Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9].[CH3:14]I>CN(C=O)C>[CH3:13][O:12][N:10]([CH3:11])[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][O:3][CH3:14]
Reactant: CON(C)C(=O)CCCCO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCCC(=O)N(C)OC
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
To sodium hydride (60% in mineral oil, 2.6 g, 66.3 mmol) in dry DMF (40 mL) was added a solution of 5-hydroxy-N-methoxy-N-methylpentanamide (8.9 g, 55.2 mmol) in DMF (50 mL) slowly at 0° C. After 30 min, methyl iodide (4.1 mL, 66.3 mmol) was added and the reaction was stirred over night. Starting material remained and more sodium hydride ((60% in mineral oil, 1 g, 25 mmol) and methyl iodide (1.7 mL, 27.2 mmol) was added followed by additional stirring for 6 h. The solvent was evaporated under vacuum. The residue was diluted with dichloromethane and treated with brine. The aqueous layer was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (120 g column, 80% ethyl acetate in hexanes to 100% ethyl acetate) to give product (5.3 g, 55%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].C[O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=O.C[C:16](=[O:19])[CH2:17][CH3:18].O>C(O)(=O)C>[CH3:13][O:12][CH:10]([C:9](=[O:8])[CH2:14][C:16](=[O:19])[CH2:17][CH3:18])[CH3:1]
Reactant: COC(=O)C(C)OC
Reactant: CCC(C)=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CCC(=O)CC(=O)C(C)OC
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
In a 200 mL-volume flask equipped with a stirrer, a thermometer and a dropping funnel was placed 25.0 g (223 mmol) of potassium t-butoxide, and the flask was purged with argon. Then, 100 mL of methylcyclohexanone was placed in the flask. Subsequently, 12.5 g (106 mmol) of methyl 2-methoxypropionate (prepared by the method of Reference Example 1) was dropped under cooling with ice, and further 7.70 g (107 mmol) of 2-butanone was slowly dropped. The mixture was cooled to 10° C. and stirred for 30 minutes for carrying out a reaction. After the reaction was complete, 70 mL of water was placed in the flask under cooling with ice. The aqueous portion was taken out, neutralized with acetic acid, and subjected to extraction with methylcyclohexane. The methylcyclohexane extract was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and distilled under reduced pressure (77° C., 1.26 kPa) to give 10.4 g (yield: 62%) of 2-methoxy-3,5-heptanedione as colorless liquid.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15]C(OC(C)(C)C)=O)[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.S(Cl)([Cl:31])=O.[CH2:33](O)[CH3:34]>>[ClH:31].[CH2:33]([O:13][C:11](=[O:12])[C@H:10]([CH3:14])[CH2:9][C@H:8]([NH2:15])[CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:2][CH:3]=1)[CH3:34]
Reactant: CCO
Reactant: O=S(Cl)Cl
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Product: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Product: Cl
Reaction time: 2 h

Procedure:
150 g (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (3-a, R1=BOC, R2=R3=H) were dissolved in 1500 ml ethanol at 70° C. 43 ml of thionyl chloride were then added over about 1 hour. The mixture was then stirred for a further 2 hours. The mixture was concentrated to dryness and then suspended in 3400 ml heptane. The precipitate was collected by filtration, yielding 133 g of (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrochloride (3-a, R1=R2=H, R3=Et). 1H-NMR (DMSO): 1.05 (3H, t, 1-CH3); 1.08 (3H, t, CH2CH3); 1.61 (1H, m, 3-CHH); 1.85 (1H, m, 3-CHH); 2.74 (1H, m, 2-CH); 2.81 (1H, dd, 5-CHH); 3.08 (1H, dd, 5-CHH); 3.36 (1H, m, 4-CH); 3.95 (2H, q, CH2CH3); 7.31 (1H, m, aromatic); 7.35 (2H, m, aromatic); 7.43 (2H, m, aromatic); 7.62 (4H, m, aromatic); 8.30 (3H, s, NH3+). m/z 312 (MN+, 100%)
Reaction SMILES: [CH2:1]=O.[C:3]([BH3-])#[N:4].[Na+].N[C:8]1[CH:12]=[C:11]([C:13]2[CH:25]=[CH:24][C:16]([O:17][CH2:18][CH2:19][NH:20][C:21]([NH2:23])=[O:22])=[CH:15][CH:14]=2)[N:10]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[N:9]=1>CO>[CH3:1][N:4]([CH3:3])[C:8]1[CH:12]=[C:11]([C:13]2[CH:25]=[CH:24][C:16]([O:17][CH2:18][CH2:19][NH:20][C:21]([NH2:23])=[O:22])=[CH:15][CH:14]=2)[N:10]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[N:9]=1
Reactant: C=O
Reactant: COc1ccc(-n2nc(N)cc2-c2ccc(OCCNC(N)=O)cc2)cc1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-n2nc(N(C)C)cc2-c2ccc(OCCNC(N)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
37% aqueous solution of formaldehyde (0.23 ml) and sodium cyanoborohydride (53 mg) were added to a solution of N-(2-{4-[3-amino-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenoxy}ethyl)urea (103.1 mg) in MeOH (2 ml). The reaction mixture was stirred at ambient temperature for 3 hours. 37% aqueous solution of formaldehyde (0.23 ml) and sodium cyanoborohydride (53 mg) were added to the mixture and the reaction mixture was stirred at ambient temperature for 4 days. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and H2O. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography developed by CHCl3:MeOH:28% aqueous NH4OH=100:10:1. The separated silica gel was extracted with same solvent and the solvent was evaporated in vacuo to give N-(2-{4-[3-(dimethylamino)-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)urea (59.9 mg) as an amorphous powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH:11]([CH3:13])[CH3:12])[N:5]=[C:4]([NH2:14])[CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[CH2:25][C:26](Cl)=[O:27].O>N1C=CC=CC=1.C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH:11]([CH3:12])[CH3:13])[N:5]=[C:4]([NH:14][C:26](=[O:27])[CH2:25][C:18]2[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=2[O:16][CH3:15])[CH:3]=1
Reactant: COc1ccc(OC)c(CC(=O)Cl)c1
Reactant: CC(C)Oc1nc(N)cc(N)c1C#N
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(OC)c(CC(=O)Nc2cc(N)c(C#N)c(OC(C)C)n2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.7 %

Procedure:
To a solution of 100 mg (0.520 mmol) of 4,6-diamino-2-isopropoxy-nicotinonitrile in 1 mL of pyridine was added 3 mL of CH2Cl2 followed by a solution of 150 mg (0.699 mmol) of 2,5-dimethoxyphenylacetyl chloride (prepared from (2,5-dimethoxyphenyl)acetic acid and oxalyl chloride in CH2Cl2) in 1 mL of CH2Cl2. The mixture was stirred at ambient temperature for 10 minutes then 1 mL of water was added, and the mixture was concentrated under reduced pressure. The residue was taken up in 20 mL of warm ethyl acetate and extracted with water (1×5 mL), 1M HCl(aq.) (2×5 mL), saturated NaHCO3(aq.) (2×5 mL), and brine (1×5 mL), dried over MgSO4, filtered, and concentrated to a solid. Recrystallization from methanol or 2-propanol provided 90 mg (47%) of a white solid. 1H NMR (300 MHz, d6-DMSO) δ 10.06 (s, 1H), 7.10 (s, 1H), 6.90 (m, 1H), 6.84 (s, 2H), 6.79 (m, 2H), 5.28 (septet, 1H, J=6.1 Hz), 3.70 (s, 3H), 3.69 (s, 3H), 3.66 (s, 2H), 1.29 (d, 6H, J=6.1 Hz); MS (ESI) m/e=329 (M−Pr+H)+, 371 (M+H)+, 369 (M−H)−.
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[CH3:3].O=O.[C:7]([OH:11])([CH3:10])([CH3:9])[CH3:8].CC(C)=[O:14]>[Mo].CO.O>[CH3:1][CH:2]([CH3:4])[CH3:3].[C:7]([O:11][OH:14])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)O
Reactant: CC(C)=O
Agent: [Mo]
Agent: CC(C)C
Agent: O=O
Solvent: CO
Solvent: O
Product: CC(C)(C)OO
Temperature: 137.77777777777777 °C
Yield: 22 %

Procedure:
The oxidation zone is in a pressurized reactor which is partially filled with a liquid reaction mixture comprising 5 ppm of soluble molybdenum catalyst. The liquid reaction mixture can be deemed to be about 66% isobutane and about 34% of a liquid mixture of oxidate, comprising products and byproducts. Fresh isobutane is injected and recycle isobutane is injected into the liquid reaction mixture. An oxygen-containing gas is injected into the liquid reaction mixture. The reactor is maintained at 700 psig and at 280° F. The average residence time for the isobutane in the reactor is about 4 hours, and the extent of conversion of the isobutane is about 34%. The yields of byproducts and products from such oxidation of isobutane correspond to about 66% tertiary butyl alcohol (TBA), about 22% tertiary butyl hydroperoxide (TBHP), about 6% acetone, about 6% of a mixture comprising about 2% water, about 1.5% methanol and minor amounts of related components. About 1% of the isobutane is converted to carbon dioxide with a measurable amount of carbon monoxide.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].Cl.[NH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)CNc1nc(Cl)nc(Cl)n1

Procedure:
36.9 g of cyanuric chloride, 27.9 g of ethyl glycinate hydrochloride and 33.6 g of sodium bicarbonate were heated under reflux in 200 ml of dioxane for 30 minutes. At the end of this time, the dioxane was removed by distillation under reduced pressure, and a mixture of ethyl acetate and water was added to the resulting residue, after which the mixture was shaken.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[OH:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: NCCCCO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccccc1NCCCCO
Yield: 98.3 %

Procedure:
2-Fluoronitrobenzene (28 g), 4-aminobutanol (18 g) and triethylamine (29 ml) were dissolved in toluene (100 ml) and heated at 100° for 6 hours. The organic phase was washed with water (50 ml) and then extracted with concentrated hydrochloric acid (2×50 ml). The combined acid extracts were diluted with water (100 ml), neutralised with concentrated aqueous ammonia and extracted with methylene chloride (3×50 ml). The organic extracts were combined, dried over Na2SO4, filtered and evaporated to leave the title compound as a dark red oil (41 g) which was used directly in the next step.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[CH2:20][CH:19]([C:24]([O:26]C)=[O:25])[CH2:18]2)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O.CO>[C:7]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[CH2:20][CH:19]([C:24]([OH:26])=[O:25])[CH2:18]2)(=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)C1Cc2ccc(C(=O)c3ccccc3)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(c1ccccc1)c1ccc2c(c1)CC(C(=O)O)C2

Procedure:
To a 100 cm3 reaction vessel equipped with a stirrer and a cooler are successively added: 2.2 g (0.026 mole+50%) of potash dissolved in 40 cm3 of water and 7.3 g (0.026 mole) of methyl 5-benzoyl-indane-2-carboxylate dissolved in 40 cm3 of methanol. The mixture is heated at reflux temperature for 1 hour, the methanol evaporated and the mixture diluted with water; the alkaline mixture is then washed with ether and then acidified by the addition of hydrochloric acid. A precipitate forms which is filtered, washed with water and dried. After recrystallization from ethyl acetate the melting point is steady at 140°-142° C. (in a capillary tube).
Reaction SMILES: CO[C:3](=[O:17])[C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([F:14])=[CH:6][C:5]=1[CH2:15]Br.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[F:14][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([C:10]([F:11])([F:12])[F:13])[CH:8]=1)[C:3](=[O:17])[N:25]([CH2:24][C:23]1[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=1)[CH2:15]2
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1c(CBr)cc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C1c2c(cc(F)cc2C(F)(F)F)CN1Cc1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 323.1 %

Procedure:
A mixture of 4-fluoro-2-bromomethyl-6-trifluoromethyl-benzoic acid methyl ester (0.100 g, 0.32 mmol), 4-trifluoromethyl-benzylamine (0.06 mL, 0.42 mmol), and K2CO3 (0.088 g, 0.64 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-fluoro-2-(4-trifluoromethyl-benzyl)-7-trifluoromethyl-2,3-dihydro-isoindol-1-one (0.39 g, 33%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.34 (s, 2H), 4.84 (s, 2H) 7.20-7.50 (m, 6H). GC-MS: m/z 377 (M)+, 356 (M−21)+.
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:15][Si](C=[N+]=[N-])(C)C.[BrH:22]>C1COCC1.C(Cl)Cl.CCOCC>[Br:22][CH2:15][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Br
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCCCC(=O)CBr
Temperature: 0 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of lauric acid chloride (10.0 g, 45.7 mmol) in anhydrous THF (91 mL) at 0° C. was added dropwise a solution of trimethylsilyldiazomethane (2 M in ether, 45.7 mL, 91.4 mmol). The mixture was stirred 1 h at 0° C. then overnight at RT. The solvents were evaporated under vacuum to give a yellow oil. This crude product was dissolved in DCM (50 mL) and stirred in the presence of the PL-AMS-Resin (Polymer Laboratories, 1.54 mmol/g, 5 g) for 5 h at RT. The resin was filtered off and washed with DCM. The combined filtrates were evaporated to give a yellow oil. This crude product was dissolved in Et2O, chilled at 0° C. and a concentrated aqueous solution of HBr (48%, 10 mL) was added dropwise carefully. After 1 h of reaction, the mixture was decanted and the organic layer was dried over MgSO4, filtered and evaporated to give the title product as a beige solid (8.32 g, 66%). 1H NMR (CDCl3, 300 MHz) δ 3.87 (s, 2H), 2.63 (t, 2H, J=7.5 Hz), 1.67-1.54 (m, 2H), 1.30-1.21 (m, 16H), 0.87 (m, 3H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH2:4][O:5][CH3:6].[Li+].CC([N-]C(C)C)C.[CH3:16][C:17]1[O:21][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:19][C:18]=1[CH2:28][CH2:29][O:30][C:31]1[C:39]2[CH:38]=[CH:37][S:36][C:35]=2[C:34]([CH:40]=[O:41])=[CH:33][CH:32]=1.Cl>C1COCC1.ClCCl.ClCCl.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:7])[CH:4]([O:5][CH3:6])[CH:40]([OH:41])[C:34]1[C:35]2[S:36][CH:37]=[CH:38][C:39]=2[C:31]([O:30][CH2:29][CH2:28][C:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:21][C:17]=2[CH3:16])=[CH:32][CH:33]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)c2sccc12
Reactant: COCC(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)C(OC)C(O)c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
To a solution of 3.17 ml methoxyacetic acid methyl ester (31.4 mmol) in 30 ml of THF, 17 ml of LDA (2M in THF/heptane/ethylbenzene, 34.2 mmol) were added dropwise within 15 min at −78° C. After stirring for additional 15 min, a solution of 5.00 g of 4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-carbaldehyde (13.7 mmol) in 70 ml of dichloromethane was added dropwise within 20 min. The dark brown reaction solution was stirred for additional 60 min, then warm up to room temperature within 150 min, cooled to 0° C. again and treated with 50 ml of ice water and 6 ml of conc. hydrochloric acid (pH 3). The organic layer was separated, washed with 25 ml water, dried over sodium sulfate and evaporated to dryness to yield 8.81 g of crude product as a brown oil. Flash chromatography (SiO2, dichloromethane/AcOEt=9/1) yielded 5.89 g (91%) of the title compound as a syn/anti mixture of 1:4 with a purity of 98.3% (GC area; method: column: DB-1 (15 m*0.32 mm); injector: 270° C.; detector: 320° C.; oven 150-310° C. (4° C./min); carrier gas: H2 (60 KPa); samples silylated with BSTFA/pyridine. Retention times: starting material (aldehyde 1), 23.8 min; syn-alcohol 6, 28.1 min; anti-alcohol 6, 28.5 min) as a yellowish crystalline solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[NH:14]([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.Cl[Sn]Cl>C(Cl)Cl.CCOC(C)=O>[CH3:15][N:14]([CH3:16])[S:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[NH2:1])(=[O:12])=[O:11]
Reactant: CNC
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1cccc(N)c1

Procedure:
Following the procedure described in part E of Example 1 (R), (S)-α-[[2-[((1,1-dimethylethyl)dimethylsilyl)oxy]-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-4-methoxybenzeneacetic acid was condensed with 3-[(dimethylamino)sulfonyl]aniline to generate the title compound. The 3-[(dimethylamino)sulfonyl]aniline was prepared by sequential treatment of commercial 3-nitrobenzenesulfonyl chloride with Me2NH in CH2Cl2 containing (i-Pr)2NEt followed by reduction with SnCl2 in EtOAc at 20° C.
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:29]3[CH2:28][CH2:27][C:26](=O)[NH:25][C:24]=3[N:23]=[C:22]([CH:31]([CH3:33])[CH3:32])[C:21]=2[C:34]([O:36][CH3:37])=[O:35])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.C1COCC1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:29]3[CH2:28][CH2:27][CH2:26][NH:25][C:24]=3[N:23]=[C:22]([CH:31]([CH3:32])[CH3:33])[C:21]=2[C:34]([O:36][CH3:37])=[O:35])=[CH:16][CH:15]=1
Reactant: COC(=O)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CCC(=O)N2
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CCCN2
Temperature: 5 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
A solution of Red-Al (185 mL, 0.613 mol, 65 weight % in toluene) in anhydrous toluene (250 mL) was cooled to 5° C. A solution of Part B methyl 4-(4-fluorophenyl)-2-isopropyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridine-3-carboxylate (100. g, 0.292 mol) in anhydrous THF (500 mL) was added over 30 min. The reaction mixture was stirred at 5° C. for 3 h. The reaction was quenched by adding a solution of potassium sodium tartrate (10%, 200 mL) slowly. After toluene (100 mL) was added, the two phases were separated. The organic phase was washed with NaH2PO4 (5%, 200 mL), followed by H2O (200 m]L), and brine (200 m]L), dried over MgSO4, and filtered. The solvent was removed under reduced pressure and the obtained solid dried at 40° C. under vacuum to provide 88.27 g (92% yield) of methyl 4-(4-fluorophenyl)-2-isopropyl-5,6,7,8-tetrahydro-[1,8]naphthyridine-3-carboxylate as an off-white solid: mp 168-170° C.; 1H NMR (400 MHz, CDCl3) δ 1.23 (d, J=7.0 Hz, 6H), 1.79 (m, 2H), 2.37 (t, J=6.4 Hz, 2H), 2.99 (m, 1H), 3.39 (m, 2H), 3.40 (s, 3H), 5.07 (s, 1H), 7.03-7.16 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 169.5, 162.9, 160.4, 155.7, 146.1, 133.8, 129.9, 117.9, 115.1, 114.9, 110.6, 52.0, 41.9, 33.4, 25.3, 23.0, 22.0; HRMS calcd for C19H22FN2O2 (M+1) 329.1665, found 329.1666.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH2:39][O:40][CH3:41])[NH:20][C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH2:39][O:40][CH3:41])[NH:20][C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: CCCCc1nc(COC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(COC)[nH]c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
A mixture of hydroxylammonium chloride (1.89 g), sodium hydrogen carbonate (3.04 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-2-(methoxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.70 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL). N,N′-carbonyldiimidazole (0.35 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.37 g, 47%).
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH:3]([C:14]([OH:16])=[O:15])[NH:2]1.[OH-].[K+].[C:19](=[S:21])=[S:20].Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29]Cl>C(O)C>[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][S:20][C:19]([N:2]1[CH:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)=[S:21]
Reactant: O=C(O)C1Cc2c([nH]c3ccccc23)CN1
Reactant: ClCc1ccccn1
Reactant: S=C=S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1Cc2c([nH]c3ccccc23)CN1C(=S)SCc1ccccn1

Procedure:
In the same manner as descsribed in Example 32, (3RS)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (3.24 g), KOH (1.75 g), carbon disulfide (0.91 ml), 50% ethanol (70 ml) and 2-pyridylmethyl chloride hydrochloride (2.95 g) are reacted and treated to give the title compound (2.07 g) as pale yellow powder.
Reaction SMILES: [CH2:1]([C:4]1([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2=[N:13][CH:14]=[CH:15][N:5]12)[CH:2]=[CH2:3].[OH2:23].C[N+]1([O-])CC[O:28]CC1>CC(C)=O.O=[Os](=O)(=O)=O>[Br:22][C:19]1[CH:18]=[CH:17][C:16]([C:4]2([CH2:1][CH:2]([OH:28])[CH2:3][OH:23])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]3=[N:13][CH:14]=[CH:15][N:5]23)=[CH:21][CH:20]=1
Reactant: O
Reactant: C=CCC1(c2ccc(Br)cc2)c2ccccc2-c2nccn21
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Product: OCC(O)CC1(c2ccc(Br)cc2)c2ccccc2-c2nccn21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-allyl-5-(4-bromophenyl)-5H-imidazo[2,1-a]isoindole (150 mg) in acetone (5.5 mL) was added water (1 mL) followed by NMO (60 mg) and OsO4 (0.536 mL, 2.5% in tert-BuOH). After stirring at room temperature for 24 h, 100 mg NMO and 0.1 mL OsO4 solution were added. After 9 h 0.1 mL more OsO4 solution was added and stirred at room temperature over the weekend. The reaction was then quenched with 1:1 aqueous saturated NaHCO3:Na2SO3 and partitioned between aqueous saturated NaHCO3 and EtOAc. Aqueous layer was extracted with EtOAc (3×). Combined organic layers were dried over Na2SO4 and concentrated. Purification by reversed phase HPLC (21×100 mm Phenomenex Gemini, 5-40% MeCN/water containing 0.1% TFA over 20 min at 20 mL/min) to give title compound as a white solid. Mass. found (M+H)+, 387.0.