Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.[CH3:24][N:25]1[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:24][N:25]1[CH:29]=[CH:28][C:27]([NH:30][C:11](=[O:13])[C@@H:10]([N:8]2[CH2:9][C:5]([O:4][C:3]3[CH:19]=[CH:20][CH:21]=[C:22]([OH:23])[C:2]=3[F:1])=[CH:6][C:7]2=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:26]1
Reactant: Cn1ccc(N)n1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(O)c2F)=CC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C)n1)N1CC(Oc2cccc(O)c2F)=CC1=O
Temperature: 0 °C
Yield: 40.8 %

Procedure:
To a solution of (S)-2-[4-(2-fluoro-3-hydroxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 126, 0.226 g, 0.70 mmol) in N,N-dimethylformamide (4 mL) was added 1-methyl-1H-pyrazol-3-ylamine (0.340 g, 3.50 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.340 g, 0.77 mmol). The mixture was stirred at 0° C. and N,N-diisopropylethylamine (0.108 g, 0.84 mmol) was added. The mixture was stirred at room temperature overnight and the solvents were evaporated. The residue was extracted with ethyl acetate and washed with a citric acid solution. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 10% to 100% (9:1 dichloromethane:methanol)/hexanes) which afforded (S)-2-[4-(2-fluoro-3-hydroxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (1-methyl-1H-pyrazol-3-yl)-amide (0.115 g, 41%) as a white solid: HR-ES-MS m/z calculated for C20H23FN4O4 [M+Na]+ 425.1595, observed 425.1597, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.4 Hz, 3H), 0.93 (d, J=6.4 Hz, 3H), 1.45 (m, 1H), 1.53-1.63 (m, 1H), 1.67-1.79 (m, 1H), 3.73 (s, 3H), 4.20 (d, J=18.5 Hz, 1H), 4.57 (d, J=18.5 Hz, 1H), 4.84-4.92 (m, 2H), 6.40 (d, J=1.7 Hz, 1H), 6.85 (t, J=7.8 Hz, 1H), 6.91 (t, J=7.8 Hz, 1H), 7.05 (t, J=7.8 Hz, 1H), H), 7.54 (d, J=1.7 Hz, 1H), 10.35 (br. s., 1H), 10.72 (s, 1H).
Reaction SMILES: [ClH:1].[CH2:2]([C:4]1[S:27][C:7]2[N:8]=[CH:9][N:10]=[C:11]([N:12]3[CH2:17][CH2:16][CH:15]([CH2:18][NH:19]C(=O)OC(C)(C)C)[CH2:14][CH2:13]3)[C:6]=2[CH:5]=1)[CH3:3]>ClCCl>[ClH:1].[CH2:2]([C:4]1[S:27][C:7]2[N:8]=[CH:9][N:10]=[C:11]([N:12]3[CH2:13][CH2:14][CH:15]([CH2:18][NH2:19])[CH2:16][CH2:17]3)[C:6]=2[CH:5]=1)[CH3:3]
Reactant: CCc1cc2c(N3CCC(CNC(=O)OC(C)(C)C)CC3)ncnc2s1
Agent: Cl
Solvent: ClCCl
Product: CCc1cc2c(N3CCC(CN)CC3)ncnc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
Excess hydrogen chloride gas was bubbled into a solution of tert-butyl N-[(1-[6-ethylthieno[2,3-d]pyrimidin-4-yl]piperidin-4-yl)methyl]carbamate (3.4 g, 9.03 mmol, 1.00 equiv) in dichloromethane (30 mL). The resulting solution was stirred for 2 h at room temperature. The product was precipitated and collected by filtration. The solid was dried in an oven under reduced pressure to give 2.5 g (88%) of Compound I-178 as a yellow solid. 1H NMR: (400 MHz, CD3OD) δ 8.59 (1H, s), 7.46 (1H, s), 4.90-4.95 (2H, d), 3.44-3.50 (2H, t), 3.02-3.07 (2H, q), 2.94-2.95 (2H, d), 2.16-2.21 (1H, m), 2.06-2.09 (2H, d), 1.49-1.55 (2H, q), 1.39-1.43 (3H, t). MS: m/z 277 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[CH3:9][O:10][C:11](=[O:19])[CH2:12][C:13]1[S:14][CH:15]=[CH:16][C:17]=1[CH3:18].Cl>C1(C)C=CC=CC=1.CO>[CH3:18][C:17]1[CH:16]=[CH:15][S:14][C:13]=1[CH:12]([C:3]([O:6][CH3:7])=[O:8])[C:11]([O:10][CH3:9])=[O:19]
Reactant: COC(=O)Cc1sccc1C
Reactant: COC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)OC)c1sccc1C
Temperature: 80 °C
Yield: 88 %

Procedure:
Under argon, 14.7 g of sodium hydride (60% in mineral oil) were added to 311 ml (332 g, 3.685 mol) of dimethyl carbonate, and the mixture was heated at 80° C. At this temperature, a solution of 41 g (0.217 mol) of methyl(3-methylthiophen-2-yl)acetate in 50 ml of toluene was slowly added dropwise, and the mixture was stirred under reflux overnight. For work-up, the mixture was diluted with about 200 ml of methanol and poured into ice-water and acidified with dilute hydrochloric acid. Extraction with dichloromethane, drying of the organic phase over sodium sulphate, filtration and removal of the solvent gave 43.6 g of dimethyl 2-(3-methylthiophen-2-yl)malonate. Yield: 88%. 1H-NMR (DMSO): δ=7.42 (d, 1H), 6.89 (d, 1H), 5.27 (s, 1H), 3.69 (s, 6H), 2.15 (s, 3H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:28][CH2:27][CH:26]3[C:21]([C:22]4[CH:32]=[CH:31][CH:30]=[N:29][C:23]=4[CH2:24][CH2:25]3)=[N:20]2)=[CH:15][CH:14]=1>ClCCl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:28][CH2:27][CH:26]3[C:21]([C:22]4[CH:32]=[CH:31][CH:30]=[N+:29]([O-:6])[C:23]=4[CH2:24][CH2:25]3)=[N:20]2)=[CH:17][CH:18]=1
Reactant: Clc1ccc(N2CCC3CCc4ncccc4C3=N2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1cccc2c1CCC1CCN(c3ccc(Cl)cc3)N=C21
Yield: 64.5 %

Procedure:
3-Chloroperoxybenzoic acid (60%) (35 mg) was added to a solution of 2-(4-Chlorophenyl)-2,3,4,4a,5,6-hexahydropyrido[2,3-h]cinnoline (example 16, 25 mg) in dichloromethane (5 ml) at 25° C. After 4 hours the reaction was diluted with dichloromethane and sequentially washed with an aqueous solution of sodium metabisulfite, saturated sodium bicarbonate solution, brine, dried and evaporated. Purification by chromatography, eluting with ethyl acetate/methanol (4:1) afforded the title compound (17 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].I[CH:11]([CH3:13])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH:11]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6])([CH3:13])[CH3:12]
Reactant: OCc1cccc(O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cccc(CO)c1
Temperature: 85 °C
Yield: 123.4 %

Procedure:
A mixture of 3-hydroxybenzyl alcohol (2.00 g, 0.014 mol), 2-iodopropane (2.4 ml, 8.29 mmol), cesium carbonate (8.00 g, 0.0246 mol) in DMF (10 ml) was heated at 85° C. for 8 h. The reaction was diluted with water (100 ml) and extracted with DCM (30 ml) and this was washed with water (2×30 ml). The product was chromatographed on silica using DCM:methanol (19:1) to afford 3-isopropoxybenzyl alcohol (1.70 g, 73%) as an orange liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[H-].[Na+].Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH3:27])[C:21]=1[N+:28]([O-:30])=[O:29]>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH3:27])[C:21]=2[N+:28]([O-:30])=[O:29])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14]
Reactant: CNc1nccc(Cl)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CNc1nccc(Oc2ccc(NC(=O)OC(C)(C)C)c(F)c2)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Tert-butyl 2-fluoro-4-hydroxyphenylcarbamate (3.25 g, 14.4 mmol) was dissolved in DMSO (25 mL) and the solution was stirred under an argon atmosphere for 20 minutes. Sodium hydride (60% in mineral oil, 580 mg, 14.4 mmol) was added portionwise and the dark solution was stirred at room temperature for 1 hour. 4-chloro-N-methyl-3-nitropyridin-2-amine (2.7 g, 14.4 mmol) dissolved in DMSO (5 mL) was added at once and the red solution was stirred at 50° C. for 2 hours. The solution was cooled, poured onto crushed ice (200 g) and extracted with ethyl acetate (3×100 mL). The organic phases were washed with brine, dried and evaporated to give the title compound as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[CH:20][CH:21]=1
Reactant: CC(C)CN(Cc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CN(Cc1ccc(Cl)cc1)C1CCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[(4-chloro-benzyl)-isobutyl-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester in dichloromethane cooled at 0° C. was added trifluoroacetic acid (20%) and warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The combined organics were dried over sodium sulfate and concentrated. The product was used without any further purification. ESI-MS m/z: 267 (M+1), UV retention time: 0.93 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([NH:26][CH2:27][CH:28]4[CH2:33][CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]4)=[O:25])=[CH:22][CH2:23][C:12]3=[CH:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH3:47].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([NH:26][CH2:27][CH:28]4[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]4)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH3:47]
Reactant: Cc1ccccc1-c1ccc(C(=O)N2C=C3CC=C(C(=O)NCC4CCCN(C(=O)OC(C)(C)C)C4)N3Cc3ccccc32)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCC4CCCNC4)n3Cc3ccccc32)cc1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.2 %

Procedure:
To a solution of tert-butyl 3-{[({10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}carbonyl)amino]methyl}piperidine-1-carboxylate of Step A (0.42 g, 0.66 mmol) in dry dichloromethane (3 mL) was added trifluoroacetic acid (0.51 mL, 6.6 mmol) and the reaction mixture stirred at room temperature under nitrogen for 20 hours. The reaction mixture was then diluted with dichloromethane (50 mL), washed with 1 M sodium hydroxide solution (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a pink glass. Purification by flash chromatography using a solvent gradient of 2.5 to 10% ammonia saturated methanol in dichloromethane gave a pale yellow oil (0.31 g). Crystallization from diethyl ether (2 mL) afforded the title compound (0.19 g) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:10])=[N:4][C:5]([CH3:9])=[N:6][C:7]=1Cl.[NH2:11][CH2:12][CH2:13][OH:14].C(N(C(C)C)CC)(C)C>CC(O)C>[NH2:1][C:2]1[C:7]([NH:11][CH2:12][CH2:13][OH:14])=[N:6][C:5]([CH3:9])=[N:4][C:3]=1[Cl:10]
Reactant: Cc1nc(Cl)c(N)c(Cl)n1
Reactant: NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1nc(Cl)c(N)c(NCCO)n1
Temperature: 150 °C
Reaction time: 27 h
Yield: 61.5 %

Procedure:
Charge a 1 L auto-clave with 5-amino-4,6-dichloro-2-methylpyrimidine (50.0 g, 0.281 mol), 2-amino ethanol (18.8 g, 0.309 mol), diisopropylethylamine (54.5 g, 0.421 mol), and IPA (500 mL). Heat the mixture to 145-155° C., with stirring for 24 to 30 h. Cool the reaction to 25-30° C. Concentrate the reaction mixture, removing the solvent under vacuum below 50° C. Charge DCM (500 mL) into the mixture and stir at 10-25° C. for 2 h. Filter the mixture and dry the cake in the oven at 45-50° C. to give the product as a pale yellow solid (35.0 g). 1H NMR (dmso-d6): δ 6.76 (s, 1H); 4.79 (s, 3H); 3.53-3.37 (m, 4H); 2.09 (s, 3H).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Mg]Br)C.[O:30]1[C:35]2[CH:36]=[CH:37][CH:38]=[C:39]([CH:40]=[O:41])[C:34]=2[O:33][CH2:32][CH2:31]1>ClCCl>[O:30]1[C:35]2[CH:36]=[CH:37][CH:38]=[C:39]([CH:40]([C:2]3[N:3]=[CH:4][N:5]([C:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:6]=3)[OH:41])[C:34]=2[O:33][CH2:32][CH2:31]1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=Cc1cccc2c1OCCO2
Agent: CC[Mg]Br
Solvent: ClCCl
Product: OC(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccc2c1OCCO2

Procedure:
A mixture of 4-iodo-1-tritylimidazole (commercially available) (8.64 g, 19.8 mmol) in dichloromethane (100 mL) at −10° C. was treated with ethyl magnesium bromide (6.3 mL, 19 mmol, 3M in THF) and allowed to react for 45 m. A solution of 2,3-dihydro-benzo[1,4]dioxine-5-carbaldehyde (Intermediate A2) (2.6 g, 15.9 mmol) in dichloromethane was added via syringe at −10° C. and stirred for 45 m. The mixture was quenched with water (50 mL) and a sat. solution of ammonium chloride (50 mL). The residue was isolated in a typical aqueous workup and purified by chromatography on silica gel with 3 to 5% NH3-MeOH:CH2Cl2 to give (2,3-dihydro-benzo[1,4]dioxin-5-yl)-(1-trityl-1H-imidazol-4-yl)-methanol (Intermediate A3) as a solid, 2.9 g (40%).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:8]([O:15][CH3:16])(=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11]>CC(C)=O>[CH3:13][O:12][C:10]([CH:9]([C:8]([O:15][CH3:16])=[O:14])[C@H:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:7])[CH2:2]1)=[O:11]
Reactant: COC(=O)CC(=O)OC
Reactant: O=C1C=CCCC1
Solvent: CC(C)=O
Product: COC(=O)C(C(=O)OC)[C@H]1CCCC(=O)C1
Temperature: 30 °C
Reaction time: 48 h
Yield: 69.2 %

Procedure:
Under an atmosphere of argon, 24.0 mg (0.04 mmol, S/C=50) of RuH[(R,R)-Tsdpen] (1,3,5-trimethylbenzene), 194 μL (2.0 mmol) of 2-cyclohexenone, 229 μL (2.0 mmol) of dimethyl malonate, and 2 mL of acetone were placed in a 20 mL Schlenk tube and stirred at 30° C. for 48 hours. This solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2) to give 316 mg (69% yield) of the title compound. The optical purity was measured by HPLC (CHIRALPAK AS manufactured by Daicel Chemical Industries, Ltd., hexane:2-propanol=85:15, flow rate 0.5 mL/min, detection at 210 nm) and it was found to be 73% ee.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[C:31]([F:32])=[CH:30][N:29]=[C:28](Cl)[N:27]=3)[CH:21]=2)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1>>[F:32][C:31]1[C:26]([C:22]2[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=2)[CH2:19][N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[S:15]([CH3:18])(=[O:16])=[O:17])=[N:27][C:28]([NH:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=2)=[N:29][CH:30]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(-c3nc(Cl)ncc3F)c2)S(C)(=O)=O)CC1
Product: CS(=O)(=O)N(Cc1cccc(-c2nc(NCCc3ccc(O)cc3)ncc2F)c1)C1CCNCC1

Procedure:
Intermediate 77 was coupled with tyramine following procedure Q. The resulting product was deprotected following procedure R. LC-MS showed the product had the expected M+H+ of 500. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.23 (d, 1H), 8.16 (s, 1H), 7.96 (d, 1H), 7.48 (m, 2H), 7.05 (d, 2H), 6.69 (d, 2H), 4.54 (s, 2H), 3.90 (m, 1H), 3.56 (t, 2H), 3.34 (m, 2H), 3.00 (s, 3H), 2.91 (m, 2H), 2.80 (t, 2H), 1.84 (m, 4H).
Reaction SMILES: [N:1]1([CH2:6][C:7]([CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])([C:10]#[N:11])[C:8]#[N:9])[CH:5]=[CH:4][CH:3]=[N:2]1.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[I:40]I>C(#N)C>[I:40][C:4]1[CH:3]=[N:2][N:1]([CH2:6][C:7]([CH2:12][CH2:13][C:14]([F:15])([F:16])[F:17])([C:10]#[N:11])[C:8]#[N:9])[CH:5]=1
Reactant: N#CC(C#N)(CCC(F)(F)F)Cn1cccn1
Reactant: II
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cc(I)cn1
Temperature: 25 °C
Reaction time: 10 h
Yield: 115.6 %

Procedure:
1.21 g of [(1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl)malononitrile (the compound of the present invention (1)) was dissolved in 50 ml of acetonitrile. 2.19 g of ammonium cerium (IV) nitrate and 1.02 g of iodine were added to the solution, followed by stirring at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.71 g of [(4-iodo-1H-pyrazole-1-yl)methyl] (3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (42), hereinafter) shown by below formula.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[C:8]([CH3:18])[C:6]=2[N:7]=1.C(N(CC)CC)C.[CH:32]([S:35](Cl)(=[O:37])=[O:36])([CH3:34])[CH3:33]>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:35]([CH:32]([CH3:34])[CH3:33])(=[O:37])=[O:36])[CH2:14][CH2:13]3)=[C:8]([CH3:18])[C:6]=2[N:7]=1
Reactant: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(CN2CCN(S(=O)(=O)C(C)C)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Temperature: 25 °C

Procedure:
To 2-Chloro-7-methyl-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine (100 mg) in anhydrous DCM (2 ml) and triethylamine (1.5 equiv., 60 μl) at 0° C. was added isopropylsulfonyl chloride (1.3 equiv., 45.5 μl) and the reaction mixture was allowed to warm up to room temperature overnight. Chloroform/brine extraction and purification on silica gave 2-chloro-7-methyl-4-morpholin-4-yl-6-[4-(propane-2-sulfonyl)-piperazin-1-ylmethyl]-thieno[3,2-d]pyrimidine (105 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[S:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=2)[N:19]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH:26]2[CH2:31][CH2:30][N:29]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:28][CH2:27]2)[S:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=2)[N:19]=1
Reactant: CC(C)c1nnc2ccc(-c3sc(C4CCNCC4)nc3-c3ccc(F)cc3F)nn12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)c1nnc2ccc(-c3sc(C4CCN(S(C)(=O)=O)CC4)nc3-c3ccc(F)cc3F)nn12
Temperature: 2 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
A mixture of 4-(2,4-difluorophenyl)-5-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-2-(piperidin-4-yl)thiazole (0.25 g, 0.57 mmol, Example #Q.1.1), TEA (0.32 mL, 2.3 mmol) and DCM (5 mL) was cooled to about 0-4° C. Methanesulfonyl chloride (0.044 mL, 0.57 mmol) was added. The reaction mixture was stirred at about 04° C. for about 1 h. The reaction was quenched with saturated aqueous Na2CO3 solution. The aqueous layer was extracted with DCM (200 mL). The organic layer was dried over Na2SO4, decanted, and concentrated. The crude product was purified by RP-HPLC (Table 1, Method e) to give the title compound (0.14 g, 48%): LC/MS (Table 1, Method a) Rt=2.49 min; MS m/z: 519.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][CH2:9][OH:10])[N:3]=1.[N+:11]([C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([N+]([O-])=O)[C:15]=1[C:16]#[N:17])([O-:13])=[O:12]>>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][CH2:9][O:10][C:18]2[CH:19]=[CH:20][CH:21]=[C:14]([N+:11]([O-:13])=[O:12])[C:15]=2[C:16]#[N:17])[N:3]=1
Reactant: Cc1cc(C)n(CCO)n1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: Cc1cc(C)n(CCOc2cccc([N+](=O)[O-])c2C#N)n1
Yield: 90.7 %

Procedure:
Prepared as in Example 197c from 2-(3,5-dimethyl-1H-pyrazol-1-yl)ethanol and 2,6-dinitrobenzonitrile in 90.7% yield. MS 287 (MH+).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][O:7][CH2:8][CH2:9][C:10]1[CH:14]=[CH:13][S:12][CH:11]=1>>[CH3:6][O:7][CH2:8][CH2:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: COCCc1ccsc1
Product: COCCc1ccsc1S(=O)(=O)Cl
Temperature: -10 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
To 56 g of chlorosulfonic acid at -15° C. was added with efficient stirring 14.2 g of 3-(2-methoxyethyl)thiophene. The mixture was stirred for one hour at -10° C. and then cautiously added to ice and the resultant mixture extracted with methylene chloride. The methylene chloride extract was washed with cold water, dried over magnesium sulfate, filtered and concentrated to yield 6.0 g of an oil. Infrared absorption spectroscopy showed peaks at 1160, 1180 and 1360 cm-1 consistent for sulfonyl chloride. This product was sufficiently pure for use as an intermediate for the preparation of compounds of this invention.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[Cs+].[Cs+].[C:19]([O:23][C:24](=[O:27])[CH2:25]Br)([CH3:22])([CH3:21])[CH3:20].O>CN(C=O)C>[C:19]([O:23][C:24](=[O:27])[CH2:25][O:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[Cl:1])[C:6]([O:8][CH3:9])=[O:7])([CH3:22])([CH3:21])[CH3:20]
Reactant: COC(=O)c1ccc(Cl)c(O)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)c(OCC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Methyl 4-chloro-3-hydroxybenzoate [Chem. Pharm. Bull. 1994, 42(11),2365-9] (0.73 g), caesium carbonate (1.27 g) and tert butylbromoacetate (0.58 mL) in DMF (6 mL) were heated and stirred at 60° C. for 3 h. Water was added and the product was extracted into ethyl acetate. The extracts were dried over sodium sulphate, filtered and the solvent was evaporated. The resulting oil was purified by flash chromatography, using 1:10 ethyl acetate/isohexane as eluent, to yield the subtitle compound as a colourless oil (1.25 g).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=2[NH:6][C:5]1=[O:14].S(Cl)([Cl:17])=O>ClC(Cl)Cl>[Cl:17][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=2[NH:6][C:5]1=[O:14]
Reactant: Cc1ccc2c(c1)[nH]c(=O)n2CCO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(c1)[nH]c(=O)n2CCCl
Reaction time: 5 h
Yield: 42 %

Procedure:
To a stirred mixture of 26 parts of 1,3-dihydro-1-(2-hydroxyethyl)-5-methyl-2H-benzimidazol-2-one and 390 parts of trichloromethane are added dropwise 48 parts of sulfinyl chloride at room temperature. Upon completion, stirring is continued for 5 hours at reflux. The reaction mixture is evaporated. The oily residue is heated with 2,2'-oxybispropane and a small amount of 2-propanol and the whole is stirred with activated charcoal. The latter is filtered off and the filtrate is stirred at room temperature till all the product is precipitated. It is filtered off and dried, yielding 12 parts (42%) of 1-(2-chloroethyl)-1,3-dihydro-5-methyl-2H-benzimidazol-2-one; mp. 120° C.