Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:26]1([CH2:32][CH2:33][C:34](Cl)=[O:35])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:34](=[O:35])[CH2:33][CH2:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:10][CH:9]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: NC(Cc1ccc(Oc2ccccc2)cc1)C(O)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(Oc2ccccc2)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(phenyloxy)phenyl)-1-propanol (550 mg, 1.63 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (360 ml, 2.45 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 purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1) and recrystallized from ethyl acetate-hexane to give the title compound (152 mg, 20%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][C:5]([Br:10])=[CH:4][N:3]=1.[C:11](OCC)(=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].N1CCCCC1>CCO>[CH2:16]([O:15][C:13]([C:12]1[C:11](=[O:18])[NH:1][C:2]2[C:7]([CH:8]=1)=[CH:6][C:5]([Br:10])=[CH:4][N:3]=2)=[O:14])[CH3:17]
Reactant: Nc1ncc(Br)cc1C=O
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1cc2cc(Br)cnc2[nH]c1=O
Temperature: 25 °C
Yield: 57.1 %

Procedure:
A mixture of 2-amino-5-bromo-pyridine-3-carbaldehyde (4.00 g, 14.2 mmol), diethyl malonate (21.6 mL, 142 mmol) and piperidine (7.00 mL, 71.0 mmol) in EtOH (70 mL) was heated to reflux overnight. The mixture was cooled to room temperature and the solid was collected by filtration to give the title compound (2.41 g, 57%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 12.65 (s, 1H), 8.70 (d, J=2.4 Hz, 1H), 8.56 (d, J=2.4 Hz, 1H), 8.45 (s, 1H), 4.29 (q, J=7.1 Hz, 2H), 1.30 (t, J=7.1 Hz, 3H).
Reaction SMILES: C(N(CC)CC)C.ClC(OCC)=O.[C:14]([CH2:17][N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH:20]([NH:28][C:29]([C:31]2[NH:35][C:34]3[S:36][C:37]([Cl:39])=[CH:38][C:33]=3[CH:32]=2)=[O:30])[C:19]1=[O:40])(O)=[O:15].[Li+].[BH4-]>C1COCC1>[Cl:39][C:37]1[S:36][C:34]2[NH:35][C:31]([C:29]([NH:28][CH:20]3[CH2:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:18]([CH2:17][CH2:14][OH:15])[C:19]3=[O:40])=[O:30])=[CH:32][C:33]=2[CH:38]=1
Reactant: O=C(O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1Cc2ccccc2N(CCO)C1=O)c1cc2cc(Cl)sc2[nH]1
Reaction time: 1 h
Yield: 87.7 %

Procedure:
Triethylamine (0.76 mL, 5.47 mmol) then ethyl chloroformate (0.52 mL, 5.47 mmol) were added to N-[1-(carboxymethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 2; 2.0 g, 4.97 mmol) in anhydrous THF (40 mL) at 0° C. followed by stirring for 1 h. LiBH4 (2.0 M in THF, 3.1 mL, 6.21 mmol) was added slowly and the mixture stirred for a further 30 min. The reaction was carefully quenched with 1M HCl (200 mL) and EtOAc (400 mL) and the organic layer was further washed with sat. aqueous NaHCO3 (100 mL), brine (100 mL), dried (MgSO4), filtered and evaporated. The residue was triturated with refluxing Et2O (30 mL) and after cooling the solid was filtered and dried to afford the title compound (1.70 g, 88%) as a white solid.
Reaction SMILES: [CH2:1]([CH:11]([CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:12]([OH:22])[CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl.[CH3:34][N:35]([CH3:42])[CH2:36][CH2:37][CH2:38][C:39](O)=[O:40].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:34][N:35]([CH3:42])[CH2:36][CH2:37][CH2:38][C:39]([O:22][CH:12]([CH:11]([CH2:1][CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:40]
Reactant: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)C(O)CC/C=C\CCCCC
Reactant: CN(C)CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)C(CC/C=C\CCCCC)OC(=O)CCCN(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To a solution of (6Z,15Z)-11-((Z)-dec-4-enyl)henicosa-6,15-dien-10-ol 17 (0.5 g, 1.1 mmol), 4-(dimethylamino)butanoic acid hydrochloride (0.3 g, 1.7 mmol), EDCI hydrochloride (0.3 g, 1.7 mmol), DIPEA (0.4 g, 3.4 mmol) in anhydrous dichloromethane (10 mL) was added DMAP (5 mg). The solution was stirred at room temperature overnight under a nitrogen atmosphere. The mixture is concentrated in vacuo to dryness then taken up in DCM (150 mL) and extracted with saturated sodium bicarbonate. The reaction mixture was purified by column chromatography on silica gel 60 (1:1 ethyl acetate/hexanes) to afford (6Z,15Z)-11-((Z)-dec-4-enyl)henicosa-6,15-dien-10-yl 4-(dimethylamino)butanoate 22 as a colorless oil (0.4 g, 67%). 1H NMR (400 MHz, CDCl3) δ 5.40-5.28 (m, 6H), 4.97-4.90 (m, 1H), 2.36-2.25 (m, 4H), 2.25-2.19 (m, 6H), 2.07-1.95 (m, 12H), 1.85-1.73 (m, 2H), 1.58-1.45 (m, 3H), 1.45-1.10 (m, 24H), 0.93-0.85 (m, 9H). Rf 0.4 (10% MeOH—CH2Cl2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11]([NH2:14])(=[O:13])=[O:12].[Br:15][CH:16]([CH3:20])[C:17](Cl)=[O:18]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11]([NH:14][C:17](=[O:18])[CH:16]([Br:15])[CH3:20])(=[O:13])=[O:12]
Reactant: COc1ccc(OC)c(S(N)(=O)=O)c1
Reactant: CC(Br)C(=O)Cl
Product: COc1ccc(OC)c(S(=O)(=O)NC(=O)C(C)Br)c1
Temperature: 25 °C

Procedure:
A stirred mixture of 7.0 g (0.032 mole) of 2,5-dimethoxyphenylsulfonamide in 10 mL of 2-bromopropionyl chloride was heated at reflux for 40 minutes then allowed to cool to room temperature. The resultant solution was poured into petroleum ether. Crystals formed after scratching the sides of the flask and were collected by filtration. The filter cake was washed four times with fresh petroleum ether to yield 10.3 g of N-(2,5-dimethoxyphenylsulfonyl)-2-bromopropionamide (mp 116°-118° C.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=O.C([O-])(=O)C.[NH4+]>C(O)(=O)C>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: O=C(c1ccccn1)c1ccccn1
Reactant: O=C1Cc2ccccc2N1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2C1=C(c1ccccn1)c1ccccn1
Temperature: 100 °C
Yield: 78.8 %

Procedure:
To 50 ml of acetic acid were poured 4.2 g of 97% oxindole, 5.0 g of di-2-pyridylketone, and 20.9 g of ammonium acetate. The mixture was heated for 12 hours at 100° C. Thereafter, the solvent was evaporated, and the residue was extracted with ethyl acetate. The extract was washed with water, saturated sodium bicarbonate water, and saturated brine, and subsequently dried over sodium sulfate. The resultant crude product was purified by silica gel column chromatography (ethyl acetate), to thereby obtain 6.4 g (yield 78.8%) of the title compound in the form of yellow crystals. The melting point and elementary analysis data are shown in Table 17, and NMR and MS spectrum data are shown in Table 18.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][C@H:12]([CH3:22])[CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])C1C=CC=CC=1>C(O)C.C1CCCCC=1.[OH-].[OH-].[Pd+2]>[Si:15]([O:14][CH2:13][C@@H:12]([CH3:22])[CH2:11][CH2:10][CH2:9][OH:8])([C:18]([CH3:20])([CH3:21])[CH3:19])([CH3:17])[CH3:16]
Reactant: C[C@@H](CCCOCc1ccccc1)CO[Si](C)(C)C(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: C[C@@H](CCCO)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 162.1 %

Procedure:
Catalytic Transfer Hydrogenolysis Protocol: 48.5 mg of Pd(OH)2 on activated charcoal (20%) (Pearlman's catalyst) is added to a solution of (S)-1-benzyloxy-5-(tert-butyldimethylsilyloxy)-4-methyl-pentane 5 (485 mg, 1.5 mmol) in 12.0 ml of absolute ethanol and 6.0 ml of cyclohexene. The mixture is heated under ref lux until the reaction is completed (tic monitoring). If starting material can still be detected after 8 h, some catalyst is added and refluxing is continued until the reaction is completed. After cooling to room temperature the catalyst is filtered off. The filtrate is concentrated in vacuo. Purification of the residue by flash column chromatography (pentane/diethyl ether 5:1) affords (S)-5-(tert-butyldimethylsilyloxy)4-methyl-pentan-1-ol 6 (565 mg, 97%) as a colourless oil.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([CH3:13])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[C:1]1([N:7]2[C:11](=[O:12])[C:10]([C:25](=[O:27])[CH3:26])=[C:9]([CH3:13])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cc(=O)n(-c2ccccc2)[nH]1
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)c1c(C)[nH]n(-c2ccccc2)c1=O

Procedure:
174 g of 1-phenyl-3-methyl-pyrazol-5-one in 700 ml of acetic anhydride, with the addition of 6 g of p-toluenesulphonic acid, are heated to the boil under reflux for 6 hours. The solvent is then distilled off under a water-pump vacuum, the residue is dissolved hot in 2 l of 5% strength sodium hydroxide solution, the solution is clarified with 8 g of active charcoal, the filtrate is acidified with hydrochloric acid at room temperature and the crystalline precipitate is filtered off, washed with water and dried in vacuo at 40° C. 183 g of 1-phenyl-3-methyl-4-acetyl-pyrazol-5-one are obtained in the form of colourless crystal needles.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([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[CH2:6][CH2:5]1.[CH3:28][O:29][C@H:30]([CH3:34])[C:31](O)=[O:32]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([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:31](=[O:32])[C@H:30]([O:29][CH3:28])[CH3:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: CO[C@H](C)C(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CO[C@H](C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (65 mg, 62%), MS (ISP) m/z=417.4 [(M+H)+], mp 159° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and (R)-2-methoxy-propanoic acid.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[CH3:12])[CH3:2].[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH:15]=[CH:14]1>C1C=CC=CC=1>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:14]([CH2:15][C:16]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]=2[CH3:12])=[O:17])[C:13]([OH:18])=[O:19])=[C:4]1[CH3:12])[CH3:2]
Reactant: CCn1c(C)cc2ccccc21
Reactant: O=C1C=CC(=O)O1
Solvent: c1ccccc1
Product: CCn1c(C)c(C(=O)CC(C(=O)O)c2c(C)n(CC)c3ccccc23)c2ccccc21
Temperature: 25 °C
Yield: 30.8 %

Procedure:
A stirred mixture of 160.0 g (0.97 mole) of 1-ethyl-2-methylindole (95 percent assay), 40.0 g (0.408 mole) of maleic anhydride and 700 ml of benzene was heated at reflux for a period of approximately eighteen hours and then cooled to ambient temperature. The separated solid was collected by filtration and dried in vacuo at 60° C. to obtain 52.4 g of 2,4-bis(1-ethyl-2-methyl-3-indolyl)-4-oxobutanoic acid (Formula VII: R=CH3CH2 ; R1 =CH3 ; Y=H), a white solid melting over the range of 221°-225° C.
Reaction SMILES: C=O.[Cl:3][C:4]1[CH:5]=[C:6]([N:11]2[CH2:16][CH2:15][O:14][NH:13][C:12]2=[O:17])[CH:7]=[CH:8][C:9]=1[Cl:10].[C:18]([O-])(=[O:20])C.[Na+]>O1CCOCC1>[OH:20][CH2:18][N:13]1[C:12](=[O:17])[N:11]([C:6]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=2)[CH2:16][CH2:15][O:14]1
Reactant: CC(=O)[O-]
Reactant: O=C1NOCCN1c1ccc(Cl)c(Cl)c1
Agent: C=O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1N(CO)OCCN1c1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 89.2 %

Procedure:
300 ml of an aqueous solution of 30% formic aldehyde were added to a mixture of 30 g of 4-(3',4'-dichlorophenyl)-3-oxo-5,6-dihydro-1,2,4-oxadiazine, 30 g of anhydrous sodium acetate and 300 ml of dioxane and then the mixture was stirred for 2 hours at 20°-25° C and was acidified. The mixture was extracted with ethyl acetate and the extracts were dried and evaporated to dryness under reduced pressure. The residue was taken up in isopropyl ether and the mixture was vacuum filtered. The recovered solids were dried to obtain 30 g of 2-hydroxymethyl-4-(3',4'-dichlorophenyl)-3-oxo-5,6-dihydro-1,2,4-oxadiazine melting at 134° C.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:7].C(P(CCCC)CCCC)CCC.Cl.C(N(CC)CC)C>O1CCCC1>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([N:8]2[CH2:2][CH2:3][NH:4][CH2:5][C:6]2=[O:7])[CH:10]=1
Reactant: O=C(CNCCO)Nc1cccnc1
Agent: CCCCP(CCCC)CCCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CNCCN1c1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.7 %

Procedure:
Bis(1,1-dimethylethyl)diazenedicarboxylate (4.1 g, 18 mmol) in tetrahydrofuran (100 mL) was added dropwise to a stirred, cooled (0° C.) solution of 2-[(2-hydroxyethyl)amino]-N-(3-pyridinyl)acetamide (Description 142, 2.5 g, 13 mmol) and tributylphosphine (4.2 mL, 16.9 mmol) in tetrahydrofuran (300 mL) and the mixture was stirred at room temperature for 16 hours. Ethereal hydrogen chloride (1M, 10 mL) was added and the mixture was stirred at room temperature for 1 hour. Triethylamine (6 mL, 42 mmol) was added the solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH/NH3(Aq.) (90:10:1), to give the title compound (800 mg, 35%). m/z (ES+) 178 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[C:4]([F:10])[C:3]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl:18][C:19]1[N:20]=[C:21]([CH3:27])[NH:22][C:23]=1[C:24](O)=[O:25].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>[Cl:18][C:19]1[N:20]=[C:21]([CH3:27])[NH:22][C:23]=1[C:24]([NH:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:4]=1[F:10])=[O:25]
Reactant: Cc1nc(Cl)c(C(=O)O)[nH]1
Reactant: NCc1ccc(Cl)c(Oc2ccccc2)c1F
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: Cc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3ccccc3)c2F)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.5 %

Procedure:
A mixture of {[4-chloro-2-fluoro-3-(phenyloxy)phenyl]methyl}amine (0.021 g, 0.083 mmol), 4-chloro-2-methyl-1H-imidazole-5-carboxylic acid (0.013 g, 0.083 mmol), HATU (0.038 g, 0.100 mmol) and DIPEA (0.017 mL, 0.100 mmol) in DMF (1 mL) was stirred at room temperature overnight. The crude reaction mixture was purified by reverse phase HPLC (acetonitrile:water with 0.1% TFA). The fractions containing product were lyophilized to give 4-chloro-N-{[4-chloro-2-fluoro-3-(phenyloxy)phenyl]methyl}-2-methyl-1H-imidazole-5-carboxamide (0.0077 g, 18%) (trifluoroacetate salt) as a white solid. 1H NMR (400 MHz, DMSO-d6) d ppm 8.05-8.18 (m, 1H), 7.41-7.48 (m, 1H), 7.34 (t, 2H), 7.27 (t, 1H), 7.08 (t, 1H), 6.87 (d, 2 H), 4.49 (d, 2H), 2.24 (s, 3H). ES MS: m/z 394 (M+1).
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:17]=[C:16]2[C:12]([C:13]([S:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]#[N:33])=[CH:14][N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:11][CH:10]=1)C)(C)(C)C>C1(C)C=CC=CC=1.CC(C)=O>[CH3:6][NH:7][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([S:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]#[N:33])=[CH:14][N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:11][CH:10]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc2c(Sc3ccccc3C#N)cn(Cc3ccccn3)c2c1
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CNc1ccc2c(Sc3ccccc3C#N)cn(Cc3ccccn3)c2c1

Procedure:
v)—Following a procedure analogous to that described under step i of Example 2, the product obtained in the previous step (0.150 g, 0.33 mmol) was methylated to give, after column chromatography (toluene/acetone 8:2), [3-(2-cyano-phenylsulfanyl)-1-pyridin-2-ylmethyl-1H-indol-6-yl]-methyl-carbamic acid tert-butyl ester (0.044 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([CH3:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:11]([CH3:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)cc1Cl
Reactant: C1CCNC1
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)cc1N1CCCC1

Procedure:
The title compound was prepared from (5-chloro-4-methyl-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example B8) (3.01 g, 10.5 mmol) and pyrrolidine (4.33 ml, 52.3 mmol) in DMSO (30 mL) at 55° C. according to the general procedure C. Obtained as a yellow solid (3.27 g, 97%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1N.[F:15][B-](F)(F)F.[H+].N(OCCC(C)C)=O>O1CCCC1.O>[F:15][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: F[B-](F)(F)F
Reactant: Cc1cccc(-c2ccccc2)c1N
Agent: CC(C)CCON=O
Agent: [H+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(-c2ccccc2)c1F
Reaction time: 0.25 h

Procedure:
A stirred solution of 3-methyl-[1,1'-biphenyl]-2-amine (7.5 g, 0.041 mole, as prepared in method K) in 20 ml of tetrahydrofuran was cooled to 5°. A solution of 40 ml tetrafluoroboric acid (48-50% solution) in 20 ml of water was added to the cooled reaction mixture, followed by dropwise addition of isoamyl nitrite (6.2 g, 0.053 mole). After complete addition, the reaction mixture was stirred for 15 minutes and filtered. The filter cake was rinsed successively with 50 ml each of 5% aqueous tetrafluoroboric acid, cold methanol, and cold diethyl ether. The filter cake was added to 100 ml of toluene and the mixture stirred and heated at 60° until the solid dissolved and bubbling subsided. The mixture was heated at reflux for 30 minutes, then held at room temperature for two days, causing separation of an oil. The toluene was decanted from the oil and evaporated under reduced pressure to give a second oil, which was purified by column chromatography on silica gel, elution by toluene:n-heptane (6:94), to give 2-fluoro-3-methyl-[1,1'biphenyl].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H][H]>[Ni].O.C(O)C>[NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: c1cnc2cc[nH]c2c1
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: c1cnc2c(c1)NCC2
Yield: 11.8 %

Procedure:
1.49 g of Raney nickel at 50% in water are added to a solution of 1.5 g of 4-azaindole in 45 ml of absolute ethanol, in an autoclave under argon. The mixture is hydrogenated under 100 bar of hydrogen at a temperature of 95° C. for 41 h. After a return to ambient temperature, the catalyst is filtered off through Clarcel and the filtrate is concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 70 g 15-40 μm silica cartridge, elution being carried out with pure dichloromethane and then with a 99/1 v/v mixture of dichloromethane/methanol with a flow rate of 80 ml/min, and then on a 30 g 15-40 μm silica cartridge, elution being carried out with pure dichloromethane with a flow rate of 30 ml/min. 0.18 g of 4-azaindoline is thus obtained in the form of a pale yellow solid which melts at 63° C. (Kofler bench).
Reaction SMILES: [CH3:1][CH2:2]C([O-])(C)C.[K+].[CH2:8]([O:10][C:11]([C:13]1[C:18]([CH2:19][S:20]([CH2:23][C:24]2[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:34])(=[O:22])=[O:21])=[N:17][CH:16]=[CH:15][N:14]=1)=[O:12])[CH3:9].ICC>CN(C)C=O>[CH2:8]([O:10][C:11]([C:13]1[C:18]([CH:19]([S:20]([CH2:23][C:24]2[C:29]([C:30]([F:32])([F:31])[F:33])=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:34])(=[O:21])=[O:22])[CH2:1][CH3:2])=[N:17][CH:16]=[CH:15][N:14]=1)=[O:12])[CH3:9]
Reactant: CCC(C)(C)[O-]
Reactant: CCOC(=O)c1nccnc1CS(=O)(=O)Cc1c(Cl)cccc1C(F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCI
Product: CCOC(=O)c1nccnc1C(CC)S(=O)(=O)Cc1c(Cl)cccc1C(F)(F)F
Reaction time: 0.33 h

Procedure:
Potassium tert-pentoxide (0.155 ml, ˜1.7M solution in toluene, Aldrich 60435) was added drop wise to a cooled (0 to 5° C.) solution of 3-(2-chloro-6-trifluoromethyl-phenylmethanesulfonylmethyl)-pyrazine-2-carboxylic acid ethyl ester (Compound B13 of Table B) (0.1 g) in N,N-dimethylformamide (1 ml) under nitrogen atmosphere and stirred cold for 20 minutes. Iodoethane (0.021 ml) was added to the cool dark red solution and stirred at this temperature for a further hour. The reaction mixture was partitioned between ether and 2M aqueous hydrochloric acid. The aqueous layer was extracted with further diethyl ether. The combined organic layers were washed further with water and brine, dried over magnesium sulfate and concentrated to give 3-[1-(2-chloro-6-trifluoromethyl-phenylmethanesulfonyl)-propyl]-pyrazine-2-carboxylic acid ethyl ester Compound No. D1 of Table D (0.106 g). MH+=451, RT=1.58 min.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[N:20]=[CH:21][NH:22][CH:23]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:25][C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[N:20]=[CH:21][N:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:23]=2)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)c2c[nH]cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cn1cnc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.4 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)-4-(1H-imidazol-4-ylcarbonyl)piperazine (Example 3, 0.60 g, 1.92 mmol), methyl bromoacetate (0.35 g, 2.3 mmol) and potassium carbonate (0.80 g, 5.8 mmol) in N,N-dimethylformamide (6.4 mL) was stirred at room temperature for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 50:50 to 0:100 then ethyl acetate/methanol 100/0 to 90/10) to give the title compound (0.49 g, 66%) as a white powder.