature for 2 hours under hydrogen atmosphere. After filtration for removing palladium-carbon, the reaction was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (silica gel 2.0 g; chloroform:methanol:water=9:1:0.1-7:3:0.3). The fraction containing the desired compound was concentrated under reduced pressure. The residue was dissolved in a small amount of THF. To the solution was added ether gradually, and the precipitate formed was filtered to give Compound (34a) (17 mg, 53%) as a powder.
Reaction SMILES: [O:1]([C:8]1[S:12][C:11]([CH2:13]O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:15]1[NH:16][N:17]=[N:18][C:19]=1[C:20]1[C:21]([NH2:26])=[N:22][CH:23]=[CH:24][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH-].[Na+]>O.CO.C1COCC1>[O:1]([C:8]1[S:12][C:11]([CH2:13][N:16]2[N:17]=[N:18][C:19]([C:20]3[C:21]([NH2:26])=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncccc1-c1nn[nH]n1
Reactant: OCc1ccc(Oc2ccccc2)s1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Nc1ncccc1-c1nnn(Cc2ccc(Oc3ccccc3)s2)n1
Reaction time: 0.33 h
Yield: 11.8 %

Procedure:
To a solution of THF (5 mL) and (5-phenoxy-thiophen-2-yl)-methanol (100 mg) described in Manufacturing Example 46-1, 3-(2H-tetrazol-5-yl)-pyridin-2-ylamine (79 mg) described in Manufacturing Example 5-1, and triphenylphosphine (250 mg) was added diethyl azodicarboxylate (170 mg, 40% toluene solution) at room temperature, which was stirred for 20 minutes. Water was added to the reaction solution, which was then extracted with ethyl acetate. The solvent was evaporated from the organic layer under a reduced pressure and purified by silica gel chromatography (hexane:ethyl acetate=2:1, then 1:1), after which was purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1). The solvent was evaporated under a reduced pressure from the organic layer thus obtained, methanol and 2N aqueous sodium hydroxide were added to the residue, which was stirred for 20 minutes at 80° C. Water was added to the reaction solution, which was extracted with ethyl acetate, and the organic layer was washed three times with water. The solvent was evaporated under a reduced pressure and the organic layer was purified by NH silica gel chromatography (ethyl acetate) to obtain the titled compound (20 mg).
Reaction SMILES: [NH2:1][C:2]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].[Cl:15]N1C(C)(C)C(=O)N(Cl)C1=O>C(O)(=O)C>[NH2:1][C:2]1[C:13]([F:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5]
Reactant: CON(C)C(=O)c1cccc(F)c1N
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Solvent: CC(=O)O
Product: CON(C)C(=O)c1cc(Cl)cc(F)c1N
Yield: 86.6 %

Procedure:
To a solution of 2-amino-3-fluoro-N-methoxy-N-methyl-benzamide (765 mg, 3.86 mmol) in acetic acid (18 ml) was added 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (783 mg, 2.7 mmol) at room temperature. The orange solution was stirred over night and was then poured carefully onto ice/saturated NaHCO3-solution. The mixture was extracted with EtOAc and the combined extracts were washed with brine, dried with Na2SO4 and evaporated. The remaining residue was purified by column chromatography (silica gel, heptane/EtOAc 90:10-80:20) to afford the title compound (544 mg, 61%) as light brown solid. MS (ESI): 233.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:11]=1)[O:8][C:7]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:6][C:5]2([CH3:20])[CH3:19].C(N(CC)CC)C.O1CCCC1.[CH3:33][Si:34]([C:37]#[CH:38])([CH3:36])[CH3:35]>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH2:15]([C:7]1([CH2:17][CH3:18])[CH2:6][C:5]([CH3:20])([CH3:19])[C:4]2[C:9](=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:11]=[C:2]([C:38]#[C:37][Si:34]([CH3:36])([CH3:35])[CH3:33])[CH:3]=2)[O:8]1)[CH3:16]
Reactant: CCC1(CC)CC(C)(C)c2cc(Br)cc(C(C)C)c2O1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC1(CC)CC(C)(C)c2cc(C#C[Si](C)(C)C)cc(C(C)C)c2O1
Yield: 78.1 %

Procedure:
Following General Procedure D and using 6-bromo-2,2-diethyl-8-isopropyl-4,4-dimethyl chroman (Intermediate 27, 0.89 g, 2.62 mmol), triethyl amine (5 mL), tetrahydrofuran (10 mL), copper(I)iodide (0.050 g, 0.26 mmol), trimethylsilyl acetylene (2.5 mL, 17.6 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.184 g, 0.26 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using hexane to 2% ethyl acetate in hexane as the eluent, the title compound (0.73 g, 79%) was obtained as a brown oil.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH2:5][CH:4]([CH3:9])[CH:3]1[CH:10]([OH:13])[CH2:11][CH3:12]>CC(C)=O.S(=O)(=O)(O)O.O.[O-2].[O-2].[O-2].[Cr+6]>[CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH2:5][CH:4]([CH3:9])[CH:3]1[C:10](=[O:13])[CH2:11][CH3:12]
Reactant: CCC(O)C1C(C)C=C(C)CC1C
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: CCC(=O)C1C(C)C=C(C)CC1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
1-(2,4,6-Trimethyl-cyclohex-3-enyl)-propan-1-ol (182 g, 1.0 mol) dissolved in acetone (400 mL) was added dropwise to a solution of chromium trioxide (CrO3, 108 g, 1.08 mol) in aqueous sulfuric acid (H2SO4, 400 mL, 172 g in water) at −10° C. The resulting mixture was aged for 2 hours as the mixture warmed to 0° C. The mixture was then diluted with water and extracted with toluene. The organic layer was concentrated by rotary evaporation and distilled via fractionation to provide 1-(2,4,6-trimethyl-cyclohex-3-enyl)-propan-1-one (113 g, 63% yield) as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[C:4](Cl)[N:3]=1.[I-].[Na+].[NH2:17][C:18]1[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH3:23][C:21]1[NH:20][N:19]=[C:18]([NH:17][C:4]2[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=2)[CH:22]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: CCOC(=O)Cc1cc(Cl)nc(Cl)n1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cc(Nc2cc(C)[nH]n2)nc(Cl)n1
Temperature: 25 °C
Yield: 41.4 %

Procedure:
A solution of ethyl 2-(2,6-dichloropyrimidin-4-yl)acetate (1.0 g, 4.25 mmol), sodium iodide (0.637 g, 4.25 mmol), 3-amino-5-methylpyrazole (0.413 g, 4.25 mmol), and N,N-diisopropylethylamine (0.96 ml, 5.53 mmol) was heated at 90° C. until reaction was complete (˜3 h). Reaction mixture was then cooled to room temperature, diluted with ethyl acetate (100 ml), washed with sat. sodium hydrogen carbonate solution (1×30 ml), water (3×30 ml), brine (30 ml), dried (MgSO4), filtered and evaporated in vacuo to leave an orange oil. Crude product was purified by flash chromatography (SiO2, 60-100% EtOAc/Petrol) to give title compound as a red sticky oil (0.520 g, 41%). 1H NMR (CDCl3) 1.29 (3H, t), 2.41 (3H, s), 3.52 (2H, s), 4.23 (2H, q), 5.20-4.60 (2H, very broad signal); ES+ 296.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[CH:16][C:17]=2[F:19])[N:12]=[C:11]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:10]=1[CH3:27].C(N(CC)CC)C.[C:35]1(=O)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.ClC(Cl)C.CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([BH3-])#N.[Na+]>C(Cl)Cl.O>[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[CH:16][C:17]=2[F:19])[N:12]=[C:11]([N:21]2[CH2:26][CH2:25][N:24]([CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[CH2:23][CH2:22]2)[C:10]=1[CH3:27]
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Cl
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: Cc1c(N2CCN(C3CCCCC3)CC2)nc2cc(F)cc(F)c2c1Cl
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
The 4-chloro-5,7-difluoro-3-methyl-2-(piperazin-1-yl)quinoline 2,2,2-trifluoroacetate (75 mg, 0.18 mmol), triethylamine (0.025 mL, 0.18 mmol) and cyclohexanone (0.019 mL, 0.18 mmol) were added to 3 mL of a 2:1 dichlorethane/MeOH mixture. The sodium triacetoxyborohydride (120 mg, 0.55 mmol) was added and the slurry was stirred at rt for 4.5 h. Sodium cyanoborohydride (55 mg, 0.87 mmol) was then added and the slurry was stirred at rt for 4.5 h. Another aliquot of sodium cyanoborohydride (55 mg, 0.87 mmol) was added and the reaction was heated to 80° C. and stirred overnight. The reaction was cooled and then diluted with DCM and water. The layers were separated and the aq. layer was extracted (2×75 mL) with EtOAc. The layers were combined and washed with brine (1×50 mL) and dried over magnesium sulfate. The crude product was purified by medium pressure chromatography (silica gel, 0 to 100% EtOAc:hexanes) to give 4-chloro-2-(4-cyclohexylpiperazin-1-yl)-5,7-difluoro-3-methylquinoline. Mass Spectrum (ESI) m/e=298.1 (M+1).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]1([CH2:20][NH2:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.O>C1C=CC=CC=1>[C:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([NH:21][CH2:20][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: NCC1CCCCC1
Solvent: c1ccccc1
Solvent: O
Product: c1ccc(C2CCC(NCC3CCCCC3)CC2)cc1
Temperature: 25 °C

Procedure:
A solution of 5 g of 4-phenylcyclohexanone and cyclohexylmethylamine in 100 ml of benzene was refluxed for 2 hours with removing water and the solvent was distilled away in vacuo. The residue was dissolved in methanol and to the solution was added 1.5 g of sodium borohydride. The mixture was stirred at room temperature and the solvent was distilled away in vacuo. To the residue was added water and extracted with diethyl ether. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled away to give 7 g of N-(4-phenylcyclohexyl)-N-cyclohexylmethylamine as an oil. (N-(4-phenylcyclohexyl)-N-cyclohexylmethylamine hydrochloride, melting at 267°-270° C. with decomposition)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[N:14]1([CH2:20][CH2:21][NH2:22])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:22][CH2:21][CH2:20][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCN1CCOCC1
Product: Nc1ccc(S(=O)(=O)NCCN2CCOCC2)cc1

Procedure:
Anilines with other sidechains will be readily prepared by a person having ordinary skill in the art having regard to that skill and this disclosure, and will be usable in the syntheses of Reaction Scheme 4. For example, diethyl (4-nitrobenzyl)phosphonate was reacted in a Wittig reaction with pyridin-3-carboxaldehyde and the resulting 3-(4-nitrostyryl)pyridine hydrogenated to give 4-[2-(pyridin-3-yl)ethyl]benzenamine, used to synthesize compound 99A, and the anilines used to synthesize compounds 97A and 98A were similarly prepared; 4-nitrobenzaldehyde was reacted with glyoxal and ammonia to give 2-(4-nitrophenyl)-1H-imidazole, which was N-methylated with methyl iodide and then reduced with stannous chloride to give 4-(1-methyl-1H-imidazol-2-yl)benzenamine, used to synthesize compound 106A; 2-fluoro-4-nitrobenzoic acid was converted to the corresponding benzoyl chloride with oxalyl chloride, then reacted with 3-(morpholin-4-yl)propan-1-amine and reduced to give 4-amino-2-fluoro-N-[3-(morpholin-4-yl)propyl]benzamide, used to synthesize compound 50A; and 4-nitrobenzenesulfonyl chloride was reacted with 2-(morpholin-4-yl)ethan-1-amine and then reduced with stannous chloride to give 4-amino-N[2-(morpholin-4-yl)ethyl]benzenesulfonamide, used to synthesize compound 128A.
Reaction SMILES: C([N:4]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH2:5][C:6]([O:8]CC)=[O:7])(=O)C.O[Li].O>CO.O>[CH3:25][C:24]1[O:23][N:22]=[C:21]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([S:11]([NH:4][CH2:5][C:6]([OH:8])=[O:7])(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: CCOC(=O)CN(C(C)=O)S(=O)(=O)c1ccc(-c2c(-c3ccccc3)noc2C)cc1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: Cc1onc(-c2ccccc2)c1-c1ccc(S(=O)(=O)NCC(=O)O)cc1
Reaction time: 120 h
Yield: 69.1 %

Procedure:
To a stirred solution of N-acetyl-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]glycine, ethyl ester (Step 1) (0.24 g, 0.54 mmol) in methanol was added LiOH.H2O (0.06 g, 1.36 mmol) in water. After 5 days the reaction was complete and the solvents were removed in vacuo. The resulting semi-solid was partitioned between ethyl acetate and 1N KHSO4 solution. The ethyl acetate phase was dried over MgSO4, filtered and concentrated in vacuo yielding N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]glycine (0.139 g, 69%) as a white powder: mp 242-248° C. 1H NMR (CDCl3 /300 MHz with DMSO-d6) 7.76 (d, 2H, J=8.5 Hz), 7.33-7.22 (m, 5H), 7.19 (d, 2H, J=8.5 Hz), 6.35 (t, 1H, J=5.4 Hz), 3.63 (d, 2H, J=5.4 Hz), 2.39 (s, 3H). FABLRMS m/z 373 (M+H). FABHRMS m/z 372.0786 (M+, Calc'd 372.0780). Anal. Calc'd for C18H16N2O5S: C, 58.06; H, 4.33; N, 7.52; Found C, 58.09; H, 4.44; N, 7.45.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]([N:15]([CH3:17])[CH3:16])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.C1([O:24][C:25](=O)[NH:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)C=CC=CC=1>O1CCOCC1>[CH3:16][N:15]([CH3:17])[C:6]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:25]([NH:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:24])[CH2:8][CH2:7]1
Reactant: CN(C)C1(c2ccccc2)CCC(CN)CC1
Reactant: O=C(NCCCc1ccccc1)Oc1ccccc1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)NCCCc2ccccc2)CC1
Yield: 7 %

Procedure:
The diastereoisomer mixture of (4-aminomethyl-1-phenyl-cyclohexyl)-dimethylamine (465.8 mg, 2.0 mmole) was added to a solution of (3-phenylpropyl)carbamic acid phenyl ester (510.6 mg, 2.0 mmole) in dioxane (15 ml). The batch was then refluxed for 12 h. Working up was performed by removing dioxane by distillation in a rotary evaporator and combining the residue with water (10 ml). The batch was adjusted to pH 11 with 5M NaOH and extracted with EE (3×20 ml). The combined EE extracts were washed with 1M NaOH (1×5 ml) and dried with Na2SO4. The solvent was removed by distillation under a vacuum. The residue was the diastereoisomer mixture of 1-(4-dimethylamino-4-phenyl-cyclohexylmethyl)-3-(3-phenyl-propyl)-urea, which was separated and purified by flash chromatography on silica gel (60 g). Ethanol/EE (1:1, 1100 ml) was used as eluent. The more nonpolar diastereoisomer of 1-(4-dimethylamino-4-phenyl-cyclohexylmethyl)-3-(3-phenyl-propyl)-urea (310 mg, yellow oil, 39%) and the more polar diastereoisomer of 1-(4-dimethylamino-4-phenyl-cyclohexylmethyl)-3-(3-phenyl-propyl)-urea (55 mg, m.p. 159-165° C., 32%) were isolated in this manner.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:35])[C@@H:6]([O:11][C@@H:12]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][O:33][CH3:34])[CH2:26]2)=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2].ClC1C=C(C=CC=1)C(OO)=[O:41].C([O-])(O)=O.[Na+]>ClCCl>[C:1]([CH2:3][NH:4][C:5](=[O:35])[C@@H:6]([O:11][C@@H:12]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][CH2:28][N+:27]([CH2:31][CH2:32][O:33][CH3:34])([O-:41])[CH2:26]2)=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCCN1CCCC(c2ccc([C@H](O[C@@H](CC(C)C)C(=O)NCC#N)c3ccccc3)cc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCC[N+]1([O-])CCCC(c2ccc([C@H](O[C@@H](CC(C)C)C(=O)NCC#N)c3ccccc3)cc2)C1
Reaction time: 0.08 h

Procedure:
To a solution of (2S)-N-(cyanomethyl)-2-{[(R)-{4-[1-(2-methoxyethyl)piperidin-3-yl]phenyl}(phenyl)methyl]oxy}-4-pentanamide from example 41 step 3 (390 mg, 0.81 mmol) in dichloromethane (12 mL) at 0° C. was added 77% quality 3-chloroperoxybenzoic acid (183 mg, 0.81 mmol). The mixture was stirred for 5 minutes and then 5% NaHCO3 solution (10 mL) was added with stirring. The dichloromethane layer was separated, dried (Na2SO4), filtered and concentrated. The residue was chromatographed on silica gel using 30% methanol in ethyl acetate as eluent to obtain the title compound as a foam.
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[S:8][CH:9]=1)[CH2:3][NH2:4].[C:14]([CH:18]=[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](=O)[CH3:29])=[CH:23][CH:22]=1)[CH3:20])([O:16][CH3:17])=[O:15]>>[C:14]([CH:18]=[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[S:8][CH:9]=2)[CH3:29])=[CH:23][CH:22]=1)[CH3:20])([O:16][CH3:17])=[O:15]
Reactant: COC(=O)C=C(C)c1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1csc(C(F)(F)F)n1
Product: COC(=O)C=C(C)c1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1

Procedure:
Prepared analogously to Example 13 by reaction of 2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine with 1-[4-(2-carbomethoxy-1-methylethenyl) phenyl]-propan-2-one followed by purification of the base on a silica gel column using chloroform/methanol/ methanolic ammonia =9.5/0.4/0.1 as eluant.