Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)C.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[C:15]1([C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([S:21]([C:24]3[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=3)(=[O:22])=[O:23])[C:6]=2[CH2:4][OH:3])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2ccccc2n1S(=O)(=O)c1ccc(C)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2c(CO)c(-c3ccccc3)c3ccccc32)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 85.5 %

Procedure:
To a stirred solution of 3-phenyl-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid ethyl ester (3.24 g, 7.72 mmol) in toluene (40 mL) cooled to −78° C. and under a nitrogen atmosphere was added 1.0M DIBAL-H in toluene (23.2 mL, 23.2 mmol). The reaction mixture was stirred at −78° C. for 15 min and then at −10° C. for 30 min. After re-cooling to −78° C., the reaction mixture was quenched with water (20 mL) and then allowed to warm to RT. The mixture was partitioned between EtOAc and 1.0M HCl and the aqueous phase was extracted with additional EtOAc (×3). The combined organic layers were washed with water, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 30-100% DCM in pentane) affording [3-Phenyl-1-(toluene-4-sulfonyl)-1H-indol-2-yl]methanol as a white foam (2.49 g, 85%). LCMS: RT 4.77 min [M+Na]+ 400.1.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=O)C.[ClH:19]>>[ClH:19].[Br:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]([CH:7]2[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]2)=[O:18])=[CH:16][CH:15]=1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(Br)cc2)CC1
Agent: Cl
Product: O=C(c1ccc(Br)cc1)C1CCNCC1

Procedure:
A sample of 30.9 g of 1-acetyl-4-(4-bromobenzoyl)piperidine is refluxed for 6 hours in 6N HCl, cooled, and the resulting insoluble salt is collected. The salt is recrystallized from an ethanol-ether mixture, then from isopropanol to give off-white crystals, mp 225°-227° C., 4-(4-bromobenzoyl)piperidine hydrochloride.
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([OH:6])=[O:5])[CH3:2].[CH2:11]([CH:13]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14]O)[CH3:12]>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4].O>[CH2:1]([CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([O:6][CH2:14][CH:13]([CH2:11][CH3:12])[CH2:16][CH2:17][CH2:18][CH3:19])=[O:5])[CH3:2]
Reactant: CCCCC(CC)C(=O)O
Reactant: CCCCC(CC)CO
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Product: CCCCC(CC)COC(=O)C(CC)CCCC
Reaction time: 9 h
Yield: 95.9 %

Procedure:
144 g (1 mol) of 2-ethylhexanoic acid and 143 g (1.1 mol) of 2-ethylhexanol were fed to a four-necked flask equipped with a stirrer, a thermometer and a water separator having a condenser tube, and the mixture was heated to 200° C. under reduced pressure in the presence of a tetraisopropyl titanate catalyst. Esterification reaction was carried out for about 9 hours while removing the formed water by the water separator. After the reaction, the excess 2-ethylhexanol was distilled off, and the product was neutralized with excess sodium hydroxide and then washed with water to neutrality. The product was then treated with activated carbon (0.3 wt. % relative to the starting materials fed) at 90° C., and was then filtered, giving 246 g of (2-ethylhexyl) 2-ethylhexanoate, which was then dehydrated for 5 hours at a temperature of 100° C. and a reduced pressure of 13.3 MPa. The resulting ester had a total acid number of 0.01 mgKOH/g, a water content of 11 ppm, a kinematic viscosity of 2.7 mm2/s (40° C.) and 1.1 mm2/s (100° C.), a volume resistivity of 3.0×1013 Ω·cm, and a two-layer separation temperature of −24° C.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=1)[CH2:3][OH:4]>O.[Rh]>[CH3:1][C:2]([CH3:13])([CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH:8]([CH3:12])[CH2:7]1)[CH2:3][OH:4]
Reactant: Cc1cccc(CC(C)(C)CO)c1
Agent: [Rh]
Solvent: O
Product: CC1CCCC(CC(C)(C)CO)C1
Temperature: 60 °C
Reaction time: 6 h
Yield: 81.4 %

Procedure:
5% Rh/C (450 mg, 15% w/w) was charged into a 50 mL autoclave vessel containing a mixture of 2,2-dimethyl-3-(3-methylphenyl)propan-1-ol (6 g, 34 mmol) in water (17 mL). The mixture was vigorously stirred under an hydrogen atmosphere (10 Bar) at 60° C. for 6 h. The reaction mixture was filtered and the filtrate was extracted with MTBE (25 mL), dried over magnesium sulphate and concentrated. The resulting crude product was distilled with a bulb-to-bulb distillation (2.5 mBar, 90° C.) to give 2,2-dimethyl-3-(3-methylcyclohexyl)propan-1-ol (5.1 g, gc purity>99%; yield 82%).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:63][CH:64]([CH2:67][OH:68])[CH2:65][OH:66]>C1COCC1>[CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:63][CH:64]([CH2:67][OH:68])[CH2:65][OH:66])=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: NC(CO)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NC(CO)CO)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (40 mg, 0.074 mmol) in THF (2 mL) were added HBTU (30 mg, 0.079 mmol) and serinol (35 mg, 0.37 mmol). The mixture was stirred at rt overnight. Solvent was removed by rotovap. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (40 mg, 88%). LC-MS m/z 595 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20])[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8][NH:7]1.CCN(C(C)C)C(C)C.[C:32](Cl)(=[O:35])[O:33][CH3:34]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[C:19]([F:22])([F:20])[F:21])[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8][N:7]1[C:32]([O:33][CH3:34])=[O:35]
Reactant: COC(=O)C1CCNC(Cc2ccc(C(F)(F)F)c(F)c2)C1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(C(F)(F)F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.8 %

Procedure:
To a solution of methyl 2-(3-fluoro-4-(trifluoromethyl)benzyl)piperidine-4-carboxylate (5.96 g, 18.67 mmol) in DCM (100 mL) cooled in an ice-bath was added DIPEA (4 mL, 22.96 mmol) followed by methyl carbonochloridate (1.617 mL, 20.53 mmol). After completed addition the reaction mixture was stirred at room temperature for 2 h. The solvents were evaporated and the residue partitioned between ethyl acetate and 3.8 M HCl. After phase separation the organic layer was washed with brine, then dried over MgSO4 and evaporated. Dimethyl 2-(3-fluoro-4-(trifluoromethyl)benzyl)piperidine-1,4-dicarboxylate (7.17 g, 102%) was isolated as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[N:7]=[CH:8][C:9]=1I)=[O:4].C([Mg]Cl)(C)C.CC1OCCC1.Br[C:24]1[CH:52]=[CH:51][C:27]([C:28]([N:30]([C:44]2[C:49]([CH3:50])=[CH:48][CH:47]=[CH:46][N:45]=2)[CH:31]2[CH2:36][CH2:35][CH2:34][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32]2)=[O:29])=[CH:26][CH:25]=1>C1COCC1.[Cl-].[Cl-].[Zn+2]>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[N:7]=[CH:8][C:9]=1[C:24]1[CH:52]=[CH:51][C:27]([C:28]([N:30]([C:44]2[C:49]([CH3:50])=[CH:48][CH:47]=[CH:46][N:45]=2)[C@@H:31]2[CH2:36][CH2:35][CH2:34][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:41])[CH3:42])=[O:38])[CH2:32]2)=[O:29])=[CH:26][CH:25]=1)=[O:4]
Reactant: Cc1cccnc1N(C(=O)c1ccc(Br)cc1)C1CCCN(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)c1c(I)cnn1C
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CC1CCCO1
Product: COC(=O)c1c(-c2ccc(C(=O)N(c3ncccc3C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc2)cnn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a solution of 4-iodo-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (8.1 g, 30.45 mmol) in THF (anhydrous, 60 mL) was added isopropyl magnesium chloride (16.5 mL, 16.5 mmol) at −45° C. The solution turned from clear to light green-yellowish. Stirred at this temperature for 30 min, GC-MS (sample in CD3OD) indicated all halogen-metal exchange completed. To the mixture was added 1.9 N ZnCl2 in 2-MeTHF (9.62 mL, 18.3 mmol) dropwise and the reaction was warmed to room temperature. The mixture was stirred for 2 h, over which time it turned from clear yellowish to an opaque yellowish mixture. To this reaction was added Preparation 2 tert-butyl 3-[(4-bromobenzoyl)(3-methylpyridin-2-yl)amino]piperidine-1-carboxylate (12.04 g, 25.37 mmol) as a solid in one batch. The reaction temperature was then raised to 50° C., 1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (166 mg, 0.254 mmol) was added. The reaction was then stirred at 60° C. for 2 h then cooled to room temperature. The reaction was quenched with water and extracted 3× EtOAc. The organic layer was dried and concentrated. Purification was performed by Combiflash ISCO column (220 g) 0-75% EtOAc/heptane to isolate the desired title compound (12.8 g, 78%).
Reaction SMILES: [CH2:1]=[C:2]1[C:8](=[O:9])[NH:7][C:6]2[N:10]=[CH:11][CH:12]=[CH:13][C:5]=2[CH2:4][CH2:3]1.Cl.[C:15]1([CH3:27])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CN(C)C=O>[C:15]1([CH3:27])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]1[CH2:26][CH2:25][N:24]([CH2:1][CH:2]2[C:8](=[O:9])[NH:7][C:6]3[N:10]=[CH:11][CH:12]=[CH:13][C:5]=3[CH2:4][CH2:3]2)[CH2:23][CH2:22]1
Reactant: Cc1ccccc1C1CCNCC1
Reactant: C=C1CCc2cccnc2NC1=O
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ccccc1C1CCN(CC2CCc3cccnc3NC2=O)CC1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
15 mg of the compound obtained in Production Example 5 was added to N,N-dimethylformamide (2 mL) solution of 19.7 mg of the compound obtained in Production Example 48, and stirred overnight at 90° C. Water was added to the reaction liquid, and extracted with ethyl acetate. The ethyl acetate layer was dried with anhydrous sodium sulfate, the solvent was evaporated off under reduced pressure, and the residue was separated and purified through preparative thin-layer chromatography (chloroform/methanol 4/1) to obtain 1.2 mg of the entitled compound and 16.6 mg of 7-methylene-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepin-8-one. 16.6 mg of the obtained 7-methylene-5,6,7,9-tetrahydro-8H-pyrido[2,3-b]azepin-8-one was dissolved in 2 mL of N,N-dimethylformamide, and 20 mg of 4-o-tolylpiperidine monohydrochloride was added thereto and stirred at 90° C. for 0.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified through preparative thin-layer chromatography (chloroform/methanol=4/1) to obtain 12.1 mg of the entitled compound.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([C:22]3[CH:23]=[N:24][C:25](SC)=[N:26][CH:27]=3)[N:6]=[C:5]2[C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)[CH2:3][CH2:2]1.CC([N:44](C)C)=O>O.NN>[NH2:44][C:25]1[N:26]=[CH:27][C:22]([C:7]2[N:6]=[C:5]([C:30]3[CH:31]=[CH:32][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:34][CH:35]=3)[N:4]([CH:1]3[CH2:2][CH2:3]3)[C:8]=2[C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[O:10])=[CH:23][N:24]=1
Reactant: CSc1ncc(-c2nc(-c3ccc(OC(F)(F)F)cc3)n(C3CC3)c2C(=O)N2CCC(N3CCCC3)CC2)cn1
Reactant: CC(=O)N(C)C
Agent: NN
Solvent: O
Product: Nc1ncc(-c2nc(-c3ccc(OC(F)(F)F)cc3)n(C3CC3)c2C(=O)N2CCC(N3CCCC3)CC2)cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
0.06 g (0.1 mmol) of [3-cyclopropyl-5-(2-methylsulfanyl-pyrimidin-5-yl)-2-(4-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 88) was dissolved in 1 ml of DMA and 0.5 ml of hydrazine monohydrate. The mixture was heated to 100° C. for 24 h after which time the solvent was evaporated, then it was re-dissolved in EtOH and a generous spatula of Rainey nickel was added. The mixture was stirred for 1 h after which time it was filtered over Hyflo and concentrated. Purification by flash column chromatography [CH2Cl2/MeOH 8:2] afforded 0.01 g (17%) of the title compound as a colorless amorphous solid. MS: 542.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[NH2:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH:5]([N:17]2[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)=[O:23])[CH2:18]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: COc1ccc(C2(N)CCC(=O)CC2)cc1
Product: COc1ccc(C2(N)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-amino-4-(4-methoxy-phenyl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.CN([CH:24]=[N:25][C:26](=O)[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)C>CO.C(O)(=O)C>[N:30]1[CH:31]=[CH:32][C:27]([C:26]2[N:19]([C:16]3[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=4)=[CH:18][CH:17]=3)[N:20]=[CH:24][N:25]=2)=[CH:28][CH:29]=1
Reactant: NNc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CN(C)C=NC(=O)c1ccncc1
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc2nc(COc3ccc(-n4ncnc4-c4ccncc4)cc3)ccc2c1
Yield: 21.8 %

Procedure:
Isonicatinamide (4.15 g) was heated in 35 ml of N,N-Dimethylformamide diethyl acetal at reflux for 3 h. The reaction mixture was cooled to ambient temperature and concentrated to give 5.02 g of N-Dimethylaminomethylene-isonicotinamide. To a solution of [4-(Quinolin-2-ylmethoxy)-phenyl]-hydrazine (3.16 g) in methanol (30 mL) and acetic acid (2.5 mL) was added N-Dimethylaminomethylene-isonicotinamide (1.10 g) and the reaction mixture heated at reflux for 72 h. The reaction mixture was concentrated onto silica gel and purified by flash chromatography to provided the title compound (514 mg). 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J=5.8 Hz, 2H), 8.22 (d, J=8.7 Hz, 1H), 8.10 (s, 1H), 8.07 (d, J=8.7 Hz, 1H), 7.85 (d, J=7.1 Hz, 1H), 7.76 (m, 1H), 7.66 (d, J=8.3 Hz, 1H), 7.56 (m, 1H), 7.56 (m, 1H), 7.38 (d, J=6.2 Hz, 2H), 7.26 (d, J=8.7 Hz, 2H), 7.11 (d, J=9.1 Hz, 2H), 5.42 (s, 2H); MS: (M+H m/z=380.3).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[S:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:12][C:13]([CH3:18])([CH3:17])[CH:14]([NH2:16])[CH3:15]>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:16][CH:14]([CH3:15])[C:13]([CH3:18])([CH3:17])[CH3:12])=[S:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(N=C=S)c1
Reactant: CC(N)C(C)(C)C
Solvent: C1CCOC1
Product: CC(NC(=S)Nc1cccc(C#N)c1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a solution of 3-cyanophenyl isothiocyanate (1.00 g, 6.24 mmol) in THF (25 mL) at room temperature was added (±) 3,3-dimethyl-2-aminobutane (1.08 mL, 9.36 mmol) and the reaction was stirred overnight at room temperature. The mixture was concentrated in vacuo and the resulting residue was triturated with diethyl ether and filtered to afford 1.2 g (78%) of 1-(3-cyanophenyl)-3-(1,2,2-trimethyl-propyl)-thiourea as a white solid which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[N:11]([CH2:20][C:21](O)=[O:22])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([CH2:32][NH:33][C:34]2[NH:38][C:37]3[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=3[N:35]=2)[CH2:28][CH2:27]1>>[NH:35]1[C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=[C:34]1[NH:33][CH2:32][CH:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:21](=[O:22])[CH2:20][N:11]2[CH2:10][CH2:9][CH:8]([CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:24])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]2=[O:19])[CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)CC1CCN(CC(=O)O)C(=O)c2ccccc21
Reactant: N[C@H]1CC[C@H](CNc2nc3ccccc3[nH]2)CC1
Product: CC(C)(C)OC(=O)CC1CCN(CC(=O)NC2CCC(CNc3nc4ccccc4[nH]3)CC2)C(=O)c2ccccc21

Procedure:
0.6 g (1.8 mmol) of compound 3 and 0.57 g (1.8 mmol) of compound 6 were reacted analogously to Example I and the reaction product was purified by means of preparative thick-layer chromatography (eluent: CH2Cl2/MeOH/ammonia, 45/5/0.2); 0.45 g of white amorphous powder; ESI-MS [M+H+]: 560.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH3:29])[C:16](=[O:28])[C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])C=C(F)[CH:18]=2)=[C:4]([O:30][CH3:31])[CH:3]=1.[F:32][C:33]([F:48])([F:47])[C:34]1C=C(C=C(C(F)(F)F)[N:42]=1)C(O)=O>>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH3:29])[C:16](=[O:28])[C:17]2[CH:18]=[C:34]([C:33]([F:48])([F:47])[F:32])[N:42]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=2)=[C:4]([O:30][CH3:31])[CH:3]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(C)C(=O)c1cc(F)cc(C(F)(F)F)c1
Product: COc1cc(F)c(F)cc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4,5-difluoro-2-methoxy-phenyl)-pyridin-3-yl]-methyl-amine (example 130, intermediate) and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 23 hours. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown solid (38%). MS (ESI): m/z=492.10 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][N:18]([C@@H:21]3[CH2:25][CH2:24][N:23]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)[C:22]3=[O:34])[CH2:17][CH:16]2[F:35])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO>[F:35][C@@H:16]1[C@@H:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[CH2:20][CH2:19][N:18]([CH:21]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[C:22]2=[O:34])[CH2:17]1
Reactant: Cc1ccc(CN2CC[C@@H](N3CC[C@H](c4ccc(OCc5ccccc5)cc4)C(F)C3)C2=O)cc1
Solvent: CO
Product: Cc1ccc(CN2CCC(N3CC[C@H](c4ccc(O)cc4)[C@@H](F)C3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
A mixture of 3-((3R,4R)-(4-(4-(benzyloxy)phenyl)-3-fluoropiperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (382 mg, 0.81 mmol) and methanol (4 mL) was flushed with nitrogen, followed by the addition of 172 mg of 10% Pd/C. Then the mixture was stirred at rt overnight under 25-99 psi hydrogen pressure. The reaction was then transferred to a 100 mL autoclave and stirred at 7 kg/cm2 hydrogen pressure for 4 days. The catalyst was removed by filtration through Celite and the solvent was evaporated off. The crude product was subjected to HPLC purification (method B) to yield 77.3 mg 3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)-piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (diastereomeric pair) LCMS (method Q) RT 1.15 min, m/z 383.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.C(N(CC)CC)C.[C:26](OC(=O)C)(=[O:28])[CH3:27].Cl>C(OCC)(=O)C.CN(C)C1C=CN=CC=1.[Pd]>[NH:8]([C:7]1[CH:6]=[CH:5][C:4]([C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])=[CH:3][C:2]=1[CH3:1])[C:26]([CH3:27])=[O:28]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(-c2ccccc2C#N)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(-c2ccccc2C#N)cc1C
Reaction time: 1 h
Yield: 51 %

Procedure:
2-(3-Methyl-4-nitrophenyl)benzonitrile (6.3 moles, 1.5 g) was hydrogenated in ethyl acetate (50 ml) over 5% Pd/C (0.50 g). The catalyst was filtered, and the solution concentrated to an oil. The oil was dissolved in 10 ml of methylene chloride and triethylamine (9.4 mmoles, 1.4 ml). Acetic anhydride (9.4 mmoles, 0.960 g) and 4-dimethylaminopyridine (50 mg) were added. The reaction was stirred for 1 hour and poured into 20 ml of 5N HCl. The organic phase was washed with saturated sodium bicarbonate solution, dried over sodium sulfate, and concentrated. The product was crystallized from ether and hexane to yield 1.2 g of 2-(4-acetamino-3methylphenyl)benzonitrile. (MS)
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12](=[O:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:9]=2)[CH2:4]1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Br)(=[O:30])=[O:29].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([NH:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12](=[O:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:9]=2)[CH2:4]1)(=[O:30])=[O:29]
Reactant: COC(=O)CCC(=O)c1ccc2c(c1)CC(N)C2
Reactant: COc1ccccc1S(=O)(=O)Br
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1OC)C2

Procedure:
Prepared analogously to Example 5 from methyl 4-(2-amino-indan-5-yl)-4-oxobutyrate hydrochloride and o-methoxybenzenesulphonyl bromide in chloroform in the presence of triethylamine.
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][C:6](=[S:15])[C:5]=12.[OH-].[Na+].[CH3:18]I>C(O)C>[CH3:18][S:15][C:6]1[C:5]2=[N:1][N:2]=[N:3][N:4]2[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]=1
Reactant: CI
Reactant: S=C1Nc2ccccc2Cn2nnnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSC1=Nc2ccccc2Cn2nnnc21
Yield: 89 %

Procedure:
To 30 mmol. of the product of Example 6 in 300 ml. of ethanol is added 33 ml. of 1 N sodium hydroxide followed by the slow addition of 54 mmol. of methyl iodide. After two hours the reaction mixture is evaporated to one fourth its volume, 100 ml. of water is added and the product is obtained by extraction into methylene chloride. The methylene chloride is removed by evaporation and the product is recrystallized from ethyl acetatehexane to afford an 89% yield (m.p. 105°-108° C.) of the title compound.