Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][C:19]([O:21]CC)=[O:20])[CH:14]=[C:13]2[C:3]=1[C:4](=[O:24])[CH2:5][C:6]1([NH:12]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.CI.[C:27](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:27][O:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][C:19]([OH:21])=[O:20])[CH:14]=[C:13]2[C:3]=1[C:4](=[O:24])[CH2:5][C:6]1([NH:12]2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)COc1cc(O)c2c(c1)NC1(CCCCC1)CC2=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(OCC(=O)O)cc2c1C(=O)CC1(CCCCC1)N2
Temperature: 40 °C
Reaction time: 9 h

Procedure:
A mixture of ethyl 2-{(5-hydroxy-4-oxospiro [1,2,3,4-tetrahydroquinoline-2,1'-cyclohexan]-7-yl)oxy}acetate (prepared in Example 51 (1)) (0.15 g, 0.45 mmol), methyl iodide (0.071 g, 0.50 mmol), anhydrous potassium carbonate (0.094 g, 0.68 mmol), and dry DMF (4 ml) is stirred at 40° C. for 9 hours. After the addition of methyl iodide (0.14 g, 1.0 mmol), the stirring is continued for additional 4 hours. The solvent is removed by distillation and the residue is dissolved in ethyl acetate. The solution is washed with saturated brine, dried, and the solvent is removed. The residue is placed on a silica gel column and eluted with a mixture of ethyl acetate and dichloromethane (1:10). The earlier fractions containing oily materials are discarded. From the succeeding fractions, the desired product is obtained as a crystalline solid (0.067 g, 43%, m.p=158°-159° C.).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[Cl:22][C:23]1[S:27][CH:26]=[C:25]([CH2:28]O)[CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:22][C:23]1[S:27][CH:26]=[C:25]([CH2:28][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:20]([CH3:21])=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:5]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)[CH:24]=1
Reactant: OCc1csc(Cl)c1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(Cl)c4)cc3=O)cn12
Temperature: 60 °C
Reaction time: 4 h
Yield: 41 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (5-chlorothiophen-3-yl)methanol (158 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg), and the mixture was stirred at 60° C. for 4 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was diluted with DCM (100 ml), washed with water and brine successively, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) to afford the title compound (90 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([C@:8]1([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:13][C@@H:12](Br)[C@@H:11]2[C@H:9]1[C@H:10]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:30]1[CH:34]=[N:33][C:32]([SH:35])=[N:31]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([C@:8]1([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:13][C@H:12]([S:35][C:32]2[N:33]=[CH:34][NH:30][N:31]=2)[C@@H:11]2[C@H:9]1[C@H:10]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C[C@@H](Br)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Reactant: Sc1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C[C@H](Sc2nc[nH]n2)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Temperature: 80 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
Add to a solution of ditert-butyl(1R,2S,4R,5R,6R)-4-bromo-2-(tert-butoxycarbonylamino)bicyclo[3.1.0]hexane-2,6-dicarboxylate (2 g, 4.20 mmol) in dimethylformamide (10 mL), 1H-1,2,4-triazole-3-thiol (525 mg, 5.04 mmol) and potassium carbonate (1.16 g, 8.4 mmol). Stir the mixture at 80° C. overnight. Cool to room temperature and dilute with ethyl acetate, wash with 10% citric acid and brine, dry over anhydrous sodium sulfate, filter and concentrate to dryness. Purify by silica gel chromatography (80 g silica column) eluting with hexane:ethyl acetate (80:20 to 0:100) to obtain the title compound (1.64 g, 78%). MS (m/z): 497 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[C:7]([CH3:27])=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[OH-:28].[K+].O>C(O)(C)(C)C>[CH3:1][CH:2]1[CH2:6][C:5]2[C:7]([CH3:27])=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:20]=[CH:21][C:22]([C:23]([NH2:24])=[O:28])=[CH:25][CH:26]=4)[CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: [OH-]
Reactant: Cc1c(C)c(N2CCN(c3ccc(C#N)cc3)CC2)c(C)c2c1OC(C)C2
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1c(C)c(N2CCN(c3ccc(C(N)=O)cc3)CC2)c(C)c2c1OC(C)C2
Yield: 47.5 %

Procedure:
The mixture of 4-[4-(2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazin-1-yl]benzonitrile (70 mg, 0.194 mmol) synthesized in Reference example 29 and potassium hydroxide (33 mg, 0.582 mmol) was stirred in tert-butanol (2.0 mL) at 80° C. for 20 hours. After adding water, solids obtained were filtered and washed with ethanol to obtain the title compound 35 mg (yield 48%). Melting point was 240 to 245° C. (ethanol).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[OH:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[OH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: OCC1CCNCC1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(N2CCC(CO)CC2)cc1
Temperature: 100 °C

Procedure:
A suspension of 4-fluorobenzaldehyde (4.3 mL), 4-hydroxymethylpiperidine (4.8 g), and cesium carbonate (26 g) in DMF (80 mL) was heated to 100° C. for 24 h and cooled to room temperature. Water (400 mL) was added, and the resulting precipitate was collected by filtration to give the title compound as a tan amorphous powder (4.1 g).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[ClH:8].[CH3:9][N:10]1[CH2:15][CH:14]=[C:13]([CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12][CH2:11]1>C(O)(=O)C>[ClH:8].[CH3:9][N:10]1[CH2:11][CH2:12][C:13]2[CH:14]([CH:3]3[C:4](=[O:5])[O:6][C:1](=[O:7])[CH:2]3[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=2)[CH2:15]1
Reactant: CN1CC=C(C=Cc2ccccc2)CC1
Reactant: O=C1C=CC(=O)O1
Agent: Cl
Solvent: CC(=O)O
Product: CN1CCC2=CC(c3ccccc3)C3C(=O)OC(=O)C3C2C1

Procedure:
A solution of 50 g. maleic anhydride and 10 g. 1,2,3,6-tetrahydro-1-methyl-4-styrylpyridine hydrochloride, from example 7, in 100 ml. acetic acid and 100 ml. acetic anhydride previously thoroughly sparged with dry nitrogen is refluxed gently for 3 hours under nitrogen. The reaction mixture is concentrated to 100 ml. volume, and flushed with 300 ml. benzene to remove most of the remaining solvent. The residue is triturated with benzene several times to give 17.5 g. of a crude brown product. This compound is not further purified. It is refrigerated in the dry state for storage.
Reaction SMILES: C[C:2]1(C)[CH2:11][CH2:10][C:9](C)(C)[C:8]2C=[C:6]([OH:14])[CH:5]=[CH:4][C:3]1=2.C(OCC)(=O)CC(C)=[O:19]>OS(O)(=O)=O.C([O-])(O)=O.[Na+]>[O:19]1[C:8]2[C:3](=[CH:2][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][C:6]1=[O:14]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC1(C)CCC(C)(C)c2cc(O)ccc21
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=c1ccc2ccccc2o1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
1,2,3,4-Tetrahydro-1,1,4,4,6-pentamethylbenzo[5,6-g]coumarin (Structure 4 of Schemes 1 and 2, where R1, R4, R6=H, R2 and R3 together form a tetramethyl saturated six-membered carbocyclic ring, R5=methyl). To a flame-dried 50-mL r.b. flask containing 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-ol (2.03 g, 9.94 mmol) in 4 mL 75% H2SO4 was added ethyl acetoacetate (Structure 3 of Scheme 1, where R5=methyl, R6=H, R′=ethyl) (3.19 mL, 25.0 mmol, 2.52 equiv), and the mixture was heated to 100° C. for 3 h. Upon cooling to room temperature, the mixture was poured over ice (50 g), diluted with saturated NaHCO3 (50 mL), and stirred for 30 min. The mixture was then extracted with EtOAc (3×50 mL) and the organic layer was washed with brine (50 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude product mixture was purified by flash column chromatography (silica gel, hexanes/EtOAc, 4:1) to remove residual ethyl acetoacetate, providing the desired coumarin as a white solid (Rf0.62, hexanes/EtOAc, 2:1). Recrystallization from hexanes/EtOAc afforded 2.12 g (79%) of 1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylbenzo[5,6-g]coumarin as white prisms (mp 126-128° C.). 1H NMR (400 MHz, CDCl3) 7.51 (s, 1H), 7.25 (s, 1H), 6.20 (d, 1H, J=0.8 Hz), 2.43 (d, 3H, J=0.9 Hz), 1.72 (s, 4H), 1.33 and 1.31 (2s, 2×3H). 13C NMR (100 MHz, CDCl3) 161.2, 152.2, 151.4, 150.4, 141.5, 122.2, 117.9, 114.3, 107.1, 34.92, 34.84, 34.58, 34.20, 32.22, 31.83, 18.49. IR (thin film) 2923 (m), 1716 (s), 1612 (m). Anal. Calcd for C18H22O: C, 79.96; H, 8.20. Found: C, 80.06; H, 8.06.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]1C=CC=CC=1)C=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:24]I>ClCCl.S([O-])([O-])(=O)=S.[Na+].[Na+]>[CH2:1]([O:8][CH2:9][CH:10]1[CH:16]([CH2:17][I:24])[O:15][C:14](=[O:23])[NH:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(COCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=C1NC(COCc2ccccc2)C(CI)O1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A mixture of benzyl [1-(benzyloxy)but-3-en-2-yl]carbamate (3.0 g, 9.6 mmol) and iodine (4.9 g, 19 mmol) in dichloromethane (200 mL) was stirred at 20° C. for 16 hours. The reaction mixture was diluted with aqueous sodium thiosulfate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product residue. The crude product residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give 4-[(benzyloxy)methyl]-5-(iodomethyl)-1,3-oxazolidin-2-one. MS ESI calc'd. for C12H15INO3 [M+H]+ 348. found 348. 1H NMR (300 MHz, CDCl3) δ 7.40-7.27 (m, 5H), 5.53 (s, 1H), 4.57 (s, 2H), 4.37-4.34 (m, 1H), 3.82-3.80 (m, 1H), 3.67-3.51 (m, 2H), 3.38-3.32 (m, 2H).
Reaction SMILES: [Cl:1][C:2]([Cl:35])([Cl:34])[CH2:3][O:4][C:5](=[O:33])[CH:6]([S:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](C)(C)[O:15][SiH2]C(C)(C)C)=[CH:10][CH:9]=1.Cl.O>C(#N)C>[Cl:34][C:2]([Cl:1])([Cl:35])[CH2:3][O:4][C:5](=[O:33])[CH:6]([S:23][CH2:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][OH:15])=[CH:12][CH:13]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1
Agent: Cl
Solvent: O
Solvent: CC#N
Product: O=C(OCC(Cl)(Cl)Cl)C(Cc1ccc(CO)cc1)SCCc1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 3-[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-propionic acid 2,2,2-trichloro-ethyl ester (5.47 g, 9.43 mmol) in anhydrous acetonitrile (200 mL) was dropwise added BF3xEt2O (1.10 mL, 9.43 mmol) at 0° C. The mixture was stirred for 30 min. 2N aq. HCl (50 mL) and H2O (100 mL) were added and the mixture was extracted with DCM. The combined organic layers were dried (MgSO4) and evaporated to give the crude product which was purified by flash chromatography using DCM/MeOH 95:5 as the eluent. The product was obtained as an (3.62 g, 82.5%). 1H NMR (400 MHz, CDCl3): δ 7.19 (d, 2H), 7.10 (d, 2H), 7.01 (m, 2H), 6.87 (t, 2H), 4.65 (d, 1H), 4.56 (m, 3H), 3.48 (dd, 1H), 3.12 (dd, 1H), 2.73-2.91 (m, 5H). Mass Spectrum: M−H+ 464.90.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[CH3:10][C:11]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1>C1COCC1>[Si:14]([O:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][CH:6]=1)([C:11]([CH3:13])([CH3:12])[CH3:10])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccc(Cl)nc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.4 %

Procedure:
A solution of (6-chloropyridin-3-yl)methanol (800 mg, 5.6 mmol) and TBSCl (1000 mg, 6.7 mmol) in THF (15 mL) was added imidazole (455 mg, 6.7 mmol) and the reaction mixture was stirred at rt for 24 h. The mixture was concentrated under vacuum to about ¼ of the original volume and then diluted with EtOAc (30 mL). The resulting mixture was washed with water, aqueous 5% KH2PO4 (30 mL), saturated NaHCO3 (20 mL) and brine (20 mL) sequentially. The organic phase was dried, filtered and concentrated to give the desired product as colorless oil (800 mg, 54%). [LCMS: RtA=1.89 min, m/z 258.2 [M+H]+].
Reaction SMILES: C(Cl)Cl.[N:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N+:5]=[N-:6].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]([CH:25]=O)=[CH:23][N:22]=[CH:21]2)=[CH:16][CH:15]=1.[O-]CC.[K+]>C(O)C>[N:4]([C:7](=[CH:25][C:24]1[N:20]([C:17]2[CH:18]=[CH:19][C:14]([Br:13])=[CH:15][CH:16]=2)[CH:21]=[N:22][CH:23]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N+:5]=[N-:6]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: O=Cc1cncn1-c1ccc(Br)cc1
Agent: CC[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(=Cc1cncn1-c1ccc(Br)cc1)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A commercially available 34% methylene chloride solution of ethyl azidoacetate (6.6 mL, 21.6 mmol) was concentrated in vacuo, the residue reconstituted in anhydrous ethanol (100 mL) and the resulting solution treated with 3-(4-bromophenyl)-3H-imidazole-4-carbaldehyde (6) (2.7 g, 10.8 mmol). The mixture was cooled to 0° C., treated dropwise with potassium ethoxide solution (5.1 mL, 13.0 mmol, 24% (w/w) EtOH solution) and the mixture stirred at 0° C. for 5 h. The resulting white solid was collected by filtration and dried in air to yield ethyl 2-azido-3-[3-(4-bromophenyl)-3H-imidazol-4-yl]acrylate (7). LC-MS (ES+): m/z 362/364 (1/1) [MH+]. 1H NMR (CDCl3, 400 MHz): δ=1.31 (t, J=7.1 Hz, 3H), 4.30 (q, J=7.1 Hz, 2H), 6.52 (d, J=0.7 Hz, 1H), 7.19 (d, J=8.7 Hz, 2H), 7.67 (s, 1H), 7.68 (d, J=8.7 Hz, 2H), 8.03 (d, J=0.7 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]2[CH:6]=[C:7]([C:9]3[C:18]([N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]4[CH3:25])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:26]([O:28]C)=[O:27])[CH:15]=4)[N:10]=3)[O:8][C:4]=2[CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:31]=[CH:30][C:5]2[CH:6]=[C:7]([C:9]3[C:18]([N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]4[CH3:25])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:26]([OH:28])=[O:27])[CH:15]=4)[N:10]=3)[O:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3cc4ccc(F)cc4o3)c(N3CCCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H]1CCCCN1c1nc2cc(C(=O)O)ccc2nc1-c1cc2ccc(F)cc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
To a solution of methyl 2-(6-fluoro-1-benzofuran-2-yl)-3-[(2S)-2-methylpiperidin-1-yl]quinoxaline-6-carboxylate (50 mg, 0.12 mmol) in methanol (25 mL) and water (5 mL) was added sodium hydroxide (14.4 mg, 0.36 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL), adjusted pH to 5 with HCl (3N) to give the precipitate, which was collected by filtration to afford 2-(6-fluoro-1-benzofuran-2-yl)-3-[(2S)-2-methylpiperidin-1-yl]quinoxaline-6-carboxylic acid (36.6 mg, 76%).
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][CH2:17][CH:18]3[N:23]([S:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[N+:47]([O-:49])=[O:48])(=[O:40])=[O:39])[C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[C:26]([F:37])[CH:25]=2)=[C:9]([CH3:50])[CH:8]=1)[CH3:2].C(O)C.[OH-].[Na+].Cl>O1CCCC1>[CH2:1]([S:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][CH2:17][CH:18]3[N:23]([S:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[N+:47]([O-:49])=[O:48])(=[O:40])=[O:39])[C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[C:26]([F:37])[CH:25]=2)=[C:9]([CH3:50])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(N(C2CCc3c(-c4c(C)cc(OCCSCC)cc4C)cccc32)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCSCCOc1cc(C)c(-c2cccc3c2CCC3N(c2ccc(CCC(=O)O)c(F)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.9 %

Procedure:
To a mixture of ethyl 3-(4-{(4-{4-[2-(ethylthio)ethoxy]-2,6-dimethylphenyl}-2,3-dihydro-1H-inden-1-yl)[(2-nitrophenyl)sulfonyl]amino}-2-fluorophenyl)propanoate (1.06 g, 1.47 mmol), ethanol (5 mL) and tetrahydrofuran (5 mL) was added 1 N aqueous sodium hydroxide solution (2.94 mL, 2.94 mmol), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was neutralized with 1 N hydrochloric acid, and concentrated under reduced pressure to evaporate the organic solvent. The residue was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (20%-100% ethyl acetate/hexane) to give the title compound (0.804 g, yield 79%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19]3=[C:20]([CH2:22][O:23][CH2:24][CH2:25][N:18]3[C@H:17]3[CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][C@@H:16]23)[CH:21]=1>>[CH3:11][O:10][C:8]1[CH:7]=[CH:6][C:3]([CH2:4][NH:12][C:13]2[CH:14]=[C:15]3[C:19]4=[C:20]([CH2:22][O:23][CH2:24][CH2:25][N:18]4[C@H:17]4[CH2:26][CH2:27][NH:28][CH2:29][C@@H:16]34)[CH:21]=2)=[C:2]([CH3:1])[CH:9]=1
Reactant: COc1ccc(C=O)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Product: COc1ccc(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)c(C)c1

Procedure:
Using 2-methyl-4-methoxybenzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into the title compound of EXAMPLE 137. 1H NMR(CDCl3) δ: 7.21 (d, 1H, J=8.5 Hz), 6.75-6.68 (m, 2H), 6.59 (broad s, 1H), 6.43 (broad s, 1H), 4.58 (ABq, 2H), 4.23-4.16 (m, 1H), 4.16 (s, 2H), 3.78 (s, 3H), 3.68 (app t, 1H), 3.50-3.40 (m, 1H), 3.37-3.15 (m, 5H), 2.70-2.50 (m, 2H), 2.30 (s, 3H), 2.23-2.10 (m, 2H). LRMS (ES)+: 380.4 (M+H)+.
Reaction SMILES: C([O:9][C:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([CH3:21])=[CH:16][CH:17]=2)[N:12]([CH3:22])[CH:11]=1)(=O)C1C=CC=CC=1.N1CCCCC1>ClCCl>[OH:9][C:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([CH3:21])=[CH:16][CH:17]=2)[N:12]([CH3:22])[CH:11]=1
Reactant: Cc1ccc2c(=O)c(OC(=O)c3ccccc3)cn(C)c2c1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: Cc1ccc2c(=O)c(O)cn(C)c2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 1,7-dimethyl-4-oxo-1,4-dihydroquinol-3-yl benzoate (1.45 g), piperidine (0.49 ml) and dichloromethane (14 ml) was stirred at ambient temperature under nitrogen for 3 days. Further piperidine (0.13 ml) was added and the mixture stirred overnight. The solvent was removed by distillation and the residue triturated with diethyl ether (20 ml) to give the novel compound 3-hydroxy-1,7- dimethyl-4quinolone, m.p. 268°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]#[N:26])=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][CH2:6][C:7]([CH3:21])([CH3:20])[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)=[O:9].O=[C:28]([CH3:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[NH2:26][C:25]1[C:3]2[C:2](=[CH:24][CH:23]=[CH:22][C:4]=2[O:5][CH2:6][C:7]([CH3:21])([CH3:20])[C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[O:9])[N:1]=[C:28]([CH3:35])[C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: COc1cccc(CNC(=O)C(C)(C)COc2cccc(N)c2C#N)c1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NCc3cccc(OC)c3)c2c1N

Procedure:
Prepared as in Example 2a from 3-(3-amino-2-cyanophenoxy)-N-(3-methoxybenzyl)-2,2-dimethylpropanamide (Example 46b) and ethyl 3-oxobutanoate as a yellow solid (42%). MS 466 (MH+).
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[C:15]([CH:17]1[CH:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:28]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]=2[C:19]2[CH2:35][CH2:36][CH2:37][C:18]1=2)#[N:16]>C1(C)C=CC=CC=1>[C:15]([C:17]1[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:28]2[C:20]([NH:21][C:22]3[C:27]2=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:19]2[CH2:35][CH2:36][CH2:37][C:18]=12)#[N:16]
Reactant: CCOC(=O)C1c2c([nH]c3ccccc23)C2=C(CCC2)C1C#N
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C#N)c2c(c3[nH]c4ccccc4c13)CCC2
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 37.9 %

Procedure:
DDQ (39 mg, 0.17 mmol, 220 mol %) was added to solution of ethyl 4-cyano-1,2,3,4,5,10-hexahydrocyclopenta[a]carbazole-5-carboxylate (24 mg, 0.078 mmol) in toluene (12 mL). The solution immediately turned dark brown, and was stirred at 20° C. for 1.5 hr. The solvent was evaporated. The residue was dissolved in EtOAc and rinsed with dilute aqueous ascorbic acid and twice with saturated NaHCO3. Evaporation of the solvent afforded crude product (21 mg) which was recrystallized from EtOAc gave the product (9 mg, 38% yield) as a beige solid, mp 229-231° C. NMR (CDCl3) δ 8.28 (s, 1H), 7.49 (s, 2H), 7.26 (s, 2H), 4.64 (q, 2H), 3.30 (t, 2H), 3.20 (t, 2H), 2.36 (quintet, 2H), 1.54 (t, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH:26]=[CH:25][C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27](#[N:29])[CH3:28].[NH2-].[Na+]>C1C=CC=CC=1>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:26]=[CH:25][C:10]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)([OH:12])[CH2:28][C:27]#[N:29])=[CH:9][CH:8]=1
Reactant: CC#N
Reactant: O=C(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1
Agent: [NH2-]
Agent: [Na+]
Solvent: c1ccccc1
Product: N#CCC(O)(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 0 °C

Procedure:
To a stirred suspension of 4,4'-diphenylbenzophenone (15.5 g) and acetonitrile in dry benzene (200 mL), was added at a rapid dropwise rate a suspension of sodamide (2.3 g) in dry benzene (20 mL). The resulting mixture was stirred at reflux for 60 minutes, then the reaction was cooled and treated carefully with ice (50 g). The layers were separated, and the aqueous Phase was extracted with toluene. The organic extracts were washed with water, then were combined, dried (MgSO4) and evaporated to furnish 13.5 g of 3,3-bis[(1,1'-biphenyl)-4-yl]-3-hydroxypropanenitrile as an oil. The material was contained a minor impurity that was presumed to be the starting ketone.