Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[Cl:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH:38]=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38][N:29]1[CH2:28][CH2:27][CH:26]([N:23]2[C:19]3=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]4[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=4)=[C:18]3[CH:25]=[N:24]2)[CH2:31][CH2:30]1
Reactant: O=Cc1cccc(Cl)c1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(Cc3cccc(Cl)c3)CC2)cc1

Procedure:
1-[1-(3-Chloro-benzyl)-piperidin-4-yl]-4-(4-methanesulfonyl-phenoxy)-1H-pyrazolo[3,4-d]pyrimidine was prepared according to General Procedure H by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with 3-chlorobenzaldehyde (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA), triethylamine, and sodium triacetoxyborohydride in 1,2-dichloroethane. 1H NMR (400 MHz, DMSO-d6) δ 1.89-1.98 (m, 2H), 2.18-2.28 (m, 4H), 2.93-2.99 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.57 (s, 2H), 4.77-4.83 (m, 1H), 7.32-7.41 (m, 4H), 7.62-7.64 (m, 2H), 8.04-8.07 (m, 2H), 8.37 (s, 1H), 8.55 (s, 1H). Mass spectrum MH+=498.
Reaction SMILES: COC(=O)[CH:4]([CH2:9][C:10]1[C:11]([NH:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=2[CH3:32])=[N:12][C:13]([CH3:22])=[CH:14][C:15]=1NC(CC)CC)[C:5]([O:7]C)=O.P(=O)(O)(O)O.[OH2:39]>>[CH2:4]([CH:9]([O:39][C:15]1[CH:14]=[C:13]([CH3:22])[N:12]=[C:11]2[C:10]=1[CH2:9][CH2:4][C:5](=[O:7])[N:23]2[C:24]1[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=1[CH3:32])[CH2:10][CH3:15])[CH3:5]
Reactant: CCC(CC)Nc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1CC(C(=O)OC)C(=O)OC
Reactant: O
Agent: O=P(O)(O)O
Product: CCC(CC)Oc1cc(C)nc2c1CCC(=O)N2c1c(C)cc(C)cc1C
Temperature: 25 °C

Procedure:
A mixture of 2-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-ylmethyl]-malonic acid dimethyl ester (100 mg, 0.219 mmol), 85% phosphoric acid (3 ml) and water (3 ml) was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated to dryness to give 91 mg of a clear oil. The oil was purified through silca gel column chromatography using 10% methanol (MeOH) in methylene chloride (CHCl2) as eluent to give a tan crystals, mp 138-140° C. 1H NMR (CDCl3) δ 6.93(s,2H), 6.31(s,1H), 4.21(m,1H), 2.93(m,2H), 2.76(m,2H), 2.31(s,3H), 2.19(s,3H), 1.99(s,6H), 1.71(m,4H), 0.96(t,6H) ppm.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[C:6]=2[N:7]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH2:16]([N:15]([CH2:18][CH3:19])[CH2:14][CH2:13][S:12][C:8]1[C:6]2[N:7]=[C:2]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:3]=[C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:5]=2[N:11]=[CH:10][N:9]=1)[CH3:17]
Reactant: C1CNCCN1
Reactant: CCN(CC)CCSc1ncnc2c(N3CCOCC3)nc(Cl)nc12
Product: CCN(CC)CCSc1ncnc2c(N3CCOCC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 2 from 2-chloro-8-(2-diethylamino-ethylthio)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (resin) and piperazine.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:28])=[C:24]([CH2:26][OH:27])[CH:25]=1>>[F:28][C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[CH:25][C:24]=1[CH2:26][OH:27]
Reactant: Nc1ccc(F)c(CO)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)c(CO)c1
Yield: 62.9 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 525 mg of (5-amino-2-fluorophenyl)-methanol in place of the 2,4-difluoroaniline. 218 mg of N-[4-fluoro-3-(hydroxymethyl)phenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([N:9]([CH:22]([CH3:24])[CH3:23])[S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16](O)=[O:17])(=[O:12])=[O:11])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH2:31][C:32]1[S:33][C:34]2[CH2:61][CH2:60][CH2:59][CH2:58][C:35]=2[C:36]=1[C:37]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][C:48]2[CH:57]=[CH:56][C:51]([C:52]([O:54][CH3:55])=[O:53])=[CH:50][CH:49]=2)=[CH:42][CH:41]=1)=[O:38]>CN(C=O)C.C(Cl)Cl.N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([N:9]([CH:22]([CH3:23])[CH3:24])[S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([NH:31][C:32]2[S:33][C:34]3[CH2:61][CH2:60][CH2:59][CH2:58][C:35]=3[C:36]=2[C:37]([NH:39][C:40]2[CH:41]=[CH:42][C:43]([CH2:46][CH2:47][C:48]3[CH:49]=[CH:50][C:51]([C:52]([O:54][CH3:55])=[O:53])=[CH:56][CH:57]=3)=[CH:44][CH:45]=2)=[O:38])=[O:17])(=[O:12])=[O:11])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(N)sc4c3CCCC4)cc2)cc1
Reactant: CCOC(=O)C1(N(C(C)C)S(=O)(=O)c2cccc(C(=O)O)c2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C1(N(C(C)C)S(=O)(=O)c2cccc(C(=O)Nc3sc4c(c3C(=O)Nc3ccc(CCc5ccc(C(=O)OC)cc5)cc3)CCCC4)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
A mixture of 307 mg of 3-{[1-(ethoxycarbonyl)cyclopropyl](isopropyl)sulfamoyl}benzoic acid, 0.10 mL of oxalyl chloride, 2.5 mL of dichloromethane, and one drop of DMF was stirred at room temperature for 2 hours, and then the reaction mixture was concentrated under reduced pressure. A mixture of the obtained crude product and 2.5 mL of dichloromethane was added to a mixture of 0.050 mL of pyridine, 250 mg of methyl 4-[2-(4-{[(2-amino-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, and 2.5 mL of methylene chloride, followed by stirring at room temperature overnight. The reaction mixture was purified by silica gel column chromatography (hexane-chloroform) to obtain 279 mg of methyl 4-(2-{4-[({2-[(3-{[1-(ethoxycarbonyl)cyclopropyl](isopropyl)sulfamoyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate as a yellow foamed solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1.N>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:9][N:8]=[C:7]([C:6]3[CH:5]=[N:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:20]=2)=[CH:15][CH:14]=1
Reactant: ON=C(Cl)c1cncc(F)c1
Reactant: C#Cc1ccc(Br)cc1
Agent: N
Product: Fc1cncc(-c2cc(-c3ccc(Br)cc3)on2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 28B (88 mg, 0.5 mmol) and 1-bromo-4-ethynylbenzene (Alfa Aesar, 80 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.43 (s, 1H), 7.72 (dt, J=8.9, 2.2 Hz, 2H), 7.85 (dt, J=8.9, 2.2 Hz, 2H), 8.17 (ddd, J=9.5, 2.7, 1.7 Hz, 1H), 8.61 (d, J=2.7 Hz, 1H), 8.96 (t, J=1.5 Hz, 1H) ppm; MS (DCI/NH3) m/z 320 (M+H)+, 318 (M+H)+.
Reaction SMILES: [Cl-].C([Al+]CC)C.C[O:8][C:9]([C:11]1[CH:15]=[C:14]([Br:16])[N:13]([CH:17]([CH3:19])[CH3:18])[C:12]=1[CH:20]([C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=1)[NH:21][C:22]1[N:23]([CH3:28])[N:24]=[C:25]([CH3:27])[CH:26]=1)=O>>[Br:16][C:14]1[N:13]([CH:17]([CH3:18])[CH3:19])[C:12]2[CH:20]([C:29]3[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=3)[N:21]([C:22]3[N:23]([CH3:28])[N:24]=[C:25]([CH3:27])[CH:26]=3)[C:9](=[O:8])[C:11]=2[CH:15]=1
Reactant: COC(=O)c1cc(Br)n(C(C)C)c1C(Nc1cc(C)nn1C)c1ccc(C#N)cc1
Agent: CC[Al+]CC
Agent: [Cl-]
Product: Cc1cc(N2C(=O)c3cc(Br)n(C(C)C)c3C2c2ccc(C#N)cc2)n(C)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Step H1, but diethylaluminium chloride (1.8M in toluene) [96-10-6] was used instead of trimethylaluminium chloride, and 5-bromo-2-[(4-cyano-phenyl)-(2,5-dimethyl-2H-pyrazol-3-ylamino)-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester (Step AX1) was used instead of 2-[(3-chloro-4-fluoro-phenylamino)-(4-cyano-phenyl)-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester to afford the title compound as a solid. ESI-MS: tR=0.99 min, [M+H]+ 438/440 (LC-MS 1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=O)[CH2:10][CH:9]1[CH2:14][O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:10][C@H:9]1[CH2:14][O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)CC1COC(=O)C(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1C[C@H](NCc2ccccc2)C[C@H]1COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 2-(2,2-dimethyl-propionyloxymethyl)-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (prepared according to WO2007017828, 8.0 g, 26.7 mmol) and benzylamine (2.9 mL, 1 eq) in DCE (100 mL) were added NaBH(OAc)3 (7.9 g, 1.4 eq) and AcOH (1.53 mL, 1 eq) and the resulting solution was stirred at rt for 1 h. The mixture was quenched by adding NH4OH and the aq. layer was extracted with EA. The combined org. layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by CC (DCM/MeOH/NH4OH 1000:25:2) to afford the title intermediate as a yellow oil (10.2 g, 98%).
Reaction SMILES: [F:1][B-](F)(F)F.[C:6]([OH:14])(=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1CCN2C(=NCCC2)CC1.Cl>ClCCl>[C:6]([F:1])(=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccccc1
Reactant: F[B-](F)(F)F
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=C(F)c1ccccc1
Reaction time: 4 h
Yield: 72.5 %

Procedure:
To a suspension of diethylaminosulfinium tetrafluoroborate (344 mg, 1.5 mmol) in dichloromethane (3.0 mL) at room temperature is added benzoic acid (122 mg, 1.0 mmol) and DBU (224 μl, 1.5 mmol). The reaction mixture is stirred for 4 hours, then an 10% aqueous solution of HCl is added and stirring is continued for 15 minutes. The resulting mixture is extracted twice using dichloromethane. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated. The crude material is diluted with pentane and the solution is passed through a pad of silica gel with pentane elution. Solvent are evaporated in vacuum to provide benzoyl fluoride (90 mg, 74%) as a clear liquid. 1H NMR (CDCl3, 300 MHz) δ 7.94 (d, J=7.8, 2H), 7.62 (t, J=7.3 Hz, 1H), 7.43 (t, J=8.2 Hz, 2H); 19F NMR (CDCl3, 282 MHz) δ 17.5 (s, 1F); 13C NMR (CDCl3, 75 MHz) δ 157.3 (d, 1JC-F=344.3 Hz), 135.5, 131.5 (d, 3JC-F=4.0 Hz), 129.2, 125.0 (d, 2JC-F=60.4 Hz).
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([OH:9])[CH2:6][CH:7]=[CH2:8])[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:13][CH:14]([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]>O1CCCC1>[CH2:16]([O:15][CH:14]([O:18][CH2:19][CH3:20])[CH2:13][O:9][CH:5]([CH2:6][CH:7]=[CH2:8])[CH2:4][CH:1]1[CH2:3][CH2:2]1)[CH3:17]
Reactant: C=CCC(O)CC1CC1
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(CC1CC1)OCC(OCC)OCC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-cyclopropylpent-4-en-2-ol (C65) (16 g, 0.127 mmol) in tetrahydrofuran (200 mL) was added to a 0° C. suspension of sodium hydride (60% in mineral oil, 15.2 g, 0.38 mol) in tetrahydrofuran (400 mL). After stirring at room temperature for 10 minutes, 2-bromo-1,1-diethoxyethane (97%, 75 g, 0.38 mol) was added drop-wise at room temperature. The reaction mixture was heated to 70° C. for 24 hours. It was then cooled to 0° C., slowly quenched with water (200 mL) and extracted with dichloromethane (3×500 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo; purification via silica gel chromatography (Gradient: 0% to 10% ethyl acetate in petroleum ether) afforded the product as a yellow oil. Yield: 20 g, 83 mmol, 65%. 1H NMR (400 MHz, CDCl3) δ 5.79-5.89 (m, 1H), 5.04 (dt, J=14.0, 1.6 Hz, 2H), 4.60 (t, J=5.2 Hz, 1H), 3.64-3.73 (m, 2H), 3.51-3.62 (m, 4H), 3.45 (quintet, J=6.0 Hz, 1H), 2.31 (t, J=6.4 Hz, 1H), 1.50 (quintet, J=6.8 Hz, 1H), 1.20-1.30 (m, 2H), 1.21 (dt, J=6.8, 1.2 Hz, 6H), 0.72-0.80 (m, 1H), 0.38-0.49 (m, 2H), −0.02-0.10 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4](Cl)[N:3]=1.C([Sn](CCCC)(CCCC)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)CCC>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.C1(C)C(C)=CC=CC=1>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:4]1[N:3]=[C:2]([NH2:1])[CH:7]=[N:6][CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Nc1cncc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: Nc1cncc(-c2ccccn2)n1
Reaction time: 20 h
Yield: 71.5 %

Procedure:
An oven dried resealable Schlenk tube was charged with 2-amino-6-chloropyrazine (1.00 g, 7.72 mmol), 2-(tributylstannyl)pyridine (3.55 g, 7.72 mmol) and xylene (40 mL). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and tetrakis(triphenylphosphine)palladium (446 mg, 0.38 mmol) was added. After three new cycles of evacuation-backfilling with argon, the Schlenk tube was capped and placed in a 150° C. oil bath. After 20 h, the mixture was cooled, partitioned between water and ethyl acetate, the aqueous phase was extracted twice with ethyl acetate, the organic layers washed with brine, dried (MgSO4) and evaporated. Silica gel flash chromatography (dichloromethane/methanol 98:2 to dichloromethane/methanol 90:10) provided the title compound as a light brown solid (950 mg, 71%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([Cl:16])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[F:17][C:18]([F:30])([F:29])[C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>N1C=CC=CC=1>[Cl:16][C:10]1[CH:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:25]([C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:29])[F:30])=[CH:24][CH:23]=3)(=[O:27])=[O:26])[CH:7]=[N:6][CH:5]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1ccc(-c2cncc(N)c2)cc1Cl
Solvent: c1ccncc1
Product: N#Cc1ccc(-c2cncc(NS(=O)(=O)c3ccc(C(F)(F)F)cc3)c2)cc1Cl
Yield: 39.4 %

Procedure:
According to General Sulfonylation Procedure 2 in Example 1, to a solution of 4-(5-amino-pyridin-3-yl)-2-chloro-benzonitrile (20 mg, 87 μmol, leg) in anhydrous pyridine (500 μl) was added 4-trifluoromethyl-benzenesulfonyl chloride (23.4 mg, 96 μmol, 1.1 eq). The crude product was purified by Isco Cornbiflash® Companion™ flash chromatography system on normal phase (4 g SiO2, flow rate 18 mL/min), eluting with mixtures of dichloromethane/methanol, to give N-[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-4-trifluoromethyl-benzenesulfonamide (15 mg, >95% purity, yield: 40%). The isolated product was lyophilized and identified by LC-MS (system 1) and NMR (system 3): ESI-MS m/z: 438 [M+H]+, retention time=2.57 min, 1H NMR (500 MHz, DMSO-d6) δ ppm 7.80 (dd, J=8.24, 1.53 Hz, 1H) 7.82 (d, J=1.98 Hz, 1H) 7.93-7.98 (m, 2H) 7.98-8.03 (m, 2H) 8.04 (s, 1H) 8.09 (d, J=8.09 Hz, 1H) 8.31 (s, 1H) 8.68 (br. s., 1H) 11.00 (br. s., 1H).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[H-].[Na+].F[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[N:19]([CH3:20])[C:18]2[CH:21]=[CH:22][C:23]([C:25]([F:28])([F:27])[F:26])=[CH:24][C:17]=2[N:16]=1.[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([O:5][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[N:19]([CH3:20])[C:18]2[CH:21]=[CH:22][C:23]([C:25]([F:28])([F:27])[F:26])=[CH:24][C:17]=2[N:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: Cn1c(-c2ccncc2F)nc2cc(C(F)(F)F)ccc21
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCCOc1cnccc1-c1nc2cc(C(F)(F)F)ccc2n1C
Reaction time: 0.17 h
Yield: 89.3 %

Procedure:
To a mixture of 0.44 g of 1-butanol and 6 ml of DMF was added 0.24 g of 60% sodium hydride (oily) under ice cool, and the mixture was stirred for 10 minutes. And, 2-(3-fluoropyridin-4-yl-)-1-methyl-5-trifluoromethyl-1H-benzimidazole (0.35 g) was added, then, the mixture was stirred for 1.5 hours at room temperature. Into the reaction mixture was poured a saturated ammonium chloride aqueous solution, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, to obtain 0.37 g of 2-(3-butoxypyridin-4-yl-)-1-methyl-5-trifluoromethyl-1H-benzimidazole (hereinafter, referred to as present active compound 206).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([CH2:18][CH2:19][CH3:20])[S:17][C:10]=12.[C:22]1([CH2:28][C:29]([N:31]=[C:32]=[S:33])=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:21][C:32]([NH:31][C:29](=[O:30])[CH2:28][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[S:33])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([CH2:18][CH2:19][CH3:20])[S:17][C:10]=12
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CCCc1cc2nccc(Oc3ccc(N)cc3F)c2s1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
A mixture of 3-fluoro-4-(2-propylthieno[3,2-b]pyridin-7-yloxy)benzenamine (8 mg, 0.03 mmol) and 2-phenylethanoyl isothiocyanate (9 mg, 0.05 mmol; prepared according to J. Org. Chem. 1964, 29, 1115-1119) in 1:1 toluene/ethanol (0.5 mL) were stirred at room temperature for 2 hours. The reaction mixture was purified by preparative TLC (5% MeOH/EtOAc). The product was obtained as a waxy solid (8 mg, 58%). 1H NMR (400 MHz, CDCl3) δ 12.49 (s, 1H), 8.57 (s, 1H), 8.45 (m, 1H), 7.94 (m, 1H), 7.44 (m, 4H), 7.32 (m, 2H), 7.25 (m, 2H, overlaps chloroform), 6.48 (m, 1H), 3.76 (s, 2H), 2.93 (m, 2H), 1.81 (m, 2H), 1.04 (m, 3H). LRMS (ESI neg) m/e 478 (M−1).
Reaction SMILES: Cl[C:2]1[N:27]=[CH:26][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:17]=[C:16]([CH2:24][OH:25])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([C:2]2[N:27]=[CH:26][C:5]3[C:6]4[N:7]([CH:11]=[C:12]([C:14]5[N:18]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:17]=[C:16]([CH2:24][OH:25])[N:15]=5)[N:13]=4)[CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C1CCNC1
Reactant: OCc1nc(-c2cn3c(n2)-c2cnc(Cl)cc2OCC3)n(CC(F)(F)F)n1
Product: OCc1nc(-c2cn3c(n2)-c2cnc(N4CCCC4)cc2OCC3)n(CC(F)(F)F)n1

Procedure:
(5-(9-chloro-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)methanol 387 was reacted with pyrrolidine to give 390 (13 mg) as a colorless solid. LCMS: 436.1. 1H NMR (400 MHz, DMSO) δ 9.05 (s, 1H), 7.93 (s, 1H), 5.95 (s, 1H), 5.84 (q, J=8.9 Hz, 2H), 5.32 (t, J=6.1 Hz, 1H), 4.50 (m, 4H), 4.45 (d, J=6.0 Hz, 2H), 3.41 (m, 4H), 1.95 (m, 4H)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[C:4](Cl)[N:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:4]2[CH:5]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[N:7]=[C:2]([Cl:1])[N:3]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(=O)Nc1cc(Cl)nc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc(Cl)n1
Temperature: 130 °C
Yield: 8 %

Procedure:
A mixture of N-(2,6-dichloro-pyrimidin-4-yl)-acetamide (0.7 g, 3.40 mmol, 1.0 equiv; intermediate B1) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.82 g, 4.08 mmol, 1.2 equiv) in anhydrous DMF (6 mL) was heated by microwave irradiation to 130° C. for 4 h. Removal of the solvent under reduced pressure and purification with column chromatography on silica eluting with a gradient of heptane/ethyl acetate (3:1→1:1) provided 0.1 g (8%) of the title compound. 1H NMR (300 MHz, CDCl3): δ1.33-1.45 (m, 2H), 1.47 (s, 9H), 1.97-2.08 (m, 2H), 2.18 (s, 3H), 2.90-2.99 (m, 2H), 4.01-4.08 (m, 3H), 5.19 (br s, 1H), 7.13 (s, 1H), 8.04 (br s, 1H). MS (ISP): 370.1 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[O:18][CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:25](=[O:27])=[O:26]>O1CCCC1>[C:1]1([CH2:7][C:8]2[CH:17]=[C:16]([C:25]([OH:27])=[O:26])[C:15]3[C:10]([C:9]=2[O:18][CH3:19])=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1c(Cc2ccccc2)ccc2ccccc12
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1c(Cc2ccccc2)cc(C(=O)O)c2ccccc12
Reaction time: 0.75 h
Yield: 90 %

Procedure:
A solution of the compound of Example 94 Part B (5.00 g, 0.015 mole) in dry tetrahydrofuran (50 mL) was cooled to -78° and treated dropwise with n-butyllithium (1.55M in hexane; 10.9 mL, 0.017 mole). The mixture was stirred at -78° for 45 minutes, and a stream of gaseous carbon dioxide was directed onto the surface of the stirred solution. The cooling bath was removed from the reaction vessel and the addition of carbon dioxide was continued for 5 minutes. The mixture was then poured into 1.0N hydrochloric acid, and the crude product isolated by extraction with methylene chloride. This was recrystallized (methylcyclohexane) to provide the title compound (4.0 g, 90%) as a pale yellow solid, mp 146°-148°.
Reaction SMILES: C[NH+]1CCOCC1.[NH2:8][C:9]1[C:14]([C:15]#[N:16])=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)(=[O:25])=[O:24])=[CH:19][CH:18]=2)[C:12]([C:33]#[N:34])=[C:11]([SH:35])[N:10]=1.Br[CH2:37][C:38]([NH2:40])=[O:39].C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:8][C:9]1[N:10]=[C:11]([S:35][CH2:37][C:38]([NH2:40])=[O:39])[C:12]([C:33]#[N:34])=[C:13]([C:17]2[CH:18]=[CH:19][C:20]([S:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)(=[O:25])=[O:24])=[CH:21][CH:22]=2)[C:14]=1[C:15]#[N:16]
Reactant: CN1CCN(S(=O)(=O)c2ccc(-c3c(C#N)c(N)nc(S)c3C#N)cc2)CC1
Reactant: NC(=O)CBr
Agent: C[NH+]1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(S(=O)(=O)c2ccc(-c3c(C#N)c(N)nc(SCC(N)=O)c3C#N)cc2)CC1

Procedure:
84 mg (0.163 mmol) of 2-amino-4-{4-[(4-methylpiperazino)sulfonyl]phenyl}-6-sulfanyl-3,5-pyridinedicarbonitrile N-methylmorpholinium salt together with 53.3 mg (0.244 mmol) of bromoacetamide and 54.7 mg (0.65 mmol) of NaHCO3 are stirred in 0.5 ml of DMF overnight. After filtration, the reaction solution is initially purified by preparative HPLC. The isolated fraction is reconcentrated under reduced pressure and the residue is purified by preparative thin-layer chromatography.