Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]1([CH2:12][NH:13]C(=O)C)[CH2:10][CH:9]2[CH2:11][CH:6]1[CH2:7][CH2:8]2)(=O)C.[ClH:17]>O>[ClH:17].[ClH:17].[NH2:4][C:5]1([CH2:12][NH2:13])[CH2:10][CH:9]2[CH2:11][CH:6]1[CH2:7][CH2:8]2
Reactant: CC(=O)NCC1(NC(C)=O)CC2CCC1C2
Agent: Cl
Solvent: O
Product: NCC1(N)CC2CCC1C2

Procedure:
2-Acetylamino-2-acetylaminomethyl-bicyclo[2.2.1]heptane (3 g), in the form of a mixture of the exo and endo racemates in a ratio of (4/1), in a 6N solution (100 cc) of hydrochloric acid in water is refluxed for 8 hours. The mixture is concentrated to dryness under reduced pressure (5.2 kPa), the residue from the evaporation is taken up in ethanol (50 cc) and diisopropyl ether (150 cc) is added dropwise. The precipitate obtained is drained on a glass frit, washed with a mixture of ethanol and diisopropyl ether (25/75 by volume) (20 cc) and then with diisopropyl ether (2×20 cc) and finally dried in an oven at 80° C. 2-Amino-2-aminomethyl-bicyclo[2.2.1]heptane dihydrochloride (2.53 g) is thus obtained in the form of white crystals which melt at 262°-4° C.
Reaction SMILES: [CH2:1]([C:3]([C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[C:23]([CH3:29])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[S:30]1[CH2:34][C:33](=[O:35])[NH:32][C:31]1=[O:36].C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1>[CH2:1]([C:3]([C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[C:34]2[S:30][C:31](=[O:36])[NH:32][C:33]2=[O:35])=[C:23]([CH3:29])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:17])([CH3:18])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: O=C1CSC(=O)N1
Reactant: CCC(CC)(c1ccc(C=O)c(C)c1)c1ccc(OCC(O)C(C)(C)C)c(C)c1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCC(CC)(c1ccc(C=C2SC(=O)NC2=O)c(C)c1)c1ccc(OCC(O)C(C)(C)C)c(C)c1
Yield: 82.6 %

Procedure:
To a mixture of enantiomer 2 of 4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzaldehyde (048 g, 1.21 mmol) and toluene (15 mL) is added 90% 2,4-thiazolidinedione (0.19 g, 1.45 mmol), and piperidine acetate (0.03 g, 0.18 mmol). The solution is heated to a reflux overnight and the water removed by a Dean-Stark trap. The solution is diluted with EtOAc (60 mL), washed with water (50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated. Purified by ISCO (20%-40% EtOAc gradient) to furnish the title compound (0.50 g, 1.00 mmol, 83%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:34][C:33]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([O:35][CH3:36])[CH:31]=4)[N:26]=[CH:25][C:24]=3[O:23][CH2:22]2)[CH2:17][CH2:16]1)(C)(C)C>ClCCl>[CH3:36][O:35][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][C:24]1[O:23][CH2:22][CH:21]([N:18]3[CH2:17][CH2:16][CH:15]([NH2:14])[CH2:20][CH2:19]3)[CH2:34][C:33]2=1
Reactant: COc1ccc2ncc3c(c2c1)CC(N1CCC(NC(=O)OC(C)(C)C)CC1)CO3
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2ncc3c(c2c1)CC(N1CCC(N)CC1)CO3
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.8 %

Procedure:
Trifluoroacetic acid (1.23 mL, 15.78 mmol, 15.0 eq) is added at 0° C. to a stirred solution of [1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthrene-3-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester (500 mg, 1.05 mmol, 1.0 eq) in dichloromethane (50 mL). After 15 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×30 mL) and water (30 mL) and the pH is adjusted to 12 by the addition of a 1N sodium hydroxide aqueous solution. The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford 1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthrene-3-yl)-piperidin-4-ylamine as a brown solid (325 mg, 84% yield).
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:8])C=CC=CC=1.[C:18]12(C(O)=O)[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2.[N:31]1[CH:36]=CC=CC=1>>[C:18]12([N:31]=[C:36]=[O:8])[CH2:19][CH:20]3[CH2:21][CH:22]([CH2:23][CH:24]([CH2:26]3)[CH2:25]1)[CH2:27]2
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: c1ccncc1
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Product: O=C=NC12CC3CC(CC(C3)C1)C2
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Diphenylphosphoryl azide (9.08 g.) was added dropwise to a solution of 1-admantanecarboxylic acid (5.4 g.) in dry pyridine (25 ml.) and stirred at 70° C. for one hour to give 1-adamantyl isocyanate [I.R.: 2250 cm-1 ].
Reaction SMILES: [CH:1]([C:4]1[N:9]=[CH:8][C:7]([CH:10]=[CH:11][CH:12]=O)=[CH:6][N:5]=1)([CH3:3])[CH3:2].N1C=CC=C[C:15]=1[CH:20]=[O:21]>>[CH:1]([C:4]1[N:5]=[CH:6][C:7]([CH:10]=[CH:11][CH:12]=[CH:15][CH:20]=[O:21])=[CH:8][N:9]=1)([CH3:2])[CH3:3]
Reactant: O=Cc1ccccn1
Reactant: CC(C)c1ncc(C=CC=O)cn1
Product: CC(C)c1ncc(C=CC=CC=O)cn1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 5 by substituting 3-(2-isopropyl-pyrimidin-5-yl)-propenal (Reference Example 15) for the 2-pyridinecarboxaldehyde of Reference Example 5. MS 203 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH:8]([OH:12])[CH2:9][CH:10]=[CH2:11])=[CH:4][CH:3]=1.CCCCCC.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[CH2:23]([O:12][CH:8]([CH2:7][O:6][C:5]1[CH:13]=[CH:14][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][CH:10]=[CH2:11])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C=CCC(O)COc1ccc(F)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C=CCC(COc1ccc(F)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 5-(4-fluorophenoxy)-1-penten-4-ol (9.81 g., 0.05 mole) in dry dimethylformamide (15 ml.) is added dropwise to a stirred suspension of hexane (2 × 10 ml.)--prewashed sodium hydride (50% dispersion in mineral oil, 2.64 g., 0.055 mole) in dry dimethylformamide (45 ml.) at 25° C. Upon cessation of gas evolution, the reaction mixture is cooled to 0°-5° C. and treated with a solution of benzyl bromide (10.3 g., 0.06 mole) in dry dimethylformamide (10 ml.). The resulting mixture is stirred at 25° C. for 16 hours, then heated at 100° C. for 1 hour. After cooling to 25° C., the reaction mixture is diluted with ice water (50 ml.) and extracted with ether four times. The combined organic extract is washed with 2 N hydrochloric acid and saturated aqueous brine, dried over magnesium sulfate and filtered. In vacuo evaporation of the filtrate leaves an oily residue which affords the title compound upon distillation as a colorless oil (13.1 g., 92%), bp0.025 112°-116° C.; pmr (CCl4) δ2.37 (2H, t), 3.5-4.0 (3H, m), 4.57 (2H, s), 4.8-5.05 (H, m), 5.05-5.25 (H, m), 5.4-6.2 (H, m), 6.6-7.1 (4H, m) and 7.19 (5H, s).
Reaction SMILES: O.C(=O)([O-])[O-].[K+].[K+].[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@@H:16]([OH:33])[C@H:17](OS(C1C=CC(C)=CC=1)(=O)=O)[C:18]([O:20][CH3:21])=[O:19].C(OCC)(=O)C>CN(C)C=O>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@H:16]1[O:33][C@H:17]1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)[C@@H](OS(=O)(=O)c1ccc(C)cc1)[C@H](O)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1O[C@@H]1c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
0.26 ml of water and 1.20 g of potassium carbonate were added to a solution of 1.12 g of methyl (2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-(p-toluenesulfonyloxy)propionate dissolved in 15 ml of dimethylformamide, and the mixture was stirred at room temperature overnight. Ethyl acetate and ice water were added to the reaction mixture, and the organic layer was collected by separation. After the organic layer was washed with water and dried, the solvent was removed. The residue was purified by silica gel column chromatography (solvent; hexane:ethyl acetate=10:1) to obtain 502 mg of methyl (2R,3R)-3-(2,4-difluorophenyl)-2-epoxypropionate.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([CH3:3])[CH3:2].C1C=CC=CC=1.C1C(=O)N([Br:24])C(=O)C1>>[Br:24][C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH2:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1ccccc1N
Solvent: c1ccccc1
Product: CC(C)c1cccc(Br)c1N
Reaction time: 2 h

Procedure:
To o-isopropylaniline in 4 l. benzene (0.74 mol, 100 g) was added 131.7 g (0.74 mol) NBS all at once. There was an exotherm to 35° C. Material was stirred two hours, then let stand overnight. The volume was reduced by three-quarters, and solid removed by filtration. Benzene was then removed from the filtrate, pentane added with ice, followed by 40 ml acetic anhydride. After ca. 15 minutes, solid was filtered off, pentane solution separated from filtrate, washed with ammonia water. After evaporation of pentane, oil was distilled 83° C. (0.25 mm) to give 64.5 g of 2-bromo-6-isopropylaniline.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]=O)=[C:4](Cl)[N:3]=1.[CH3:12][NH:13][NH2:14].C(N(CC)CC)C.Cl.[CH:23]12[O:30][CH:27]([CH2:28][CH2:29]1)[CH2:26][NH:25][CH2:24]2>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]2[N:13]([CH3:12])[N:14]=[CH:9][C:5]2=[C:6]([N:25]2[CH2:24][CH:23]3[O:30][CH:27]([CH2:28][CH2:29]3)[CH2:26]2)[N:7]=1
Reactant: C1CC2CNCC1O2
Reactant: O=Cc1c(Cl)nc(Cl)nc1Cl
Reactant: CNN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cn1ncc2c(N3CC4CCC(C3)O4)nc(Cl)nc21
Temperature: 25 °C

Procedure:
To a cloudy solution of 2,4,6-trichloro-pyrimidine-5-carbaldehyde (1.1 g, 5.2 mmol) in chloroform (50 mL) cooled to −78° C. was added in drops methylhydrazine (0.24 g, 5.2 mmol), followed by triethylamine (1.4 mL). The cooling bath was then removed, allowing the mixture to warm to room temperature. The mixture was concentrated to dryness under reduced pressure, and the residue was dissolved in ethanol (50 mL). Triethylamine (1 mL) was added to the mixture, followed by 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (0.51 g, 3.4 mmol). The mixture was concentrated under reduced pressure and the residue was purified by automated flash chromatography (methanol/chloroform) to provide 3-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane. MS (ES+): 280.0, 281.9 (M+H)+
Reaction SMILES: C(N1[C@H:12]([CH3:13])[C@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)OC1=O)(=O)CCCCC.[Li+].[OH-:22].[OH:23]O>C1COCC1.O>[CH2:11]([C@H:14]([CH2:15][CH2:16][CH2:17][CH3:18])[C:19]([OH:23])=[O:22])[CH:12]=[CH2:13]
Reactant: OO
Reactant: [OH-]
Reactant: CCCCCC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC[C@H](CCCC)C(=O)O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a solution of the compound of step G (2) (1.22 g, 3.86 mmol) in THF (15.6 mL) was added water (3.86 mL), and the mixture cooled to 0° C. A solution of LiOH (185.7 mg, 7.75 mmol) and 30% H2O2 (3.51 mL) in water (12.1 mL) was added, and the combined mixture stirred for 10 minutes at 0° C. The ice bath was removed, and the reaction was allowed to continue for 1 h at rt. A solution of sodium sulfite (440 mg) was added, and the reaction stirred for 10 min. Saturated sodium carbonate solution was added, and the reaction was extracted with methylene chloride. The aqueous layer was acidified to pH 1 with 6 N HCl, and extracted 3 times with diethyl ether. The combined ether layers were washed with brine, and dried over MgSO4. The extract was filtered, and concentrated in vacuo to afforded the desired product (63% yield). 1H NMR (500 MHz, CDCl3) δ ppm 0.88 (t, J=7.0 Hz, 3H) 1.22-1.41 (m, 4H) 1.43-1.57 (m, 1H) 1.57-1.73 (m, 1H) 2.18-2.31 (m, 1H) 2.32-2.53 (m, 2H) 4.97-5.14 (m, 2H) 5.65-5.87 (m, 1H) 9.85 (s, 1H).
Reaction SMILES: C1C2C(=CC=CC=2)CCC1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[CH2:18][CH2:17][CH2:16]2.S(=O)(=O)(O)O.[N+:29]([O-:32])([OH:31])=[O:30]>CC(C)=O>[CH3:11][O:12][C:13]1[C:14]([N+:29]([O-:31])=[O:30])=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[CH2:18][CH2:17][CH2:16]2.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[N+:29]([O-:32])=[O:30])[C:19](=[O:23])[CH2:18][CH2:17][CH2:16]2
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: c1ccc2c(c1)CCCC2
Solvent: CC(C)=O
Product: COc1cc2c(cc1[N+](=O)[O-])C(=O)CCC2
Product: COc1ccc2c(c1[N+](=O)[O-])CCCC2=O
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A procedure for the synthesis of mono-amino substituted tetralone from tetrahydronaphthalene is illustrated with an exemplary synthetic route in FIG. 4. To an ice-cold, stirred solution of 6-methoxy-1-tetralone (20, 17.6 g, 0.10 mol) in acetone (30 mL) was added dropwise a mixture of sulfuric acid (18 mL, 96.0%) and nitric acid (15 mL, 68.0–70.0%). After the addition was complete, the reaction was stirred at 0° C. for 6 hours, and TLC was employed to monitor the reaction progress. The reaction mixture was poured into ice-water, and the mixture was partitioned between CH2Cl2 (3×200 mL) and water (200 mL). The organic layer was washed by saturated NaHCO3 solution and water (200 mL each), dried over anhydrous sodium sulfate, and, after filtration, the organic layer was concentrated in vacuo to provide a yellow oil. 6-Methoxy-5-nitro-1-tetralone (21, 7.74 g, 0.035 mol) and 6-methoxy-7-nitro-1-tetralone (22, 6.63 g, 0.030 mol) were obtained after purification by column chromatography:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:16][C@H:15]3[N:12]([C:13](=[O:20])[C@@H:14]3[C@H:17]([OH:19])[CH3:18])[C:11]=2[C:21]([O-:23])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Na+].[C:25]([O:31][CH2:32]I)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27].C(OCC)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:16][C@H:15]3[N:12]([C:13](=[O:20])[C@@H:14]3[C@H:17]([OH:19])[CH3:18])[C:11]=2[C:21]([O:23][CH2:32][O:31][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CC(C)(C)C(=O)OCI
Reactant: COc1ccc(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(C2=C(C(=O)OCOC(=O)C(C)(C)C)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1F
Reaction time: 0.25 h
Yield: 55.2 %

Procedure:
To sodium (5R,6S)-3-(3-fluoro-4-methoxyphenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (100 mg) in DMF (3 mL) was added at 0° C. pivaloyloxymethyl iodide (77 mg), and the mixture was stirred for 15 minutes. To the reaction mixture was added diethyl ether (50 mL), and the mixture was washed with saturated brine (50 mL×3times), dried over magnesium sulfate, filtered, and the solvent was removed in vacuo. The residue was purified under silica gel column chromatography (chloroform:methanol=100:0˜100:3) to give [(2,2-dimethylpropanoyl)oxy]methyl (5R,6S)-3-(3-fluoro-4-methoxyphenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (70 mg, 55%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH2:10][C:9]1([CH3:20])[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH3:22].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH:10]([CH3:22])[C:9]1([CH3:20])[CH3:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1c2ccccc2C(=O)CC1(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1C(=O)c2ccccc2N(C(=O)OC(C)(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To a solution of 1-tert-butoxycarbonyl-1,2,3,4,-tetrahydro-2,2-dimethyl-4-quinolinone (0.10 g, 0.36 mmol) and iodomethane (0.50 mL, 8.0 mmol) in DMF (4 mL ) was added NaH (60% in mineral oil, 20 mg, 0.50 mmol) and the resulting mixture was stirred at rt for 2 h. The reaction was quenched with water (5 mL) and was extracted with EtOAc (2×15 mL). Removal of solvent and chromatography of the crude residue on a silica gel column using a 10% mixture of EtOAc and hexane as solvents afforded 90 mg (86%) of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2,3-trimethyl-4-quinolinone as a colorless oil. The oil (90 mg, 0.32 mmol) was treated with NaBH4 (50 mg, 1.3 mmol) in methanol (5 mL) for 1 h and the reaction mixture was concentrated. Filtration from the inorganic material through a silica gel pad provided a colorless oil, which was then subjected to hydrogenation over 10% Pd/C (10 mg) in EtOAc (5 mL) under a hydrogen balloon for 15 h. Filtration from the catalyst through a Celite™ pad followed by removal of solvent gave 70 mg (82%) of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2,3-trimethylquinoline as a colorless oil. The crude oil (70 mg, 0.26 mmol) was treated with TFA (0.50 mL, 6.5 mmol) in CH2Cl2 for 30 min. and was quenched with 5% NaOH (6 mL). The mixture was extracted with EtOAc (2×15 mL) and was concentrated. Chromatography on silica gel using a 10% mixture of EtOAc and hexane afforded 1,2,3,4-tetrahydro-2,2,3-trimethylquinoline as a colorless oil (40 mg, 89%). Data for 1,2,3,4-tetrahydro-2,2,3-trimethylquinoline: 1H NMR (400 MHz, CDCl3) 7.00-6.91 (m, 2H), 6.60 (t, J=7.3, 1H), 6.45 (d, J=7.3, 1H), 3.61 (br s, 1H), 2.74 (dd, J=16.6, 5.3, 1H), 2.47 (dd, J=16.6, 10.3, 1H), 1.82 (m, 1H), 1.20 (s, 3H), 1.05 (s, 3H), 0.97 (d, J=7.2, 3H).
Reaction SMILES: [CH:1]1([C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=3)[CH2:8][CH2:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>O1CCCC1>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9]([CH2:8][CH2:7][N:6]=[C:5]2[C:1]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:2][CH2:3][CH2:4]2)=[CH:10][CH:11]=1
Reactant: COc1ccc2c(c1)C(C1CCC1)=NCC2
Reactant: Clc1ccccn1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(C1(c3ccccn3)CCC1)=NCC2
Temperature: -23 °C
Reaction time: 0.25 h

Procedure:
After 15 minutes, the solution was cooled to -23° C. and a solution of 1-cyclobutyl-7-methoxy-3,4-dihydroisoquinoline (3 g) in tetrahydrofuran (34 ml) was added. After 30 minutes the mixture was cooled to -78° C., treated with 2-chloropyridine (1.56 ml), stirred for 1 hour then warmed to ambient temperature. The mixture was heated under reflux for 5 minutes, stirred for 16 hours at ambient temperature, then heated under reflux for 30 minutes. The reaction mixture was poured onto water and extracted with ethyl acetate. The extracts were dried and concentrated and the residual orange oil heated at 90° C. at 13.3 mbar to remove excess 2-chloropyridine. The residue was purified by flash chromatography over silica gel using a 5:1 mixture of light petroleum and triethylamine as eluant to give 7-methoxy-1-[1-(2-pyridyl)cyclobutyl]-3,4-dihydroisoquinoline as a solid (0.58 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C:13]([N:17]1[C:21](=[O:22])[C:20]([NH:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[C:19]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[S:18]1(=[O:37])=[O:36])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([N:17]1[C:21](=[O:22])[C:20]([NH:23][CH:24]2[CH2:29][CH2:28][N:27]([CH2:2][C:3]3[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=3)[C:6]([O:8][CH3:9])=[O:7])[CH2:26][CH2:25]2)=[C:19]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[S:18]1(=[O:37])=[O:36])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CC(C)(C)N1C(=O)C(NC2CCNCC2)=C(c2ccccc2)S1(=O)=O
Product: COC(=O)c1cccc(CN2CCC(NC3=C(c4ccccc4)S(=O)(=O)N(C(C)(C)C)C3=O)CC2)c1
Yield: 48 %

Procedure:
The title compound was prepared as described for Example 104 from methyl 3-(bromomethyl)benzoate and 2-tert-butyl-5-phenyl-4-(piperidin-4-ylamino)isothiazol-3(2H)-one 1,1-dioxide (Example 75) to give the title compound (0.101 g, 48%) as a solid. 1H NMR (500 MHz CDCl3): δ 7.95-7.87 (m, 2H), 7.54-7.32 (m, 7H), 5.20 (d, 1H), 3.92 (s, 3H), 3.38 (s, 2H), 3.00-2.80 (m, 1H), 2.66-2.58 (m, 2H), 1.80-1.54 (m, 13H), 1.42-1.30 (m, 2H); 13C NMR (125 MHz CDCl3): δ 167.4, 159.9, 139.1, 134.3, 133.6, 131.8, 130.4, 130.2, 129.9, 128.8, 128.6, 125.4, 106.8, 62.5, 61.8, 52.3, 51.9, 50.2, 32.5, 27.8; Mass Spectrum: M+H+ 512.
Reaction SMILES: [CH:1]1[C:2]2[N:3]([CH:12]=[CH:13][CH:14]=2)[CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)Cl>[Br:15][C:12]1[N:3]2[CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=[CH:1][C:2]2=[CH:14][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cn2cccc2cn1
Solvent: ClCCl
Product: CCOC(=O)c1cn2c(Br)ccc2cn1
Reaction time: 1 h
Yield: 57 %

Procedure:
To a solution of ethyl pyrrolo[1,2-a]pyrazine-3-carboxylate (0.60 g, 3.18 mmol) in CH2Cl2 (60 mL) is added N-bromosuccinimide (0.56 g, 3.18 mmol) in one portion. After 1 h, solvent is removed in vacuo and the crude solid purified using preparative HPLC (1% IPA/heptane (0-5 minutes) to 2% isocratic) to give a brown solid for ethyl 6-bromopyrrolo[1,2-a]pyrazine-3-carboxylate. Yield 57%. MS (ESI+) for C10H9BrN2O2 m/z 271.01 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.Cl.[NH2:17][C@H:18]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:33]=[C:32]3[C:27]([CH:28]=[CH:29][N:30]=[C:31]3[Cl:34])=[CH:26][CH:25]=2)[C:19]1=[O:35]>>[Cl:34][C:31]1[C:32]2[C:27](=[CH:26][CH:25]=[C:24]([CH2:23][N:20]3[CH2:21][CH2:22][C@H:18]([NH:17][S:12]([C:9]4[S:8][C:7]([C:5]5[S:6][C:2]([Cl:1])=[CH:3][CH:4]=5)=[CH:11][CH:10]=4)(=[O:14])=[O:13])[C:19]3=[O:35])[CH:33]=2)[CH:28]=[CH:29][N:30]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(Cl)s2)s1
Reactant: N[C@H]1CCN(Cc2ccc3ccnc(Cl)c3c2)C1=O
Agent: Cl
Product: O=C1[C@@H](NS(=O)(=O)c2ccc(-c3ccc(Cl)s3)s2)CCN1Cc1ccc2ccnc(Cl)c2c1

Procedure:
The title compound is prepared as described in EXAMPLE 56, Part A using 5′-chloro-[2,2′]bithiophenyl-5-sulfonyl chloride and 3-(S)-amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-one hydrochloride as starting material. The crude product is purified by column chromatography eluting with 5% MeOH/CH2Cl2 to give the title compound as a white solid.
Reaction SMILES: [CH:1]([C@@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[CH3:20][NH:21][CH3:22].C1COCC1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[CH3:20][N:21]([CH3:22])[CH2:1][C@@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)CSc1ccccc1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C[C@H](CSc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
A solution of Example 134A (1.25 g, 4.44 mmol), 2M dimethylamine in THF (2.7 mL, 5.4 mmol), and NaBH(OAc)3 (1.32 g, 6.22 mmol) in dichloromethane at room temperature was stirred for 18 hours, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% ethyl acetate/hexanes to provide the desired product. MS (ESI(+)) m/e 311 (M+H)+.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].[Cl:14][CH2:15][C:16](=[O:21])[C:17](Cl)=[N:18][OH:19]>C(#N)C>[Cl:14][CH2:15][C:16]([C:17]1[CH2:1][CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[O:19][N:18]=1)=[O:21]
Reactant: O=C(CCl)C(Cl)=NO
Reactant: C=Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C(CCl)C1=NOC(c2ccccc2)C1
Reaction time: 1 h

Procedure:
To a mixture of styrene (6.79 g, 65.3 mmol) and sodium bicarbonate (32.1 g, powder) in acetonitrile (100 mL), 3-chloro-N-hydroxy-2-oxopropanimidoyl chloride (i.e. the product of Example 7, Step B) (10 g, 64.1 mmol) was added in 10 portions over 20 minutes. The reaction mixture was then stirred for an additional 1 h and filtered. The filtered solid was rinsed with acetonitrile, and the combined filtrates were concentrated under reduced pressure to leave an oil, which was triturated first with hexanes and then with 1-chlorobutane to give 13.6 g of the title compound as a white solid.