Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[CH:19][C:20]([O:22]C)=[O:21])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+].O.Cl>O1CCCC1.C(OCC)(=O)C>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([CH:18]=[CH:19][C:20]([OH:22])=[O:21])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(-c2ccc(C=CC(=O)OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCc1ccc(-c2ccc(C=CC(=O)O)cc2)cc1
Yield: 104.8 %

Procedure:
To a mixture of Methyl 3-[4-(4-pentylphenyl)phenyl]acrylate (0.41 g) in tetrahydrofuran (5ml) was added 3N NaOH aqueous solution (1.3 ml), and the resultant mixture was heated to 85° C. for 10 hours. The reaction mixture was poured into a mixture of cold water and ethyl acetate, and adjusted to about pH 2 with 6N hydrochloric acid. The separated organic layer was washed in turn with water and brine, and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 3-[4-(4-Pentylphenyl)phenyl]acrylic acid (0.41 g).
Reaction SMILES: [CH:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)([CH2:3][CH3:4])[CH3:2].[C:18](N1C=CN=C1)(N1C=CN=C1)=[S:19]>CN(C)C=O>[N:17]([C:14]1[CH:13]=[CH:12][C:11]([N:8]2[CH2:9][CH2:10][N:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[CH2:6][CH2:7]2)=[CH:16][CH:15]=1)=[C:18]=[S:19]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CCC(C)N1CCN(c2ccc(N)cc2)CC1
Solvent: CN(C)C=O
Product: CCC(C)N1CCN(c2ccc(N=C=S)cc2)CC1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 87.1 %

Procedure:
A solution of 4-[4-(sec-butyl)-1-piperazinyl]benzenamine (3.5 g, 15 mmol) (from Step B above) in N,N-dimethylformamide (40 mL) was added dropwise over 20 min to a cooled (−15° C.) solution of thiocarbonyldiimidazole (2.68 g, 15.03 mmol) (Aldrich) in N,N-dimethylformamide (15 mL). After the addition was complete, the mixture was stirred at −15° C. for 20 min, then the cooling bath was removed and the solution was stirred for 1 h. Ice-water (800 ml) was added and the mixture was stirred for 30 min. The solid was filtered off and washed with water and dried under vacuum to give 1-(4-isothiocyanatophenyl)-4-(sec-butyl)piperazine (3.6 g, 87%) as a purple solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH:13]=[CH:12][CH2:11][C@@H:10]2[N+:15]([O-:17])=[O:16])=[CH:5][C:4]=1[O:18][CH3:19].Cl>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[N+:15]([O-:17])=[O:16])=[CH:5][C:4]=1[O:18][CH3:19]
Reactant: COc1ccc([C@@H]2CC=CC[C@@H]2[N+](=O)[O-])cc1OC
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc([C@@H]2CCCC[C@@H]2[N+](=O)[O-])cc1OC

Procedure:
8.4 g of (+/−)-cis-1,2-dimethoxy-4-(2-nitrocyclohex-4-enyl)benzene are dissolved in 450 ml of methanol, treated with 2 ml of conc. hydrochloric acid and hydrogenated after addition of 500 mg of 10% strength Pd/C. The reaction mixture is filtered and the filtrate is concentrated. M.p.: 84-86.5° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[CH:15]=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH:4]=[N:3]1.C[N+](C)=C.[I-].[OH-].[K+].CI.C[N:26]([CH2:28][C:29]1C2C=CC=CC=2NC=1)C>C(#N)C.C(O)(=O)C.C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:15]([CH2:29][C:28]#[N:26])=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cnc3[nH]ccc3c2)cn1
Reactant: CN(C)Cc1c[nH]c2ccccc12
Agent: C=[N+](C)C
Agent: [I-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Solvent: CC(=O)O
Product: Cn1cc(-c2cnc3[nH]cc(CC#N)c3c2)cn1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (780 mg, 3.94 mmol) and Eschenmoser's Salt (1.46 g, 7.88 mmol) were combined in acetonitrile:acetic acid (19:1, 12.3 ml and 700 uL, respectively) and heated for 5 hours at 40° C. Next, 4N potassium hydroxide was added until pH>9. The solution was transferred to a separatory funnel and extracted with copious amount of ethyl acetate. The organic layer was dried over Na2SO4 and concentrated down. Next methyl iodide (246 uL, 3.94 mmol) in ethanol (11 mL) was added to the crude gramine and the solution was stirred at room temperature overnight. The solution was concentrated under vacuum and redissolved in dimethylformamide (10 mL) and water (2 mL). This was then heated to 70° C. for 3 hours. The reaction was allowed to return to room temperature, transferred to a separatory funnel with ethyl acetate (250 mL) and washed with water (2×200 mL). The aqueous layers were combined and back extracted with ethyl acetate (200 mL). The organic layer was dried over Na2SO4 and concentrated down to afford the crude [5-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetonitrile. This material was then dissolved in methanol (6 mL) and 4N potassium hydroxide (8 mL) and heated at 90° C. overnight. The solution was then acidified with 1N hydrochloric acid (aq) until precipitate formed. The precipitate was then filtered and washed with water to afford the crude product. The product was purified by flash chromatography (0-15% methanol/dichloromethane gradient) to afford the title compound (284 mg, 28%). MS m/z=257 [M+H+]+
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH2:4]=[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[N:11]=[C:10]2[C:22]1[N:27]=[C:26]([O:28][C@H:29]2[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34][CH2:33][C:30]32[CH2:32][CH2:31]3)[CH:25]=[N:24][CH:23]=1)[CH3:6].CC(O)=O>C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:4][C:5]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[N:11]=[C:10]3[C:22]2[N:27]=[C:26]([O:28][C@H:29]3[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34][CH2:33][C:30]43[CH2:32][CH2:31]4)[CH:25]=[N:24][CH:23]=2)[CH2:3][CH2:6]1
Reactant: C=C(C)c1ccc2c(c1)c(-c1cncc(O[C@H]3CN(C(=O)OC(C)(C)C)CCC34CC4)n1)nn2C1CCCCO1
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(C5(C)CC5)cc34)n2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
Diazomethane (˜0.25M in Et2O (prepared according to Aldrich Technical Bulletin AL-180, Aldrich, St. Louis, Mo.); 2.0 mL, 0.500 mmol) was added dropwise to a solution of (4R)-tert-butyl 4-(6-(5-(prop-1-en-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (110.4 mg, 0.202 mmol) and palladium(II) acetate (4.54 mg, 0.020 mmol) in DCM (2.0 mL) at 0° C. and the resulting solution was stirred at 0° C. for 30 min. Additional diazomethane (˜0.25M in Et2O; 2.0 mL, 0.500 mmol) was added, and the resulting solution was stirred at 0° C. for 30 min. HOAc (0.069 mL, 1.214 mmol) was added to quench excess diazomethane, and the resulting mixture was stirred at 25° C. for 12 h. The mixture was concentrated onto silica gel and chromatographically purified (ISCO, 12 g silica gel column, 0-60% EtOAc/hexanes, 15 min, 254 nm) to provide (4R)-tert-butyl 4-(6-(5-(1-methylcyclopropyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (96.3 mg, 0.172 mmol, 85% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ ppm 9.04 (1 H, s), 8.28 (1 H, s), 8.19 (1 H, br. s.), 7.57 (1H, d, J=8.8 Hz), 7.37 (1 H, d, J=8.4 Hz), 5.78 (1 H, d, J=9.0 Hz), 4.68 (1 H, d, J=8.0 Hz), 4.49 (1 H, br. s.), 4.28 (1 H, d, J=11.9 Hz), 4.03 (1 H, d, J=11.3 Hz), 3.70-3.84 (1 H, m), 3.28 (1 H, d, J=13.7 Hz), 2.97 (1 H, t, J=11.2 Hz), 2.57-2.73 (1 H, m), 2.41-2.54 (1 H, m), 2.16-2.28 (1 H, m), 2.07-2.15 (1 H, m), 1.63-1.86 (3 H, m), 1.47 (4 H, s), 1.12 (9H, br. s.), 0.85-0.93 (2 H, m), 0.80 (2 H, br. s.), 0.73 (1 H, br. s.), 0.62 (1 H, br. s.), 0.56 (2 H, br. s.). MS (ESI, pos. ion) m/z: 560.3 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:14][OH:15])[CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[F:10])[CH3:2]>ClCCCl.O=[Mn]=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[F:10])[CH:14]=[O:15])[CH3:2]
Reactant: CCOc1cc(CO)cc(OCC)c1F
Agent: O=[Mn]=O
Solvent: ClCCCl
Product: CCOc1cc(C=O)cc(OCC)c1F
Temperature: 50 °C
Reaction time: 21 h

Procedure:
To a solution of (3,5-diethoxy-4-fluoro-phenyl)-methanol (2.30 g, 10.7 mmol, 1.0 equiv) in 1,2-dichloroethane (50 mL) was added activated MnO2 (2.89 g, 33.3 mmol, 3.1 equiv). The reaction mixture was stirred for 21 h at 50° C. and then filtered through Hyflo Super Cel providing after evaporation of the solvent under reduced pressure 1.90 g (83%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.38 (t, J=7.0 Hz, 6H), 4.09 (q, J=7.0 Hz, 4H). 7.04 (d, J=7.2 Hz, 2H), 9.75 (s, 1H). MS (EI): 212.1 [M]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]1[CH2:21][C@@H:10]2[CH2:11][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][C@@H:9]2[CH2:8]1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:6][CH:7]1[CH2:21][C@@H:10]2[CH2:11][N:12]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:13][C@@H:9]2[CH2:8]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CC(O)C[C@H]2C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H]2CC(OS(C)(=O)=O)C[C@H]2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.18 mL, 2.33 mmol), was added dropwise to a solution of 1,1-dimethylethyl(3aR,6aS)-5-(hydroxy)-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.44 g, 1.94 mmol) and triethylamine (0.81 mL, 5.81 mmol) in 10 mL dichloromethane at 0° C. and the reaction mixture was stirred for 1 h at room temperature. The solvent was evaporated, the resulting crude mixture was diluted with 100 mL ethyl acetate and washed with water (30 mL), brine, 1M aqueous hydrochloric acid and brine again. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude 1,1-dimethylethyl(3aR,6aS)-5-{[(methylsulfonyl)oxy]}hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate was used without further purification. MS (EI) for C13H23NO5S: 306 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[Cl:13].[N-:14]=[N+:15]=[N-:16].[Na+]>CN(C=O)C.O>[N:14]([C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[Cl:13])=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1nc(Br)cc(Br)c1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(Br)cc(N=[N+]=[N-])c1Cl
Temperature: 50 °C
Yield: 66.7 %

Procedure:
To a solution of methyl 4,6-dibromo-3-chloropyridine-2-carboxylate (6.0 g 0.018 mol) in DMF (50 mL) was added sodium azide (2.0 g 0.03 mol) and the solution warmed to 50° C. for 1 hr. The reaction was diluted with water (200 mL) and cooled to 0° C. for 1 hr. The solid was collected to give methyl 4-azido-6-bromo-3-chloropyridine-2-carboxylate (4.4 g, 0.012 mol, 66%); mp 84-86° C.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C@H:12]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1.NN>C(O)C>[NH2:3][C@H:12]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](c3ccccc3)N3C(=O)c4ccccc4C3=O)CC2)c1
Agent: NN
Solvent: CCO
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Yield: 84.3 %

Procedure:
A mixture of N-(3-{1-[(3S)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (4.60 g, 9.06 mmol) and hydrazine (3.62 g, 72.4 mmol) in ethanol (150 mL) was refluxed for 12 h. The resulting white precipitate was filtered out and the filtrate was concentrated under vacuum. The residue was washed with CH2Cl2/EtOAc. (1:1, 3×50 mL) and the combined organic fractions were concentrated in vacuo to give the desired product (2.90 g, 95%). 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.39–7.30 (m, 6H), 7.297.19 (m, 2H), 6.95 (d, 1H, J=7.2), 4.01 (t, 1H, J=6.8 Hz), 3.04 (t, 2H, J=10.6 Hz), 2.62–2.30 (m, 6H) 2.05–1.70 (m, 8H), 1.24 (d, 6H, J=6.8 Hz); ESMS m/e: 380.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6][CH:7]([CH3:9])[CH3:8])=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.Cl.N(CC(O)=O)C.C(=O)C1C=CC=CC=1>>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]=[CH:11][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:15][CH:14]=1
Reactant: CC(C)Nc1ccc(F)cc1
Reactant: O=Cc1ccc(Br)cc1
Agent: CNCC(=O)O
Agent: Cl
Solvent: O=Cc1ccccc1
Product: CC(C)N(Cc1ccc(Br)cc1)c1ccc(F)cc1
Yield: 93 %

Procedure:
When the product of Step A and 4-bromobenzaldehyde were substituted for sarcosine hydrochloride salt and 4-(5-(((4-fluorophenyl)) isopropyl)amino)methyl)thiophen-2-yl)benzaldehyde, respectively, in Example 22, Step C, the similar process afforded the title compound in 93% yield, as a pale paste. 1H-NMR (CDCl3) 7.39 (d, 2H, J=8.18 Hz); 7.14 (d, 2H, J=8.08 Hz); 6.91-6.81 (m, 2H); 6.62-6.57 (m, 2H); 4.26 (s, 2H); 4.11-4.04 (m, 1H); 1.18 (d, 2H, J=5.34 Hz).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[C:7]([CH3:24])=[N:8][S:9][C:10]=1[NH:11][C:12](=[O:23])[CH:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=1)[CH3:14]>ClCCl>[Cl:5][C:6]1[C:7]([CH3:24])=[N:8][S:9][C:10]=1[NH:11][C:12](=[O:23])[CH:13]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[CH3:14]
Reactant: COc1ccc(C(C)C(=O)Nc2snc(C)c2Cl)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1nsc(NC(=O)C(C)c2ccc(O)cc2)c1Cl
Temperature: 25 °C
Yield: 99.4 %

Procedure:
Boron tribromide (1.0 M solution in dichloromethane, 110 ml, 0.11 mol) was added dropwise to a stirred solution of N-(4-chloro-3-methylisothiazol-5-yl)-2-(4-methoxyphenyl)propionamide (125 g, 0.040 mol) in dichloromethane (200 ml) at −70° C. Once the addition was complete the cooling bath was removed and the mixture was allowed to warm to room temperature overnight. The mixture was cooled to 0° C. and excess methanol added cautiously. The solvent was evaporated in vacuo, and the residue was partitioned between ethyl acetate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo to give N-(4-chloro-3-methylisothiazol-5-yl)-2-(4-hydroxyphenyl)propionamide (11.8 g), which was used without further purification in the next step.
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]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:3]=1.[CH3:29][N:30]1[CH2:34][CH2:33][NH:32][C:31]1=[O:35]>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:32]4[CH2:33][CH2:34][N:30]([CH3:29])[C:31]4=[O:35])=[CH:3][C:4]=3[S:25]([CH3:28])(=[O:27])=[O:26])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: CN1CCNC1=O
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 84.9 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (466 mg) described in Preparation Example 254 and 1-methylimidazolidin-2-one (120 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (412 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[NH:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].C1OCCOCCOCCOCCOC1.[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1.[Cl-].[Na+].O>[F:1][C:2]1[N:3]([S:41]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:43])=[O:42])[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(-c2ccccc2)[nH]c1F
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: C1COCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2ccccc2)c1F
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
To a solution (20 mL) of ethyl 2-fluoro-5-phenyl-1H-pyrrole-3-carboxylate (300 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 155 mg) at room temperature and the mixture was stirred for 30 min. 15-Crown-5 (850 mg) was added dropwise and the mixture was stirred for 30 min. Benzenesulfonyl chloride (591 mg) was added, and the mixture was further stirred for 24 hr. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=85:15) to give the title compound as a colorless oil (yield 390 mg, 81%).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:19])[N:3]=1)=[C:11]([F:16])[CH:10]=[C:9]([O:17][CH3:18])[CH:8]=3.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:11]1[CH:10]=[C:9]([O:17][CH3:18])[CH:8]=[C:7]2[C:12]=1[N:13]=[C:14]([CH3:15])[C:5]1[N:6]2[C:2]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH3:20])=[N:3][C:4]=1[CH3:19]
Reactant: Cc1ccccc1B(O)O
Reactant: COc1cc(F)c2nc(C)c3c(C)nc(Br)n3c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(F)c2nc(C)c3c(C)nc(-c4ccccc4C)n3c2c1
Yield: 29.8 %

Procedure:
Following the general Suzuki coupling procedure, reaction of bromide 6A (65 mg, 0.2 mmol), 2-methylphenylboronic acid (40 mg, 0.3 mmol), K2CO3 (82 mg, 0.6 mmol) and Pd(PPh3)4 (5 mg, 0.004 mmol) provided the coupling product as an off-white powder (20 mg, 30% yield). EIMS 336.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10](=[O:13])[N:9]([CH2:14][C:15]3[CH:16]=[C:17]([C:21]4[N:26]=[CH:25][C:24]([N:27]5CCN(C(OC(C)(C)C)=O)CC5)=[CH:23][N:22]=4)[CH:18]=[CH:19][CH:20]=3)[N:8]=2)[CH:4]=[N:3]1.Cl>O1CCOCC1>[NH2:27][C:24]1[CH:23]=[N:22][C:21]([C:17]2[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=2)[CH2:14][N:9]2[C:10](=[O:13])[CH:11]=[CH:12][C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)=[N:8]2)=[N:26][CH:25]=1
Reactant: Cn1cc(-c2ccc(=O)n(Cc3cccc(-c4ncc(N5CCN(C(=O)OC(C)(C)C)CC5)cn4)c3)n2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc(=O)n(Cc3cccc(-c4ncc(N)cn4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
90 mg (0.17 mmol) of tert-butyl 4-(2-{3-[3-(1-methyl-1H-pyrazol-4-yl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yl)piperazine-1-carboxylate are dissolved in 10 ml of dioxane, and 1 ml of 4 N HCl in dioxane is added. The reaction mixture is stirred at room temperature for 15 h and subsequently evaporated to dryness; yield: 80 mg of “A292” hydrochloride; HPLC: 2.05 min (method C); LC-MS: 429 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].[CH:11]1([Mg]Br)[CH2:13][CH2:12]1.CO.[BH4-].[Na+]>C1COCC1.CCOC(C)=O.O>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]([CH:11]1[CH2:13][CH2:12]1)[NH2:5]
Reactant: Br[Mg]C1CC1
Reactant: N#Cc1cc(Cl)ccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: NC(c1cc(Cl)ccc1Br)C1CC1
Reaction time: 0.25 h
Yield: 33.8 %

Procedure:
To a solution of 2-bromo-5-chlorobenzonitrile (20 g, 93 mmol) in THF (200 mL) was added cyclopropylmagnesiumbromide (558 mL, 279 mmol) at 0° C. The resulting reaction mixture was stirred at 0-5° C. for 5 hours before MeOH (100 mL) was added and stirring continued at room temperature for 15 min. NaBH4 (7.1 g, 186 mmol) was added subsequently and the reaction mixture was stirred at room temperature overnight. Water was added and reaction mixture was exacted with AcOEt (300 mL×3). The combined organic layers were concentrated in vacuo to give a crude product which was then purified by chromatography to give (2-bromo-5-chlorophenyl)(cyclopropyl)methanamine (8.2 g, yield 34%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][C:13]([CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)=[CH:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(OCC)(=O)C.[ClH:39]>C(O)C>[ClH:39].[F:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][C:13]([CH2:23][NH:24][CH3:25])=[CH:12]2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2cccc(F)c2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2cccnc2F)n(S(=O)(=O)c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of tert-butyl ({1-[(3-fluorophenyl)sulfonyl]-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}methyl)methylcarbamate (194 mg) in ethanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (4 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound (yield 90 mg, 54%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:16][C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31](=[O:43])[NH:32][C:33]3[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=3)[CH2:21][CH2:20]2)=[O:18])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][CH:9]=2)=[O:5])C>O.CO.O1CCOCC1>[Cl:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:16][C:17]([N:19]1[CH2:20][CH2:21][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31](=[O:43])[NH:32][C:33]3[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:40])=[O:41])=[CH:35][CH:34]=3)[CH2:23][CH2:24]1)=[O:18])[C:6]([C:4]([OH:5])=[O:3])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2n1CC(=O)N1CCN(c2ccccc2C(=O)Nc2ccc(S(C)(=O)=O)cc2)CC1
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(NC(=O)c2ccccc2N2CCN(C(=O)Cn3c(C(=O)O)cc4cc(Cl)ccc43)CC2)cc1
Temperature: 50 °C
Yield: 19.1 %

Procedure:
A suspension of 5-chloro-1-(2-{4-[2-(4-methanesulfonyl-phenylcarbamoyl)-phenyl]-piperazin-1-yl}-2-oxo-ethyl)-1H-indole-2-carboxylic acid ethyl ester (0.14 g, 0.22 mmol) of in a 1:1:1 mixture of water/MeOH/1,4-dioxane (9 mL) is heated at 50° C. for 1 hour during which time all of the solids went into solution. The mixture is cooled to room temperature and concentrated under reduced pressure to remove volatile organics. The pH of the mixture is adjusted to slightly acidic (approx pH 5) by the addition of a 2N solution of hydrochloric acid which caused a solid to precipitate from solution. The formed solid is collected by filtration, washed with water and dried on the filter pad to provide 0.025 g of 5-chloro-1-(2-{4-[2-(4-methanesulfonyl-phenylcarbamoyl)-phenyl]-piperazin-1-yl}-2-oxo-ethyl)-1H-indole-2-carboxylic acid as an off white powder.