Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:15]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=2)[CH2:6][CH2:5]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-piperazin-1-yl-phenol (1.78 g, 10 mmol) in DMF (20 mL) was added bromomethyl-benzene (1.71 g, 10 mmol) dropwise and then the reaction was stirred at room temperature for 16 h. The mixture was poured into water and pH was adjusted to 7 with sat. aqueous NaHCO3, and then extracted with ethyl acetate (100 ml×2). The combined organic layers were washed with water and dried over anhy. Na2SO4. After removing the solvent under vacuum, the title compound was obtained (1.1 g, 41%) and MS (ESI) m/z 269 (M+H). 1H NMR (400 MHz, CDCl3) δ 2.62 (t, J=4.8 Hz, 4H), 3.08 (t, J=4.8 Hz, 4H), 3.57 (s, 2H), 6.74 (d, J=8.8 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 7.28-7.34 (m, 5H).
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)S(O[C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]=1[C:30]([O:32][CH3:33])=[O:31])(=O)=O.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:8]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[C:30]([O:32][CH3:33])=[O:31])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Reactant: c1ccc(Pc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12

Procedure:
Diphenylphosphine (0.55 mL, 3.16 mmol, 1 eq) was added to a stirred solution of methyl 2-trifluoromethanesulfonyloxy-1-naphthoate (1.047 g, 3.13 mmol, 1 eq), triethylamine (0. 5 mL, 3.59 mmol, 1.1 eq), 1,4-bis(diphenylphosphino)butane (dppb) (0.03 g, 0.07 mmol, 0.02 eq) and palladium acetate (0.005 g, 0.02 mmol, 0.006 eq) in degassed MeCN (10 mL) instantly giving a red coloration. The solution was heated at reflux under nitrogen for 17 hours. The blood-red solution was allowed to cool and an aliquot taken for NMR analysis.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.[NH2:25][C:26]1[S:27][CH:28]=[C:29]([CH3:31])[N:30]=1>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:5]2[CH:4]=[N:3][C:2]([NH:25][C:26]3[S:27][CH:28]=[C:29]([CH3:31])[N:30]=3)=[C:11]3[C:6]=2[CH:7]=[CH:8][C:9]([CH3:12])=[N:10]3)[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Reactant: Cc1csc(N)n1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2cnc(Nc3nc(C)cs3)c3nc(C)ccc23)c1

Procedure:
The title compound, MS: m/e=363.2 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 3-methoxyphenylboronic acid and 2-amino-4-methylthiazole.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[CH2:23]([O:25][C:26]1[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH:31]=1)[CH3:24].CN(C)C=O.[H-].[Na+]>O>[CH2:23]([O:25][C:26]1[CH:27]=[CH:28][C:29]([O:37][CH2:2][C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[CH:5][CH:4]=2)=[C:30]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH:31]=1)[CH3:24]
Reactant: CCOc1ccc(O)c(CC(=O)OC)c1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c(CC(=O)OC)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.4 %

Procedure:
To a mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.72 g), methyl 2-(5-ethoxy-2-hydroxyphenyl)acetate (0.40 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60%, oil, 0.08 g) under ice-cooling and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration of the organic layer, the residue was subjected to silica gel column chromatography to give methyl 2-[5-ethoxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate as an oil (0.56 g, 60%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(Cl)Cl>[CH2:27]([O:26][C:24]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)[CH2:10][CH2:9]1)=[O:25])[CH3:28]
Reactant: CCOC(=O)Cl
Reactant: c1ccc(CN2CCC(n3ccc4ccccc43)CC2)cc1
Solvent: ClCCl
Product: CCOC(=O)N1CCC(n2ccc3ccccc32)CC1
Temperature: 25 °C
Yield: 53 %

Procedure:
To a solution of 1-N-(1-benzyl-piperidin-4-yl)-indole (100 g, 0.344 mol) in methylene chloride (1 L) was added ethyl chloroformate (99.2 mL) dropwise with stirring. The mixture was refluxed for 48 hours, cooled to room temperature, and concentrated. The residue was crystallized from i-propanol to give the title compound as colorless crystals (50 g, 53% yield). M.Pt.: 127° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=[O:18].I[CH2:20][CH:21]([CH3:23])[CH3:22].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.O>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=[O:18])[CH:21]([CH3:23])[CH3:22]
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(O)cc12
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)COc1ccc2c(c1)c(C=O)nn2C1CCCCO1
Temperature: 70 °C
Reaction time: 5 h
Yield: 67.4 %

Procedure:
A mixture of (R/S) 5-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (200 mg, 0.81 mmol, 1.00 equiv), 1-iodo-2-methylpropane (300 mg, 1.63 mmol, 2.01 equiv) and Cs2CO3 (270 mg, 0.83 mmol, 1.02 equiv) in N,N-dimethylformamide (10 mL) was stirred under nitrogen at 70° C. for 5 h. The resulting solution was cooled to room temperature and diluted with 10 mL of H2O. The mixture was extracted with 3×20 mL of ethyl acetate. The combined organic layers were washed with 3×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-15% of ethyl acetate in petroleum ether to give 0.165 g (67%) of (R/S) 5-iso-butoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde as a white solid. 1H-NMR (300 MHz, DMSO-d6): δ 10.16 (s, 1H), 7.83 (d, J=9.3 Hz, 1H), 7.51 (d, J=2.1 Hz, 1H), 7.22 (dd, J=9.3 Hz, 2.4 Hz, 1H), 6.04-6.01 (m, 1H), 4.07-4.00 (m, 1H), 3.92-3.75 (m, 4H), 2.12-2.00 (m, 2H), 1.63-1.62 (m, 2H), 1.24-1.16 (m, 2H), 1.04 (d, J=6.6 Hz, 6H) ppm. LCMS (method A, ESI): RT=1.71 min, m/z=218.9 [M+H−THP]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11](Cl)=[CH:12][CH:13]=2)[N:8]([C:18]2[S:19][CH:20]=[C:21]([F:23])[N:22]=2)[CH:7]=1)=[O:5])[CH3:2].[C:24]([O:28][C:29]([NH:31][CH:32]1[CH2:36][CH2:35][NH:34][CH2:33]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([N:34]3[CH2:35][CH2:36][CH:32]([NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:33]3)=[CH:12][CH:13]=2)[N:8]([C:18]2[S:19][CH:20]=[C:21]([F:23])[N:22]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CCOC(=O)c1cn(-c2nc(F)cs2)c2nc(Cl)ccc2c1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cn(-c2nc(F)cs2)c2nc(N3CCC(NC(=O)OC(C)(C)C)C3)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
A mixture composed of 7-chloro-1-(4-fluoro-2-thiazoly)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (30 mg) obtained in Example A-2, 3-(t-butoxycarbonylamino)pyrrolidine (19 mg), triethylamine (26 mg) and acetonitrile (10 ml) was stirred at room temperature for 30 minutes. Solvent was distilled off under reduced pressure, and water was added, and then, the resulting mixture was extracted with chloroform. The obtained extract was dried over anhydrous sodium sulfate, and solvent was distilled off under reduced pressure. The resulting residue was subjected to recrystallization with use of ethyl acetate, and thus, there was obtained 7-(3-t-butoxycarbonylamino-1-pyrrolidinyl)-1-(4-fluoro-2-thiazolyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (40 mg).
Reaction SMILES: [N+](=[C:3]([C:17](=[O:28])[C@@H:18]([C@@H:20]1[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[NH:21]1)[CH3:19])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-]>ClCCCl.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[OH:26][C@@H:24]([C@H:23]1[C:22](=[O:27])[N:21]2[C@H:20]1[C@@H:18]([CH3:19])[C:17](=[O:28])[CH:3]2[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])[CH3:25]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@@H]12

Procedure:
To a solution of 4-nitrobenzyl (4R)-2-diazo-4-[(2R, 3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (0.60 g) in 1,2-dichloroethane (15 ml) was added rhodium(II) acetate (2 mg) under reflux. The mixture was refluxed for 30 minutes under nitrogen atmosphere and concentrated under reduced pressure to give 4-nitrobenzyl (4R, 5S, 6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3, 7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate. The compound obtained above was dissolved in acetonitrile (15 ml) and N,N-diisopropyl-N-ethylamine (0.32 ml). Diphenyl phosphorochloridate (0.33 ml) was added thereto at -10°∫-5° C. in a nitrogen stream, followed by stirring at the same temperature for 30 minutes. To the solution were added N,N-diisopropyl-N-ethylamine (0.32 ml) and a solution of a mixture of (2S ,4S)-4-mercapto-2-(1-methyl-1H-tetrazol-5-yl) -1-(4-nitrobenzyloxycarbonyl)pyrrolidine and (2S, 4S)-4-mercapto-2-(2-methyl-2H-tetrazol-5-yl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.55 g) in acetonitrile (2 ml) successively at -20° C. The mixture was stirred at the same temperature for 30 minutes and at 0°-10° C. for 3 hours. The mixture was poured into ethyl acetate (150 ml) and water (100 ml). The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of acetone and dichloromethane (10: 90, V/V) to give 4-nitrobenzyl (4R,5S ,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[(2S, 4S)-2{1(or 2)-methyl-1H(or 2H)-tetrazol-5-yl}-1-(4-nitrobenzyloxycarbonyl) pyrrolidin-4-yl]thio-7-oxo-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylate (isomer A) (0.32 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][NH2:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[C:14]1[C:15]([NH2:21])=[N:16][CH:17]=[C:18]([Br:20])[N:19]=1.C(N(C(C)C)CC)(C)C>ClCCl.C(O)C>[Br:20][C:18]1[N:19]=[C:14]([NH:12][CH2:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)[C:15]([NH2:21])=[N:16][CH:17]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: NCc1ccc2ncccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCO
Product: Nc1ncc(Br)nc1NCc1ccc2ncccc2c1
Temperature: 130 °C
Yield: 48 %

Procedure:
A mixture of quinolin-6-ylmethanamine (13 g, 82 mmol), 3,5-dibromopyrazin-2-amine (21 g, 82 mmol) and di-isopropylethylamine (16 mL, 89 mmol) was heated to 130° C. for five hours. The reaction was diluted with dichloromethane:ethanol (9:1) and the resulting suspension was filtered. The precipitate was washed sequentially with water and ether and air dried to afford 6-bromo-N2-(quinolin-6-ylmethyl)pyrazine-2,3-diamine (13 g, 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:37])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:31][C@@H:32]([OH:36])[C:33]([OH:35])=[O:34])[NH:16][C:17]([C:19]3[NH:23][C:22](=[O:24])[N:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:20]=3)=[O:18])=[CH:10][CH:9]=2)[CH:7]=1.[C:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40]Cl.[Na+].[I-].CC1C=CC=C(C)N=1>CN(C=O)C.O>[CH2:43]([O:42][C:38]([O:39][CH2:40][O:34][C:33](=[O:35])[C@H:32]([OH:36])[CH2:31][N:15]([CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:37])=[CH:13][CH:12]=1)[NH:16][C:17]([C:19]1[NH:23][C:22](=[O:24])[N:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:20]=1)=[O:18])=[O:45])[CH3:44]
Reactant: CCOC(=O)OCCl
Reactant: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1nn(-c2ccccc2)c(=O)[nH]1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Solvent: O
Product: CCOC(=O)OCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1nn(-c2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.5 %

Procedure:
To a solution of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(5-oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carbonyl)hydrazino]-2-hydroxypropionic acid (200 mg, 335 μmol) in dry DMF (10 mL) was added chloromethyl ethyl carbonate (69 mg, 503 μmol), NaI (101 mg, 670 μmol) and 2,6-dimethylpyridine (143 mg, 1.3 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature for 8 hours. Water (15 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (PE:EtOAc=3:1˜1:100) to yield the title compound as a white solid (9.5 mg). LC-MS: 627.9 [M+H]+. 1H NMR: (CDCl3, 400 MHz) δ 1.25 (t, J=7.1 Hz, 3H), 3.44 (br, 2H), 4.17-4.35 (m, 4H), 4.50 (s, 1H), 5.75-5.78 (m, 2H), 7.10 (t, J=9.3 Hz, 1H), 7.28-7.40 (m, 1H), 7.42-7.52 (m, 7H), 7.87 (s, 2H), 8.37 (s, 1H).
Reaction SMILES: [CH:1]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([F:14])=[CH:11][C:12]=2[F:13])=[CH:5][C:4]([C:15]([OH:17])=[O:16])=[C:3]([OH:18])[CH:2]=1.Cl.CN(C)[CH2:22][CH2:23]CN=C=N.O.ON1C2C=CC=CC=2N=N1.C(O)C>CN(C)C=O.O>[F:13][C:12]1[CH:11]=[C:10]([F:14])[CH:9]=[CH:8][C:7]=1[C:6]1[CH:5]=[C:4]([C:15]([O:17][CH2:22][CH3:23])=[O:16])[C:3]([OH:18])=[CH:2][CH:1]=1
Reactant: CN(C)CCCN=C=N
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
Diflunisal (250 mg), 1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (382 mg), 1-hydroxybenzotriazole hydrate (306 mg), and ethanol (2 ml) were dissolved in N,N-dimethylformamide to prepare a solution which was then stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give ethyl 5-(2,4-difluorophenyl)salicylate (188 mg, yield 34%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:16]([CH3:30])=[C:17]([C:27](=[O:29])[CH3:28])[C:18]4[O:22][C:21]([CH3:24])([CH3:23])[CH2:20][C:19]=4[C:25]=3[CH3:26])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[BH4-].[Na+]>O.C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:16]([CH3:30])=[C:17]([CH:27]([OH:29])[CH3:28])[C:18]4[O:22][C:21]([CH3:23])([CH3:24])[CH2:20][C:19]=4[C:25]=3[CH3:26])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCN(c3c(C)c4c(c(C(C)=O)c3C)OC(C)(C)C4)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(c3c(C)c4c(c(C(C)O)c3C)OC(C)(C)C4)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.7 %

Procedure:
To the THF (1.5 ml)/methanol (1.5 ml) mixture solution of 1-{5-[4-(4-methoxyphenyl)piperazin-1-yl]-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-7-yl}ethanone (120 mg, 0.294 mmol) synthesized in Example 80, sodium borohydride (133 mg, 3.52 mmol) was added and the mixture was stirred for 3 hours at room temperature. After diluting the reaction solution with water, THF and methanol in the reaction solution was removed by distillation under reduced pressure. The residue was extracted with ethyl acetate. The extract solution was washed with saturated brine, dried over anhydrous magnesium sulfate, and then solvent was removed by distillation under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 99:1-80/20) and crystallized from ethyl acetate-hexane to obtain the title compound 60 mg (yield 50%). Melting point was 183 to 186° C.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([O:16][CH2:17][CH2:18][CH2:19][C:20]1[C:28]3[C:23](=[C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])[CH:25]=[CH:26][CH:27]=3)[NH:22][C:21]=1[C:36]([O:38]CC)=[O:37])=[CH:11][CH:10]=[CH:9]2)(=[O:4])[CH:2]=[CH2:3].[OH-].[Na+]>O1CCCC1.CO>[C:1]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([O:16][CH2:17][CH2:18][CH2:19][C:20]1[C:28]3[C:23](=[C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])[CH:25]=[CH:26][CH:27]=3)[NH:22][C:21]=1[C:36]([OH:38])=[O:37])=[CH:11][CH:10]=[CH:9]2)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Nc1ccc2c(OCCCc3c(C(=O)OCC)[nH]c4c(-c5ccccc5C)cccc34)cccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=CC(=O)Nc1ccc2c(OCCCc3c(C(=O)O)[nH]c4c(-c5ccccc5C)cccc34)cccc2c1

Procedure:
To a mixture of EXAMPLE 565B (62.8 mg), acrylic acid (9.91 μl) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate Methanaminium (HATU, 54.9 mg) in tetrahydrofuran (3 ml) was added triethylamine (36.6 μl). The reaction was stirred at room temperature overnight, diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography, eluting with dichloromethane, to provide ethyl 3-(3-(6-acrylamidonaphthalen-1-yloxy)propyl)-7-o-tolyl-1H-indole-2-carboxylate. This ester was hydrolyzed with aqueous NaOH in tetrahydrofuran and methanol to provide the title compound. 1H NMR (500 MHz, methanol-d4) δ 8.22-8.25 (m, 2 H), 7.68 (dd, J=5.95, 3.20 Hz, 1 H), 7.59 (dd, J=9.15, 2.14 Hz, 1 H), 7.25-7.37 (m, 6 H), 7.05-7.08 (m, 2 H), 6.74 (dd, J=6.10, 2.44 Hz, 1 H), 6.46-6.55 (m, 1 H), 6.38-6.44 (m, 1 H), 5.80 (dd, J=10.07, 1.83 Hz, 1 H), 4.20 (t, J=5.95 Hz, 2 H), 3.40-3.56 (m, 2 H), 2.34 (t, J=6.71 Hz, 2 H), 2.11 (s, 3 H).
Reaction SMILES: [Br-:1].[NH4+].CC1C=CC(S(O[C:14]2[CH2:18][CH:17]([C:19](=[O:36])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[C:28](=[O:35])[NH:29][CH:30]([CH:32]3[CH2:34][CH2:33]3)[CH3:31])[N:16]([C:37]3[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][N:38]=3)[N:15]=2)(=O)=O)=CC=1.CN(C)C=O>O>[Br:1][C:14]1[CH2:18][CH:17]([C:19]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28](=[O:35])[NH:29][CH:30]([CH:32]2[CH2:34][CH2:33]2)[CH3:31])=[O:36])[N:16]([C:37]2[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][N:38]=2)[N:15]=1
Reactant: [Br-]
Reactant: Cc1ccc(S(=O)(=O)OC2=NN(c3ncccc3Cl)C(C(=O)Nc3ccc(Cl)cc3C(=O)NC(C)C3CC3)C2)cc1
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(Br)=NN1c1ncccc1Cl)C1CC1
Temperature: 93 °C
Yield: 12.9 %

Procedure:
0.54 g of ammonium bromide was added to a mixed liquid comprising 1.0 g of 5-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenylcarbamoyl)-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazol-3-yl 4-methylbenzenesulfonate and 25 ml of N,N-dimethylformamide, followed by heating to 93° C. One hour later, the reaction liquid was poured to 50 ml of water, followed by extraction with diethyl ether. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 1/1) to obtain 0.11 g of the desired product in the form of a paste.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([I:11])[CH:3]=1.[OH:12][C:13]1[CH:14]=[N:15][CH:16]=[N:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>Cl>[I:11][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=1)[O:12][C:13]1[CH:14]=[N:15][CH:16]=[N:17][CH:18]=1
Reactant: O=[N+]([O-])c1cc(F)cc(I)c1
Reactant: Oc1cncnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(I)cc(Oc2cncnc2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 168.8 %

Procedure:
Two vials were each charged with 1-fluoro-3-iodo-5-nitrobenzene (1.0 g, 3.8 mmol, 1.0 eq), 5-hydroxypyrimidine (430 mg, 4.47 mmol, 1.20 eq), potassium carbonate (780 mg, 5.64 mmol, 1.50 eq), and DMF (12 mL) and stirred overnight at 100° C. The reaction mixtures were combined, diluted with 0.5N HCl, and extracted (3×) with CH2Cl2. The combined organics were dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 2.2 g (87%) of the title compound as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 9.13 (s, 1H), 8.58 (s, 2H), 8.38 (t, J=1.8 Hz, 1H), 7.82 (t, J=2.2 Hz, 1H), 7.70 (dd, J=2.3, 1.4 Hz, 1H); ES-MS [M+1]+: 344.0.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:25]1([CH:31]([CH3:35])[C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.C1COCC1>[O:1]=[C:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH:7]1[C:32](=[O:33])[CH:31]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C(=O)Cl)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O)c1ccccc1
Temperature: 0 °C
Yield: 67.1 %

Procedure:
tert-Butyl 4-oxopiperidine-1-carboxylate (2.363 g, 11.86 mmol) was dissolved in toluene (7 mL) and cooled to 0° C. LHMDS (12.45 mL, 12.45 mmol) in THF was added. After 2 min 2-phenylpropanoyl chloride (0.855 mL, 5.93 mmol) was added. After 2 min the cooling bath was removed and after 5 min 1:1 acetic acid:water (3 ml) was added. The water phase was separated after hard stirring and the organic phase was dried with MgSO4 and the solvent was evaporated. Purification by flash column chromatography (0-25% EtOAc in heptane) yielded tert-butyl 4-oxo-3-(2-phenylpropanoyl)piperidine-1-carboxylate (1.319 g, 67.1%). MS (ES−) m/z 330.1 (M−H)−