Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12][C:13](=[O:19])[O:14]C(C)(C)C)[CH2:5][CH2:4][CH2:3]1.[OH-].[K+]>C(O)C>[C:2]12([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:12][C:13](=[O:14])[O:19]1)[CH2:3][CH2:4][CH2:5]2
Reactant: CC(C)(C)OC(=O)Nc1ccccc1C1(O)CCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1Nc2ccccc2C2(CCC2)O1
Yield: 57.7 %

Procedure:
A solution of tert-butyl [2-(1-hydroxycyclobutyl)phenyl]carbamate (0.86 g, 3.3 mmol) in ethanol (30 mL) was stirred with potassium hydroxide (0.39 g, 6.9 mmol) at room temperature for 3 hours. The product was extracted with ethyl acetate (50 mL), dried with sodium sulfate, and concentrated to give spiro[3,1-benzoxazine-4,1′-cyclobutan]-2(1H)-one (0.36 g, 58%) as a white solid. 1H NMR (DMSO-d6): δ 10.21 (s, 1H), 7.47 (dd, 1H, J=7.6, 1.2 Hz), 7.28 (td, 1H, J=7.6, 1.4 Hz), 7.08 (td, 1H, J=7.5, 1.2 Hz), 6.9 (dd, 1H, J=7.9, 0.9 Hz), 2.49–2.41 (m, 2H), 2.06–1.96 (m, 2H), 1.88–1.77 (m, 2H). MS (ESI) m/z 190 ([M+H]+).
Reaction SMILES: [CH:1]1([C:4]2[S:5][CH:6]=[C:7]([CH2:9]O)[N:8]=2)[CH2:3][CH2:2]1.S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl>[ClH:13].[CH:1]1([C:4]2[S:5][CH:6]=[C:7]([CH2:9][Cl:13])[N:8]=2)[CH2:3][CH2:2]1
Reactant: OCc1csc(C2CC2)n1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cl
Product: ClCc1csc(C2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In chloroform (10 ml) was dissolved 2-cyclopropyl-4-hydroxymethylthiazole (0.9 g), to which was added dropwise, under ice-cooling, thionyl chloride (0.68 ml), followed by stirring for 30 minutes at room temperature. Excess thionyl chloride was distilled off under reduced pressure. To the residue was added diethyl ether to yield 2-cyclopropyl-4-chloromethyl thiazole hydrochloride (1.1 g) as pale brown powder. m.p. 108°-110° C.
Reaction SMILES: [S:1]1[C:5]2([CH2:10][CH2:9][S:8][CH2:7][CH2:6]2)[CH2:4][N:3]=[C:2]1[C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:15][C:14]=2[N:25]([CH3:35])[S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)(=[O:28])=[O:27].[OH:36]OS([O-])=O.[K+].S([O-])([O-])=O.[Na+].[Na+]>CO.O.ClCCl>[CH3:24][O:23][CH2:22][CH2:21][O:20][C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([N:25]([CH3:35])[S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)(=[O:27])=[O:28])[CH:15]=1)[NH:12][C:11]([C:2]1[S:1][C:5]3([CH2:6][CH2:7][S:8](=[O:36])[CH2:9][CH2:10]3)[CH2:4][N:3]=1)=[CH:19]2
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC4(CCSCC4)S3)cc2c1
Reactant: O=S([O-])OO
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC4(CCS(=O)CC4)S3)cc2c1
Reaction time: 18 h
Yield: 20 %

Procedure:
To a solution of N-[2-(1,8-dithia-3-azaspiro[4.5]dec-2-en-2-yl)-5-(2-methoxyethoxy)-1H-indol-7-yl]-N-methylpyridine-2-sulfonamide (50.7 mg) in methanol (2 mL), water (1 mL) and dichloromethane (1 mL) was added OXONE (registered trade mark, 29 mg) at room temperature, and the mixture was stirred for 18 hr. Aqueous sodium sulfite solution was added to the reaction mixture, and the mixture was stirred for 30 min. The organic solvent was evaporated under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to basic silica gel column chromatography, and eluted with ethyl acetate to give two steric isomers (10.3 mg, yield 20% (retention time: shorter), and 1.7 mg, yield 3% (retention time: longer)) of the title compound as a colorless amorphous solid, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:13]([CH2:22][OH:23])=[N:12][C:11]=2[CH:24]([CH3:26])[CH3:25])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])N.[C:31]([N:46]=[C:47]=[O:48])(=[O:45])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>>[C:31]([NH:46][C:47](=[O:48])[O:23][CH2:22][C:13]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:24]([CH3:26])[CH3:25])[N:12]=1)(=[O:45])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCCCCCCCCC(=O)N=C=O
Reactant: CC(C)c1nc(CO)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Agent: NC(=O)[O-]
Product: CCCCCCCCCCCCCC(=O)NC(=O)OCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1Cc1ccncc1
Yield: 46 %

Procedure:
The compound 89 (245 mg, 0.6 mmol) was converted to the carbamate with myristoyl isocyanate (5 eq.) in the same manner as the example 66 to give the compound 94 (182 mg, 46%) as oil. Rf 0.41 (EtOAc).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.CCN(C(C)C)C(C)C.[CH:32]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>CS(C)=O.O>[CH:32]1([NH:38][C:2]2[C:3]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: NC1CCCCC1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NC3CCCCC3)nc2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (200 mg, 0.63 mmol) in DMSO (10 mL) was added DIEA (163.3 mg, 1.27 mmol) and cyclohexanamine (250.7 mg, 2.53 mmol), and the reaction was allowed to proceed with stirring overnight at 90° C. in an oil bath. The reaction mixture was cooled down to room temperature and diluted with water (150 mL). The mixture was extracted with ethyl acetate (3×80 mL), the organic layers combined and dried over magnesium sulfate, concentrated in vacuo to give the residue, which was purified by a silica gel column chromatography (1% ethyl acetate in petroleum ether) to afford methyl 3-(cyclohexylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a light yellow solid (200 mg, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.C([N:24]=[C:25]=[S:26])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:25]([NH2:24])=[S:26])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (500 mg, 2.46 mmol) in THF (30 ml) at 0° C. was slowly added benzoyl isothiocyanate (0.366 ml, 2.583 mmol) and the reaction mixture was stirred at rt for 2 hours. The solvents were evaporated and the residue was dissolved in methanol (50 ml). A solution of potassium carbonate (1.02 g, 7.38 mmol) in water (23 ml) was added dropwise at rt, the reaction mixture was stirred for 3 h at rt. The methanol was evaporated, water (10 ml) was added and stirred at rt for 1 hour. The solids were filtered off, washed with diethyl ether and dried in vacuo. After trituration with diethyl ether the title compound was obtained as light yellow solid (490 mg, 76%). MS ISP (m/e): 263.1 (100) [(M+H)+].
Reaction SMILES: C(Cl)(Cl)Cl.CO.[O:7]=[P:8]1([CH:18]=[CH2:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1.ClP1(=O)C2C(=CC=CC=2)CCC1>C(O)C>[O:7]=[P:8]1([CH:18]=[CH2:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH2:9]1
Reactant: C=CP1(=O)CCCc2ccccc21
Agent: O=P1(Cl)CCCc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCO
Product: C=CP1(=O)CC=Cc2ccccc21

Procedure:
A solution of the crude 4-bromo-1-oxo-1-vinyl-1,2,3,4-tetrahydrophosphinoline (5.5g) in anhydrous dimethyl formamide (30 ml) was heated under nitrogen at 110° for 45 min, after which time an n.m.r. spectrum indicated that dehydrobromination was complete. The excess of dimethyl formamide was evaporated in vacuum, and the brown semi-solid residue was dissolved in chloroform. This solution was washed with water, dried, and evaporated. Distillation of the residue through a short Vigreux column gave a colourless liquid b.p. 134°-138°/0.005 (3.6g, 90%). Preparative t.l.c. on silica gel plates developed with chloroform-methanol 30-1, followed by bulb-to-bulb distillation gave the "pure" compound. However, complete removal of water was not achieved, nor was a unique hydrate obtained, and the compound failed to give satisfactory microanalytical figures. Infrared spectrum νmax : 3030, 2930, 2860, 1630, 1590, 1475, 1440, 1390, 1275, 1180, 1140, 990, 865, 785, 720 cm-1. N.m.r. spectrum (CDCl3): 7.0-8.0, m. 4H (aromatic); 5.6-6.8, m, 5H (olefinic); 2.6-3.1, m, 2H (methylene). Mass spectrum: m/e 190 (57%), 141 (41), 128 (38), 116 (66), 115 (100), 89 (27), 65 (34), 51 (50). Ultraviolet spectrum λmax (ethanol): 222 (19600) 262 (4200), 298 (2300).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:18]([N:20](CC)CC)C.COC(Cl)=O.CN>O.O1CCCC1>[OH:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:20][CH3:18])=[O:12])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(Oc2ccc(O)cc2)cc1
Agent: CN
Agent: COC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(Oc2ccc(O)cc2)cc1
Reaction time: 0.25 h

Procedure:
To a mixture of 4-(4-Hydroxy-phenoxy)-benzoic acid (0.25 g, 1.09 mmol), triethylamine (0.15 mL, 1.07 mmol) and tetrahydrofuran (THF) (5.0 mL) at 0° C. was added methylchloroformate (0.084 mL, 0.10 g, 1.1 mmol). After stirring for 15 minutes, excess methylamine was added via a sparge tube, and stirring was continued for 10 minutes. The mixture was diluted with water, extracted three times with ethyl acetate, and the combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo, affording 1 4-(4-Hydroxy-phenoxy)-N-methyl-benzamide as a colorless syrup.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[Si]([C:11]#[C:12][C:13]1[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=1)[CH2:16][CH2:17][O:18][CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])(C)C.CO>C(Cl)Cl.O>[C:12]([C:13]1[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=1)[CH2:16][CH2:17][O:18][CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])#[CH:11]
Reactant: CC(C)(C)OC(=O)CCOCCc1cccc(C#C[Si](C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: C#Cc1cccc(CCOCCC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium carbonate (1.20 g) was added in one portion to tert-butyl 3-(3-((trimethylsilyl)ethynyl)phenethoxy)propanoate [Example 4, Step i)] (2.09 g) in DCM (20 mL) and methanol (20 mL) at 25° C. under nitrogen. The resulting mixture was stirred at 25° C. for 1 h. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and evaporated to afford tert-butyl 3-(3-ethynylphenethoxy)propanoate (1.65 g). 1H NMR (300 MHz, CDCl3) δ 7.38-7.30 (m, 2H), 7.25-7.18 (m, 2H), 3.68 (t, J=6.5 Hz, 2H), 3.64 (t, J=7.0 Hz, 2H), 3.05 (s, 1H), 2.85 (t, J=7.2 Hz, 2H), 2.48 (t, J=6.4 Hz, 2H), 1.44 (s, 9H).
Reaction SMILES: C(O[O:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:24])[CH:13]=[CH:14][CH:15]=1)C1C=CC=CC=1.[N:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:40][CH2:39][CH:35]([C:36](Cl)=[O:37])[CH2:34][CH2:33]2)=[CH:28][CH:27]=1>>[N:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:40][CH2:39][CH:35]([C:36]([NH:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]([NH:16][C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:11]=3)=[O:25])=[O:37])[CH2:34][CH2:33]2)=[CH:28][CH:27]=1
Reactant: Nc1ccccc1C(=O)Nc1cccc(OOCc2ccccc2)c1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Product: O=C(Nc1cccc(OCc2ccccc2)c1)c1ccccc1NC(=O)C1CCN(c2ccncc2)CC1
Yield: 164.8 %

Procedure:
Using the procedure described in Example 138, N-(3-benzyloxyoxyphenyl)-2-aminobenzamide (0.97 mmol) and N-(4-pyridyl)isonipecotoyl chloride (1.9 mmol), yielded 405 mg (82%) of the title compound.
Reaction SMILES: CO[C:3](OC)([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH:4]=[O:5].[CH3:15]O.[H][H]>[Pd]>[CH3:15][O:5][CH2:4][CH2:3][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: CO
Reactant: [H][H]
Reactant: COC(C=O)(OC)c1ccc(O)cc1
Agent: [Pd]
Product: COCCc1ccc(O)cc1
Yield: 59 %

Procedure:
The procedure of Example 2 was repeated with a solution of 3.00 g (15.3 mmol) 4-hydroxyphenylglyoxal dimethyl acetal in 10 g methanol containing 0.16 g (4.4 mmol) hydrogen chloride and 0.15 g moist 10% Pd/C catalyst being reacted with hydrogen gas pressurized at 300 psig at 50° C. 300 rpm. A 59% yield of 4-(2'-methoxyethyl)phenol was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][C:4]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCc1cc(CCO)ccc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCc1cc(CCOS(C)(=O)=O)ccc1OC

Procedure:
1.2 g (0.0054 mol) of the compound 2d) from the previous step, 20 ml of dichloromethane, 0.75 ml (0.0054 mol) of triethylamine and, at 0-5° C., 0.42 ml (0.0054 mol) of methanesulfonyl chloride are placed in a round-bottom flask.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)CC)C.O>C1COCC1>[CH3:1][S:2]([NH:6][CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1)(=[O:4])=[O:3]
Reactant: NC1CCCOc2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)NC1CCCOc2ccccc21
Reaction time: 8 h
Yield: 74.7 %

Procedure:
1.54 g (13.4 mmol) of methanesulfonyl chloride were added dropwise with ice cooling to a solution of 2.0 g (12.2 mmol) of 5-amino-2,3,4,5-tetrahydro-1-benzoxepine (Example 6b) and 3.7 g (36.6 mmol triethylamine in 40 ml of THF. The mixture was allowed to come to RT and was stirred overnight and treated with 50 ml of water, and the THF was distilled off in vacuo. The residue was diluted with a further 50 ml of water and stirred for 3 h, and the deposited product was filtered off with suction. After drying in vacuo, 2.2 g of 5-methylsulfonylamino-2,3,4,5-tetrahydro-1-benzoxepine were obtained, m.p. 105-106° C. b) A solution of 1.1 g (6.2 mmol) of 5-methylsulfonylamino-2,3,4,5-tetrahydro-1-benzoxepine in 15 ml of THF was added dropwise to a suspension of 0.23 g (6.2 mmol) of 80 percent sodium hydride in 10 ml of THF. After 2 h at RT, 0.94 g (6.7 mmol) of iodomethane were added and the mixture was stirred overnight at RT. After distilling off the solvent in vacuo, the residue was taken up in EA, and the solution was washed with dilute hydrochloric acid and water, dried over magnesium sulfate and concentrated. Subsequent recrystallization of the product from isopropanol yielded 0.5 g of 5-(N-methyl-N-methylsulfonylamino)-2,3,4,5-tetrahydro-1-benzoxepine, m.p. 143-145° C.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[NH:8][CH:9]=[CH:10][N:11]=1.[CH3:12][CH2:13][C:14]([CH2:16][C:17](OC)=[O:18])=O>C(O)(=O)C>[CH2:13]([C:14]1[CH:16]=[C:17]([OH:18])[N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[N:6]=1)[CH3:12]
Reactant: CCC(=O)CC(=O)OC
Reactant: Nc1ncc[nH]1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCc1cc(O)n2ccnc2n1
Temperature: 25 °C

Procedure:
20.0 g (151.4 mmol) commercially available (Aldrich) 2-aminoimidazole sulfate and 19.7 g (151.4 mmol) methyl 3-oxo-n-valerate were heated with reflux in 27 ml acetic acid for 7 h. After cooling to room temperature remaining solids were removed by filtration, and the filtrate was diluted with water, neutralized with sodium hydroxide, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, evaporated in vacuo, while the title compound crystallized in colorless crystals, which were filtered with suction, washed with hexane, and dried in vacuo, m.p. 93°-94° C.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C:13]([CH3:37])([CH3:36])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([NH:31][CH2:32][CH2:33]SC)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH:40][S:41]([O-:44])(=O)=O.OS(O[O-])(=O)=O.OS(O[O-])(=O)=O.[O-]S([O-])(=O)=O.[K+].[K+].[K+].[K+].[K+].[CH3:67]O>>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([C:13]([CH3:37])([CH3:36])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([NH:31][CH2:32][CH2:33][S:41]([CH3:67])(=[O:44])=[O:40])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: CO
Reactant: O=S(=O)([O-])O
Reactant: CSCCNc1cc(-c2ccccc2Cl)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Agent: O=S(=O)(O)O[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(NCCS(C)(=O)=O)cc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 55 %

Procedure:
A mixture of 50 mg (0.087 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-methylsulfanyl-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide and 130 mg (0.212 mmol) potassium monopersulfate triple salt in 1 ml methanol was stirred at room temperature for 3 days. The reaction was quenched with 1 ml sodium hydrogen sulfite solution 38%. The mixture was treated with 3 ml saturated sodium carbonate solution and extracted with three 5-ml portions of ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography to give 29 mg (55%) of the title compound as a white foam.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1>>[Cl:22][C:23]1[CH:24]=[C:25]([S:29]([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(S(=O)(=O)c3cccc(Cl)c3)CC1)O2

Procedure:
Compound 82 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-chlorobenzenesulfonyl chloride and conditions outlined in procedure P. M.p.=255-256° C.; 400 1H NMR (DMSO-d6) δ: 7.98-7.9 (m, 1H), 7.89-7.82 (m, 1H), 7.8-7.7 (m, 3H), 7.58-7.4 (m, 2H), 7.3 (d, J=7.6 Hz, 1H), 3.65-3.58 (m, 2H), 3.1 (s, 2H), 2.6-2.5 (m, 2H), 2.15-2.05 (m, 2H), 1.95-1.84 (m, 2H) LCMS: 476 [M+H].
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].[C:19]([O:23][C:24](=[O:44])[N:25]([CH3:43])[C@@H:26]([C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=1)[CH3:27])([CH3:22])([CH3:21])[CH3:20]>>[CH3:13][O:12][C:11]1[CH:10]=[C:9]([CH3:14])[C:8]2[NH:7][C:6](=[O:15])[C:5]3[S:16][CH:17]=[CH:18][C:4]=3[C:3]=2[C:2]=1[C:31]1[CH:30]=[CH:29][C:28]([C@H:26]([N:25]([CH3:43])[C:24](=[O:44])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])[CH3:27])=[CH:33][CH:32]=1
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Reactant: C[C@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N(C)C(=O)OC(C)(C)C
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)N(C)C(=O)OC(C)(C)C)cc1
Yield: 66 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one (150 mg, 0.46 mmol) was reacted with (R)-tert-butylmethyl(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate (250 mg, 0.69 mmol to afford the desired product (145 mg, 66%) as a light brown solid: ESI MS m/z 479 [C27H30N2O4S+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C@@H:8]2[CH2:11][CH2:10][C@H:9]2[C:12]([OH:14])=O)=O)=[CH:4][CH:3]=1.[NH:17]([CH2:19][CH:20]([OH:23])[CH2:21][CH3:22])[NH2:18].C1(C)C=CC=CC=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[CH:8]3[CH:9]([C:12](=[O:14])[N:17]([CH2:19][CH:20]([OH:23])[CH2:21][CH3:22])[N:18]=2)[CH2:10][CH2:11]3)=[CH:15][CH:16]=1
Reactant: CCC(O)CNN
Reactant: O=C(O)[C@@H]1CC[C@H]1C(=O)c1ccc(Cl)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(O)CN1N=C(c2ccc(Cl)cc2)C2CCC2C1=O
Temperature: 25 °C

Procedure:
Into a flask equipped with a stirrer, heating mantle and Dean - Stark water separator is charged 7.2 g (0.30 mole) of a mixture of cis-and trans-2-p-chlorobenzoylcyclobutane carboxylic acid, 3.5 g (0.033 mole) of 1-hydrazino-2-butanol and 100 ml. of toluene. The mixture is stirred and refluxed until the water layer in the Dean-Stark tube remains constant (ca. 5hr). The solvent is removed in vacuo on a rotary evaporator, and the residue is dissolved in hot diethyl ether and allowed to cool to room temperature. The resultant solid is filtered off and yields 2-(p-chlorophenyl)-4-(2-hydroxybutyl) 3,4-diazabicyclo [4.2.0]-oct-2-ene-5-one(isomer B;m.p. 133°-135°). The filtrate is further concentrated to give Isomer A (m.p. 115.5°-119° C).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH2:13][CH2:14][CH3:15])[C:10]=1[O:11][CH3:12])[CH2:6][OH:7].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH2:13][CH2:14][CH3:15])[C:10]=1[O:11][CH3:12])[CH2:6][O:7][S:24]([CH3:23])(=[O:26])=[O:25]
Reactant: CCCc1cc(CO)cc(OC)c1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1cc(COS(C)(=O)=O)cc(OC)c1OC
Yield: 51.6 %

Procedure:
To a stirred solution of 3,4-dimethoxy-5-propylbenzylalcohol (171 mg, 0.82 mmol) in CH2Cl2 (5.0 mL) at room temperature was added triethylamine (0.23 mL, 1.63 mmol) followed by methanesulfonyl chloride (95 μL, 1.22 mmol, 1.5 eq.). After 30 min the reaction mixture was diluted with hexanes (20 mL) and filtered through a pad of silica gel. The pad was then washed with 25% EtOAc in hexanes (100 mL). The combined organic filtrate was then concentrated to give methanesulfonic acid 3,4-dimethoxy-5-propylbenzyl ester (122 mg) as oil, which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:15]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[NH:18][CH2:17][CH2:16]2.C(N(CC)CC)C>CO>[N:15]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[N:18]([C:2]1[CH:3]=[C:4]([C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH2:17][CH2:16]2
Reactant: COC(=O)c1cc(Cl)ncc1[N+](=O)[O-]
Reactant: C1CN2CCC(CC2)N1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cc(N2CCN3CCC2CC3)ncc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
To a solution of methyl 2-chloro-5-nitroisonicotinate (Intermediate 26A) (0.1 g, 0.46 mmol) in methanol (3 mL) under nitrogen was added 1,4-diazabicyclo[3.2.2]nonane (0.18 g, 0.55 mmol) and triethylamine (7 mg, 0.69 mmol), reaction then stirred overnight. The reaction mixture was concentrated and purified by a 10 g silica column eluting with 40% ethylacetate in hexane to afford methyl 2-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-5-nitroisonicotinate.