Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1.[CH3:15][C:16]1[C:20]([S:21](Cl)(=[O:23])=[O:22])=[C:19]([CH3:25])[O:18][N:17]=1.C1OCCOCCOCCOCCOCCOC1>C(#N)C.O>[Cl:7][C:8]1[CH:14]=[CH:13][C:11]([NH:12][S:21]([C:20]2[C:16]([CH3:15])=[N:17][O:18][C:19]=2[CH3:25])(=[O:23])=[O:22])=[CH:10][CH:9]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1noc(C)c1S(=O)(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a suspension of potassium carbonate (0.18 g (1.28 mmol)) in acetonitrile (5.0 ml), 4-chloroaniline (0.33 g (2.56 mmol)), 3,5-dimethyl-4-isoxazolesulfonyl chloride (0.50 g (2.56 mmol)), 18-crown-6 (0.20 g (0.77 mmol)), were added with stirring at room temperature and the resulting mixture was stirred for 16 hours at the same temperature. Then, water (15.0 ml) was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with chloroform as eluent, to give 0.68 g (92%) of N-(4-chlorophenyl)-3,5-dimethyl-4-isoxazolesulfonamide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]([C:15]2[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=2[F:25])[C:13]2[C:12](=[O:26])[CH2:11][NH:10][CH2:9][C:8]=2[NH:7][C:6]=1[CH3:27])=[O:4].[O:28]([CH2:35][CH2:36][CH2:37]Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[CH3:1][O:2][C:3]([C:5]1[CH:14]([C:15]2[C:16]([F:25])=[C:17]([F:24])[C:18]([F:23])=[C:19]([F:22])[C:20]=2[F:21])[C:13]2[C:12](=[O:26])[CH2:11][N:10]([CH2:37][CH2:36][CH2:35][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:9][C:8]=2[NH:7][C:6]=1[CH3:27])=[O:4]
Reactant: COC(=O)C1=C(C)NC2=C(C(=O)CNC2)C1c1c(F)c(F)c(F)c(F)c1F
Reactant: BrCCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: COC(=O)C1=C(C)NC2=C(C(=O)CN(CCCOc3ccccc3)C2)C1c1c(F)c(F)c(F)c(F)c1F
Reaction time: 18 h
Yield: 20.8 %

Procedure:
A mixture of 10 g of 1,4,5,6,7,8-hexahydro-2-methyl-5-oxo-4-(2,3,4,5,6-pentafluorophenyl)-1,7-naphthyridine-3-carboxylic acid methyl ester, 5.6 g of 3-phenoxypropylbromide, 10 g of sodium carbonate and 175 ml of n-butanol was stirred and refluxed for 18 hours. The mixture was filtered and the filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate and extracted with water. After drying over magnesium sulfate, the ethyl acetate was removed in vacuo. The residue was dissolved in methanol and saturated with hydrogen chloride. The solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate and left at room temperature for 18 hours. The solid was separated and recrystallized from ethanolether. A second recrystallization from methanol afforded 2.8 g of the title compound as the hydrochloride salt, m.p. 205° C. dec.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:31])=[C:8]2[C:15]([C:16]#[N:17])=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:13]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:9]2=[C:10]([CH3:12])[N:11]=1)=[O:5])C.[NH2:32][CH2:33][C:34]([OH:36])=[O:35].C[O-].[Na+].CO>>[C:16]([C:15]1[C:8]2[C:9](=[C:10]([CH3:12])[N:11]=[C:6]([C:4]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:5])[C:7]=2[OH:31])[N:13]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:14]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)#[N:17]
Reactant: CCOC(=O)c1nc(C)c2c(c1O)c(C#N)c(-c1ccc(F)cc1)n2-c1ccccc1
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2c(C#N)c(-c3ccc(F)cc3)n(-c3ccccc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 3-cyano-2-(4-fluoro-phenyl)-4-hydroxy-7-methyl-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 445 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[O:30][CH2:29]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:37]1([S:40]([NH2:43])(=[O:42])=[O:41])[CH2:39][CH2:38]1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:43][S:40]([CH:37]3[CH2:39][CH2:38]3)(=[O:42])=[O:41])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][C:26]2([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[O:30][CH2:29]2)[CH2:27][CH2:28]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Reactant: NS(=O)(=O)C1CC1
Product: O=C(NS(=O)(=O)C1CC1)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Yield: 46.3 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-(2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.105 g, 0.217 mmol) obtained in Example 125, step 2 and cyclopropanesulfonamide (0.131 g, 1.09 mmol), the title compound (0.059 g, 47%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:25]([O:26][CH3:27])=[CH:24][C:6]2[S:7][C:8]([C:10](N3CCOCC3)([CH:13]([CH3:17])[CH2:14][C:15]#[N:16])C#N)=[CH:9][C:5]=2[CH:4]=1.C(O)(=[O:30])C>O>[CH3:1][O:2][C:3]1[C:25]([O:26][CH3:27])=[CH:24][C:6]2[S:7][C:8]([C:10](=[O:30])[CH:13]([CH3:17])[CH2:14][C:15]#[N:16])=[CH:9][C:5]=2[CH:4]=1
Reactant: CC(=O)O
Reactant: COc1cc2cc(C(C#N)(C(C)CC#N)N3CCOCC3)sc2cc1OC
Solvent: O
Product: COc1cc2cc(C(=O)C(C)CC#N)sc2cc1OC
Temperature: 0 °C

Procedure:
A mixture of 2-(5,6-dimethoxy-benzo[b]thien-2-yl)-3-methyl-2-(4-morpholinyl)-pentanedinitrile (7.4 g), glacial acetic acid (37.5 ml) and water (12.5 ml) was stirred and heated at reflux under an atmosphere of nitrogen. After 45 min. the reaction mixture was cooled and poured into crushed ice (200 g). The ice was allowed to melt and the resultant precipitate was filtered and dried at 65° C. under vacuum to give 4-(5,6-dimethoxybenzo[b]thien-2-yl)-3-methyl-4-oxo-butane nitrile as a pale yellow solid (5.2 g). A portion crystallized from dichloromethane/diethyl ether had m.p. 148°-150° C.
Reaction SMILES: [B:1](OC(C)C)([O:6]C(C)C)[O:2]C(C)C.Br[C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C([Li])CCC.O>O1CCCC1>[CH3:30][N:27]1[CH2:28][CH2:29][N:24]([S:21]([C:18]2[CH:19]=[CH:20][C:15]([B:1]([OH:6])[OH:2])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[CH2:25][CH2:26]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CN1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(S(=O)(=O)c2ccc(B(O)O)cc2)CC1
Temperature: -78 °C
Reaction time: 16 h
Yield: 57.6 %

Procedure:
Triisopropyl borate (0.64 mL, 2.8 mmol) was added to a solution of 1-[(4-bromophenyl)sulfonyl]-4-methylpiperazine (0.602 g, 1.9 mmol; described: in Keasling, H. H. et el. J. Med. Chem. 1965, 8, 548-550) in anhydrous tetrahydrofuran (7 mL) at −78° C. under a nitrogen atmosphere followed by dropwise addition of n-butyllithium (1.4 mL, 2.2 mmol). The resulting mixture was stirred at −78° C. for 2 h and at room temperature for another 16 h. Water (2.0 mL) was added and the mixture stirred for 30 min and evaporated to dryness. The residue was pre-adsorbed onto silica and purified by column chromatography using methylene chloride/methanol, (9:1 to 1:9), as the eluent. The product was re-crystallized from water to give 311 mg (58% yield) of the title compound as white crystals: mp 215-218° C.; 1H NMR (DMSO-d6, 400 MHz) δ 10.89 (br s, 1H), 8.47 (br s, 2H), 8.05 (d, J=8 Hz, 2H), 7.73 (d, J=8 Hz, 2H), 3.77 (m, 2H), 3.40 (m, 2H), 3.13 (m, 2H), 2.71 (s, 3H), 2.65 (m, 2H); 13C NMR (DMSO-d6, 100 MHz) δ 133.7, 133.3, 124.7, 49.8, 41.6, 41.4; MS (TSP) m/z 285 (M++1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16](=[O:24])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[Br:25]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C1C=CC=CC=1>[Br:25][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:16](=[O:24])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2nc3ccccc3c(=O)n2-c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: O=c1c2ccccc2nc(-c2ccc(CBr)cc2)n1-c1ccccc1

Procedure:
A 0.62 g quantity of 2-(4-methylphenyl)-3-phenyl-4(3H)-quinazolinone, 0.39 g of N-bromosuccinimide (NBS) and 0.05 g of benzoyl peroxide were suspended in 20 ml of benzene and refluxed with heating for 10 hours. After adding 50 ml of water, the reaction mixture was extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give 2-(4-bromomethylphenyl)-3-phenyl-4(3H)-quinazolinone as light yellow crude crystals.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].[NH2:9][C:10]1[N:15]=[C:14]([NH2:16])[N:13]=[C:12]([NH:17][CH:18]2[CH2:20][CH2:19]2)[N:11]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH:18]1([NH:17][C:12]2[N:11]=[C:10]([NH:9][C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3])[N:15]=[C:14]([NH:16][C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3])[N:13]=2)[CH2:20][CH2:19]1
Reactant: CC(C)COC(=O)Cl
Reactant: Nc1nc(N)nc(NC2CC2)n1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)COC(=O)Nc1nc(NC(=O)OCC(C)C)nc(NC2CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
16.4 g (0.12 mol) of isobutyl chloroformate are added dropwise to a mixture of 8.3 g (0.05 mol) of 2,4-diamino-6-cyclopropylamino-s-triazine, 0.5 g of 4-dimethylaminopyridine and 125 ml of pyridine. The batch is stirred for 1 hour at room temperature and then for 1 hour at 55°-60° C. After the precipitate has been filtered off, the reaction mixture is concentrated by evaporation in a water-jet vacuum, the residue is taken up in 150 ml of chloroform and extracted with 100 ml of water. After drying over sodium sulfate, the solvent is distilled off, and the crude product is purified by column chromatography through silica with methylene chloride as eluant.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[C:21](Cl)=[N:20][S:19][N:18]=1.CCN(C(C)C)C(C)C>CN(C=O)C.Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([C:21]2[C:17]([Cl:16])=[N:18][S:19][N:20]=2)[CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1nsnc1Cl
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC1CCN(c2nsnc2Cl)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
4-(tert-Butoxycarbonylaminomethyl)piperidine (3.96 g, 18.4 mmol) was dissolved in DMF (3.5 ml) and heated to 100° C. 3,4-Dichloro-1,2,5-thiadiazole (0.85 mL, 9.0 mmol) was added and the mixture stirred at 100° C. overnight. DIEA (2.0 ml, 11.5 mmol) was added and heating at 100° C. continued until the reaction was complete (˜3 h). The reaction mixture was diluted with 1N HCl and extracted with EtOAc (3×). The combined EtOAc extractions were washed with H2O (1×), sat'd NaCl (1×), dried (MgSO4), and concentrated in vacuo to give 2.39 g (80%) of [1-(4-chloro-[1,2,5]thiadiazol-3-yl)-piperidin-4-ylmethyl]-carbamic acid tert-butyl ester as a tan solid. 1H NMR (DMSO-d6) 6.91 (t, 1H), 3.87 (m, 2H), 2.84 (m, 4H), 1.69 (m, 2H), 1.56 (m, 1H), 1.36 (s, 9H), 1.24 (m, 2H) ppm. LC-MS (MH+)=333.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:2].[CH3:13][Si:14](Cl)([CH3:16])[CH3:15]>>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([Si:14]([CH3:16])([CH3:15])[CH3:13])[C:5]=1[C:4]([NH:3][CH2:1][CH3:2])=[O:12]
Reactant: C[Si](C)(C)Cl
Reactant: CCNC(=O)c1ccccc1Cl
Product: CCNC(=O)c1c(Cl)cccc1[Si](C)(C)C

Procedure:
The compound of Example f (2.2 g, 0.012 mol) was reacted with TMSCl (3.91 g, 0.036 mol) using General Method A. The title compound was recrystallized from ether/hexanes as a solid. m.p. 105-107° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:23][NH2:24]>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:23][NH2:24])=[O:6]
Reactant: NN
Reactant: O=C(O)c1cccc(I)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: NNC(=O)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 78 %

Procedure:
Commercially available 3-iodobenzoic acid (7.41 g, 29.9 mmol) was dissolved in THF (121 mL), and the mixture was stirred at room temperature for 45 minutes after adding 1,1′-carbonyldiimidazole (5.33 g, 32.9 mmol). The mixture was further stirred at room temperature for 2 hours after adding hydrazine.monohydrate (5.3 mL, 109 mmol). The mixture was then concentrated under reduced pressure, and recrystallized from methanol and water to give 3-iodobenzohydrazide (6.08 g, 78%).
Reaction SMILES: [O:1]=[C:2]([CH3:42])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([CH:25]2[CH2:29][CH2:28][CH:27]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[O:26]2)[CH:10]=[C:11]([O:17]CC2C=CC=CC=2)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5]>C(O)(=O)C.C(OCC)(=O)C.[Pd]>[O:1]=[C:2]([CH3:42])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([CH:25]2[CH2:29][CH2:28][CH:27]([C:30]3[CH:31]=[C:32]([O:40][CH3:41])[C:33]([O:38][CH3:39])=[C:34]([O:36][CH3:37])[CH:35]=3)[O:26]2)[CH:10]=[C:11]([OH:17])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:5])=[O:6]
Reactant: CCCOc1c(OCc2ccccc2)cc(C2CCC(c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCOc1c(O)cc(C2CCC(c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Reaction time: 0.75 h

Procedure:
A mixture of 1.2 g of 2-[3-(2-oxopropylsufonyl)-4-n-propoxy-5-benzyloxy- phenyl]-5-(3,4,5-trimethoxyphenyl) tetrahydrofuran, 400 mg 10% Pd/C, 1-2 drops of acetic acid in 100 mL of ethyl acetate was stirred under H2 at 40 psi for 45 minutes. The reaction mixture was filtered over a bed of celite and evaporated in vacuo to yield the title compound: NMR(200 MHz, CDCl3) δ 1.10 (t, CH2CH2CH3), 1.92 (m, CH2CH2CH3), 1.9-2.6 (m, 3-CH2 & 4-CH2), 2.40 (s, CH3C(O)CH2), 3.86 (s, OCH3), 3.90 (s, 2 OCH3), 4.12 (t, OCH2CH2CH3), 4.42 (s, CH3C(O)CH2), 5.10-5.28 (m, 2-CH & 5-CH), 6.64 (s, 5-ArH), 7.35 & 7.47(2 d, 2-ArH).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH2:4].[Cl:5][C:6]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14](Cl)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.C(N(CC)CC)C>ClCCl>[Cl:5][C:6]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14]([NH:1][CH2:2][CH2:3][NH2:4])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.1 %

Procedure:
1,2-Diaminoethane (7.55 mL, 113 mmol) was added to a 0° C. solution of 2,4-dichloro-3-nitroquinoline (28.9 g, 119 mmol) and triethylamine (24.9 mL, 179 mmol) in dichloromethane (600 mL). The solution was allowed to warm slowly to room temperature and stir for 20 hours. The solvent was removed under reduced pressure and 5% aqueous Na2CO3 (300 mL) was added. The resulting slurry was stirred vigorously at 0° C. for four hours. A yellow solid was isolated by vacuum filtration and dried under vacuum. The solid was purified by suction filter chromatography (silica gel, gradient elution from 98:2 to 93:7 dichloromethane/methanol) to provide the product N-(2-chloro-3-nitroquinolin-4-yl)ethane-1,2-diamine (16.0 g) that contained a small amount of an impurity.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:4][OH:5].[F:10][C:11]1[CH:16]=[C:15](F)[C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]=1[N:21]1[C:29](=[O:30])[C:24]2=[CH:25][CH2:26][CH2:27][CH2:28][N:23]2[C:22]1=[O:31].Cl>C(OCC)(=O)C.O1CCOCC1>[CH2:8]([O:7][C:3]([CH2:4][O:5][C:15]1[C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]([N:21]2[C:29](=[O:30])[C:24]3=[CH:25][CH2:26][CH2:27][CH2:28][N:23]3[C:22]2=[O:31])=[C:11]([F:10])[CH:16]=1)=[O:6])[CH3:9]
Reactant: O=C1C2=CCCCN2C(=O)N1c1cc([N+](=O)[O-])c(F)cc1F
Reactant: CCOC(=O)CO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cc(F)c(N2C(=O)C3=CCCCN3C2=O)cc1[N+](=O)[O-]
Yield: 48.9 %

Procedure:
Sodium hydride (0.06 g, 2.4 mmol) was put in to a flask, to which 1,4-dioxane (5 mL) and ethyl glycolate (0.12 mL, 1.32 mmol) was added with stirring under cooling in an ice-water bath after replacing the inside of flask throughly with argon gas, and the mixture was stirred for 15 minutes at the ambient temperature. Then, 2-(2,4-difluoro-5-nitrophenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.37 g, 1. mmol) was added to the mixture at the same temperature. The reaction mixture was wormed up to room temperature and stirred for 3 hours, and further stirred for 13 hours at 80° C. 1N Hydrochloric acid (10 mL) and ethyl acetate (10 mL) were added to the resulting mixture and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (10 mL ×2 times). The organic layer combined was washed with a saturated sodium bicarbonate (20 mL) and a saturated sodium chloride solution (20 mL), and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by silica gel column (Wakogel C-200, ethyl acetate/hexane=1/2) to obtain a white solid of 2-(4-ethoxycarbonylmethoxy-2-fluoro-5-nitrophenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.23 g, yield:48.9%).
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][NH:10][C:11]([C:13]2[CH:24]=[CH:23][C:16]([O:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)=[O:12])=[O:8])=[CH:5][CH:4]=1)#[N:2].[SH2:27]>N1C=CC=CC=1.C(N(CC)CC)C>[C:1]([C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][NH:10][C:11]([C:13]2[CH:24]=[CH:23][C:16]([O:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)=[O:12])=[O:8])=[CH:5][CH:4]=1)(=[S:27])[NH2:2]
Reactant: S
Reactant: COC(=O)COc1ccc(C(=O)NNC(=O)c2ccc(C#N)cc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COC(=O)COc1ccc(C(=O)NNC(=O)c2ccc(C(N)=S)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the product of step (b) (10 g) in a mixture of pyridine (500 ml) and triethylamine (80 ml) was covered with a blanket of H2S gas and stirred at ambient temperature overnight. The dark green reaction mixture was evaporated to dryness and the residue was triturated with dry ether. The resultant solid was collected and washed thoroughly with ether to give methyl 4-[3-(4-thiocarbamoylbenzoyl)carbazoyl]phenoxyacetate (10.5 g) as a yellow solid; NMR Spectrum (DMSO-d6) 3.72 (3H, s), 4.90 (2H, s), 7.06 (2H, d), 7.90 (2H, d), 7.95 (4H, m), 9.62 (1H, br s), 10.01 (1H, br s), 10.40 (1H, br s), 10.55 (1H, br s); Mass Spectrum m/Z 388 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[Cl:24])[N:3]=1.[CH2:25]([NH2:29])[CH:26]([CH3:28])[CH3:27]>>[Cl:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[C:4]1[N:3]=[C:2]([NH:29][CH2:25][CH:26]([CH3:28])[CH3:27])[C:7]([C:8]#[N:9])=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(F)cc2Cl)nc1Cl
Reactant: CC(C)CN
Product: CC(C)CNc1nc(-c2ccc(F)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N

Procedure:
2-chloro-6-(2-chloro-4-fluorophenyl)-5-(4-chlorophenyl)pyridine-3-carbonitrile (prepared from 6-(2-chloro-4-fluorophenyl)-5-(4-chlorophenyl)-1,2-dihydro-2-oxopyridine-3-carbonitrile using conditions similar to Step C Example 1) was reacted with isobutylamine using the conditions of Step A EXAMPLE 27 to afford the title compound. HPLC/MS: 414.1 (M+1), 415.9 (M+3); Rt=4.68 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH:21]C(=O)OC(C)(C)C)=[N:9]3)[CH:7]=1.[F:30][C:31]([C:34]1[N:35]=[CH:36][C:37]([C:40](O)=[O:41])=[N:38][CH:39]=1)([F:33])[CH3:32]>>[NH2:21][C:10]1[S:11][CH2:12][C@@H:13]2[C@@H:14]([C:17]([F:20])([F:19])[F:18])[O:15][CH2:16][C@:8]2([C:6]2[CH:7]=[C:2]([NH:1][C:40]([C:37]3[CH:36]=[N:35][C:34]([C:31]([F:33])([F:30])[CH3:32])=[CH:39][N:38]=3)=[O:41])[CH:3]=[CH:4][C:5]=2[F:29])[N:9]=1
Reactant: CC(F)(F)c1cnc(C(=O)O)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Product: CC(F)(F)c1cnc(C(=O)Nc2ccc(F)c([C@]34CO[C@H](C(F)(F)F)[C@H]3CSC(N)=N4)c2)cn1

Procedure:
Synthesized from tert-butyl [(4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-trifluoromethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate and 5-(1,1-difluoroethyl)pyrazine-2-carboxylic acid according to the general procedure. 1H NMR (600 MHz, CDCl3) δ ppm 2.03 (t, J=18.8 Hz, 3H), 2.82 (d, J=12.0 Hz, 1H), 3.14 (d, J=12.4 Hz, 1H), 3.35-3.46 (m, 1H), 3.77-4.07 (m, 1H), 4.20-4.93 (m, 4H), 7.08 (dd, J=11.7, 9.0 Hz, 1H), 7.56 (d, J=4.5 Hz, 1H), 7.80-7.93 (m, 1H), 8.87 (s, 1 H), 9.43 (s, 1H), 9.59 (br. s., 1H)
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH3:7])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH2:19]([S:1][C:2]1[S:3][C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH3:7])[N:6]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)Cc1sc(S)nc1C
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)Cc1sc(SCc2ccccc2)nc1C

Procedure:
2.03 g (0.01 mole) of methyl 2-mercapto-4-methyl-1,3thiazol-5-ylacetate are reacted with potassium carbonate and benzyl chloride in acetone and worked up in accordance with Example 1, stage 2.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[C:14]([NH2:16])=[O:15].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N:23]2[CH2:28][CH2:27][CH:26]([C:29](OCC)=O)[CH2:25][CH2:24]2)[CH:18]=1>C(O)C>[CH3:13][C:4]1[C:3]2[C:14](=[O:15])[NH:16][C:29]([CH:26]3[CH2:25][CH2:24][N:23]([C:19]4[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=4)[CH2:28][CH2:27]3)=[N:1][C:2]=2[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=1
Reactant: CCOC(=O)C1CCN(c2cccnc2)CC1
Reactant: Cc1nn(-c2ccccc2)c(N)c1C(N)=O
Solvent: CCO
Product: Cc1nn(-c2ccccc2)c2nc(C3CCN(c4cccnc4)CC3)[nH]c(=O)c12

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed a solution of Na (64 mg, 2.78 mmol, 6.00 equiv) in ethanol (5 mL) at room temperature. To the resulting mixture was then added a solution of 5-amino-3-methyl-1-phenyl-1H-pyrazole-4-carboxamide (100 mg, 0.46 mmol, 1.00 equiv) in C4H10O (10 mL), in portions at room temperature, followed by a solution of ethyl 1-(pyridin-3-yl)piperidine-4-carboxylate (650 mg, 2.78 mmol, 6.00 equiv) in C4H10O (20 mL), in portions at room temperature. The resulting solution was heated to reflux for 5 hr. The reaction was then quenched by the addition of water (10 mL). The resulting solution was extracted with DCM (3×30 mL) and the organic layers combined. The resulting mixture was washed with sodium chloride (2×50 mL), then dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (50:1) to yield 3-methyl-1-phenyl-6-(1-(pyridin-3-yl)piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one as a white solid.