Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=O)[CH:11]([NH:16][C:17]([C:19]2[S:20][C:21]3[C:27]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:26][CH:25]=[C:24]([O:34][CH3:35])[C:22]=3[N:23]=2)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+:40].C(=O)(O)[O-].[Na+]>O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[N:40]=[C:17]([C:19]3[S:20][C:21]4[C:27]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[CH:26][CH:25]=[C:24]([O:34][CH3:35])[C:22]=4[N:23]=3)[NH:16][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CCC3=O)nc12
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(C(=O)OC(C)(C)C)CC4)nc12
Temperature: 25 °C
Yield: 69.3 %

Procedure:
A mixture of 0.15 g 4-[(4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonyl)-amino]-5-oxo-azepane-1-carboxylic acid tert-butyl ester and 0.46 g ammonium acetate was melted at 120° C. for 3 hours and, after cooling to room temperature, suspended in a 1:1 mixture of water and saturated aqueous sodiumbicarbonate. Extraction with dichloromethane and chromatography on silicagel with dichloromethane/methanol 98:2 gave 0.10 g (72%) 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepine-6-carboxylic acid tert-butyl ester as yellow solid; M.p.: 142–144° C.; MS (ISP): m/e=486 (M+H+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=O)=[CH:13][CH:12]=2)[CH:8]=[N:9][CH:10]=1)[CH3:2].[CH2:23]([NH2:27])[CH:24]([CH3:26])[CH3:25]>>[CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([CH3:22])([CH3:21])[C:18]([NH:27][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])=[CH:15][CH:16]=2)[CH:8]=[N:9][CH:10]=1)[CH3:2]
Reactant: CCOCc1cncc(-c2ccc(C(C)(C)C(=O)O)cc2)c1
Reactant: CC(C)CN
Product: CCOCc1cncc(-c2ccc(C(C)(C)C(=O)NCC(C)C)cc2)c1
Yield: 80 %

Procedure:
Prepared in a similar manner to Example 3 from 2-(4-(5-(ethoxymethyl)pyridin-3-yl)phenyl)-2-methylpropanoic acid (example 26a) and isobutylamine. Yield: 80%. 1H NMR (400 MHz, dMSO): δ 0.72 (s, 3H); 0.74 (s, 3H); 1.15 (t, 3H, J=6.8); 1.46 (s, 6H); 1.68 (m, 1H); 2.83 (t, 2H, J=5.6); 3.51 (q, 2H, J=7.2); 4.54 (s, 2H); 7.4 (t, 1H); 7.41 (d, 2H, J=6.4); 7.66 (d, 2H, J=6.8); 7.95 (t, 1H, J=2.4); 8.49 (d, 1H, J=1.6); 8.78 (d, 1H, J=2.8). MS (M+H, 355).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6](\[Cl:11])/[C:7](=[O:10])[O:8][CH3:9])[C@H:3]1[C:12](Cl)=[O:13].[OH:16][CH:17]1[CH2:21][C:20](=[O:22])[C:19]([CH2:23][CH:24]=[CH2:25])=[C:18]1[CH3:26]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6](\[Cl:11])/[C:7](=[O:10])[O:8][CH3:9])[C@H:3]1[C:12]([O:16][CH:17]1[CH2:21][C:20](=[O:22])[C:19]([CH2:23][CH:24]=[CH2:25])=[C:18]1[CH3:26])=[O:13]
Reactant: C=CCC1=C(C)C(O)CC1=O
Reactant: COC(=O)/C(Cl)=C/[C@H]1[C@@H](C(=O)Cl)C1(C)C
Solvent: ClC(Cl)Cl
Product: C=CCC1=C(C)C(OC(=O)[C@@H]2[C@H](/C=C(\Cl)C(=O)OC)C2(C)C)CC1=O

Procedure:
(1R,cis) 2,2-dimethyl-3(Z)-[2-chloro-3-oxo-3-methoxy-propenyl]-cyclopropane-1-carboxylic acid chloride and (4S) hydroxy-3-methyl-2-(2-propenyl)-2-cyclopenten-1-one were reacted to obtain (1S) 2-methyl-4-oxo-3-(2-propenyl)-2-cyclopenten-1-yl (1R,cis) 2,2-dimethyl-3(Z)-[2-chloro-3-oxo-3-methoxy-propenyl]-cyclopropane-1-carboxylate with a specific [α]D20 =+27°±2.5° (c=0.3% in chloroform).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20](C(OCC3C=CC=CC=3)=O)[CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:4])=[O:3]>[Pd].C(O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCc3ccccc3)CC2)nc1
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCNCC2)nc1

Procedure:
Benzyl 4-((1R,2S)-2-(2-(5-(methylsulfonyl)pyridin-2-yloxy)ethyl)cyclopropyl)piperidine-1-carboxylate (Intermediate 12; 1.20 g, 2.62 mmol) and palladium on activated carbon (10%, wet, 240 mg) in ethanol (50 mL) were stirred under an atmosphere of hydrogen (1 atm) at RT for 3 h. The mixture was filtered (glass wool filter paper, Whatman 1821 110), and washed with ethanol. The filtrate was concentrated to dryness under reduced pressure to provide the title compound as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.72 (dd, J=0.5, 2.5 Hz, 1H), 8.03 (dd, J=2.5, 8.7 Hz, 1H), 6.84 (dd, J=0.6, 8.7 Hz, 1H), 4.48 (t, J=7.2 Hz, 2H), 3.20-3.05 (m, 2H), 3.07 (s, 3H), 2.65-2.50 (m, 2H), 2.20-1.90 (m, 2H), 1.85-1.65 (m, 2H), 1.60-1.45 (m, 1H), 1.45-1.20 (m, 2H), 1.00-0.80 (m, 2H), 0.70-0.60 (m, 2H), −0.13 (q, J=4.2 Hz, 1H). MS (Multimode) m/z 325 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)=[O:4].[N+:18]([C:21]1[CH:51]=[CH:50][C:24]([CH2:25][O:26][C:27]([N:29]=[C:30]([NH:36][C:37](=[O:49])[O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)N2C=CC=N2)=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19].C(OCC)(=O)C>O1CCCC1>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][O:26][C:27]([N:29]=[C:30]([NH:36][C:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)=[O:49])[NH:1][CH2:2][C:3]([NH:5][C@H:6]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]2)=[O:4])=[O:28])=[CH:50][CH:51]=1)([O-:20])=[O:19]
Reactant: O=C(N=C(NC(=O)OCc1ccc([N+](=O)[O-])cc1)n1cccn1)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)CN)C1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)CNC(=NC(=O)OCc2ccc([N+](=O)[O-])cc2)NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (3S)-3-(2-aminoacetylamino)-1-pyrrolidinecarboxylate (3.07 g) in anhydrous tetrahydrofuran (45 ml), a solution of 4-nitrobenzyl [(4-nitrobenzyloxy)carbonylimino-pyrazol-1-ylmethyl]carbamate (5.38 g) in tetrahydrofuran (35 ml) was added under ice cooling, followed by stirring at room temperature for 30 minutes. Ethyl acetate was added to the reaction mixture. The resulting mixture was washed with water, an aqueous solution of potassium hydrogensulfate and saturated saline, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column (ethyl acetate-dichloromethane), whereby the title compound (7.82 g) was obtained as an amorphous substance.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:12]=[CH:11][C:10]2[N:9]=[C:8](SC)[N:7]3[N:15]=[C:16]([C:18]4[O:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:6]3[C:5]=2[CH:4]=1>[OH-].[NH4+]>[Cl:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[NH:1])[N:7]3[N:15]=[C:16]([C:18]4[O:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:6]3[C:5]=2[CH:4]=1
Reactant: N
Reactant: CSc1nc2ccc(Cl)cc2c2nc(-c3ccco3)nn12
Agent: [NH4+]
Agent: [OH-]
Product: N=c1[nH]c2ccc(Cl)cc2c2nc(-c3ccco3)nn12

Procedure:
A mixture of concentrated aqueous ammonium hydroxide (300 ml) saturated with ammonia gas at 0° and 9-chloro-2-(2-furyl)-5-methylthio[1,2,4]triazolo[1,5-c]quinazoline (5.7 g) in a stainless steel pressure vessel is heated at an outside temperature of 150° over 18 hours, during which time the pressure rises to 250 p.s.i. The reaction mixture is cooled and the solid material collected, washed with water and air dried. The 9-chloro-2-(2-furyl)-5-imino-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazoline thus obtained (2.9 g, mp 269°-271°) is converted to the methanesulphonate salt by dissolution in 2-methoxyethanol (150 ml) followed by methanesulphonic acid (0.66 ml) and dry ether (25 ml) to afford the pure salt identical to that from Example 32.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5](=O)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[C:3]([O:2][CH3:1])[N:4]=1
Reactant: COc1cc2ccccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2ccccc2c(Cl)n1
Yield: 44 %

Procedure:
3-Methoxyisoquinolin-1(2H)-one (2.8 g, 16.0 mmol) in POCl3 (10 mL) was heated to reflux for 3 h then evaporated in vacuo. The residue was poured into iced NaHCO3 solution (50 mL). The product was extracted with EtOAc (2×). The organic layer was washed with brine, dried over MgSO4, filtered, evaporated. The residue was purified by flash chromatography with 20% then 40% of EtOAc/hexane to afford 1.36 g (44%) of the desired product 1-chloro-3-methoxyisoquinoline as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.29-8.16 (d, J=8.3 Hz, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.63 (ddd, J=8.3, 6.8, 1.1 Hz, 1H), 7.47 (ddd, J=8.5, 7.0, 1.1 Hz, 1H), 6.98 (s, 1H), 4.05 (s, 3H). MS: MS m/z 194.0 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:20]([OH:22])=O)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:23])=[CH:4][N:3]=1.[NH:24]1[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]1>>[O:30]=[S:27]1(=[O:31])[CH2:28][CH2:29][N:24]([C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=3)=[C:9]([F:23])[CH:10]=2)=[O:22])[CH2:25][CH2:26]1
Reactant: O=S1(=O)CCNCC1
Reactant: Nc1cnc(-c2ccc(-c3ccccc3C(=O)O)cc2F)cn1
Product: Nc1cnc(-c2ccc(-c3ccccc3C(=O)N3CCS(=O)(=O)CC3)cc2F)cn1

Procedure:
The title compound was prepared using methods analogous to those described in Step C of Example 504 using 4′-(2-aminopyrazin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid and thiomorpholine 1,1-dioxide. MS (ESI): mass calcd. for C21H19FN4O3S, 426.12; m/z found, 427.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.11 (s, 1H), 8.11-8.02 (m, 1H), 7.58-7.47 (m, 3H), 7.43 (d, J=7.5, 1H), 7.37 (dd, J=8.1, 1.8, 1H), 7.32 (dd, J=12.1, 1.7, 1H), 4.74 (s, 2H), 4.23 (s, 1H), 4.05 (s, 1H), 3.57-3.48 (m, 1H), 3.38 (s, 1H), 3.01 (s, 1H), 2.85 (s, 1H), 2.62 (s, 1H), 2.05 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>>[F:13][C:14]1[CH:15]=[C:16]([S:20]([N:9]2[CH2:10][CH2:11][CH2:12][CH:8]2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: Fc1ccc(C2CCCN2)cc1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Product: O=S(=O)(c1cccc(F)c1)N1CCCC1c1ccc(F)cc1

Procedure:
The title compound, off-white solid, m.p. 101° C. and MS: m/e=323 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 3-fluoro-benzenesulfonyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([OH:14])[CH:7]=1)[CH3:2].[Cl:16][C:17]1[CH:18]=[CH:19][C:20](F)=[C:21]([CH:24]=1)[CH:22]=[O:23]>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:20]2[CH:19]=[CH:18][C:17]([Cl:16])=[CH:24][C:21]=2[CH:22]=[O:23])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(O)c1
Reactant: O=Cc1cc(Cl)ccc1F
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Cl)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 4, using the following starting materials: (3-hydroxy-4-methoxy-phenyl)-acetic acid ethyl ester and 5-chloro-2-fluorobenzaldehyde.
Reaction SMILES: [CH2:1]1COCC1.[CH:6]1([NH:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17](=[O:34])[C:18]([C:28](N(OC)C)=[O:29])=[CH:19][N:20]3[CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:15][C:14]=2[F:35])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>O>[C:28]([C:18]1[C:17](=[O:34])[C:16]2[C:21](=[CH:22][C:13]([NH:12][CH:6]3[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]3)=[C:14]([F:35])[CH:15]=2)[N:20]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:19]=1)(=[O:29])[CH3:1]
Reactant: CON(C)C(=O)c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reactant: C1CCOC1
Solvent: O
Product: CC(=O)c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a 10 ml THF solution of 500 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-N-methoxy-N-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamide was added 1.2 ml of a 1 M methyl lithium THF solution, followed by stirring at room temperature for 3 days. Water was added to the reaction mixture to carry out celite filtration. After evaporation under a reduced pressure, the resulting residue was purified by silica gel column chromatography to obtain 150 mg of 3-acetyl-7-(cyclohexylamino)-1-cyclopentyl-6-fluoroquinolin-4(1H)-one.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH3:10])[CH:9]=1)=[O:4]>CO.O1CCCC1.[OH-].[Na+]>[CH3:10][C:8]1[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[S:6][CH:7]=1
Reactant: COC(=O)c1cc(C)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1csc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
5-Bromo-4-methyl-2-thiophenecarboxylic acid (3.33 g) was dissolved in dimethylformamide (50 ml), and potassium carbonate (4.0 g) and iodomethane (4.0 ml) were added. The mixture was stirred at room temperature for 2 hours, diluted with ethyl acetate, washed with 1N hydrochloric acid, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-bromo-4-methyl-2-thiophenecarboxylic acid methyl ester (3.47 g). A mixture of 5-bromo-4-methyl-2-thiophenecarboxylic acid methyl ester (2.36 g), zinc powder (1.65 g), acetic acid (10 ml) and water (10 ml) was stirred under reflux for 3 hours. Zinc powder (1 g) and acetic acid (10 ml) were further added. The mixture was stirred under reflux for 1 day, cooled, poured into concentrated aqueous ammonia and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-methyl-2-thiophenecarboxylic acid methyl ester (1.42 g). 4-Methyl-2-thiophenecarboxylic acid methyl ester (1.42 g) was dissolved in a mixture of methanol (10 ml) and tetrahydrofuran (30 ml), and 1N aqueous sodium hydroxide (15 ml) was added. The mixture was stirred at room temperature for 1 hour and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-methyl-2-thiophenecarboxylic acid (1.16 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13](=O)[CH2:14][CH3:15])=[C:6](OS(C)(=O)=O)[CH:7]=1.[CH3:17][NH:18][NH2:19].C([O-])(=O)C.[NH4+]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([C:13]([CH2:14][CH3:15])=[N:19][N:18]2[CH3:17])=[CH:4][CH:3]=1
Reactant: CNN
Reactant: CCC(=O)c1ccc(Br)cc1OS(C)(=O)=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: ClCCl
Product: CCc1nn(C)c2cc(Br)ccc12
Temperature: 135 °C
Yield: 77.1 %

Procedure:
Methanesulfonic acid 5-bromo-2-propionyl-phenyl ester (2.00 g, 6.51 mmol) was combined with methylhydrazine (0.69 mL, 13 mmol) and ammonium acetate (1.30 g, 16.9 mmol) in xylenes (12 mL). The reaction mixture was heated to 135° C. for 18 hours using a Dean Stark apparatus. The reaction was cooled to room temperature, diluted with dichloromethane (50 mL), and washed with water (50 mL) and 1N aqueous hydrochloric acid (50 mL). The organic extracts were dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on silica gel eluting with 4:1 hexanes/ethyl acetate to yield 1.20 g of 6-bromo-1-methyl-3ethyl-1H-indazole (75% yield). 1H NMR (400 MHz, CDCl3) δ 1.35 (t, 3, J=7.7), 2.94 (q, 2, J=7.7), 3.95 (s, 3), 7.18 (dd, 1, J=8.5, 1.5), 7.50 (d, J=0.8), 7.52 (dd, 1, J=8.5, 0.6). 13C NMR (100 MHz, CDCl3) δ 13.66, 20.29, 35.21, 111.82, 120.61, 121.35, 121.60, 123.05, 141.68, 147.08. IR 2970, 2935, 1609, 1506, 1458, 1223, 1047, 819, 805 cm-1. Analysis calculated for C10H11BrN2 : C, 50.23; H, 4.64; N, 11.72. Found: C, 50.14; H, 4.57; N, 11.46.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[I:11])[C:5](O)=[O:6].C1COCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[I:11])[CH2:5][OH:6]
Reactant: O=C(O)c1cc(Cl)c(I)c(Cl)c1
Solvent: C1CCOC1
Product: OCc1cc(Cl)c(I)c(Cl)c1

Procedure:
Using essentially the same procedure as for Example 8-1, Step 2, 3,5-dichloro-4-iodobenzoic acid (1900 mg, 6.0 mmol) was reduced to the title intermediate (1050 mg) using 2M borane-methyl sulfide complex in THF (4.0 mL, 8.0 mmol).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]2[C:8]3=[C:9]([C:11]([NH:13][C:14](=[O:15])[C:7]3=[CH:6][CH:5]=[CH:4]2)=[O:12])[CH:10]=1.CN(C)C=O.[OH-].[K+].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>CO>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][N:13]1[C:14](=[O:15])[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]3[C:8]=2[C:9](=[CH:10][CH:1]=[CH:2]3)[C:11]1=[O:12]
Reactant: BrCCCCBr
Reactant: O=C1NC(=O)c2cccc3cccc1c23
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCBr
Reaction time: 1 h

Procedure:
100 g. (0.5 mole) of 1,8-naphthalimide is suspended in 2100 ml. of dimethylformamide and the mixture is heated to 90° to form a complete solution. A solution of 36.3 g. (0.55 mole) of potassium hydroxide (85%) in 100 ml. of methanol is added resulting in the immediate formation of a yellow precipitate. The resulting mixture is stirred for one hour at 90° and cooled to 25°. 245 g.(1.0 mole) of 1,4-dibromobutane is added and the mixture is again heated to 90° and stirred for an additional hour. A precipitate remains in the mixture but is more granular than the initial material. The reaction mixture is cooled and the precipitate filtered off. The solvent is removed under vacuum and the residue is diluted with 500 ml. of hexane immediately precipitating crude 2-(4-bromobutyl)-1H-benz[de] isoquinoline-1,3 (2H)-dione. The precipitate is filtered off, washed with fresh hexane and dried for 2 hours at 50° (0.1 mm.) to yield 2-(4-bromobutyl)-1H-benz[de] isoquinoline-1,3 (2H)-dione. An analytically pure sample is prepared by dissolving the above product in hot 95% ethanol and recrystallizing by allowing the solution to cool to 25°. The resulting precipitate is dried for two hours at 50° (0.1 mm.) to yield pure 2-(4-bromobutyl)-1H-benz[de] isoquinoline-1,3 (2H)-dione, m.p. 113°-115°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]=[CH:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:16]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=4)=[N:19][N:18]4[CH2:28][CH2:29][CH2:30][C:17]=34)=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:16]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=4)=[N:19][N:18]4[CH2:28][CH2:29][CH2:30][C:17]=34)=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: COC(=O)C=Cc1ccc2c(-c3c(-c4cccc(C)n4)nn4c3CCC4)ccnc2c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc2c(-c3c(-c4cccc(C)n4)nn4c3CCC4)ccnc2c1
Reaction time: 18 h

Procedure:
To a solution of 3-{4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinolin-7-yl}-acrylic acid methyl ester (0.041 g, 0.1 mmol) in methanol (1 mL) is added 10% Pd/C (0.1 g). The resulting mixture is placed under one atmosphere of hydrogen and: stirred for 18 h. The mixture is filtered and concentrated in vacuo. The residue is chromatographed on SiO2 (2% methanol in dichloromethane) to yield the desired product as a pale yellow solid, 0.035 g (85%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][C@@H:15]([CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH2:14][CH2:13]2)=[O:10])=[CH:4][C:3]=1[O:23][CH3:24]>C(O)C.[Pt]=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][C@@H:15]([CH2:18][CH2:19][CH:20]([CH3:21])[CH3:22])[CH2:14][CH2:13]2)=[O:10])=[CH:4][C:3]=1[O:23][CH3:24]
Reactant: COc1cc(CC(=O)N[C@H]2CC[C@@H](CC=C(C)C)CC2)ccc1O
Agent: O=[Pt]
Solvent: CCO
Product: COc1cc(CC(=O)N[C@H]2CC[C@@H](CCC(C)C)CC2)ccc1O

Procedure:
To a solution of the compound (315 mg) of Example 47 in ethanol (10 ml) was added platinum oxide (30 mg), and the mixture was hydrogenated at 25° C. The catalyst was removed by filtration from the reaction mixture, and the solvent was evaporated under reduced pressure. The residue was purified by a silica gel chromatography (eluent: gradient from 100% hexane/0% ethyl acetate to 0% hexane/100% ethyl acetate) to give 275 mg of the desired compound.
Reaction SMILES: C(O[C:4](=[O:21])[C:5](=[CH:11][NH:12][C:13]1[N:17]([CH2:18][CH3:19])[N:16]=[C:15]([CH3:20])[CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[CH2:9]([O:8][C:6]([C:5]1[C:4]([OH:21])=[C:14]2[C:15]([CH3:20])=[N:16][N:17]([CH2:18][CH3:19])[C:13]2=[N:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1cc(C)nn1CC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)c1cnc2c(c(C)nn2CC)c1O

Procedure:
14.8 g. of [[(1-Ethyl-3-methyl-5-pyrazolyl)amino]methylene]malonic acid diethyl ester (0.05 mol.) are dissolved in 50 g. of diphenyl ether. The reaction mixture is heated to 235°-250° (bath temperature) and allowed to react at this temperature for 1 to 2 hours, while the resulting ethanol is continuously distilled off. The last part of the alcohol is removed by means of a water aspirator. The diphenyl ether is separated by distillation with a fractionating column in vacuo. The 1-ethyl-4-hydroxy-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester is obtained at b.p. 0.1-0.5 125°-129°, yield 10.7 g. (86%), m.p. 91°-93°. The compound is recrystallized from ligroin (90°-100°), m.p. 93°-94°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10](=O)[CH2:11]Br)[S:7][CH:6]=1)=[O:4].[CH:14]([NH2:16])=[O:15]>>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[N:16]=[CH:14][O:15][CH:11]=2)[S:7][CH:6]=1)=[O:4]
Reactant: NC=O
Reactant: COC(=O)c1csc(C(=O)CBr)c1
Product: COC(=O)c1csc(-c2cocn2)c1
Temperature: 170 °C

Procedure:
5-(2-Bromo-acetyl)-thiophene-3-carboxylic acid methyl ester (0.4 g, 1.52 mmol) was dissolved in formamide (2 mL) and the tube purged with nitrogen and then sealed. The mixture was heated at 170° C. for 20 minutes. The resultant solution was diluted with HCl (1 M) and water and washed with ethyl acetate. The organic phase was evaporated then purified by chromatography on a silica II cartridge, eluting with 2:1 pentane:DCM to neat DCM, to give the side product, 5-oxazol-4-yl-thiophene-3-carboxylic acid methyl ester as white solid (0.049 g). LCMS m/z 251.35 [M+MeCN+H]+ R.T.=3.07 min (Analytical Method 6).