Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].Cl[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1>C(O)CCC>[CH2:6]([O:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH2:7][CH2:8][CH3:9]
Reactant: [OH-]
Reactant: Clc1ccccn1
Agent: [Na+]
Solvent: CCCCO
Product: CCCCOc1ccccn1
Temperature: 112 °C
Reaction time: 15 h
Yield: 142.9 %

Procedure:
Into a solution of 55 g (1,38 mole) of sodium hydroxide in 245 g of n-butanol heated to 100° C., were added dropwise over four hours 113.5 g (1 mole) of 2-chloropyridine and the mixture was stirred for about 15 hours at this temperature, then heated for 2 hours at reflux (ca. 112° C.). After cooling, precipitated sodium chloride was removed by filtering and the residue was washed with about 500 ml of n-butanol. The combined filtrates were distilled in vacuum and the first fraction to distill was a butanol-water azeotrope, then followed n-butanol and a 2-chloropyridine/n-butanol intermediate run. 2-butoxypyridine distilled last at 75° C. at 10 Torr as a colorless liquid to obtain 108 g (72%) of 2-butoxypyridine with a purity of >98%.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1.[Cl-].[NH4+]>C1COCC1>[CH3:15][C:14]([CH3:16])([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1)[C:13]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(C)C
Reactant: BrCCCCCOC1CCCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(C)CCCCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (1.78 mL) in dry THF (10 mL) at 0° C. under nitrogen was treated dropwise with n-butyl lithium (2.5M in hexanes, 5.09 mL) to generate a pale yellow solution which was stirred at 0° C. for 30 minutes then cooled to −78° C. and treated dropwise with ethyl isobutyrate (1.55 mL). The solution was stirred at −78° C. for 45 minutes then a solution of 2-(5-bromopentyloxy)tetrahydro-2H-pyran (example 285, step a) (3.20 g) in dry THF (1 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 10 minutes then was allowed to warn to room temperature overnight. The reaction mixture was cooled to 0° C. then treated with saturated aqueous ammonium chloride solution (3 mL) and extracted with ethyl acetate. The aqueous phase was extracted with ethyl acetate (×2) and the combined organic phase was washed with water, saturated aqueous sodium bicarbonate solution and brine then dried over sodium sulfate, filtered and evaporated. Purification was by silica gel chromatography eluting with 0-5% ethyl acetate in cyclohexane to afford the subtitled compound as colourless liquid. Yield 2.22 g.
Reaction SMILES: [CH2:1]1[CH2:22][O:21][C:3]2([CH2:8][CH2:7][C:6]([C:9]3[CH:14]=[C:13]([F:15])[C:12]([C:16]([F:19])([F:18])[F:17])=[C:11]([F:20])[CH:10]=3)=[CH:5][CH2:4]2)[O:2]1.[H][H]>C(O)C.[Pd]>[CH2:22]1[CH2:1][O:2][C:3]2([CH2:4][CH2:5][CH:6]([C:9]3[CH:14]=[C:13]([F:15])[C:12]([C:16]([F:17])([F:18])[F:19])=[C:11]([F:20])[CH:10]=3)[CH2:7][CH2:8]2)[O:21]1
Reactant: Fc1cc(C2=CCC3(CC2)OCCO3)cc(F)c1C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Fc1cc(C2CCC3(CC2)OCCO3)cc(F)c1C(F)(F)F
Yield: 90.2 %

Procedure:
1,1-Ethylenedioxy-4-(3',5'-difluoro-4'-trifluoromethylphenyl)-3-cyclohexene (17.3 g) was dissolved in ethanol (200 ml), followed by adding Pd/C (5%) (5 g), carrying out a catalytic reduction with stirring in a hydrogen gas atmosphere, filtering off the catalyst after completion of the reaction, and distilling off the organic layer under reduced pressure, to obtain 1,1-ethylenedioxy-4-(3',5'-difluoro-4'-trifluoromethylphenyl)cyclohexane (15.7 g).
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([NH:12][C:13]2[CH:14]=[C:15]([C:20]3[N:24]=[C:23]([CH:25]4[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]4)[O:22][N:21]=3)[CH:16]=[CH:17][C:18]=2[CH3:19])=[O:11])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl>O1CCOCC1.CC#N>[NH:27]1[CH2:26][CH:25]([C:23]2[O:22][N:21]=[C:20]([C:15]3[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([NH:12][C:10]([C:3]4[N:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]5=[N:1][CH:2]=4)=[O:11])[CH:14]=3)[N:24]=2)[CH2:28]1
Reactant: Cc1ccc(-c2noc(C3CN(C(=O)OC(C)(C)C)C3)n2)cc1NC(=O)c1cnc2ccccn12
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: Cc1ccc(-c2noc(C3CNC3)n2)cc1NC(=O)c1cnc2ccccn12
Reaction time: 0.75 h

Procedure:
To a vial was added tert-butyl 3-(3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F39) (145 mg, 0.3 mmol) and 4N HCl in 1,4-dioxane (2 mL) and CH3CN (1 mL). The reaction was stirred for 45 minutes. The solvent was concentrated and placed under high vacuum. The solid was taken in water/acetonitrile and the pH was adjusted to neutral with an aqueous solution of ammonium carbonate and lyophilized to afford N-(5-(5-(azetidin-3-yl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (21) which was used directly in the next step. 1H NMR (400 MHz, d6-DMSO) δ 10.85 (s, 1H), 9.66-9.64 (m, 1H), 9.42 (bs, 1H), 9.28 (s, 1H), 8.10-8.08 (m, 2H), 8.02-7.98 (m, 1H), 7.89-7.87 (m, 1H), 7.59-7.53 (m, 2H), 4.53-4.47 (m, 1H), 4.36-4.29 (m, 4H), 2.40 (s, 3H). MS m/z 375.1 (M+1)+.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[CH:12]1([NH2:15])[CH2:14][CH2:13]1>CCO>[CH:12]1([NH:15][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N+:9]([O-:11])=[O:10])[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: COc1ccncc1[N+](=O)[O-]
Solvent: CCO
Product: O=[N+]([O-])c1cnccc1NC1CC1

Procedure:
A solution of 4-methoxy-3-nitropyridine (7.71 g, 50 mmol) and cyclopropylamine (7.14 g, 125 mmol) in EtOH (20 mL) was heated at 80° C. in a sealed tube for 2 h. The solvent was evaporated to give cyclopropyl-(3-nitro-pyridin-4-yl)-amine as a yellow solid.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH3:8][C:9]1[C:18]2[C:13](=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([NH2:22])[N:10]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:8][C:9]1[C:18]2[C:13](=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([NH:22][C:5](=[O:7])[CH3:6])[N:10]=1
Reactant: Cc1nc(N)cc2c([N+](=O)[O-])cccc12
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc2c([N+](=O)[O-])cccc2c(C)n1
Reaction time: 3.5 h
Yield: 32.6 %

Procedure:
Acetic anhydride (1.4 mL, 15 mmol) was added to a suspension of Example 141C (5 mmol) and triethylamine (0.76 mL, 5.5 mmol) in CH2Cl2 (20 mL) at ambient temperature. The mixture was stirred for 3.5 hours, then the volatiles were removed under reduced pressure. The residue was chased with toluene (3×25 mL) and concentrated under reduced pressure to afford the title compound (0.40 g, 33% yield over three steps). MS (ESI) m/z 246 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:36])[C@@H:15]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:27][CH:26]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:37][C:38]([F:55])([F:54])[C:39]1[CH:40]=[C:41]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1)[CH2:42][CH2:43][C:44](O)=[O:45]>>[CH2:16]([C@H:15]([N:23]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:29][CH:30]=1)[C:44](=[O:45])[CH2:43][CH2:42][C:41]1[CH:47]=[C:48]([C:50]([F:51])([F:52])[F:53])[CH:49]=[C:39]([C:38]([F:54])([F:55])[F:37])[CH:40]=1)[C:14]([N:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]1)=[O:36])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCCCc1ccc(CN[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Reactant: O=C(O)CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CCCCCc1ccc(CN(C(=O)CCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Yield: 82 %

Procedure:
Acylation of 1-(4-benzyl-piperazin-1-yl)-(S)-2-(4-pentyl-benzylamino)-3-phenyl-propan-1-one (43.5 mg, 0.09 mmol) according to the procedure described for the preparation of Example 1 with 3,5-bis-trifluoromethyl-hydrocinnamic acid (28.33 mg, 0.099 mmol) gave 55.5 mg (82%) of N—[(S)-1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-3-(3,5-bis-trifluoromethyl-phenyl)-N-(4-pentyl-benzyl)-propionamide. LC-MS: tR=1.05 min; [M+H]+=752.45.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16](O)[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([Cl:21])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Oc1nc(-c2ccc(Cl)cc2)nc2c1CCCC2
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc(-c2nc(Cl)c3c(n2)CCCC3)cc1
Reaction time: 3 h

Procedure:
8.0 g of 2-(4-chlorophenyl)4-hydroxy-5,6,7,8-tetrahydroquinazoline were heated to 100° C. in 10 ml of phosphorus oxychloride. After 3 hours, the cooled solution was carefully poured onto ice water. The crystalline product was filtered off with suction, washed well with water and dried in vacuo at room temperature. Yield: 6.2 g; m.p.: 121° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C1N=CN([C:16](N2C=NC=C2)=[O:17])C=1>CN(C=O)C.O>[O:17]=[C:16]1[NH:1][C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=2[O:10]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N#Cc1ccc(O)c(N)c1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2oc(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 74.2 %

Procedure:
To a solution of 3-amino-4-hydroxybenzonitrile (730 mg) in DMF (10 ml) was added CDI (1.06 g) at 0° C., followed by stirring at room temperature for 3.5 hours. The reaction solution was diluted with water (10 ml), and extracted with EtOAc (200 ml). The organic layer was dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:CH3OH=98:2 to 93:7) to obtain 2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile (647 mg) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21](O)=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH2:26]([CH2:28][NH2:29])[OH:27]>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([NH:29][CH2:28][CH2:26][OH:27])=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: NCCO
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(CCC(=O)O)cc2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2ccc(CCC(=O)NCCO)cc2)=C(C)C1=O
Yield: 31 %

Procedure:
3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (200 mg, 0.58 mmol) obtained in Example 1 and ethanolamine (47 mg, 0.75 mmol) were used, and a method similar to that described in Example 3 was employed to obtain the title compound (65 mg, 0.18 mmol, yield 29%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:10])[NH2:9])=[C:6]([CH:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:3]=1.C(N(CC)CC)C.Cl[C:46](Cl)([O:48]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH2:31]([O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:4]1[CH:5]=[C:6]([CH:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)[C:7]2[C:8](=[O:10])[NH:9][C:46](=[O:48])[NH:1][C:2]=2[N:3]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3OCc3ccccc3)nc(N)c2C(N)=O)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3OCc3ccccc3)nc3[nH]c(=O)[nH]c(=O)c23)C1
Temperature: 0 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
To a cooled (0° C.), stirred solution of tert-butyl 3-{2-amino-6-[2-(benzyloxy)phenyl]-3-carbamoyl-4-pyridinyl}-1-piperidinecarboxylate (0.400 g, 0.800 mmol), which was obtained in the step (1) of Example 7-1, in THF (10 mL) were added triethylamine (0.50 mL, 3.58 mmol) followed by triphosgene (0.354 g, 1.19 mmol). The reaction mixture was stirred at room temperature for 12 hrs. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1-1/1) and recrystallized from ethanol to give tert-butyl 3-{7-[2-(benzyloxy)phenyl]-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl}-1-piperidinecarboxylate as a white solid. (0.406 g, yield; 97%)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:3]=1[CH3:21].[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][C:29]=2[NH2:40])[CH2:24][CH2:23]1.Cl.O1CCOCC1>CO>[N:25]1([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:30][C:29]=2[NH:40][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[C:9]([F:12])[CH:10]=3)[N:5]=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:3]=2[CH3:21])[CH2:26][CH2:27][O:22][CH2:23][CH2:24]1
Reactant: Cc1c(-c2ccccc2F)nc2cc(F)c(F)cc2c1Cl
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2F)nc2cc(F)c(F)cc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to Procedure K, Method 1 using 4-chloro-6,7-difluoro-2-(2-fluorophenyl)-3-methylquinoline (100 mg, 325 μmol), 2,5-dimorpholinobenzenamine (86 mg, 325 μmol) and 4N hydrochloric acid solution in dioxane (0.081 mL, 325 μmol) in MeOH (3.00 mL) to afford product as a colorless solid after purification by chromatography on silica gel eluting with MeOH gradient in DCM. 1H NMR (400 MHz, chloroform-d) δ ppm 7.91 (1H, dd, J=11.0, 7.8 Hz), 7.55-7.71 (2H, m), 7.43-7.54 (1H, m, J=7.9, 7.9, 5.4, 2.0 Hz), 7.31-7.40 (1H, m), 7.09-7.25 (3H, m), 6.46 (1H, dd, J=8.6, 2.7 Hz), 6.01 (1H, br. s.), 3.87-4.05 (4H, m), 3.73-3.83 (4H, m), 3.06 (4H, dd, J=2.5, 1.8 Hz), 2.90-3.01 (4H, m), 2.21 (3H, d, J=2.0 Hz). Mass Spectrum (ESI) m/e=535.3 (M+1).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2-].[Li+].[Cl:12][C:13]1[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=1>O1CCCC1>[C:1]1([CH:7]([C:16]2[N:15]=[N:14][C:13]([Cl:12])=[CH:18][CH:17]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1ccccc1
Reactant: Clc1ccc(Cl)nn1
Agent: [Li+]
Agent: [NH2-]
Solvent: C1CCOC1
Product: N#CC(c1ccccc1)c1ccc(Cl)nn1
Reaction time: 8 h
Yield: 42.8 %

Procedure:
To a solution of 8.2 g (0.07 mole) of phenylacetonitrile in 50 ml of dry tetrahydrofuran was added 1.61 g (0.07 mole) of pulverized lithium amide. The mixture was refluxed for 5 hours. To the reaction mixture thereafter cooled were added 8.2 g (0.055 mole) of 3,6-dichloropyridazine and 10 ml of tetrahydrofuran on a water-ice bath. The mixture was then allowed to stand overnight at room temperature. The resulting mixture was neutralized and then distilled to remove the tetrahydrofuran. The residue was chromatographed over silica gel, followed by recrystallization from a mixture of ethanol and isopropyl ether, giving 5.4 g (42.9% yield) of 2-phenyl-2-(6-chloro-3-pyridazinyl)acetonitrile in the form of pale red needles, m.p. 131° C.
Reaction SMILES: C1(S([O:10][C:11]2[CH:22]=[CH:21][C:14]3[S:15][CH:16]=[C:17]([C:18]([OH:20])=[O:19])[C:13]=3[CH:12]=2)(=O)=O)C=CC=CC=1.Cl>[OH-].[Na+]>[OH:10][C:11]1[CH:22]=[CH:21][C:14]2[S:15][CH:16]=[C:17]([C:18]([OH:20])=[O:19])[C:13]=2[CH:12]=1
Reactant: O=C(O)c1csc2ccc(OS(=O)(=O)c3ccccc3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1csc2ccc(O)cc12
Temperature: 40 °C
Yield: 99.6 %

Procedure:
5-Benzenesulfonyloxybenzo[b]thiophene-3-carboxylic acid (6) (100 mg, 0.3 mmol) prepared in Examples above was dissolved in 1 N sodium hydroxide (1.2 ml) and heated at 40° C. for 8 hours with stirring. To the reaction solution was added 1 N hydrochloric acid (1.2 ml), and the deposited crystals were filtered, washed with water and dried to provide 58 mg of the title compound (11). Yield: 96.6% mp 262-263° C.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O.[NH2:29][NH2:30].O>CN(C=O)C>[CH2:20]([C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:30][N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cc1ccccc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccccc3)n[nH]c2c2cccnc2n1-c1ccccc1
Temperature: 105 °C
Reaction time: 4 h
Yield: 82.4 %

Procedure:
To a suspension of 4-hydroxy-3-(1-oxo-2-phenylethyl)-1-phenyl-1,8-naphthyridin-2 (1H)-one (2.33 g, 6.54 mmol, prepared in Synthetic Example 5) in DMF (50 ml) was added hydrazine monohydrate (80%, 970 μl, 24.21 mmol, 3.7 eq.) and the mixture was then stirred at 100 to 110° C. for 4 hours, admixed with water to precipitate crystals, and allowed to stand until it was cooled. Next, the cooled mixture was filtered, washed with water, and dried to give 3-benzyl-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (1.90 g, 82%).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[C:7]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:8]=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[CH:10]=2)[CH2:5][CH2:4][NH:3]1.C1C(=O)N([Cl:31])C(=O)C1>CC#N>[Cl:31][C:10]1[C:9]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:8][C:7]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[C:6]2[C:11]=1[C:2](=[O:1])[NH:3][CH2:4][CH2:5]2
Reactant: CC(C)Oc1cc(NC(=O)OC(C)(C)C)c2c(c1)C(=O)NCC2
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CC(C)Oc1cc(NC(=O)OC(C)(C)C)c2c(c1Cl)C(=O)NCC2
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A solution of tert-butyl [1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinolin-5-yl]carbamate (77b, 875 mg, 2.73 mmol) and NCS (401 mg, 3.00 mmol) in MeCN (80 mL) was stirred at 75° C. for 2 hours. After cooling down to room temperature and concentrating under vacuum, the resulting residue was purified by column chromatography (0-100% EtOAc/heptanes) to give tert-butyl [8-chloro-1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinolin-5-yl]carbamate (77c, 893 mg, 92%) as a solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH:14]([CH2:16][O:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=3)[CH2:13][C:12]2=[O:28])=[CH:7][CH:6]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>C(Cl)Cl>[CH3:29][S:30]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH:14]([CH2:16][O:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][CH:27]=3)[CH2:13][C:12]2=[O:28])=[CH:7][CH:6]=1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(OCCO)cc3)C2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(OCCOS(C)(=O)=O)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 4-[1-[4-(2-hydroxyethoxy)phenyl]-2-pyrrolidon-4-yl]methoxybenzoate (3.00 g) is dissolved in methylene chloride (30 ml) and the mixture is cooled with ice. Thereto are added methanesulfonyl chloride (0.90 ml) and triethylamine (2.16 ml) severally and the mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated under reduced pressure and ethyl acetate (60 ml) is added to the residue. The mixture is washed with water three times, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography and eluted with chloroform to give the desired product (3.39 g) as powder.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=[C:13]3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Cl)(C)C.[C:26]([O:30][C:31](=[O:51])[N:32]([C:42]1[CH:47]=[CH:46][C:45]([CH:48]=[O:49])=[C:44]([F:50])[N:43]=1)[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)([CH3:29])([CH3:28])[CH3:27].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:26]([O:30][C:31](=[O:51])[N:32]([C:42]1[CH:47]=[CH:46][C:45]([CH:48]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=3)[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:11]=2)[OH:49])=[C:44]([F:50])[N:43]=1)[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2cc(Br)cnc21
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C=O)c(F)n2)cc1
Agent: CC(C)[Mg]Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn(S(=O)(=O)c4ccccc4)c4ncc(Br)cc34)c(F)n2)cc1
Temperature: 5 °C
Yield: 88.1 %

Procedure:
To a solution of 1-benzenesulfonyl-5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (165, 1.00 g, 2.16 mmol) in 7 mL of tetrahydrofuran at −50° C. under nitrogen, isopropylmagnesium chloride (1.18 mL, 2.35 mmol) was added slowly. The reaction was warmed to 5° C. over 70 minutes, then cooled to −45° C. and (6-fluoro-5-formyl-pyridin-2-yl)-(4-methoxy-benzyl)-carbamic acid tert-butyl ester (83, 0.678 g, 1.88 mmol) in 3.0 mL of tetrahydrofuran was added. The reaction was allowed to warm to room temperature over 2-3 hours. The reaction was mixed with aqueous 1 N citric acid and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a white solid (166, 1.155 g). MS (ESI) [M+H]+=696.4 and 698.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[N:22]([O-])=O.[Na+].[I-].[Na+]>CS(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[N:22]=[N:16][C:4]=2[CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1cc(Br)ccc1Nc1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Fc1ccc(-n2nnc3cc(Br)ccc32)cc1
Reaction time: 0.33 h
Yield: 89 %

Procedure:
To a stirred room temperature solution of 4-bromo-N1-(4-fluorophenyl)benzene-1,2-diamine (1.4 g, 5 mmol) in DMSO (12 mL), was added 30% sulfuric acid (12 mL). The mixture was then cooled (ice-bath) and a solution of sodium nitrite (380 mg, 5.5 mmol) in water (1 mL) was added dropwise. After 20 minutes, a solution of sodium iodide (2.4 g, 15.8 mmol) in water (2 mL) was added dropwise and the cold bath was removed. After 30 minutes, LCMS showed only a single product [MS m/z 292/294 (MH+)] consistent with the desired product. The mixture was poured into 150 mL of ice water and the resulting precipitate was filtered, washed with sodium thiosulfate solution, water and dried to afford 1.3 g of 5-bromo-1-(4-fluorophenyl)-1H-benzotriazole as a light purple solid. MS m/z 292/294 (MH+).