Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:8][CH:9]([CH:11]=[CH:12][CH:13]1[C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15][C:14]1([CH3:21])[CH3:20])[CH3:10])(OC(C)(C)C)=O.O.[OH-].[K+].F[C:26](F)(F)C(O)=O>>[NH2:8][C:9]([CH3:10])([CH:11]=[CH:12][CH:13]1[C:14]([CH3:20])([CH3:21])[CH2:15][CH2:16][C:17]1([CH3:18])[CH3:19])[CH3:26]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C=CC1C(C)(C)CCC1(C)C)NC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)(N)C=CC1C(C)(C)CCC1(C)C
Reaction time: 8 h

Procedure:
N-Boc-2-amino-4-(2,2,5,5-tetramethyl-1-cyclopentyl)-3-butene is dissolved in trifluoroacetic acid and the solution is stirred overnight. Water is added and the mixture is made basic with 20% KOH. The mixture is extracted with ether and the organic layer is dried over Na2SO4 and evaporated to yield 2-amino-2-methyl-4-(2,2,5,5-tetramethyl-1-cyclopentyl)butene.
Reaction SMILES: CS[C:3]([S:8][CH3:9])=[CH:4][N+:5]([O-:7])=[O:6].[NH2:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]([C:20]2[S:21][CH:22]=[CH:23][C:24]=2[NH:25][CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=[CH:29][CH:28]=2)=[O:19])[CH:14]=[CH:15][CH:16]=1>CO>[CH3:9][S:8][C:3]([NH:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]([C:20]2[S:21][CH:22]=[CH:23][C:24]=2[NH:25][CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=[CH:29][CH:28]=2)=[O:19])[CH:14]=[CH:15][CH:16]=1)=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: Nc1cccc(NC(=O)c2sccc2NCc2ccnc3ccccc23)c1
Solvent: CO
Product: CSC(=C[N+](=O)[O-])Nc1cccc(NC(=O)c2sccc2NCc2ccnc3ccccc23)c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a solution of 1,1-bis(methylthio)-2-nitroethylene (1.4 g, 8.33 mmol) in MeOH (75 mL) was added N-(3-Aminophenyl)-3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide (2.1 g, 8.33 mmol) and the mixture was stirred at 85° C. overnight. The reaction mixture was cooled to rt and the yellow precipitate formed was filtered, washed with MeOH, and dried under vacuum to give N-(3-{[1-(methylthio)-2-nitrovinyl]amino}phenyl)-3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide as yellow solid. MS (ES): m/z 492.02 (100) [MH+]; 1H NMR (DMSO-d6, 400 MHz): δ 2.47 (s, 2H), 3.17 (d, J=5.6 Hz, 1H), 5.10 (d, J=5.2 Hz, 2H), 6.78 (s, 1H), 6.81 (d, J=5.2 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 7.35-7.43 (m, 2H), 7.63 (d, J=5.2 Hz, 1H), 7.65-7.72 (m, 2H), 7.77-7.85 (m, 3H), 8.05-8.15 (m, 2H), 8.24 (dd, J=8.0, 7.2 Hz, 1H), 8.42 (d, J=4.0 Hz, 1H), 9.56 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11].[CH:13](OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:1][O:2][C:3]([C:4]1[C:5]2[N:11]=[CH:13][NH:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:12]
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)c1cccc(N)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)c1cccc2[nH]cnc12
Temperature: 90 °C

Procedure:
Ester 2 (1.7 g, 10.2 mmol), triethyl orthoformate (2.5 mL) and p-toluenesulfonic acid (10 mg) were mixed in “Performance Fluid” (3M Co., 40 mL) and refluxed with reversed Dean-Stark trap at 90° C. for 3 h. The reaction mixture was cooled to room temperature and the solid formed was filtered, washed with hexanes and dried to give 1.65 g (92%) of pure 3: 1H NMR (DMSO-d6) δ 12.59 (br.s, 1H), 8.32 (s, 1H), 7.97 (d, 1H, J=8.0 Hz), 7.86 (d, 1H, J=6.5 Hz) 7.32 (t1, 1H, J=8.0 Hz), 3.95 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[I:15]Cl.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[I:15][C:7]1[C:8]([CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:9][C:4]2[O:3][CH2:2][O:1][C:5]=2[CH:6]=1
Reactant: CC(=O)NCc1ccc2c(c1)OCO2
Reactant: ClI
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NCc1cc2c(cc1I)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
N-(benzo[d][1,3]dioxol-5-ylmethyl)acetamide (9.24 g, 47.9 mmol) was added to 1.0 M solution of iodine monochloride in methylene chloride (80 mL). The mixture was stirred at room temperature for 2 hours, and then the mixture was poured into 10% Na2S2O3 and stirred until the red color faded. It was then extracted with CH2Cl2 and the organic layer was washed with water and brine, dried and concentrated to get the crude product which was purified by column chromatography (mobile phase: petroleum/methylene chloride=1/19) to give N-((6-iodobenzo[d][1,3]dioxol-5-yl)methyl)acetamide compound as a white solid (5.82 g, 38%). LC-MS: 320 [M+1]+. 1H-NMR (DMSO-d6): δ 1.89 (s, 3H), 4.11 (d, 2H, J=6.0 Hz), 6.04 (s, 2H), 7.07 (s, 1H), 7.37 (s, 1H), 8.28 (t, 1H, J=6.0 Hz).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:16][C:17](=[O:29])[CH2:18][N:19]1[C:23](=[O:24])[C:22]([CH3:26])([CH3:25])[N:21]([CH3:27])[C:20]1=[O:28].O>CN(C)C=O>[CH2:1]([S:8][CH2:16][C:17](=[O:29])[CH2:18][N:19]1[C:23](=[O:24])[C:22]([CH3:25])([CH3:26])[N:21]([CH3:27])[C:20]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1C(=O)N(CC(=O)CBr)C(=O)C1(C)C
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)N(CC(=O)CSCc2ccccc2)C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.1 %

Procedure:
Benzyl mercaptan (256 μl, 2.2 mmol) was stirred with cesium carbonate (712 mg, 2.2 mmol) in dimethyl formamide (5 ml) at room temperature for 1 hour. 3-(3-bromo-2-oxopropyl)-1,5,5-trimethylimidazolidine-2,4-dione (552 mg, 1.99 mmol) prepared as in WO99/06361 was added and the mixture stirred 18 hours at room temperature. The reaction mixture was treated with water, extracted into ethyl acetate (3×25 ml), the organic phases combined, brine washed and dried. The product was purified by silica chromatography, eluting with 50% ethyl acetate/iso-hexane to give 300 mg product.
Reaction SMILES: [NH2:1][CH:2]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[OH:4].[C:29]1([CH2:35][CH2:36][C:37](Cl)=[O:38])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[OH:4][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:10]=1)[CH:2]([NH:1][C:37](=[O:38])[CH2:36][CH2:35][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-phenoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (400 mg, 1.03 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (230 ml, 1.55 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (416 mg, 78%).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C:52]1[CH:57]=[C:56]([O:58][CH3:59])[CH:55]=[CH:54][C:53]=1[C:60]1[CH:65]=[CH:64][CH:63]=[C:62]([NH2:66])[CH:61]=1>CN(C=O)C>[CH3:50][O:51][C:52]1[CH:57]=[C:56]([O:58][CH3:59])[CH:55]=[CH:54][C:53]=1[C:60]1[CH:65]=[CH:64][CH:63]=[C:62]([NH:66][C:23]([C:18]2[C:19](=[O:22])[O:20][C:21]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH3:10])=[O:25])[CH:61]=1
Reactant: COc1ccc(-c2cccc(N)c2)c(OC)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC)c4oc3=O)c2)c(OC)c1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.072 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′,4′-dimethoxy-biphenyl-3-ylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.024 g of product in 86% yield: LCMS (ESI) m/z 432 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:25]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])(=[O:27])[NH2:26]>>[CH3:24][C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([S:25]([NH2:26])(=[O:28])=[O:27])[CH:34]=3)[CH:7]=[CH:6][CH:5]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)c2)n1
Reactant: NS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.21) (0.200 g, 0.51 mmol) and 3-sulfamoyl-benzeneboronic acid (example F.2) (0.102 g, 0.51 mmol) according to the general procedure VI. Obtained as a white solid (0.120 g, 50%). MS (ISP) 467.1 [(M+H)+]; mp 196° C.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([N:25]=[C:26]=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:26](=[O:27])[NH:25][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCN=C=O
Reactant: Oc1ccc2c(c1)CCCN2Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCNC(=O)Oc1ccc2c(c1)CCCN2Cc1ccccc1
Reaction time: 48 h

Procedure:
Mixture of 1-benzyl-1,2,3,4-tetrahydro-quinolin-6-ol (0.239 g., 1 mmol), hexyl isocyanate (0.174 ml, 1.2 mmol) and triethylamine (1 ml) in dry chloroform (10 ml) was heated with stirring for 48 hours. The reaction mixture was cooled, washed with water (2×5 ml), dried over sodium sulphate and concentrated under vaccum. The residue so obtained was chromatographed with 20:80 chloroform:hexane as eluant to give 2 h; yield. 0.25 g. (68.3%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C(Cl)(Cl)Cl.Cl.Cl.[NH2:13][C:14]1[CH:25]=[CH:24][C:17]([CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C>[CH2:20]([N:19]([CH2:18][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:2](=[O:3])[O:4][CH2:5][CH3:6])=[CH:25][CH:24]=1)[CH2:22][CH3:23])[CH3:21]
Reactant: CCOC(=O)Cl
Reactant: CCN(CC)Cc1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1ccc(CN(CC)CC)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
At 0° C., ethyl chloroformate (455 μL) was added to a chloroform solution (13 mL) of N-(4-aminobenzyl)-N,N-diethylamine dihydrochloride (1.0 g) obtained in Reference Example 2-1-(2) and triethylamine (2.2 mL), and stirred at 0° C. for 1.5 hours and then at room temperature for 2 hours. Aqueous sodium hydrogencarbonate solution was added to the reaction liquid to stop the reaction, and this was extracted with chloroform. The organic layer was washed with water and saturated saline water, and then dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (chloroform/methanol=9/1) to obtain ethyl N-{4-[(diethylamino)methyl]phenyl}carbamate (530 mg) as an orange oily substance.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[CH3:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([CH:33]=1)[C:30](O)=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:30](=[O:31])[C:29]3[CH:33]=[C:25]([CH3:24])[CH:26]=[N:27][CH:28]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: Cc1cncc(C(=O)O)c1
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NC(=O)c3cncc(C)c3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (0.10 g) with 5-methyl nicotinic acid (0.13 g) under the agency of HATU (0.18 g) and N,N-diisopropylethylamine (0.28 ml) in dichloromethane (2 ml) was performed according to the method described in example 11.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:16]([Mg]Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[NH4+]>C(OCC)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([OH:7])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][CH:15]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: Nc1ccc(C(O)(Cc2ccccc2)c2ccccc2)cc1
Reaction time: 18 h

Procedure:
Combine 4-aminobenzophenone (50 g, 0.25 mol) and diethyl ether (500 mL). Slowly, add benzylmagnesium chloride (1 L of a 1M solution in diethyl ether over 1.5 hours. After 18 hours, pour the reaction onto ice and an aqueous solution of ammonium chloride. Separate the layers, extract the organic layer with water, dry over MgSO4, filter, and evaporate in vacuo to give a residue. Recrystallize from isopropanol to give 1-(4-aminophenyl)-1,2-diphenyl-ethanol: mp; 105°-107° C.
Reaction SMILES: CS([Cl:5])(=O)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:31])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][CH:24]=3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:31])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][Cl:5])=[CH:25][CH:24]=3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: O=C(CCc1ccc(CO)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCc1ccc(CCl)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.43 mL (5.6 mmol) of methanesulfonic acid chloride is slowly added dropwise at ambient temperature to a solution of 2 g (5.47 mmol) of N-(4′-chlorobiphenyl-4-yl)-3-(4-hydroxymethylphenyl)propionamide and 1.56 mL (11.2 mmol) of triethylamine in 50 mL of dichloromethane and the reaction mixture is stirred for 24 hours at ambient temperature. It is extracted with water and the organic phase is dried over sodium sulfate. The solvent is distilled off and the residue is stirred with diisopropyl ether and suction filtered. Yield: 1.45 g (69% of theory); C22H19Cl2NO (M=384.3); calc.: molecular ion peak (M+H)+: 384/86/88 (Cl2) Found: molecular ion peak (M+H)+: 384/86/88 (Cl2); Rf value: 0.45 (silica gel, dichloromethane/ethanol (50:1)).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[NH2:9].[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11]>C1COCC1>[CH3:1][N:2]1[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[NH:9][C:10]1=[O:11]
Reactant: CNc1cnccc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cn1c(=O)[nH]c2ccncc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
To a solution of 2.80 g (22.7 mmol) of N3-methylpyridine-3,4-diamine in 125 mL of THF was added 4.42 g (27.3 mmol) of 1,1′-carbonyldiimidazole and the reaction was stirred overnight at room temperature. The reaction slurry was concentrated in vacuo to a volume of about 65 mL and cooled in a −10° C. bath, filtered, and the solids washed with 25 mL of THF. The solids were dried under high vacuum to give 2.35 g (69%) of the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH:12]=O)[C:6]=2[CH:5]=[CH:4]1)[CH3:2].[CH3:14][NH2:15].[BH4-].[Na+].O>CO>[CH2:1]([N:3]1[C:11]2[C:6](=[C:7]([CH2:12][NH:15][CH3:14])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)[CH3:2]
Reactant: CCn1ccc2c(C=O)cccc21
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCn1ccc2c(CNC)cccc21
Reaction time: 3 h
Yield: 90.8 %

Procedure:
1-Ethyl-1H-indole-4-carbaldehyde (2.40 mg, 13.8 mmol) was dissolved in anhydrous methanol (62 mL). Methylamine (6.00 mL of 33% solution in ethanol, 48.2 mmol) was added and the reaction was stirred for 3 h. The solution was concentrated to a greenish brown oil and then dissolved in anhydrous methanol (62 mL). Sodium borohydride (539 mg, 14.3 mmol) was added and the mixture was stirred overnight at room temperature. Water (90 mL) was added and the solution was concentrated. Sodium hydroxide (15 mL, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×50 mL). Combined organic layers were dried over Na2SO4, filtered and concentrated to afford the title compound ((1-ethyl-1H-indol-4-yl)-N-methylmethanamine) (2.36 g, 91%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 7.33-7.30 (m, 2H), 7.10-6.97 (m, 2H), 6.52 (d, J=3.0 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 3.88 (s, 2H), 2.30 (s, 3H), 1.33 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH3:16])[CH2:15][CH2:14][C:9]2(OCC[O:10]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C1COCC1.Cl.CCOC(C)=O>[CH3:16][C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8][C:9](=[O:10])[CH2:14][CH2:15]1
Reactant: CCOC(=O)C1(C)CCC2(CC1)OCCO2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8-Methyl-1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester (Compound 282G) was dissolved in THF (20 mL) and 3N aq. HCl (30 mL). The resulting mixture was stirred at rt overnight. The mixture was diluted with EtOAc (50 mL), washed with brine (20 mL), and dried over anhydrous sodium sulfate. 1H NMR (CDCl3): 1.28 (t, J=7.1 Hz, 3H), 1.29 (s, 3H), 1.63-1.70 (m, 2H), 2.30-2.74 (m, 6H), 3.94 (s, 4H), 4.19 (q, J=7.1 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH2:28]([C@@H:30]1[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[NH:31]1)[CH3:29]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:31]4[C@H:30]([CH2:28][CH3:29])[CH2:34][CH2:33][S:32]4(=[O:36])=[O:35])=[CH:3][C:4]=3[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: CC[C@@H]1CCS(=O)(=O)N1
Product: CC[C@@H]1CCS(=O)(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)c(S(C)(=O)=O)c1
Yield: 25.4 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (664 mg) described in Preparation Example 112 and (R)-3-ethylisothiazolidine 1,1-dioxide (238 mg) described in Preparation Example 3 and by the reaction and treatment in the same manner as in Example 1, the title compound (194 mg) was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(O)(=O)C>[C:17]([N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH2:5][CH2:6]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: CC(=O)O
Product: CC(=O)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-piperidin-4-yl-1,3-dihydro-benzimidazol-2-one (0.2 g, 0.9 mmol) and acetic anhydride (0.2 ml, 2 mmol) was dissolved in acetic acid (5 ml) and stirred at room temperature for 30 minutes, then added water (10 ml) and evaporated to and oil. This was crystallized from ethanol (96%). Yield 0.18 g (0.7 mmol, 77 %). M.p. 212-214° C.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].CS([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[O:23])[CH2:17][CH2:16]1)(=O)=O>>[F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][S:5]([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=2)=[O:23])[CH2:17][CH2:16]1)(=[O:7])=[O:6]
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Reactant: CS(=O)(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)NC1CCN(S(=O)(=O)CCC(F)(F)F)CC1
Yield: 51 %

Procedure:
3,3,3-Trifluoropropylsulfonyl chloride (96 mg, 0.487 mmol) was reacted with PTU (70 mg, 0.244 mmol) as the same manner as the synthesis of 1-(1-(methylsulfonyl)piperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea yielding the final product (55 mg, 0.123 mmol, 51% yield). 1H NMR (d6-DMSO, 300 Mhz): δ 8.78 (s, 1H), 7.57 (s, 4H), 6.38 (d, J=7.5 Hz, 1H), 4.19 (d, J=Hz, 1H), 3.82 (d, J=Hz, 1H), 3.73 (m, 1H), 3.18 (t, J=12.4 Hz, 1H), 2.82 (m, 1H), 2.78 (t, J=Hz, 1H), 1.80 (t, J=9.6, 2H), 1.43 (m, 2H), 0.97 (s, 6H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][CH:20]=[C:19]3[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:34]C(OC(Cl)=O)C.Cl.C(OCC)C>ClCCCl>[ClH:34].[C:28]1([S:25]([C:19]2[C:18]3[C:22](=[CH:23][CH:24]=[C:16]([CH2:15][CH2:14][N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:17]=3)[NH:21][CH:20]=2)(=[O:26])=[O:27])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: O=S(=O)(c1ccccc1)c1c[nH]c2ccc(CCN3CCN(Cc4ccccc4)CC3)cc12
Agent: Cl
Solvent: ClCCCl
Solvent: CCOCC
Product: O=S(=O)(c1ccccc1)c1c[nH]c2ccc(CCN3CCNCC3)cc12

Procedure:
A stirred mixture of 5-[2-(4-benzylpiperazin-1-yl)ethyl]-3-(phenylsulfonyl)-1H-indole (0.110 g, 0.24 mmol) and 1-chloroethylchloroformate (0.05 mL, 0.36 mmlole) in 1,2-dichloroethane (2 mL) was heated to reflux for 12 hours. The reaction mixture was cooled and concentrated in vacuo to a brown glass. The glass was taken up in methanol (4 mL) and heated to reflux for 6 h, then cooled and concentrated in vacuo to a semi solid. This solid was dissolved in diethyl ether and treated with 1 N HCl in diethyl ether (0.22 mL, 0.22 mmol) to afford a white precipitate isolated by vacuum filtration. Mp: 220° C. MS (ES+): 370 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:11][C:12]([F:26])([F:25])[C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[CH2:16]Br>>[F:11][C:12]([F:25])([F:26])[C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:20]=1)[CH2:16][O:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: N#Cc1ccc(O)cc1F
Product: N#Cc1ccc(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1F
Yield: 99 %

Procedure:
As described for example 1a, 2-fluoro-4-hydroxy-benzonitrile (1.5 g, 10.5 mmol) [using 3,5-bis(trifluoromethyl)benzylbromide instead of 3-fluorobenzylbromide] was converted to the title compound (3.8 g, 99%) which was obtained as a white solid. MS: m/e=363.0 (M+).