Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([CH3:23])[C:13]([O:19]C(=O)C)=[CH:14][CH:15]=3)[O:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CN=C1>CCO>[OH:19][C:13]1[C:12]([CH3:23])=[C:11]2[C:16]([C:17](=[O:18])[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)[CH2:9][O:10]2)=[CH:15][CH:14]=1
Reactant: CC(=O)Oc1ccc2c(c1C)OCC(c1ccc(O)cc1)C2=O
Agent: c1c[nH]cn1
Solvent: CCO
Product: Cc1c(O)ccc2c1OCC(c1ccc(O)cc1)C2=O
Reaction time: 8 h

Procedure:
Acetic acid 3-(4-hydroxy-phenyl)-8-methyl-4-oxo-chroman-7-yl ester (18.37 g), imidazole (21.18 g, 6 equivalents) and 100% EtOH (536 ml) were added to a round bottom flask (2 L). The reaction mixture was refluxed and monitored by HPLC. The reaction was completed at 8 hours. The reaction mixture was reduced (˜130 ml) on a rotary evaporator and poured into stirred, chilled distilled water (1.9 L). The water crash out was left stirring in the cold room overnight. The pale pink solid was collected by suction filtration. 1H NMR of the solid indicated it was 7-Hydroxy-3-(4-hydroxy-phenyl)-8-methyl-chroman-4-one with >95% purity. The solid was dried on the freeze dryer for 3 hours (8.31 g, 59%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.Cl.N([O-])=O.[Na+].[N-:31]=[N+:32]=[N-].[Na+]>C(O)C>[N:1]([C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[CH:4][C:3]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[N+:31]=[N-:32]
Reactant: COc1ccc(-c2cc(C#N)c(N)c(-c3ccc(OC)cc3)c2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2cc(C#N)c(N=[N+]=[N-])c(-c3ccc(OC)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 44.6 %

Procedure:
4′-Amino-4,4″-dimethoxy-[1,1′:3′,1″-terphenyl]-5′-carbonitrile (226 mg, 0.68 mmol) was heated in ethanol (28 mL) to bring most of the material into solution. After cooling to room temperature, 17% aqueous HCl (4 mL) was added and the reaction was cooled in an ice bath. Sodium nitrite (76 mg, 1.09 mmol) was added and the orange-red solution was stirred for 15 min in the ice bath. Sodium azide (71 mg, 1.09 mmol) was then added. After 20 min, the reaction was partitioned between ethyl acetate and sufficient saturated aqueous sodium bicarbonate to neutralize the reaction. The organic phase was separated, washed with brine, and dried with sodium sulfate. Silica gel radial chromatograph using step gradient elution with hexane containing 5 to 20% ethyl acetate afforded 4′-azido-4,4″-dimethoxy-[1,1′:3′,1″-terphenyl]-5′-carbonitrile (108 mg, 44%) as a solid. 1H NMR (500, CDCl3) δ ppm 7.72 (1H, d, J=2.14 Hz), 7.62 (1H, d, J=2.14 Hz), 7.47 (2H, d, J=8.55 Hz), 7.39 (2H, d, J=8.55 Hz), 7.01 (2H, d, J=8.55 Hz), 6.97 (2H, d, J=8.85 Hz), 3.87 (3H, s), 3.84 (3H, s).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[CH:9]=2)[NH:4][N:3]=1.[CH3:14]C([O-])(C)C.[K+].CI>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[CH:9]=2)[N:4]([CH3:14])[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)c1ccc2[nH]nc(I)c2c1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)c1ccc2c(c1)c(I)nn2C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-iodo-5-isopropyl-1H-indazole (0.75 g, crude) in 50 mL of THF at 0° C. was added t-BuOK (0.59 g, 5.2 mmol) in one portion. The mixture was stirred at 0° C. for 30 minutes. CH3I (1.1 g, 7.7 mmol) was added and the solution was stirred at room temperature overnight. The reaction was quenched with 30 mL of water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL) and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated under reduced pressure to give crude 3-iodo-5-isopropyl-1-methyl-1H-indazole which contained some N-2 alkylation isomer (0.7 g) as oil. LCMS: (M+H)+=301.
Reaction SMILES: [N:1]1([C:6]2[N:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]#[N:9])[CH:5]=[N:4][CH:3]=[N:2]1>O.N.CO.[Ni]>[N:1]1([C:6]2[C:7]([CH2:8][NH2:9])=[CH:10][CH:11]=[CH:12][N:13]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: N#Cc1cccnc1-n1cncn1
Agent: [Ni]
Agent: N
Solvent: O
Solvent: CO
Product: NCc1cccnc1-n1cncn1
Temperature: 25 °C
Reaction time: 11 h
Yield: 91.6 %

Procedure:
A catalytic amount of Raney 2800 nickel in water (Aldrich; withdrawn as a wet slurry with the tip of a spatula) was added under air to a translucent slurry of 2-[1,2,4]triazol-1-yl-nicotinonitrile (1.053 g, 6.16 mmol), as prepared in the previous step, in 2 M NH3/MeOH (50 mL). The flask was then sealed with a septum, the air was removed from the system, and the flask was flushed with H2 gas under balloon pressure. The reaction was stirred at rt under H2 for 11 h (TLC showed no starting material remained), and the bulk of the Raney nickel was then removed with a magnet. The translucent white reaction mixture was then diluted with DCM (50 mL), filtered, and the translucent filtrate was concentrated under vacuum to provide the title compound as a beige crystalline solid (988 mg, 92%).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].C1COCC1.Cl[C:10]1[CH:23]=[CH:22][C:13]([C:14]([NH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[O:15])=[CH:12][C:11]=1[N+:24]([O-:26])=[O:25]>>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][NH:16][C:14](=[O:15])[C:13]1[CH:22]=[CH:23][C:10]([NH:3][CH2:1][CH3:2])=[C:11]([N+:24]([O-:26])=[O:25])[CH:12]=1
Reactant: CCN
Reactant: CN(C)CCNC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: CCNc1ccc(C(=O)NCCN(C)C)cc1[N+](=O)[O-]
Temperature: 65 °C
Yield: 73 %

Procedure:
To 2.0 M solution of ethylamine in THF (8 mL, 16 mmol) slowly added 4-chloro-N-(2-dimethylaminoethyl)-3-nitrobenzamide (0.40 g, 1.5 mmol). After heating at 65° C. for 16 h, the reaction mixture was cooled, concentrated and chromatographed (silica gel, MeOH/DCM, 3:22) to afford the title compound (0.30 g, 73%) as a yellow solid. 1H-NMR (CD3OD): δ 8.75 (1H, d), 8.32 (1H, br s), 7.98 (1H, dd), 7.08 (1H, d), 3.58–3.64 (3H, m), 3.43–3.51 (2H, m), 2.94 (2H, br t), 2.62 (6H, s), 1.35 (3H, t).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][N:17]=1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O.C(O)(C)C>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[C:6]([CH2:20][C:19]1[CH:18]=[N:17][C:16]([C:15]([F:25])([F:14])[F:24])=[CH:23][CH:22]=1)=[C:5]2[OH:13]
Reactant: O=c1cc(O)c2cc(Br)ccc2[nH]1
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Solvent: c1ccncc1
Solvent: CC(C)O
Product: Oc1nc2ccc(Br)cc2c(O)c1Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 6-bromo-4-hydroxyquinolin-2(1H)-one (3.2 g, 18.3 mmol, Intermediate 45: step a), 6-(trifluoromethyl)nicotinaldehyde (4.0 g, 16.7 mmol) and diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (4.2 g, 16.7 mmol) in pyridine (34 mL) was heated to 105° C. for 3 hours. The solution was allowed to cool to ambient temperature, resulting in the formation of solid. Minimal isopropanol was added to the mixture and the slurry was stirred for 1 hour, sonicated, and filtered. The filtered solids were rinsed with isopropanol and dried under continuous air flow to provide the title compound as an off-white solid. Additional product was recrystallized from the filtrate, filtered, and rinsed with isopropanol.
Reaction SMILES: C(OC([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([O:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26]C(=O)OC(C)(C)C)[N:21]=2)=[CH:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([O:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[N:21]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1nccc(Oc2ccc(NC(=O)OC(C)(C)C)c3ccccc23)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nccc(Oc2ccc(N)c3ccccc23)n1
Reaction time: 3 h
Yield: 97.8 %

Procedure:
To a solution of tert-butyl 4-(4-(tert-butoxycarbonylamino)naphthalen-1-yloxy)pyrimidin-2-ylcarbamate (1.35 g, 2.98 mmol) in DCM (15 mL) was added TFA (5.0 mL) and the reaction mixture was set aside at RT for 3 hr. The mixture was evaporated in vacuo and the residue was taken up into EtOAc (25 mL) and washed with saturated NaHCO3 solution (25 mL) and brine (25 mL) and then dried (MgSO4) Evaporation in vacuo afforded the title compound as a beige solid (735 mg, 96%); Rt 0.98 min (Method 2); m/z 253 (M+H)+, (ES+)+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[CH:25]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[NH:24][CH:25]=2)=[O:34])=[O:10])[N:12]=1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c[nH]c3ccccc23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 1H-Indole-3-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]2[C:14]=1[C:13](=[O:15])[CH:12]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11]1.S(=O)(=O)(O)O.[C:22](NC(N)=O)([CH3:25])([CH3:24])[CH3:23]>O>[C:22]([C:3]1[C:2]([OH:1])=[C:14]2[C:6]([CH:7]3[CH:12]([C:13]2=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]3)=[C:5]([CH3:16])[CH:4]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)NC(N)=O
Reactant: Cc1ccc(O)c2c1C1CCCCC1C2=O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(C(C)(C)C)c(O)c2c1C1CCCCC1C2=O
Temperature: 90 °C
Yield: 78.1 %

Procedure:
To 20 g of 8-hydroxy-5-methyl-1,2,3,4,4a,9a-hexahydro-9-fluorenone were added 200 ml of water and 200 ml of concentrated sulfuric acid and the mixture was stirred with heating at 90° C. At the same temperature, thereto was gradually added 53.71 g of N-tert-butylurea, followed by stirring with heating for 14 hours. Then, 10 g of N-tert-butylurea was further added, followed by further stirring at 90° C. for 5 hours. The reaction mixture was poured into 2 liters of water and extracted with chloroform. The chloroform layer was washed with saturated aqueous sodium chloride solution and then dried with magnesium sulfate. The solvent was distilled off and the residue was purified by a silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:10) and thereafter recrystallized from n-hexane to obtain 19.67 g of 7-tert-butyl-8-hydroxy-5-methyl-1,2,3,4,4a,9a-hexahydro-9-fluorenone.
Reaction SMILES: CC1(C)[O:6][C:5](=O)[C@H:4]([C@@H:8]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:17][CH2:16]2)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[O:3]1.[NH2:28][OH:29]>CC(O)C>[OH:29][NH:28][C:5](=[O:6])[C@@H:4]([OH:3])[C@@H:8]([C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: NO
Reactant: CC(C)C[C@H](C(=O)N1CCN(c2ccccn2)CC1)[C@@H]1OC(C)(C)OC1=O
Solvent: CC(C)O
Product: CC(C)C[C@H](C(=O)N1CCN(c2ccccn2)CC1)[C@H](O)C(=O)NO
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 31.5 %

Procedure:
To a solution of (5S)-2,2-dimethyl-5-((1S)-3-methyl-1-{[4-(2-pyridinyl)-1-piperazinyl]carbonyl}butyl)-1,3-dioxolan-4-one (250 mg; 0.67 mmol; 1.0 eq.) in iPrOH (5 mL) was added an aqueous solution of hydroxylamine (50%; 0.195 mL; 3.35 mmol; 5.0 eq.) and the resulting reaction mixture was stirred at RT for 2.5 h. After evaporation of the solvents, the crude mixture was purified by reverse-phase chromatography to give the title compound (1) as a white powder (74 mg; 31%). M−(ESI): 349.2; M+(ESI): 351.1. HPLC: Rt: 1.3 min (HPLC purity: 100%).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:19])=[CH:9][C:10]2[O:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]=2[C:17]=1[CH3:18])=[O:5].C1C[O:25][CH2:24]C1.CCCCCC>>[CH:24]([C:9]1[C:10]2[O:14][C:13]([CH3:15])([CH3:16])[CH2:12][C:11]=2[C:17]([CH3:18])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:21])([CH3:20])[CH3:1])[C:8]=1[CH3:19])=[O:25]
Reactant: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)CC(C)(C)O2
Reactant: C1CCOC1
Solvent: CCCCCC
Product: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)CC(C)(C)O2
Yield: 85 %

Procedure:
Using 3,3-dimethyl-N-(2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)butanamide obtained in Example 339, the title compound was synthesized in the same manner as in Example 20. Yield: 85%. Melting point: 180-181° C. (THF-hexane).
Reaction SMILES: [CH2:1]([N:3]1[CH2:15][CH2:14][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].[CH3:16][C:17]1[CH:25]=[CH:24][C:20]([CH:21]2[O:23][CH2:22]2)=[CH:19][CH:18]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([N:3]1[CH2:15][CH2:14][C:6]2[N:7]([CH2:22][CH:21]([C:20]3[CH:24]=[CH:25][C:17]([CH3:16])=[CH:18][CH:19]=3)[OH:23])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: CCN1CCc2[nH]c3ccccc3c2C1
Reactant: Cc1ccc(C2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCc2c(c3ccccc3n2CC(O)c2ccc(C)cc2)C1

Procedure:
2-Ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (400 mg, 2.0 mmol), 4-methylstyrene oxide (2.01 g, 15 mmol) and NaH (240 mg, 6 mmol) were heated in DMF (6 mL) at 120° C. for 16 h to obtain 120 mg of racemic-2-(2-ethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-1-p-tolyethanol as a TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL). 1H NMR (CDCl3, TFA salt) δ (ppm): 13.40-13.10 (bs, 1H), 7.40-7.30 (t, 2H), 7.29-7.10 (m, 6H), 5.07-4.95 (m, 1H), 4.75-4.60 (t, 1H), 4.25-4.02 (m, 3H), 3.75-3.65 (m, 1H), 3.40-3.0 (m, 5H), 2.35 (S, 3H), 1.47-1.40 (t, 3H).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[NH2:10][CH:11]([C:17]([OH:19])=O)[CH2:12][CH2:13][CH2:14][CH2:15][NH2:16].C(O)C>Cl[Si](C)(C)C.C1(C)C(C)=CC=CC=1>[NH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]1=[O:19]
Reactant: NCCCCC(N)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CCO
Solvent: Cc1ccccc1C
Product: NC1CCCCNC1=O
Reaction time: 48 h
Yield: 60.5 %

Procedure:
Hexamethyldisilazane (30 ml) and chloro-trimethylsilane (several drops) were added to a suspension of DL-lysine (3.0 g, 20.5 mmol) in xylene (270 ml) at room temperature, and the reaction was carried out at 140° C. for 48 hours. The reaction mixture was cooled and then poured into ethanol (600 ml), and the resulting mixture was concentrated. The resulting residue was suspended in chloroform, followed by filtration and concentration, whereby 3-amino-2-azepanone (1.59 g, 60%) was obtained.
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][N:3]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2]2.[N-:14]=[N+:15]=[N-:16].[Na+].[NH4+].[Cl-].[OH-].[Na+]>CO.O>[N:14]([C@H:1]1[C@H:5]([OH:6])[CH2:4][N:3]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2]1)=[N+:15]=[N-:16]
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N=[N+]=[N-])C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a stirred solution of tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (110 g, 0.595 mol) in MeOH/water (1200 mL/200 mL) were added NaN3 (77.6 g, 1.19 mol) and NH4Cl (32 g, 0.598 mol). The resulting mixture was stirred at 60° C. overnight. NaOH (0.5 N, 200 mL) was added and the mixture was concentrated to remove MeOH. The residue was extracted with CH2Cl2 (3×400 mL) and the combined organic extracts were washed with water, brine, dried over Na2SO4, and then concentrated to give the title compound as a yellow liquid (quantitative yield). Used as is in next step.
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[C:12]([O:25][CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)#[N:2].Cl.[NH2:32][OH:33]>N1C=CC=CC=1>[C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[C:12]([O:25][CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)[CH:11]=2)[CH2:4][CH2:5][C:6](=[N:32][OH:33])[CH2:7][CH2:8]1)#[N:2]
Reactant: N#CC1(c2ccc(OCc3ccc(F)cc3)c(OC3CCCC3)c2)CCC(=O)CC1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: N#CC1(c2ccc(OCc3ccc(F)cc3)c(OC3CCCC3)c2)CCC(=NO)CC1
Yield: 71.5 %

Procedure:
A solution of 4-cyano-4-[3-cyclopentyloxy-4-(4-fluorobenzyloxy)phenyl)cyclohexan-1-one (0.525 g, 1.49 mmol) and hydroxylamine hydrochloride (0.114 g, 1.63 mmol) in pyridine (5 mL) was was stirred at room temperature under an argon atmosphere for 18 h. The mixture was partitioned between 1N hydrochloric acid and methylene chloride, the organic extract was dried (magnesium sulfate) and the solvent was removed in vacuo. Purification by flash chromatography, eluting with 35% ethyl acetate/hexanes, provided a white solid (0.45 g, 82%): m.p. 55°-57° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([N:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:18])[C:12]=3[C:11]3=[N:19][O:20][C:21]([CH3:22])=[C:10]3[C:9]2=[O:23])[CH2:3]1.[C:24]1([NH:30][CH2:31][C:32](O)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.ON1C2N=CC=CC=2N=N1.Cl.C(N=C=N)C.CC1C=C(C)C=C(C)N=1>CN(C)C=O>[Cl:18][C:13]1[C:12]2[C:11]3[C:10](=[C:21]([CH3:22])[O:20][N:19]=3)[C:9](=[O:23])[N:8]([CH:4]3[CH2:5][CH2:6][CH2:7][CH:2]([NH:1][C:32](=[O:33])[CH2:31][NH:30][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:3]3)[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)CNc1ccccc1
Reactant: Cc1onc2c1c(=O)n(C1CCCC(N)C1)c1cccc(Cl)c21
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: Cc1onc2c1c(=O)n(C1CCCC(NC(=O)CNc3ccccc3)C1)c1cccc(Cl)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Anhydrous dimethylformamide (10 mL) in a nitrogen atmosphere was used to dissolve 5-(3-aminocyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin4-one (50 mg; 0.151 mmol), N-phenylglycine (29.6 mg; 0.196 mmol; 1.3 equiv), 1-hydroxy-7-azabenzotriazole (26.7 mg; 0.196 mmol; 1.3 equiv), 1-[3-(dimethylamino)propyl[-3-ethylcarbodiimide hydrochloride (37.6 mg; 0.196 mmol; 1.3 equiv), and 2,4,6-trimethylpyridine (199 μL; 1.51 mmol; 10 equiv). After overnight stirring at room temperature, the reaction solution was treated in a manner similar to Example 159. The resulting material was purified by three consecutive radial chromatography runs on a 2 mm thick silica gel rotor with a 1% methanol/dichloromethane (v/v) mobile phase, a 1% methanol/0.25% triethylamine/dichloromethane (v/v/v) mobile phase, and a 5% acetonitrile/dichloromethane mobile phase. The desired product was isolated as a white solid 56% yield (30 mg). MS(ES) calc'd: [M+M]+=465.16 m/z; [M−H]−=463.16 m/z; [M+OAc]−=523.16 m/z. Found: 465.1 m/z; 463.2 m/z; 523.2 m/z.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].N1C=CC=CC=1.[CH2:14](O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH3:25].CCOC(C)=O>C(Cl)Cl.C(OCC)C>[C:5]([O:4][CH2:1][CH2:2][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]/[CH:17]=[CH:16]\[CH2:15][CH3:14])(=[O:7])[CH3:6]
Reactant: CC/C=C\CCCCCCCCO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC/C=C\CCCCCCCCCCOC(C)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.9 %

Procedure:
Acetic anhydride (0.17 mL, 1.8 mmol), then pyridine (86 μL, 1.1 mmol), were added sequentially to alcohol 7 (0.19 g, 0.89 mmol) in CH2Cl2 (1.8 mL), and stirred at room temperature for 12 hours. The mixture was diluted with diethyl ether, washed with saturated aqueous NaHCO3, then brine, dried with Na2SO4, and concentrated. Flash chromatography of the residue (SiO2, 5% EtOAc in hexanes) provided 10 (0.19 g, 84% yield, 77% Z as determined by 13C-NMR) as a colorless oil; 1H NMR (CDCl3): δ 5.29-5.43 (2H, m), 4.05 (2H, t, J=6.8 Hz), 2.04 (7H, m), 1.61 (2H, m), 1.27 (14H, m), 0.95 (3H, m); 13C NMR (CDCl3): δ 171.4, 131.7, 129.4, 64.8, 32.7, 29.9, 29.7 (2C), 29.4 (2C), 28.7, 27.2, 26.1, 21.2, 20.7, 14.6; HRMS (FAB): 255.2324, [C16H30O2+H]+ requires 255.2319.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.C(N)(N)=[O:13].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O.COC(C1C(C)=[N+]([O-])C=CN=1)=O>C(Cl)Cl>[CH3:11][O:10][C:8]([C:3]1[C:2]([CH3:1])=[N:7][CH:6]=[CH:5][N+:4]=1[O-:13])=[O:9]
Reactant: COC(=O)c1nccnc1C
Reactant: NC(N)=O
Agent: COC(=O)c1ncc[n+]([O-])c1C
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(C)ncc[n+]1[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
To a solution of methyl 3-methylpyrazine-2-carboxylate (9.1 g, 59.8 mmol) in DCM (100 mL) at 0° C., was added urea hydrogen peroxide adduct, 97% (7.81 g, 83 mmol) and trifluoroacetic acid anhydride (10.8 ml, 78 mmol) dropwise. The resulting mixture was stirred at 0° C. for 1 h, and at room temperature for 18 h. The reaction was diluted with DCM and quenched with saturated Na2SO3 solution; the aqueous layer was back-extracted with DCM. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude mixture was purified with ISCO (20% to 80% EtOAc/Hexanes) to afford a mixture of products: 2-(methoxycarbonyl)-3-methylpyrazine 1-oxide (5.2 g, 51.7% yield) and 3-(methoxycarbonyl)-2-methylpyrazine 1-oxide. The mixture was taken to next step without further purification.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:23][CH2:22][C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:14][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].CN(C=O)C.Br[CH2:30][CH2:31][CH2:32][Cl:33]>CCOC(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:23][CH2:22][C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]([CH2:30][CH2:31][CH2:32][Cl:33])[C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: ClCCCBr
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccccc3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCCCl)c3ccccc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (335 mg, 60%) was added to a solution of 3-tert-butyloxycarbonyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.99 g) and DMF (21.0 mL) at 0° C. The solution was stirred at 0° C. for 30 min and then 1-bromo-3-chloropropane (0.74 mL) was added. The solution was stirred at 0° C. for 1 h and 16 h at room temperature. The solution was diluted with EtOAc, which was washed with water (3×20 mL). The combined aqueous layers were extracted with EtOAc (2×20 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude material was purified by chromatography (Biotage, silica gel, 4:1-1:1 hexane:EtOAc) to give 1.38 g of the title compound as an oil: 1H NMR (300 MHz, CDCl3) δ 7.50, 7.10-7.40, 4.28, 3.55-3.82, 3.52, 2.95-3.10, 2.15-2.30, 1.51; MS (ESI) m/z 363 (M+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][NH2:16].C(O)C.O>C(O)C>[CH3:15][NH:16][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CN
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: CCO
Solvent: O
Product: CNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 96.9 %

Procedure:
4-Fluoro-3-nitrobenzotrifluoride (25 g) was dissolved in ethanol (50 mL), and 30% methylamine-ethanol solution (97.9 g) was gradually added dropwise under ice-cooling, and the mixture was stirred at room temperature for 40 min. The reaction mixture was added to water, and the precipitated solid was collected by filtration to give 4-methylamino-3-nitrobenzotrifluoride (25.5 g) as yellow crystals.