Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][C:12]=2[F:19])=[C:4]([C:20]([O:22]C)=O)[CH:3]=1.[CH:24]([O:26][CH2:27][CH2:28][O:29][NH2:30])=[CH2:25].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[F:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][C:12]=2[F:19])=[C:4]([C:20]([NH:30][O:29][CH2:28][CH2:27][O:26][CH:24]=[CH2:25])=[O:22])[CH:3]=1
Reactant: C=COCCON
Reactant: COC(=O)c1cc(F)c(=O)n(C)c1Nc1ccc(SC)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=COCCONC(=O)c1cc(F)c(=O)n(C)c1Nc1ccc(SC)cc1F
Reaction time: 0.33 h

Procedure:
To a mixture of methyl 5-fluoro-2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylate (0.100 g, 0.294 mmol) and O-(2-(vinyloxy)ethyl)hydroxylamine (0.045 ml, 0.441 mmol) in THF (2 mL) at 0° C. was added lithium bis(trimethylsilyl)amide (1.18 ml, 1.18 mmol, 1 M solution in hexanes) dropwise. The reaction mixture was stirred for 20 minutes, quenched with 1 M HCl, and then partitioned between EtOAc and sat NaCl. The layers were separated and the aqueous layer was backextracted with EtOAc (1×). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure to yield a crude yellow solid that was used without purification in the next step.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.C(#N)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CP(C)C.CCCCCCCCCCCCC>C1COCC1.[Zn+2].[Br-].[Br-]>[C:1]1([C:7]#[C:8][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccccc1
Reactant: C#Cc1ccccc1
Agent: CCCCCCCCCCCCC
Agent: CP(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: C(#Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 44 h
Yield: 71.5 %

Procedure:
A solution of phenylacetylene (0.439 ml; 0.409 g; 4.00 mmol) in THF (2 ml) was treated at 0° C. with n-butyllithium (1.6 ml; 4.0 mmol; 2.5 M in hexanes) and the resulting solution was allowed to warm to room temperature for 10 min. The solution was cooled to 0° C., then treated with a solution of ZnBr2 (0.901 g; 4.00 mmol) in THF (2 ml) and allowed to warm to room temperature for 30 min. Solvent was removed in vacuo, then THF (2 ml) was added. This solution was then added to a room temperature solution of benzonitrile (0.204 ml; 0.206 g; 2.00 mmol), dichlorobis(trimethylphosphine)nickel (0.0282 g; 5 mol %), trimethylphosphine (0.20 ml; 0.20 mmol; 1.0 M in THF), and tridecane (0.244 ml; 0.184 g; 1.00 mmol) in THF (2 ml). The reaction mixture was then heated to 65° C. and stirred for 44 h; then a sample was withdrawn and quenched in a mixture of 1 M sodium citrate (aq) and MTBE. GC analysis of the organic phase of the hydrolyzed reaction sample showed the presence of 1.43 mmol (72% yield) of diphenylacetylene and 0.36 mmol of benzonitrile remaining in the reaction mixture.
Reaction SMILES: [C:1]1([N:7]2[C:11]([S:12][CH3:13])=[N:10][C:9]([OH:14])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OO)(=[O:17])C>C(OCC)(=O)C.C(O)(=O)C>[C:1]1([N:7]2[C:11]([S:12]([CH3:13])=[O:17])=[N:10][C:9]([OH:14])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSc1nc(O)nn1-c1ccccc1
Reactant: CC(=O)OO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CS(=O)c1nc(O)nn1-c1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
An amount of 41.4 g of 1-phenyl-5-methylmercapto-3-hydroxy-1,2,4-triazole is suspended at 50°C in 400 ml of ethyl acetate. An addition is then made dropwise, within 15 minutes, of 60 ml of a 60% solution of peroxyacetic acid in glacial acetic acid at 45°-50°C. After completion of the addition, the solution is stirred for 2 hours at 50°C, and the cooled to 20°C. The precipitated product is filtered off, washed with water, and dried in vacuo. The resulting product is 1-phenyl-5-methylsulphinyl-3-hydroxy-1,2,4-triazole in the form of white crystals, M.P. 180°-182°C.
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([CH2:11][CH:12]([CH3:17])[CH2:13][NH:14]2)[CH2:9]1)C1C=CC=CC=1>CO.[Pd].C>[CH3:17][CH:12]1[CH2:11][CH:10]2[CH:15]([CH2:16][NH:8][CH2:9]2)[NH:14][CH2:13]1
Reactant: CC1CNC2CN(Cc3ccccc3)CC2C1
Agent: [Pd]
Solvent: CO
Product: CC1CNC2CNCC2C1

Procedure:
8.0 g (35 mmol) of 8-benzyl-4-methyl-2,8-diazabicyclo[4.3.0]nonane are dissolved in 60 ml of methanol and hydrogenated over palladium on active charcoal at 100° C. and under 100 bar. Then the catalyst is filtered off, the filtrate is concentrated by evaporation and the residue is distilled.
Reaction SMILES: CC([O-])(C)C.[K+].CC1C=CC(S([CH2:17][N+:18]#[C-])(=O)=O)=CC=1.[CH2:20]([O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH:31]=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CO>C1COCC1.O>[CH2:20]([O:27][C:28]1[CH:29]=[C:30]([CH2:31][C:17]#[N:18])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CC#N)cc1OCc1ccccc1
Reaction time: 0.25 h
Yield: 38 %

Procedure:
To a suspension of t-BuOK (20.15 g, 0.165 mol) in THF (250 mL) was added a solution of TosMIC (16.1 g, 82.6 mmol) in THF (100 mL) at −78° C. The mixture was stirred for 15 minutes, treated with a solution of 3-benzyloxy-4-methoxy-benzaldehyde (10.0 g, 51.9 mmol) in THF (50 mL) dropwise, and continued to stir for 1.5 hours at −78° C. To the cooled reaction mixture was added methanol (50 mL). The mixture was heated at reflux for 30 minutes. Solvent of the reaction mixture was removed to give a crude product, which was dissolved in water (300 mL). The aqueous phase was extracted with EtOAc (100 mL×3). The combined organic layers were dried and evaporated under reduced pressure to give crude product, which was purified by column chromatography (Petroleum Ether/EtOAc 10:1) to afford 2-(3-(benzyloxy)-4-methoxyphenyl)acetonitril (5.0 g, 48%). 1H NMR (300 MHz, CDCl3) δ 7.48-7.33 (m, 5 H), 6.89-6.86 (m, 3 H), 5.17 (s, 2 H), 3.90 (s, 3 H), 3.66 (s, 2 H). 13C NMR (75 MHz, CDCl3) δ 149.6, 148.6, 136.8, 128.8, 128.8, 128.2, 127.5, 127.5, 122.1, 120.9, 118.2, 113.8, 112.2, 71.2, 56.2, 23.3.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.[C:12]1(=[O:28])[N:16]([CH2:17][CH2:18][CH2:19][C:20](=[S:22])[NH2:21])[C:15](=[O:23])[C:14]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:13]12>>[C:15]1(=[O:23])[N:16]([CH2:17][CH2:18][CH2:19][C:20]2[S:22][C:2]3[CH2:10][C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[C:3]=3[N:21]=2)[C:12](=[O:28])[C:13]2=[CH:27][CH:26]=[CH:25][CH:24]=[C:14]12
Reactant: NC(=S)CCCN1C(=O)c2ccccc2C1=O
Reactant: O=C1c2ccccc2CC1Br
Product: O=C1c2ccccc2C(=O)N1CCCc1nc2c(s1)Cc1ccccc1-2

Procedure:
2-Bromo-1-indanone, 4-phthalimidobutanethioamide
Reaction SMILES: [CH2:1]([OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C>O1CCCC1>[CH3:24][S:25]([O:23][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCCCCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCCCCCOS(C)(=O)=O
Temperature: 40 °C
Reaction time: 1 h

Procedure:
247.4 g of behenyl alcohol (1-docosanol) was dissolved in 640 mL of tetrahydrofuran, 116.1 mL of methanesulfonyl chloride was gradually added, and 64.7 mL of triethylamine was then added dropwise under ice cooling over 30 minutes. After stirring for one hour, the mixture was heated at 40° C. and further stirred for 30 minutes. The reaction mixture was poured into 3.5 L of ice water, and the resulting mixture was ultrasonically dispersed for 15 minutes and further stirred at room temperature for 4 hours. The dispersion was filtered under reduced pressure, and a crystal was washed with 2 L of water. The resulting white crystal was stirred in 1.5 L of acetonitrile for one hour, filtered under reduced pressure and then washed with 0.5 L of acetonitrile. The resulting crystal was dried under reduced pressure to obtain 303.4 g of a white crystal.
Reaction SMILES: [CH2:1]([N:3]([CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([F:33])[CH:27]=3)[N:18]=2)[CH:14]=[CH:15][CH:16]=1)[CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH3:2].[CH:34](=O)[CH2:35][CH3:36]>>[CH2:1]([N:3]([CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([F:33])[CH:27]=3)[N:18]=2)[CH:14]=[CH:15][CH:16]=1)[CH:4]1[CH2:5][CH2:6][N:7]([CH2:34][CH2:35][CH3:36])[CH2:8][CH2:9]1)[CH3:2]
Reactant: CCN(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(F)c3)n2)c1)C1CCNCC1
Reactant: CCC=O
Product: CCCN1CCC(N(CC)Cc2cccc(-c3ccnc(NCCc4ccc(O)c(F)c4)n3)c2)CC1

Procedure:
Intermediate 92 was coupled with propionaldehyde following procedure E. The product was purified by HPLC. LC-MS showed the product had the expected M+H+ of 492. 1H NMR (Varian 300 MHz, DMSO, shifts relative to the solvent peak at 2.50 ppm) δ 7.9 (d, 1H), 7.4-7.3 (m, 2H), 7.2 (t, 1H), 7.0-6.9 (m, 2H), 6.8 (m, 3H), 3.6 (s, 2H), 3.5 (d, 2H), 3.1 (m, 3H), 2.7 (q, 2H), 2.6 (m, 4H), 2.2 (t, 2H), 1.7-1.6 (m, 4H), 1.5-1.4 (m, 2H), 0.94 (t, 3H), 0.80 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]([CH3:22])([OH:21])[CH3:20])=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:25][N:26]1[C:30]([CH3:31])=[C:29]([C:32](O)=[O:33])[C:28](=[O:35])[N:27]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CCOC(C)=O.O>[OH:21][C:19]([CH3:22])([CH3:20])[CH2:18][O:17][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([O:6][C:5]3[CH:23]=[CH:24][C:2]([NH:1][C:32]([C:29]4[C:28](=[O:35])[N:27]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:26]([CH3:25])[C:30]=4[CH3:31])=[O:33])=[CH:3][CH:4]=3)=[CH:8][CH:9]=[N:10]2)=[CH:15][CH:14]=1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Reactant: CC(C)(O)COc1ccc2c(Oc3ccc(N)cc3)ccnc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCC(C)(C)O)ccc34)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 45 °C
Reaction time: 4 h
Yield: 48.7 %

Procedure:
To a solution of 1-((4-(4-aminophenoxy)quinolin-7-yl)oxy)-2-methylpropan-2-ol (3.75 g, 11.6 mmol) in DCM (31 mL) was added 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (2.7 g, 11.8 mmol), HOAT (0.32 g, 2.32 mmol), EDCI (2.7 g, 13.9 mmol). The reaction mixture was refluxed for 3 hours, then cooled to 45° C. and continued to stir for 4 hours. Additional EDCI (0.4 eq., 0.90 g, 4.64 mmol) was added and the reaction was stirred overnight at 45° C. The mixture was cooled to room temperature and diluted with a mixture of EtOAc (30 mL) and water (30 mL). After stirring at room temperature for 2 hours, the mixture was filtered. The solid was stirred in 95% EtOH (15 mL) at −5° C. for 5 hours. The solid was collected through filtration, dried in vacuo at 50° C. overnight to give the title compound as a gray-white solid (3.04 g, 48.87%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([NH:12][CH:13]2[CH2:15][CH2:14]2)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH2:29]([O:36][NH2:37])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C1COCC1>[CH2:29]([O:36][NH:37][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([F:11])[C:2]([Cl:1])=[CH:3][C:4]=1[NH:12][CH:13]1[CH2:15][CH2:14]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)c1cc(F)c(Cl)cc1NC1CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NOCc1ccccc1)c1cc(F)c(Cl)cc1NC1CC1
Yield: 100.3 %

Procedure:
Following the procedure of Example A, 4-chloro-2-cyclopropylamino-5-fluoro-benzoic acid (Example C-3, 2.0 g, 8.7 mmol) was reacted with carbonyldiimidazole (1.7 g, 10.5 mmol), O-benzylhydroxylamine hydrochloride (1.67 g, 10.5 mmol), and triethylamine (1.5 mL, 10.5 mmol) in THF (50 mL) to give 2.92 g of the title compound.
Reaction SMILES: Cl.Cl.[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.[C:20]1([CH3:29])[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>>[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([CH3:29])=[CH:21][CH:22]=2)=[O:28])=[CH:15][CH:14]=1
Reactant: Nc1ccc(N2CCc3ccncc3C2)cc1
Reactant: Cc1ccc(N=C=O)cc1
Agent: Cl
Product: Cc1ccc(NC(=O)Nc2ccc(N3CCc4ccncc4C3)cc2)cc1
Yield: 71.1 %

Procedure:
In a manner similar to that described in Example 163, 4-(3,4-dihydro-2,7-naphthyridin-2(1H)-yl)aniline dihydrochloride (75.0 mg, 0.251 mmol) and para-tolyl isocyanate (0.047 mL, 0.377 mmol) were reacted to give the title compound as a white solid (64 mg, 71%). 1H NMR (DMSO-d6) δ: 8.42 (s, 2H), 8.34 (s, 1H), 8.31 (d, J=5.0 Hz, 1H), 7.29-7.34 (m, 4H), 7.17 (d, J=5.3 Hz, 1H), 7.06 (d, J=8.5 Hz, 2H), 6.95-7.02 (m, 2H), 4.33 (s, 2H), 3.47 (t, J=5.9 Hz, 2H), 2.91 (t, J=5.9 Hz, 2H), 2.23 (s, 3H).
Reaction SMILES: S(O)(=O)(=O)C.[NH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9]([SH:14])[N:8]=1.[H-].[Na+].Cl[CH:18]([C:20]1[N:21]=[CH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:19].O>CN(C)C=O>[NH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9]([S:14][CH:18]([C:20]2[N:21]=[CH:22][C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:19])[N:8]=1
Reactant: Nc1cc(Cl)nc(S)n1
Reactant: CC(Cl)c1cc2ccccc2cn1
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Sc1nc(N)cc(Cl)n1)c1cc2ccccc2cn1
Reaction time: 1 h
Yield: 57.3 %

Procedure:
4-Amino-6-chloro-2-mercapto-pyrimidine mesylate salt (1.79 g, 6.94 mmole) is dissolved in 12 ml dry dimethylformamide in a 50 ml one neck round bottom flask under nitrogen. The solution is treated with 60% sodium hydride (605 mg, 15.1 mmole) (exotherm) and the mixture is stirred one hour. 3-(1-chloroethyl)-isoquinoline (1.33 g, 6.94 mmole) in 2×3 ml dry dimethylformamide, is added to the reaction and the mixture is stirred 6 hours at room temperature. The reaction mixture is poured into 300 ml water and is extracted with 3×100 ml ethyl acetate. The combined organics are backwashed with 4×50 ml 50% saturated sodium chloride. The organics are dried over potassium carbonate and are concentrated in vacuo to a yellow oil. The crude material is chromatographed over 75 g silica gel (230-400 mesh), eluting with 40% acetone/hexane while collecting 9 ml fractions. Fractions 26-39 are combined and concentrated to afford 1.26 g (57%) of 4-Amino-6-chloro-2-(1-(3-isoquinolyl)ethyl)thio-pyrimidine as a white solid.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[Cl:8][C:9]1[CH:10]=[N:11][C:12](=[O:15])[NH:13][CH:14]=1.Br[CH2:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1>CN(C=O)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([S:18][CH2:17][N:11]2[CH:10]=[C:9]([Cl:8])[CH:14]=[N:13][C:12]2=[O:15])=[CH:20][CH:21]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: Clc1ccc(SCBr)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1ncc(Cl)cn1CSc1ccc(Cl)cc1

Procedure:
Potassium tert-butoxide (40 mmol) in DMF (25 ml) was added to a solution of 5-chloropyrimidin-2-one hydrochloride (20 mmol) in DMF (125 ml). The mixture was stirred at room temperature for 15 min before 1-bromomethylsulfenyl-4-chlorobenzene [see U.S. Pat. No. 2,827,492; Chem. Abstract 52 Pl 6296 d (1958)] (25 mmol) was added. The resultant mixture was stirred at room temperature at 60° C. for 3h, the solvent removed at reduced pressure and the residue triturated with water and dried. The residual product was a mixture of the N- and O-alkylated isomers in the ratio 3:1 (1H NMR); yield 4.2 g (73%). The isomers were separated by their different solubilities in acetone, the less polar O-isomer being the more soluble isomer. The title compound, the N- isomer had m.p. 191° C. (acetone). (Found C45.90; H2.78. Calc. for C11H8Cl2N2OS: C46.00; H2.81) 1H NMR (CDCl3): δ 5.25 (CH2), 7.35 (Ph, s), 8.20 and 8.50 (H-4, H-6, d, J 4Hz). IR (KBr): 1660 cm-1 (CO). MS (70 eV; m/z (% rel. int)): 286 (4, M), 157 (11), 156 (11), 145 (33), 143 (100), 116 (27).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19](=[O:60])[NH:20][C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([S:30]([C:33]5[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=5)(=[O:32])=[O:31])[CH:28]=4)[N:23](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:22]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CO>O1CCOCC1>[F:40][C:35]1[CH:34]=[C:33]([S:30]([C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[NH:23][N:22]=[C:21]3[NH:20][C:19]([C:17]2[CH:16]=[N:15][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:18]=2)=[O:60])(=[O:31])=[O:32])[CH:38]=[C:37]([F:39])[CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(C(=O)Nc3nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c4ccc(S(=O)(=O)c5cc(F)cc(F)c5)cc34)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(Nc1n[nH]c2ccc(S(=O)(=O)c3cc(F)cc(F)c3)cc12)c1cnn(C2CCNCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude 4-{4-[5-(3,5-difluoro-benzenesulfonyl)-1-trityl-1H-indazol-3-ylcarbamoyl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester was dissolved into 15 mL of 1,4-dioxane and added with 3 mL of 4M hydrochloric acid in 1,4-dioxane and stirred at room temperature overnight. Methanol was then added and the mixture stirred for additional 2 hours. The volatiles were removed under reduced pressure, the residue re-dissolved into ethyl acetate, washed with 10% ammonium hydroxide in water, dried over sodium sulfate and evaporated to dryness. The residue was stirred overnight with diethyl ether/methanol 95:5, filtered, washed with diethyl ether/methanol 9:1 then with diethyl ether and dried in oven at 60° C. affording 170 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([NH:13][CH:14]2[CH2:17]C[CH2:15]2)[C:5]([C:6](OCC)=[O:7])=[CH:4][N:3]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[C:11]([NH:13][CH:14]([CH3:17])[CH3:15])[CH:12]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1NC1CCC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)Nc1cc(Cl)ncc1CO
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of ethyl 6-chloro-4-(isopropylamino)nicotinate (2) (1 g, 4.12 mmol) in dry DCM (30 mL), DIBAL-H (8.24 mmol, 2 equiv.) (1.0 M in DCM) was added dropwise at −78° C. The reaction mixture was stirred at −78° C. for 2 h, gradually, the reaction was allowed to warm up to −10° C. over 1 h. The reaction mixture was quenched with saturated solution of sodium potassium tarterate and allowed to stir at room temperature. The reaction mixture was filtered through a small pad of celite. The filtrate was washed with brine solution, dried over Na2SO4, filtered and concentrated to give crude alcohol. The crude material obtained was purified by flash column chromatography through silica gel and MeOH:CHCl3 as eluent to afford (6-chloro-4-(isopropylamino)pyridin-3-yl)methanol. LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 μm; Solvent A=10% MeOH: 90% H2O: 0.1% TFA; Solvent B=90% MeOH: 10% H2O: 0.1% TFA; gradient 0-100% B over 2 min (3 min run time); retention time: 0.806 min; LCMS (ES-API), m/z 201.0 (M+H).
Reaction SMILES: [CH2:1]([N:3]([CH2:9][CH3:10])[C:4]([CH3:8])([C:6]#[CH:7])[CH3:5])[CH3:2].[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[CH:26]=[C:27](I)[S:28][C:21]=12)[NH2:15]>>[CH2:1]([N:3]([CH2:9][CH3:10])[C:4]([CH3:8])([CH3:5])[C:6]#[C:7][C:27]1[S:28][C:21]2[C:22](=[N:23][CH:24]=[CH:25][C:20]=2[O:19][C:18]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=2[F:11])[CH:26]=1)[CH3:2]
Reactant: C#CC(C)(C)N(CC)CC
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Product: CCN(CC)C(C)(C)C#Cc1cc2nccc(Oc3ccc(N)cc3F)c2s1
Temperature: 50 °C
Yield: 32.7 %

Procedure:
Prepared from N,N-diethyl-2-methylbut-3-yn-2-amine (21 mg, 0.15 mmol) and 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 39 mg, 0.10 mmol) using the procedure described for Example 6, Step B, except the reaction was heated to 50° C. for 24 hours. The crude was purified by preparative TLC (10% MeOH/CH2Cl2). The product was obtained as a waxy solid (13 mg, 31%). 1H NMR (400 MHz, CDCl3) δ 8.47 (m, 1H), 7.51 (s, 1H), 7.02 (m, 1H), 6.49 (m, 3H), 3.85 (s, 2H), 2.76 (m, 4H), 1.52 (s, 6H), 1.14 (m, 6H).
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[CH:20]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)[C:23](=[O:37])[CH:22](O)[CH2:21]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:19][O:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH3:10])[C:13]=1[CH:20]1[N:24]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][C:33]([F:35])([F:36])[F:34])=[CH:30][CH:31]=2)[C:23](=[O:37])[CH:22]([F:7])[CH2:21]1
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1cccc(OC)c1C1CC(O)C(=O)N1Cc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cccc(OC)c1C1CC(F)C(=O)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A cooled (−78° C.) mixture of DAST (117 mg; 0.72 mmol) in anh. DCM (0.5 ml) was treated dropwise with a solution of rac-(3R*,5S*)-5-(2,6-dimethoxyphenyl)-3-hydroxy-1-(4-(trifluoromethoxy)benzyl)-pyrrolidin-2-one (100 mg; 0.24 mmol) in anh. DCM (0.5 ml). The resulting mixture was further stirred at −78° C., under nitrogen, for 1 h, at 0° C. for 30 min., and finally at rt for 1 h. Aq. sat. NaHCO3 was added, and the resulting mixture was extracted with DCM. The mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by preparative HPLC afforded rac-(3S*,5S*)-5-(2,6-dimethoxyphenyl)-3-fluoro-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one as a colorless solid. LC-MS (conditions A): tR=0.90 min.; [M+H]+: 414.12 g/mol.
Reaction SMILES: [C:1]1([C:7]2[CH2:13][C:12](=O)[NH:11][C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20].N1C=CC=CC=1>O>[C:1]1([C:7]2[CH2:13][C:12](=[S:20])[NH:11][C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1CC(c2ccccc2)=Nc2ccccc2N1
Solvent: O
Solvent: c1ccncc1
Product: S=C1CC(c2ccccc2)=Nc2ccccc2N1

Procedure:
A mixture of 23.6 parts of 2,3-dihydro-4-phenyl-1H-1,5-benzodiazepin-2-one and 24.4 parts of phosphorus pentasulfide in 400 parts by volume of pyridine is stirred at reflux temperature for one hour. This solution is then added dropwise with stirring to about 2000 parts by volume of 60° C. warm water. The solid which forms is separated by filtration, washed with water and dried in air overnight. The product thus obtained is recrystallized from ethyl acetate to give, as beige crystals, 2,3-dihydro-4-phenyl-1H-1,5-benzodiazepine-2-thione. This product has the formula ##STR12##
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[CH:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:21](Cl)=[O:22])=[CH:15][CH:14]=1>[Cl-].[Na+].O>[CH2:19]([O:20][C:21]([N:1]1[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6]1)=[O:22])[C:16]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1=CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(OCc1ccccc1)N1CC=CCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1,2,3,6-Tetrahydro-pyridine (3 g, 36.1 mmol) are treated with 10% aqueous sodium carbonate (2.1 ml) and cooled to 0° C. Within 1 h, benzyl chloroformiate (Z-chloride, 5.1 ml, 36 mmol) is added dropwise within 1 h. After additional stirring for 2 h, the mixture is treated with 30 ml of brine and extracted four times with diethyl ether. The organic layers are dried over sodium sulphate and evaporated. The crude product, 7 g of a colorless oil, is purified by Flash-chromatography (silica gel, cyclohexane/ethyl acetate 9:1).