Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][CH:5]=[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[C:7](=[O:9])[N:8]=1.[CH3:17]I>C1COCC1.[H-].[Na+]>[CH3:17][N:4]1[CH:5]=[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[C:7](=[O:9])[N:8]=[C:3]1[S:2][CH3:1]
Reactant: CSc1nc(=O)c(Cc2cncnc2)c[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc(=O)c(Cc2cncnc2)cn1C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
2-Methylsulfanyl-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (50 mg, 0.213 mmol, 1 eq) was dissolved in dry THF (0.7 ml) and NaH, 60% (24.7 mg, 0.618 mmol, 2.9 eq) was added. After 30 min, the reaction mixture was treated with methyl iodide (133 μl, 2.13 mmol, 10 eq) and was stirred overnight. After overnight the excess NaH was quenched by a slow addition of water, diluted with brine (30 ml) and extracted with Et2O (3×20 ml). Combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated to give a crude residue. Crude residue was purified via Biotage SP-1 Snap Si 10 g; 15 ml/min in the gradient of MeoH in DCM: 1% for 1 CV then from 1-5% for 20 CV. The appropriate fractions were combined and evaporated in vacuo to give the required product 1-methyl-2-methylsulfanyl-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (25.5 mg, yield=47.4%, purity=98%). [M+H]+=249.31 1H NMR (300 MHz; DMSO-d6) δ/ppm 2.49 (s, 3H), 3.53 (s, 3H), 3.58 (s, 2H), 7.80 (s, 1H), 8.72 (s, 2H), 9.03 (s, 1H)
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[N:27]1([CH2:33][CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.[OH-].[Na+]>CN(C=O)C.CO>[N:27]1([CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH:39]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:40][CH:41]=2)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1ccc(CCN2CCCCC2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(CCN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(2-piperidinoethyl)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:18][N:19]([CH2:24][CH2:25][CH2:26][NH2:27])[CH2:20][CH2:21][CH2:22][NH2:23]>C1(C)C=CC=CC=1>[CH3:18][N:19]([CH2:24][CH2:25][CH2:26][NH:27][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1)[CH2:20][CH2:21][CH2:22][NH:23][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CN(CCCN)CCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(NCCCN(C)CCCNc2ccc([N+](=O)[O-])c(C)c2)ccc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
To 5-fluoro-2-nitrotoluene (50.0 g, 0.32 mol) was added sodium carbonate (17.1 g, 0.16 mol) at 60° C. 3,3′-Diamino-N-methyldipropylamine (23.7 g, 0.16 mol) was then carefully added dropwise (exothermic reaction). The resulting mixture was heated at 100° C. for 12 hours. 100 ml toluene were added to the cooled reaction mixture causing the inorganic salts to precipitate, which were filtered off. The organic phase was then concentrated down under vacuum in a rotovap to afford the product as a residue in the form of a yellow orange oil. Yield: 52.5 g (78.4%); 1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.71 (m, 4H); 2.18 (s, 3H); 2.40 (m, 4H); 2.55 (s, 6H); 3.17 (m, 4H); 6.45 (s, 2H); 6.48 (d, 2H); 7.08 (br., 2×NH); 7.92 (d, 2H).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]([F:18])([F:17])[CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C1COCC1.[OH-].[Na+]>CO>[CH2:10]([O:9][C:7]([NH:6][CH2:5][C:4]([F:17])([F:18])[C:3]([OH:19])=[O:2])=[O:8])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)C(F)(F)CNC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NCC(F)(F)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
3-Benzyloxycarbonylamino-2,2-difluoropropionic acid methyl ester (3.3 g, 12.1 mmol), THF (50 ml), methanol (50 ml) and 1 N sodium hydroxide solution (50ml) were mixed and stirred for 16 hours at room temperature. After adjusting the pH to acidic reaction and removal of organic solvent by evaporation, the aqueous residue was extracted twice with ethyl acetate. The combined organic layers were washed twice with 5% brine, dried over magnesium sulphate and filtered through a short silica column before concentration in vacuo to afford 2.6 g (83%) of 3-benzyloxycarbonylamino-2,2-difluoropropionic acid as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CC(C)=O>[CH2:29]([O:22][C:18]1[CH:17]=[C:16]([CH2:15][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:21]=[CH:20][CH:19]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C(Cc1cccc(O)c1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Cc1cccc(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 88 %

Procedure:
158 (760 mg, 1 equivalent) was dissolved in 15 ml of acetone, then potassium carbonate (373 mg, 1.1 equivalent) and benzylbromide (1.1équivalent, 323 μl) were added successively. The reaction mixture was let overnight at room temperature. The reaction mixture is concentrated and 50 ml of AcOEt are added. The organic phase are washed with 10% citric acid, saturated NaHCO3 and brine then dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (AcOEt/Hexane 2/8) to afford 159 as white solid (860 mg, 88%). 1H NMR (CDCl3): δ 1.38 (t, 3H, J=7.4 Hz), 1.69 (s, 9H), 3.22 (m, 2H), 4.31 (q, 2H, J=7.4 Hz), 4.71 (s, 2H), 5.13 (m, 1H), 5.20 (s, 2H), 6.90 (d, 1H, J=7.1 Hz), 6.94 (s, 1H), 7.01 (d, 1H, J=8.2 Hz), 7.36 (t, 1H, J=7.7 Hz), 7.49 (m, 1H), 7.56 (m, 4H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[NH:10])[NH2:9].[Cl:11][C:12]([SH:15])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:11][C:12]1[S:15][N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[N:10]=1
Reactant: N=C(N)c1ccccn1
Reactant: SC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Clc1nc(-c2ccccn2)ns1
Temperature: 25 °C
Yield: 41.8 %

Procedure:
To a solution of pyridine-2-carboximidamide hydrochloride (2.00 g, 12.7 mmol) and perchloromethyl mercaptan (1.75 ml, 16.3 mmol) in dichloromethane (40 ml) was added dropwise a solution of sodium hydroxide (3.26 g, 81.5 mmol) in water (6 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 1.05 g (42.0%) of the desired product as an oil.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][N:6]=1>O1CCCC1>[CH3:1][N:2]([CH3:3])[C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][N:6]=1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: CNC
Solvent: C1CCOC1
Product: Cc1cc(N(C)C)ncc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
Dimethylamine (50% solution in water, 20 mL) was added to a stirred solution of 2-chloro-4-methyl-5-nitropyridine (15.0 g, 86.9 mmol) in tetrahydrofuran (150 mL), and the mixture was stirred at 0° C. for 2 hr. The mixture was concentrated in vacuo, diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a yellow solid (15.7 g, 86.6 mmol, 99%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:29][C:9]2=[N:10][CH:11]=[C:12]([C:27]#[N:28])[C:13]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)=[C:8]2[CH:7]=1.[I-].[Na+].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[N:32]1([CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[S:29][C:9]3=[N:10][CH:11]=[C:12]([C:27]#[N:28])[C:13]([NH:14][C:15]4[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=4)=[C:8]3[CH:7]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: COc1cc(Nc2c(C#N)cnc3sc(CCCCBr)cc23)cc(OC)c1OC
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Product: COc1cc(Nc2c(C#N)cnc3sc(CCCCN4CCOCC4)cc23)cc(OC)c1OC

Procedure:
To a solution of 2-(4-hydroxybutyl)-4-[(3,4,5-trimethoxyphenyl)amino]-thieno[2,3-b]pyridine-5-carbonitrile (413 mg, 1.0 mmol) and carbon tetrabromide (464 mg, 1.4 mmol) in 10 mL of dichloromethane is added a solution of triphenylphosphine (314 mg, 1.2 mmol) in 5 mL of dichloromethane with stirring. The mixture is stirred at room temperature for 2 hours and concentrated. The residue is purified by flash column chromatography eluting with a gradient of 9:1 hexane:ethyl acetate to 1:2 hexane:ethyl acetate to provide crude 2-(4-bromobutyl)-4-[(3,4,5-trimethoxyphenyl)amino]-thieno[2,3-b]pyridine-5-carbonitrile. The crude 2-(4-bromobutyl)-4-[(3,4,5-trimethoxyphenyl)amino]-thieno[2,3-b]pyridine-5-carbonitrile is heated 70° C. in 2 mL of morpholine in the presence of sodium iodide (100 mg, 0.67 mmol) for 1 hour. The mixture is concentrated, and the residue is purified by flash column chromatography eluting with a gradient of ethyl acetate to 10% methanol in ethyl acetate to provide 2-[4-(4-morpholinyl)butyl]-4-[(3,4,5-trimethoxyphenyl)amino]-thieno[2,3-b]pyridine-5-carbonitrile as a yellow oil; 1H NMR (DMSO-d6) δ 1.49 (quintet, J=7 Hz, 2H), 1.68 (quintet, J=7 Hz, 2H), 2.31 (m, 6H), 2.87 (t, J=7 Hz, 2H), 3.55 (m, 4H), 3.67 (s, 3H), 3.74 (s, 6H), 6.59 (s, 2H), 7.23 (s, 1H), 8.37 (s, 1H), 9.46 (s, 1H); MS 483.5 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:17]=[CH:16][O:15][C:14]=2[C:18]([O-:20])=[O:19])=[CH:9][CH:8]=1)([CH3:6])[CH3:5]>O.O1CCCC1>[CH3:6][C:4]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:17]=[CH:16][O:15][C:14]=2[C:18]([OH:20])=[O:19])=[CH:11][CH:12]=1)([CH3:3])[CH3:5]
Reactant: CC(C)(C)c1ccc(-c2ccoc2C(=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2ccoc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Sodium hydroxide (1.42 g) in water (17.75 ml) was added to a vigorously stirred solution of methyl 5-(4-(1,1-dimethylethyl)phenylfuran-2-carboxylate (4.579 g) in tetrahydrofuran (100 ml) and stirred at room temperature for 17 hours, the solvent was removed in vacuo and the residue dissolved in 10% sodium hydrogen carbonate solution (200 ml) then acidified with 2 M hydrochloric acid. The mixture was extracted with diethyl ether (3 x 200 ml), the ether washed with water and dried (MgSO4) The solvent was removed in vacuo to give 5-(4-(1,1-dimethylethyl)phenylfuran-2-carboxylic acid, m.p. 230° C.
Reaction SMILES: [H-].[Na+].[Br-].[CH2:4]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[O:30]1[C:34]2([CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]2)[O:33][CH2:32][CH2:31]1>CS(C)=O>[CH:4](=[C:37]1[CH2:38][CH2:39][C:34]2([O:33][CH2:32][CH2:31][O:30]2)[CH2:35][CH2:36]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C(=C1CCC2(CC1)OCCO2)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
To a suspension of NaH (0.306 g, 12.8 mmol) in DMSO (10 mL), a solution of benzyl-triphenylphosphonium bromide (5.44 g, 12.8 mmol) in DMSO (30 mL) was slowly added at rt. The solution was stirred 30 min at rt and then further 30 min at 50° C. Upon the crude mixture turning into dark red color, a solution of 1,4-dioxaspiro[4.5]decan-8-one (2.0 g, 12.8 mmol) in DMSO (14 mL) was added. The solution was stirred at 50° C. for 16 h. The reaction mixture was quenched with water and the aqueous layer extracted with AcOEt (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness to give a crude product, which was purified by column chromatography using a Teledyne ISCO apparatus, eluting with Cy/AcOEt (from 100:0 to 40:60) to afford the title compound (1.8 g, 61%) as a white solid. 1H NMR (CDCl3): δ 1.66-1.73 (m, 2H), 1.77-1.84 (m, 2H), 2.40-2.47 (m, 2H), 2.49-2.57 (m, 2H), 3.99 (s, 4H), 6.31 (s, 1H), 7.17-7.23 (m, 3H), 7.28-7.35 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH3:26][C@H:27]([NH2:38])[C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:38][CH:27]([C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[CH3:26])=[O:20]
Reactant: C[C@H](N)c1cccc2ccccc12
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(NC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), S-(-)-1-(1-naphthyl)ethylamine (0.570 g, 3.33 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-{1-(1-naphthyl)ethyl}-3,4,5,6-tetrahydrophthalamide as white crystals (0.410 g, 27.9% yield).
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][C:6]([CH:9]2[NH:14][C:13]([NH2:15])=[N:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[N:22]1[CH:27]=[CH:26][C:25]([C:28](=O)[CH2:29][C:30]([O:32]CC)=O)=[CH:24][CH:23]=1>C(O)C>[N:22]1[CH:23]=[CH:24][C:25]([C:28]2[N:15]=[C:13]3[NH:14][CH:9]([C:6]4[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=4)[CH2:10][CH2:11][N:12]3[C:30](=[O:32])[CH:29]=2)=[CH:26][CH:27]=1
Reactant: NC1=NCCC(c2ccncc2)N1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=c1cc(-c2ccncc2)nc2n1CCC(c1ccncc1)N2
Reaction time: 0.08 h
Yield: 21.2 %

Procedure:
A suspension containing 1.0 g (4.01 mmoles) of 6-(4-pyridinyl)-1,4,5,6-tetrahydro-2-pyrimidinamine dihydrochloride in 30 ml of ethanol was treated with 1.94 g (14.05 mmoles) of potassium carbonate and allowed to stir for 5 min. 1.0 g (4.01 mmoles) of ethyl 3-(pyridin-4-yl)-3-oxopropionate were added and the resulting mixture was heated at reflux temperature for 18 h. The cooled solution was evaporated to remove solvent and the residue was dissolved in water and extracted with dichloromethane. The organic extracts were washed with a saturated solution of aqueous sodium chloride, dried and the solvent evaporated under reduced pressure. The crude product thus obtained was purified using silica gel chromatography eluting with a gradient of dichloromethane/methanol/concentrated aqueous ammonia solution in the proportions 95/5/0.5 to 80/20/2. 0.26 g (21%) of pure product was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1F)[C:30]#[N:31].C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:13])([F:14])[F:12])[O:8][C:34]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][C:27]=1[F:26]
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn(C)c1=O
Reactant: N#Cc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc(C(O)(C(C)c2ccc(Oc3ccc(C#N)cc3F)cc2Cl)C(F)(F)F)cn(C)c1=O

Procedure:
In analogy to Example 156, step 1, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1H-pyridin-2-one (Example 203, step 5) was reacted with 3,4-difluorobenzonitrile and cesium carbonate to give the title compound as a colorless solid. MS (m/e)=495.2 [M+H+].
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[S:9]1[C:13]([S:14](Cl)(=[O:16])=[O:15])=[CH:12][C:11]2[CH:18]=[CH:19][CH:20]=[CH:21][C:10]1=2>C(Cl)Cl.N1C=CC=CC=1>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][S:14]([C:13]1[S:9][C:10]2[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=2[CH:12]=1)(=[O:15])=[O:16]
Reactant: Nc1ccccc1N
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
To a solution of o-phenylenediamine (5 mmol) in DCM (25 mL) and pyridine (5 mL) at 0° C., benzo[b]thiophene-2-sulfonyl chloride (5.5 mmol) was added in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (25 mL). The organic phase was washed with water (2×25 mL) and 25 mL of brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to give 1.2 g of benzo[b]thiophene-2-sulfonic acid (2-amino-phenyl)-amide. Tr 0.94 min, MS: 305.7 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ 6.40 (t, 1H), 6.60 (d, 1H), 6.78 (d, 1H), 6.89 (t, 1H), 7.45 (t, 1H), 7.50 (t, 1H), 7.80 (s, 1H), 7.90 (d, 1H), 8.80 (d, 1H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8](Cl)=[C:7]([S:10]([CH3:13])(=[O:12])=[O:11])[S:6](=[O:14])[N:5]=1)[CH3:2].C[Si]([NH:19][Si](C)(C)C)(C)C.CO>C(#N)C>[CH2:1]([O:3][C:4]1[C:8]([NH2:19])=[C:7]([S:10]([CH3:13])(=[O:12])=[O:11])[S:6](=[O:14])[N:5]=1)[CH3:2]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CCOC1=NS(=O)C(S(C)(=O)=O)=C1Cl
Solvent: CO
Solvent: CC#N
Product: CCOC1=NS(=O)C(S(C)(=O)=O)=C1N
Temperature: 25 °C
Yield: 60.3 %

Procedure:
To a solution of crude 3-ethoxy-4-chloro-5- methylsulfonylisothiazole-1-oxide (0.90 g, 1.6 mmol) in acetonitrile (10 ml) under a nitrogen atmosphere was added hexamethyldisilizane (0.70 ml, 3.3 mmol). The reaction mixture was heated at 70° for 11/2 hours, cooled to room temperature and methanol (1.0 ml) was added. The reaction was filtered and evaporated. The residue was triturated with methanol/ethyl acetate to afford crude title compound (0.3 g). Recrystallization from methanol/ethyl acetate after treatment with charcoal gave 0.23 g of pure product, mp 191°-193°.
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:23][CH:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:21]3)[N:9]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:5]=2[N:4]=1.[H-].[Na+].[CH3:41]I>C1COCC1>[F:38][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:21][CH:22]([N:24]([CH3:41])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23]3)[N:9]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CC(NC(=O)OC(C)(C)C)C2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CC(N(C)C(=O)OC(C)(C)C)C2)n1
Yield: 95 %

Procedure:
Reaction of tert-butyl 1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinylcarbamate (Example 30) with NaH/MeI in THF as in previous examples gave tert-butyl 1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl(methyl)-carbamate in 95% yield: mp (CH2Cl2/MeOH) 186-188° C.; 1H NMR (DMSO-d6) δ 8.00 (d, J=8.3 Hz, 1H), 7.75 (t, JHF=53.0 Hz, 1H), 7.39 (t, J=8.2 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 4.88 (br, 1H), 4.40-4.15 (m, 4H), 3.97 (s, 3H), 3.80-3.78 (m, 4H), 3.69 (m, 4H), 2.89 (s, 3H), 1.41 (s, 9H); Anal. Calcd. for C25H32F2N8O4: C, 54.9; H, 5.9; N, 20.5. Found: C, 55.1; H, 5.9; N, 20.6%.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][CH2:12][C:13](Cl)=[O:14].[C:16]1([S:22]([N:25]2[C:29]3=[N:30][CH:31]=[C:32]([NH:41][C:42](=[O:50])[CH2:43][C:44]4[C:45]([CH3:49])=[N:46][O:47][CH:48]=4)[C:33]([NH:34][CH:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)=[C:28]3[CH:27]=[CH:26]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[C:16]1([S:22]([N:25]2[C:29]3=[N:30][CH:31]=[C:32]([NH:41][C:42](=[O:50])[CH2:43][C:44]4[C:45]([CH3:49])=[N:46][O:47][CH:48]=4)[C:33]([NH:34][CH:35]4[CH2:40][CH2:39][N:38]([C:13](=[O:14])[CH2:12][O:11][CH3:10])[CH2:37][CH2:36]4)=[C:28]3[CH:27]=[CH:26]2)(=[O:23])=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COCC(=O)Cl
Reactant: Cc1nocc1CC(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)N1CCC(Nc2c(NC(=O)Cc3conc3C)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Diisopropylethylamine (0.107 ml, 0.615 mmol) and methoxyacetyl chloride (0.028 ml, 0.308 mmol) were added sequentially to a solution of N-[1-benzenesulfonyl-4-(piperidin-4-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-(3-methyl-isoxazol-4-yl)-acetamide (hydrochloride salt) (0.205 mmol) in CH2Cl2 (2 ml) at 25° C. The reaction mixture was stirred for 3 h at 25° C., then was partitioned between saturated NaHCO3 (6 ml) and CH2Cl2 (2 ml). The phases were separated using a phase separation column (Biotage) and the organic layer was concentrated under reduced pressure to give crude N-{1-benzenesulfonyl-4-[1-(2-methoxy-acetyl)-piperidin-4-ylamino]-1H-pyrrolo[2,3-b]pyridin-5-yl}-2-(3-methyl-isoxazol-4-yl)-acetamide as a brown oil/solid. LCMS (Method G, ESI): RT=0.73 min, m+H=567.3. This material was used in the next step below without additional purification or characterization.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:13]=[CH:12][C:8]2[NH:9]C=N[C:7]=2[CH:6]=1)[NH2:4].[NH:14]1[C:22]2C(=CC(C#N)=CC=2)C=N1>>[OH:1][N:2]=[C:3]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:12][CH:13]=1)[NH:9][N:14]=[CH:22]2)[NH2:4]
Reactant: N#Cc1ccc2[nH]ncc2c1
Reactant: NC(=NO)c1ccc2[nH]cnc2c1
Product: NC(=NO)c1ccc2[nH]ncc2c1

Procedure:
The title compound was prepared following procedure described for Intermediate 1, step 2, but starting from 1H-indazole-5-carbonitrile (JW-Pharmalab, 0.50 g; 3.49 mmol) as a beige solid (560 mg, 91%). 1H NMR (DMSO-d6) δ 13.12 (s, 1H), 9.54 (s, 1H), 8.10 (s, 1H), 8.04 (s, 1H), 7.71 (d, J=8.7 Hz, 1H), 7.49 (d, J=8.7 Hz, 1H), 5.82 (bs, 2H).