Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:38]1[C@@H:46]2[C@@H:41]([CH2:42][CH2:43][CH2:44][CH2:45]2)[CH2:40][NH:39]1>O1CCCC1>[CH2:16]([C@@H:11]([CH2:12][C:13]([N:39]1[CH2:40][C@H:41]2[C@H:46]([CH2:45][CH2:44][CH2:43][CH2:42]2)[CH2:38]1)=[O:15])[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C1CC[C@H]2CNC[C@H]2C1
Reactant: O=C(O)C[C@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(OCc1ccccc1)[C@H](CC(=O)N1C[C@H]2CCCC[C@H]2C1)Cc1ccccc1
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 84.6 %

Procedure:
To a solution of (S)-3-benzyloxycarbonyl-4-phenylbutyric acid (671 mg) in anhydrous tetrahydrofuran (15 ml) were added N-methylmorpholine (0.5 ml) and isobutyl chloroformate (0.38 ml) with stirring at -20° C. for 20 minutes. To the mixture was added a solution of cis-hexahydroisoindoline (313 mg) in anhydrous tetrahydrofuran (5 ml) with stirring at -10 - -20° C. After 1 hour, the deposit was filtered off and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with 0.5N hydrochloric acid, saturated sodium bicarbonate solution, and brine and dried over MgSO4. After the solvent was evaporated under reduced pressure, the residue was recrystallized from dichloromethane-hexane to give 772 mg of benzyl (S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1Cl
Reaction time: 2 h
Yield: 71.4 %

Procedure:
A solution of 4-chloro-3-methoxybenzoic acid (1.12 g, 5.98 mmol) in THF (30 mL) was stirred on an ice bath and treated with a 1.0 M tetrahydrofuran solution of lithium aluminum hydride (7.18 mL, 7.18 mmol) over about a 5 min. period. The solution was stirred on ice for 2 h, and then quenched with rapid stirring by the slow dropwise addition of water (0.27 mL), followed by 15% aqueous sodium hydroxide (0.27 mL), then water (0.82 mL) again. Upon completion of addition, the resulting suspension was filtered and the collected solid was washed with ethyl acetate. The filtrate was concentrated under vacuum to provide (4-chloro-3-methoxyphenyl)methanol as a colorless oil (737 mg, 71%). 1H NMR (400 MHz, CDCl3) δ ppm 3.92 (s, 3 H) 4.67 (s, 2 H) 6.87 (d, J=7.6 Hz, 1 H) 6.98 (s, 1 H) 7.33 (d, J=7.6 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[NH:23]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:23]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH:11]=[CH:10]2
Reactant: C1CNCCNC1
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CCCNCC3)ccc12
Yield: 40.4 %

Procedure:
Prepared according to the method of example 2 using N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1 (a)) (200 mg) and homopiperazine (600 mg). Recrystallisation from acetonitrile afforded the title compound as a solid (96 mg).
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]1.Cl[C:21]1[N:22]=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH:37]=[CH:36][CH:35]=[N:34]3)=[CH:29][C:28]=2[O:38][CH3:39])=[CH:25][CH:26]=1.O>C1COCC1>[CH3:39][O:38][C:28]1[CH:29]=[C:30]([N:33]2[CH:37]=[CH:36][CH:35]=[N:34]2)[CH:31]=[CH:32][C:27]=1[C:24]1[N:23]=[N:22][C:21]([O:7][CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: COc1cc(-n2cccn2)ccc1-c1ccc(Cl)nn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(-n2cccn2)ccc1-c1ccc(OC2CCN(C(=O)OC(C)(C)C)C2)nn1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
Potassium tert-butoxide (1.0 M in THF, 0.98 mL, 0.98 mmol) was added to tert-butyl 3-hydroxypyrrolidine-1-carboxylate (0.18 g, 0.98 mmol) in THF (3.3 mL) at 0° C. and the mixture was stirred for 10 min at 50° C. 3-Chloro-6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazine Intermediate 2-1 (0.12 g, 0.40 mmol) was added to the reaction at 0° C. and the mixture was stirred for 2 h at RT. Water (0.1 mL) was added and the solvent was concentrated under reduced pressure to afford (0.18 g, 100%) of a brown solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:21]=[CH:20][C:8]2[CH:9]=[C:10]([C:17]([OH:19])=[O:18])[CH:11]([C:13]([F:16])([F:15])[F:14])[O:12][C:7]=2[CH:6]=1)([CH3:4])[CH3:3].[Br:22]Br>[Fe].C(Cl)(Cl)Cl>[Br:22][C:21]1[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[CH:6][C:7]2[O:12][CH:11]([C:13]([F:14])([F:15])[F:16])[C:10]([C:17]([OH:19])=[O:18])=[CH:9][C:8]=2[CH:20]=1
Reactant: CC(C)(C)c1ccc2c(c1)OC(C(F)(F)F)C(C(=O)O)=C2
Reactant: BrBr
Agent: [Fe]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc2c(cc1Br)C=C(C(=O)O)C(C(F)(F)F)O2

Procedure:
7-(1,1-Dimethylethyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid (Example 12)(0.6 g, 2 mmol), chloroform (50 mL), iron filings (0.01 g, 0.2 mmol), and bromine (0.48 g, 3.00 mmol) were stirred at reflux for 16 h. The mixture was allowed to cool and was washed with brine (2×50 mL). After drying over MgSO4, the mixture was filtered, concentrated in vacuo, and the residue crystallized from ether-hexanes yielding the title compound as a white solid (0.5 g, 66%): mp 198.6–199.9° C. 1H NMR (acetone-d6/300 MHz) 7.85 (s, 1H), 7.72 (s, 1H), 7.13 (s, 1H), 5.83 (q, 1H, J=7.2 Hz), 1.5 (s, 9H). Anal. Calc'd for C15H14O3F3Br: C, 47.52; H, 3.72; N, 21.07. Found: C, 47.42; H, 3.68; N, 21.15.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39]1([CH2:45][C:46](Cl)=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:46](=[O:47])[CH2:45][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Yield: 81.5 %

Procedure:
200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 35a with 72 μl (0.5 15 mmol) of triethylamine and 62 μl (0.468 mmol) of phenylacetyl chloride to give the title compound (208 mg, 81%). TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.54, FD-MS: M+ =545.
Reaction SMILES: [O:1]=[C:2]1[N:9]2[C:4]([CH3:12])([CH2:5][CH2:6][O:7][C:8]2([CH3:11])[CH3:10])[CH:3]1[CH:13]([CH3:15])C.C(Br)[C:17]1[CH:22]=[CH:21]C=[CH:19][CH:18]=1>>[O:1]=[C:2]1[N:9]2[C:4]([CH3:12])([CH2:5][CH2:6][O:7][C:8]2([CH3:10])[CH3:11])[CH:3]1[CH2:13][C:15]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)C1C(=O)N2C(C)(C)OCCC12C
Reactant: BrCc1ccccc1
Product: CC1(C)OCCC2(C)C(Cc3ccccc3)C(=O)N12

Procedure:
Following the procedure described for the preparation of 8-oxo-3-oxa-2,2,6-trimethyl-7-isopropyl-1-azabicyclo[4.2.0]octane from 8-oxo-3-oxa-2,2,6-trimethyl-1-azabicyclo[4.2.0]-octane (Example 4a, above) and using benzyl bromide instead of isopropyl iodide there is obtained 8-oxo-2,2,6-trimethyl-7-benzyl-3-oxa-1-azabicyclo[4.2.0]octane.
Reaction SMILES: O[C:2]1[N:7]=[N:6][C:5]([CH:8]([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:14])=O.[OH-].[Na+]>>[Cl:14][C:2]1[N:7]=[N:6][C:5]([CH:8]([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: CC(C#N)c1ccc(O)nn1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C#N)c1ccc(Cl)nn1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
1.5 g (10 mmol) of 2-(6-hydroxy-pyridazin-3-yl)-propanenitrile are mixed with 5 g of phosphorus oxychloride and the mixture is stirred at 80°-90° C. for 45 minutes. The mixture is poured onto 30 g of ice, adjusted to pH 6 using 2N NaOH and extracted using ether. After removal of the solvent, an oil remains which solidifies on standing. Yield: 1 g (59.7% of theory); m.p.: 65° C. from hexane.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[CH:9]1([CH2:15][C:16]#[N:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C1(C)C=CC=CC=1>C(O)(C)C>[CH:9]1([CH2:15][C:16](=[NH:17])[NH:2][OH:3])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: NO
Reactant: N#CCC1CCCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: N=C(CC1CCCCC1)NO
Reaction time: 0.21 h

Procedure:
To a solution of 0.846 g (8.1 mmol) of hydroxylamine hydrochloride in 11 mL of isopropyl alcohol, 1.499 g (17.8 mmol) of sodium bicarbonate was added. The resulting mixture was stirred at 25° C. to 30° C. for 10-15 min. 1.0 g (8.1 mmol) of 2-cyclohexylacetonitrile was added and stirred at 80° C. to 85° C. for 3-4 h. After completion of the reaction, the reaction mixture was cooled to 25° C. to 30° C., filtered and washed with 2 mL of isopropyl alcohol. The filtrate was collected and distilled out completely to obtain a crude residue. The residue was chased with 5 mL of toluene to yield the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C([O-])(=O)C.[Na+].[C:10]([C:13]1[C:14]([CH2:20][S:21][C:22]2[CH2:26][C:25]([CH3:28])([CH3:27])[O:24][N:23]=2)=[C:15]([CH3:19])[S:16][C:17]=1[CH3:18])(=O)[CH3:11].O>C(O)C>[CH3:27][C:25]1([CH3:28])[O:24][N:23]=[C:22]([S:21][CH2:20][C:14]2[C:13]([C:10](=[N:4][O:3][CH3:2])[CH3:11])=[C:17]([CH3:18])[S:16][C:15]=2[CH3:19])[CH2:26]1
Reactant: CON
Reactant: CC(=O)c1c(C)sc(C)c1CSC1=NOC(C)(C)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CON=C(C)c1c(C)sc(C)c1CSC1=NOC(C)(C)C1
Reaction time: 5 h
Yield: 36 %

Procedure:
0.57 g (6.8 mmoles) of O-methylhydroxylamine hydrochloride and 0.56 g (6.8 mmoles) of sodium acetate were added to a solution of 1.0 g (3.4 mmoles) of 3-(4-acetyl-2,5-dimethylthiophen-3-ylmethylthio)-5,5-dimethyl-2-isoxazoline dissolved in 50 ml of ethanol. The mixture was stirred for 5 hours under refluxing, to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.4 g (36.4%) of 5,5-dimethyl-3-[2,5-dimethyl-4-(1-methoxyiminoethyl)-thiophen-3-ylmethylthio]-2-isoxazoline as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[N:11]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:4][CH:3]=1.O.NN>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:10][C@H:9]2[NH2:11])=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1C1CC1c1ccc(Cl)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: N[C@@H]1C[C@@H]1c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-[2-(4-chloro-phenyl)-cyclopropyl]-isoindole-1,3-dione (320 mg, 1.07 mmol) and hydrazine hydrate (0.5 ml) in ethanol (8 ml) was stirred for 0.5 hour at 50° C. The solution was evaporated under reduced pressure. The resulting amine (compound Z1.001) was used in example P1 without further purification.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.ClC1C=C(C=CC=1)C(OO)=[O:29]>ClCCCl>[O-:29][N+:6]1[CH:7]=[CH:8][CH:9]=[C:4]2[N:3]([CH:11]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]3)[C:2](=[O:1])[NH:10][C:5]=12
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3c2ccc[n+]3[O-])CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
2-Oxo-1-(1-t-butoxycarbonylpiperidin-4-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine (63 mg, 0.198 mmol) was dissolved in 1,2-dichloroethane (10 mL) and 3-chloroperoxybenzoic acid (137 mg, 0.792 mmol) was added at 0° C. The reaction was warmed to room temperature and stirred for 4 h. The reaction was quenched with saturated aqueous sodium bicarbonate and sodium thiosulfate, extracted with methylene chloride (3×), dried over sodium sulfate, filtered and evaporated to give the title compound (45 mg). MS 335.1 (M+1).
Reaction SMILES: [F:1][CH:2]([F:30])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([N+:21]([O-])=O)[CH:19]=3)[N:14]=[C:13]([C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[N:12]=2)[CH:7]=[CH:8][CH:9]=1.[NH4+].[Cl-]>CO.O.[Fe]>[F:30][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH2:21])[CH:19]=3)[N:14]=[C:13]([C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc2nc(-c3cnccn3)nc(Nc3cccc(OC(F)F)c3)c2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1ccc2nc(-c3cnccn3)nc(Nc3cccc(OC(F)F)c3)c2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
To a mixture of N-(3-(difluoromethoxy)phenyl)-6-nitro-2-(pyrazin-2-yl) quinazolin-4-amine (1.40 g, 3.4 mmol, 1.0 eq.) in MeOH-H2O (v/v, 3:1, 110 mL) was added NH4Cl (1.80 g, 34 mmol, 10.0 eq.) and Fe (1.91 g, 34 mmol, 10.0 eq.). The resulting mixture was stirred at 60° C. for 3 h. After the reaction was completed, the mixture was cooled to room temperature, and the iron was filtered off. The filtrate was concentrated to 15 ml, and a precipitate formed and was collected and dried in vacuo to give 1.13 g of N4-(3-(difluoromethoxy)phenyl)-2-(pyrazin-2-yl)quinazoline-4,6-diamine as a pale yellow solid (87.5%). LCMS m/z=381.1 (M+1) (Method B) (retention time=1.60 min), 1H-NMR (400 MHz, DMSO-d6): δ 9.69 (s, 1H), 9.52 (d, J=1.2 Hz, 1H), 8.75 (d, J=2.4 Hz, 1H), 8.69 (d, J=2.4 Hz, 1H), 8.30 (s, 1H), 7.87 (dd, J=8.4, 0.8 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.49-7.42 (m, 2H), 7.33-7.32 (m, 1H), 7.31 (t, J=7.4 Hz, 1H), 5.85 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:32])[N:17]3[C:22](=[C:23]([C:25]([O:27]C)=[O:26])[CH:24]=2)[C:21]2[S:29][CH:30]=[CH:31][C:20]=2[CH:19]=[CH:18]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16](=[O:32])[N:17]3[C:22](=[C:23]([C:25]([OH:27])=[O:26])[CH:24]=2)[C:21]2[S:29][CH:30]=[CH:31][C:20]=2[CH:19]=[CH:18]3)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12
Yield: 748.6 %

Procedure:
0.23 g (0.5 mmol) of methyl 8-[p-(benzyloxy)phenyl]-7-oxo-7H-thieno[2,3-a]-quinolizine-10-carboxylate in 2 ml of ethanol was stirred overnight under reflux with a solution of 0.06 g of potassium hydroxide in 1.25 ml of water. Acidification to pH 1 with 1N hydrochloric acid and removal of the precipitate by filtration yielded 1.6 g (72%) of 8-[p-(benzyloxy)phenyl]-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid with m.p. 197°-199° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:3]=1
Reactant: C1CCNC1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Product: Nc1nc(N2CCCC2)c2nc[nH]c2n1

Procedure:
2-Amino-6-chloropurine (Sigma, lot #69F4064, 5.0 g, 29.5 mmol) was stirred in pyrrolidine (Kodak, lot #B161, 30mL) at 80° C. for 24 hours. The solvent was evaporated to a gold solid which was recrystalized from methanol to yield 3.41 g (16.7 mmol, 58%); mp=265°C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:14]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[NH:12][C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH:22]2[C:27](O)=[O:28])=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].Cl.[CH3:36][O:37][NH2:38].CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][C@H:22]2[C:27](=[O:28])[NH:38][O:37][CH3:36])[NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[N:14]1
Reactant: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CCOC(=O)C1=C(CN2CCOC[C@H]2C(=O)NOC)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
A mixture of (3S)-4-(((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (0.5 g, 0.9 mmol), O-methylhydroxylamine hydrochloride (0.2 g, 2.25 mmol), EDC.HCl (1 g, 5.2 mmol), HOAt (1 g, 7.3 mmol) and TEA (1.45 g, 14.3 mmol) in DCM (30 mL) was stirred at 0 t for 1 hour. Then the mixture was warmed to 25° C. and stirred for another 10 hours. The mixture was concentrated in vacuo and the residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=30/1) to give the title compound as a yellow solid (0.4 g, 76%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[N:29]1[CH2:34][CH2:33][O:32][C:31]2[CH:35]=[C:36]([S:39](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:41])=[O:40])[CH:37]=[CH:38][C:30]1=2.C(O)(=O)C>C1COCC1>[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:22]=[CH:21][C:20]=1[N:29]1[CH2:34][CH2:33][O:32][C:31]2[CH:35]=[C:36]([S:39]([NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][N:3]=3)(=[O:40])=[O:41])[CH:37]=[CH:38][C:30]1=2
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1ccncn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=S(=O)(Nc1ccncn1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Cl
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 10.9 %

Procedure:
A sealable vial was charged with 4-aminopyrimidine (0.101 g, 1.067 mmol) sealed with a septa cap and placed under an N2 atmosphere. THF (2 mL) was added and the solution was cooled to −78° C. Lithium bis(trimethylsilyl)amide, 1.0 M in THF (1.067 mL, 1.067 mmol) was added dropwise and the solution was maintained at −78° C. for 15 min. Perfluorophenyl 4-(2-chloro-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (INTERMEDIATE F, 0.543 g, 0.970 mmol) was added as a solution in THF (3 mL) and the solution was allowed to warm to rt, and the mixture was stirred for 40 min. To the solution was added acetic acid (0.2 mL) to provide a bright yellow/orange mixture. The mixture was concentrated to dryness. The residue was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (40 g), eluting with a gradient of 10% to 100% EtOAc in heptane, to provide 4-(2-chloro-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.050 g, 0.106 mmol) as tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.60-3.84 (m, 2 H) 4.24-4.48 (m, 2 H) 6.32 (d, J=8.51 Hz, 1 H) 6.98-7.05 (m, 1 H) 7.24-7.31 (m, 1 H) 7.34 (s, 1 H) 7.71-7.79 (m, 1 H) 7.82-7.89 (m, 1 H) 8.03-8.11 (m, 1 H) 8.31-8.43 (m, 1 H) 8.56-8.75 (m, 1 H). m/z (ESI) 471.0 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].Cl[CH2:12][C:13]([CH3:20])=[CH:14][CH2:15][O:16][C:17](=[O:19])[CH3:18]>CN(C)C=O>[C:1]1([S:7]([CH2:12][C:13]([CH3:20])=[CH:14][CH2:15][O:16][C:17](=[O:19])[CH3:18])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S([O-])c1ccccc1
Reactant: CC(=O)OCC=C(C)CCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCC=C(C)CS(=O)(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 24.2 g. of sodium benzenesulfinate in 150 ml. of dimethylformamide (DMF) was added 19.9 g. of 1-chloro-2-methyl-4-acetoxybut-2-ene in 50 ml. of DMF. The mixture was then heated to 60°C. for 4.5 hours. A second portion, 19.0 g. of sodium benzenesulfinate was added and the heating continued for 1.5 hours. The reaction mixture was poured into 1.5 l. of water and filtered to remove the solid which was dissolved in 500 ml. of ethyl acetate. This solution was washed with three 300 ml. portions of water and dried over magnesium sulfate. Evaporation of the solvent afforded 25.2 g. of crude sulfone acetate, m.p. 86°-92°C. Ethyl acetate extraction, washing and drying of the aqueous filtrate afforded an additional 6.07 g. of less pure product. Recrystallization of the main portion from ethyl acetate gave analytically pure 1-phenylsulfonyl-2-methyl-4-acetoxy-but-2-ene, m.p. 93°-94°C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][S:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[CH3:16][C:17]1[N:25]([C:26]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)=[O:27])[C:24]2[CH:23]=[CH:22][C:21]([O:35][CH3:36])=[CH:20][C:19]=2[C:18]=1[CH2:37][C:38](O)=[O:39].CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([C:26]([N:25]2[C:24]3[C:19](=[CH:20][C:21]([O:35][CH3:36])=[CH:22][CH:23]=3)[C:18]([CH2:37][C:38]([NH:1][CH2:2][CH2:3][S:4][S:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:39])=[C:17]2[CH3:16])=[O:27])=[CH:33][CH:32]=1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCSSCCN
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: COc1ccc2c(c1)c(CC(=O)NCCSSCCNC(=O)OC(C)(C)C)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.6 %

Procedure:
tert-Butyl 2-(2-(2-aminoethyl)disulfanyl)ethylcarbamate (150 mg, 0.595 mmol) was taken up in CH2C22 (10 mL) along with indomethacin (213 mg, 0.595 mmol) and EDCI (125 mg, 0.65 mmol). The resulting reaction mixture was stirred at room temperature for 18 h and diluted with CH2Cl2. The organic layer was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by chromatography (CH2Cl2) to afford 312 mg of tert-butyl 2-(2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethyl)disulfanyl)ethylcarbamate (89% yield).