Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[SH:19][C:20]1[N:24]([CH3:25])[N:23]=[N:22][N:21]=1.P(Cl)(Cl)(OP(Cl)(Cl)=O)=O.N>C(#N)C.O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:19][C:20]3[N:24]([CH3:25])[N:23]=[N:22][N:21]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cn1nnnc1S
Agent: N
Agent: O=P(Cl)(Cl)OP(=O)(Cl)Cl
Solvent: O
Solvent: CC#N
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: -40 °C
Yield: 87.2 %

Procedure:
In 5.4 ml of acetonitrile were suspended 0.909 g of 7-ACA and 0.504 g of 5-mercapto-1-methyl-1H-tetrazole, and 0.256 g of water was added. The suspension was cooled at -40° C. under stirring, and 3.58 g of diphosphoryl tetrachloride was added dropwise to it at -50° to -35° C. The reaction mixture was stirred at -35° to 0° C. for 5 minutes after the dropwise addition and placed in a warm water bath at 40° C. to warm, followed by stirring at the same temperature for 20 minutes. The reaction solution was cooled over an ice water bath and, after the addition of 11 ml of cold water, it was adjusted to pH 4.0 with aqueous concentrated ammonia. The separated-out precipitate was recovered by filtration, washed with water and dried, thereby affording 0.956 g of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4 -carboxylic acid. The yield was 87.2%.
Reaction SMILES: [CH2:1]([C:3]([CH2:7][CH3:8])=[CH:4][CH2:5][OH:6])[CH3:2].[N:9]([O:11]CCCCC)=O.[ClH:17]>C(O)(=O)C>[Cl:17][C:3]([CH2:7][CH3:8])([CH2:1][CH3:2])[CH:4]([N:9]=[O:11])[CH2:5][OH:6]
Reactant: Cl
Reactant: CCC(=CCO)CC
Reactant: CCCCCON=O
Solvent: CC(=O)O
Product: CCC(Cl)(CC)C(CO)N=O
Yield: 43 %

Procedure:
2-Cyclohexylidene ethanol (VI) (23 g) was dissolved in glacial acetic acid (76 ml). Amyl nitrite (21.5 g) was added and the mixture was cooled in an ice-salt bath. The cooled solution was treated dropwise with cold concentrated hydrochloric acid (23 ml) with stirring. After the addition of the acid was complete the reaction mixture was stirred at the same temperature for 30 min, followed by cooling in an acetone-carbon dioxide bath for 10 min. The buff-coloured solid was filtered off, washed with cold methanol and recrystallised from acetone to give the nitrosochloride (V) (15 g; yield 43%) as colourless needles, m.p. 130°.
Reaction SMILES: C[N+]([O-])=O.[C:5]1([C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N1C=CC=CC=1.[OH:23]O>C(Cl)Cl>[C:5]1([C:11]23[O:23][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]3)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OO
Reactant: C1=C(c2ccccc2)CCCC1
Solvent: c1ccncc1
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: c1ccc(C23CCCCC2O3)cc1
Reaction time: 6 h
Yield: 91 %

Procedure:
The wide scope of this process is revealed in FIGS. 5-8 and 15-16. Due to practical considerations, we used CH2Cl2 as solvent for all examples even though CH3NO2 is slightly superior with regard to reaction rate. Standard experimental procedure (exemplified for the epoxidation of 1-phenyl-cyclohexene) is as follows: In a 50 mL flask equipped with a magnetic stirrer, 7.9 g (50 mmol) of 1-phenylcyclohexene and 63 mg (0.25 mmol, 0.5 mol %) of MTO are dissolved in 25 mL CH2Cl2. To this solution is added 0.48 mL (6 mmol, 12 mol %) of pyridine followed by 7.6 mL (75 mmol; 1.5 equivalents) of 30% aqueous H2O2 added dropwise from a syringe (circa 5-10 minutes). During the H2O2 -addition the temperature is kept at 20-25° C. by applying an external cooling bath. The reaction is complete after 6 h and the aqueous phase is separated and discarded. The remaining H2O2 in the yellow organic phase is decomposed to O2 and H2O by stirring with a catalytic amount of MnO2 (circa 5 mg). After the yellow color has completely disappeared the mixture is dried over Na2SO4, concentrated, and purified by filtration through a short column of silica gel which has been deactivated with NEt3. The column is washed with hexane/CH2Cl2 and concentration of the eluate affords 7.9 g (91%) of 1-phenyl-1,2-epoxycyclohexane as a colorless oil).
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:3].O.[N+]([O-])([O-])=O.[Ag+:18]>C(OCCCC)(=O)C>[O-:3][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:1].[Ag+:18]
Reactant: CCCCCCCCCC(=O)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CCCCOC(C)=O
Product: CCCCCCCCCC(=O)[O-]

Procedure:
A solution of 8.6 g of capric acid in 100 ml of butyl acetate was maintained at a temperature of 5° C., to which 200 ml of water was added with stirring to form an emulsion. 50 ml of an aqueous solution of silver ammonium complex containing 8.5 g of silver nitrate (chillset at 5° C.) was added to the above emulsion over a 30 second period in order to allow the capric acid to react with the silver ion. After the removal of an aqueous phase, a silver caprate-containing butyl acetate phase was dispersed into 120 g of isopropanol solution containing 15 weight percent of polyvinyl butyral to produce a polymer dispersion of silver caprate. A composition containing the several components setforth below were added to the polymer dispersion of silver caprate in their listed order every ten minutes while maintaining the temperature at 50° C., resulting in the formation of a heat developable light-sensitive coating composition.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1
Reactant: COc1ccc(Br)cc1
Product: COc1ccc(C(=O)c2cn(-c3cccc(-c4ccccc4Cl)c3)cn2)cc1

Procedure:
This compound is prepared by method C using compound 12e and 4-bromoanisole
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:12])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:13]([NH+:20]1[CH:24]=[CH:23][N:22]([CH3:25])[C:21]1=[S:26])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl-:1].[CH2:13]([NH+:20]1[CH:24]=[CH:23][N:22]([CH3:25])[CH:21]1[S:26][CH2:2][C:3](=[O:12])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN1C=C[NH+](Cc2ccccc2)C1=S
Reactant: O=C(CCl)COc1ccccc1
Product: CN1C=C[NH+](Cc2ccccc2)C1SCC(=O)COc1ccccc1
Product: [Cl-]

Procedure:
The above-identified compound, m.p. 110°-112° C. was prepared in substantially the same manner as described in Example XX from 1-chloro-3-phenoxy-propan-2-one and 1-benzyl-3-methyl-imidazolium-2-thione.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[NH:10][C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[C:27]([S:35][CH2:36][C@H:37]([CH3:41])[C:38](Cl)=[O:39])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[N:10]([C:38](=[O:39])[C@H:37]([CH3:41])[CH2:36][S:35][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]1=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](CSC(=O)c1ccccc1)C(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@@H]1CN(Cc2ccccc2)C(=O)N1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@H](CSC(=O)c1ccccc1)C(=O)N1C(=O)N(Cc2ccccc2)C[C@H]1C(=O)OC(C)(C)C
Yield: 76.6 %

Procedure:
27.6 g of tert.-butyl (4S)-1-benzyl-2-oxo-imidazolidine-4-carboxylate, 11.2 g of potassium tert.-butoxide, (2S)-3-benzoylthio-2-methylpropionyl chloride (prepared from 22.4 g of (2S)-3-benzoylthio-2-methylpropionic acid and 25 ml of thionyl chloride) and 200 ml of tetrahydrofuran are treated in the same manner as described in Example 2-(2). Then, the oily residue obtained is purified by silica gel chromatography (Solvent, toluene-ethyl acetate(20:1)) and triturated with n-hexane. 34.1 g of tert.-butyl (4S)-1-benzyl-3-[(2S)-3-benzoylthio-2-methylpropionyl]-2-oxo-imidazolidine-4-carboxylate are obtained as colorless crystals. Yield: 70.7%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[Cl-].[K+:20].O[S:22]([OH:25])(=[O:24])=[O:23].[O:26]=[S:27](=[O:29])=[O:28]>>[K+:20].[K+:20].[S:8]([C:11]1[CH:16]=[C:15]([S:27]([O-:29])(=[O:28])=[O:26])[C:14]([Cl:17])=[CH:13][CH:12]=1)([C:5]1[CH:6]=[C:7]([S:22]([O-:25])(=[O:24])=[O:23])[C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:9])=[O:10]
Reactant: O=S(=O)(O)O
Reactant: O=S(=O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=S(=O)=O
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: O=S(=O)([O-])c1cc(S(=O)(=O)c2ccc(Cl)c(S(=O)(=O)[O-])c2)ccc1Cl
Temperature: 120 °C
Yield: 62 %

Procedure:
57.44 g of bis(4-chlorophenyl)sulfone are dissolved in 60%-oleum in a round-bottomed flask with a drying conduit under cooling with ice and stirring, heated to 120° C., and kept at this temperature overnight. The reaction mixture is added to water and the product is salted out with potassium chloride. It precipitates as a white deposit, is syphoned off, washed with a saturated potassium chloride solution, and recrystallized from ethanol/water (5:4). 65.4 g (62% yield) are obtained as product in white needles, which crumble to a white powder by drying under high vacuum at 120° C. The melting or decomposition point is above 250° C. The characterization takes place with 1H-NMR and 13C-NMR spectroscopy.
Reaction SMILES: [Br:1][CH2:2][C:3](OCC)([O:38]CC)[C:4](=[N:35][O:36][CH3:37])[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]12)=[O:6].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][CH2:2][C:3](=[O:38])[C:4](=[N:35][O:36][CH3:37])[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([OH:19])=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)C(CBr)(OCC)OCC)[C@H]2SC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)C(=O)CBr)[C@H]2SC1
Yield: 74.1 %

Procedure:
To a solution of benzhydryl 7-(4-bromo-3,3-diethoxy-2-methoxyiminobutyramido)-3-vinyl-3-cephem-4-carboxylate (syn isomer) (3.36 g) and anisole (2.1 g) in methylene chloride (20 ml) was added trifluoroacetic acid (8.0 g) under ice-cooling with stirring, and the stirring was continued at ambient temperature for an hour. After removal of the solvent, the residue was dissolved in a mixture of ethyl acetate and water. To the separated ethyl acetate solution was added water, followed by adjusting to pH 7 with a saturated aqueous sodium bicarbonate. To the separated aqueous solution was added ethyl acetate, followed by adjusting to pH 2 with 10% hydrochloric acid. The ethyl acetate layer was separated out, washed with an aqueous sodium chloride and then dried over anhydrous magnesium sulfate. Removal of the solvent gave 7-(4-bromo-2-methoxyiminoacetoacetamido)-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.6 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH3:23]>CN(C=O)C>[CH2:22]([O:13][C:12]([C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[Br:1])[CH:7]=[CH:8][CH:9]=1)=[O:14])[CH3:23]
Reactant: O=C(O)c1cccc2cccc(Br)c12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc2cccc(Br)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 8-bromo-naphthalene-1-carboxylic acid (1.6 g) in DMF (15 ml) was treated with potassium carbonate (2.2 g) and iodoethane (1.03 ml). The reaction mixture was stirred overnight at r.t., then quenched with water and extracted with ethyl acetate. The organics were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 1:1) to give 8-bromo-naphthalene-1-carboxylic acid ethyl ester (1.57 g) as colorless liquid. MS (ISP): 279.1 ((M+H)+.).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([CH3:12])([CH3:11])[CH2:6][S:7]([NH2:10])(=[O:9])=[O:8].Cl[C:14]1[C:15]([CH3:24])=[C:16]([CH3:23])[C:17]2[N:18]([N:20]=[CH:21][N:22]=2)[N:19]=1.Cl>CN(C)C=O.O>[CH3:24][C:15]1[C:14]([O:3][CH2:4][C:5]([CH3:12])([CH3:11])[CH2:6][S:7](=[O:9])(=[O:8])[NH2:10])=[N:19][N:18]2[N:20]=[CH:21][N:22]=[C:17]2[C:16]=1[CH3:23]
Reactant: CC(C)(CO)CS(N)(=O)=O
Reactant: Cc1c(Cl)nn2ncnc2c1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(OCC(C)(C)CS(N)(=O)=O)nn2ncnc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.3 %

Procedure:
In 30 ml of dimethylformamide was suspended 1.38 g of 60% sodium hydride in oil, followed by addition of 2.51 g of 3-hydroxy-2,2-dimethyl-1-propanesulfonamide and the mixture was stirred under reduced pressure at room temperature for 1 hour. To this was added 2.56 g of 6-chloro-7,8-dimethyl[1,2,4]triazolo[1,5-b]pyridazine and the mixture was stirred at room temperature for 3 hours. Following addition of 100 ml of iced water, the reaction mixture was adjusted to pH 6 with 5N-hydrochloric acid and extracted with 3 portions of ethyl acetate-tetrahydrofuran (2:1). The extract was washed with 20 ml of saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was subjected to silica gel column chromatography, elution being carried out with dichloromethane-methanol (30:1). The fractions containing the desired product were pooled and concentrated to provide 0.63 g of the title compound. m.p. 175°-177° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25](=O)[CH3:26]>>[CH2:1]([N:8]([CH2:25][CH3:26])[C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[O:17][N:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)OCc1cc(-c2ccc(NCc3ccccc3)cc2)no1
Reactant: CC=O
Product: CCN(Cc1ccccc1)c1ccc(-c2cc(COC(N)=O)on2)cc1

Procedure:
An experiment was performed using carbamic acid 3-(4-benzylamino-phenyl)-isoxazol-5-ylmethyl ester in Example 74 as a starting material and acetaldehyde in the same manner as in Example 74.4 to obtain carbamic acid 3-[4-(benzyl-ethyl-amino)-phenyl]-isoxazol-5-ylmethyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[CH:10]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28])C(OCC1C=CC=CC=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Li+].CS(C)=O>O>[CH2:1]([O:8][C:9](=[O:30])[CH2:10][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)C(C(=O)OCc1ccccc1)c1ccncc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(Cc1ccncc1[N+](=O)[O-])OCc1ccccc1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
The title compound is prepared following the procedures of WO, 00 55159 as follows. A solution of 2-(3-nitropyridin-4-yl)malonic acid dibenzyl ester (1.58 g, 5.6 mmol), lithium chloride (250 mg, 10.6 mmol), dimethylsulfoxide (35 mL) and water (95 mL) is heated at reflux for 8 hr. After cooling to room temperature, the reaction is diluted with water and extracted with ethyl acetate. The combined extract is extracted with water, with brine, dried, filtered and concentrated to yield (3-nitropyridin-4-yl)acetic acid benzyl ester (1.13 g, 99% yield) as a yellow-orange oil. The material is purified by chromatography eluting with pentane-20 to 30% ethyl acetate to afford the product as a pink oil. MS 273 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1.C(N(C(C)C)CC)(C)C>C(O)C.[Pd]>[F:16][C:13]([F:14])([F:15])[C:4]1[N:3]=[CH:2][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(C(F)(F)F)nc1Cl
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1cnc(C(F)(F)F)nc1
Reaction time: 6 h
Yield: 97.7 %

Procedure:
To a solution of ethyl 4-chloro-2-(trifluoromethyl)pyrimidine-5-carboxylate (30.2 g, 119.0 mmol) in ethanol (594 mL) under nitrogen were added palladium (10% on carbon, 50% water wet; 2.58 g, 1.21 mmol) and diisopropylethylamine (50.0 mL, 286.0 mmol). The mixture stirred under hydrogen (1 atm). After 6 h, the mixture was filtered with Celite. The filtrate was concentrated and ethyl acetate was added. The mixture was washed with saturated aqueous sodium bicarbonate (2×), saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated to give the title compound (25.6 g). MS 221.1 (M+1).
Reaction SMILES: N[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=O)N.[CH3:11][CH2:12][CH2:13]C(NC1C2N=CN([C@@H]3O[C@@H]4COP(O)(O[C@H]4[C@H]3OC(CCC)=O)=O)C=2N=CN=1)=O.C1[C@H:47]([N:48]2C(=O)NC(=O)C(Br)=C2)O[C@H](CO)[C@H]1O>>[CH2:11]1[CH2:12][CH2:13][C:3]([CH2:47][NH2:48])([CH2:2][C:8]([OH:10])=[O:9])[CH2:4][CH2:5]1
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: CCCC(=O)Nc1ncnc2c1ncn2[C@@H]1O[C@@H]2COP(=O)(O)O[C@H]2[C@H]1OC(=O)CCC
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1Br
Product: NCC1(CC(=O)O)CCCCC1
Reaction time: 204 h

Procedure:
IMR-32 cells were grown in MEM media (Gibco BRL, 11095-080), supplemented with 10% fetal bovine serum (Gibco BRL, 26140-087), 1% antibiotic-antimycotic (Gibco BRL, 15240-096), and 1% L-glutamine (Gibco BRL, 25030-032). Cells, grown to confluency, were differentiated for a period of 7 to 10 days, or longer, by adding 1 mM dibutyryl cAMP (Sigma D-0627) and 2.5 μM 5-bromo-2-deoxyuridine (Sigma B-9285) to the media. The differentiation media was fed continuously to cells until the cells were used in an experiment. Cells were divided into groups and preincubated for 30 minutes either in the presence or absence of indicated concentration of gabapentin then subsequently challenged with 50 nM PMA for 5 minutes. Cells were washed with cold PBS buffer containing 1 mM sodium orthovanadate and 1 mM phenylmethylsulfonyl fluoride, then solubilized in lysis buffer (10 mM Hepes, pH 7.4, 70 mM NaCl, 50 mM b-glycerol phosphate, 1% Triton X-100, 1 mM sodium orthovanadate, 1 mM phenylmethylsulfonyl fluoride, and 1× protease inhibitor cocktail). Proteins in cell extracts were separated by SDS-PAGE and transferred to nitrocellulose membrane. The nitrocellulose membrane was blocked overnight at 4° C. with 4% BSA in Tris-buffered saline containing 0.2% (v/v) Tween 20 (TBST). The membrane was then incubated for 1 hour at RT with antiphospho MAP kinase antibody (1:1000 dilution) in 1% BSA and TBST, then washed with TBST followed by incubation with antirabbit IgG HRP antibody. After a final wash with TBST, the membrane was visualized using enhanced chemiluminescence reagents.
Reaction SMILES: [ClH:1].[NH2:2][OH:3].C(=O)([O-])[O-].[K+].[K+].[Cl:10][C:11]1[CH:12]=[C:13]([CH:27]=[C:28](Cl)[CH:29]=1)[O:14][C:15]1[C:16]([CH2:25][CH3:26])=[N:17][N:18]([CH2:22][C:23]#[N:24])[C:19]=1[CH2:20][CH3:21]>CO.O>[Cl:1][C:28]1[CH:27]=[C:13]([CH:12]=[C:11]([Cl:10])[CH:29]=1)[O:14][C:15]1[C:16]([CH2:25][CH3:26])=[N:17][N:18]([CH2:22][C:23](=[NH:24])[NH:2][OH:3])[C:19]=1[CH2:20][CH3:21]
Reactant: Cl
Reactant: NO
Reactant: CCc1nn(CC#N)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCc1nn(CC(=N)NO)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Yield: 99.3 %

Procedure:
Hydroxylamine hydrochloride (1.1 g, 15.8 mmol) and potassium carbonate (2.1 g, 15.2 mmol) were added to a suspension of the nitrile (1 g, 3.1 mmol) of Example 4 in a mixture of methanol (25 ml) and water (10 ml) which was then heated under reflux for 3 days. After cooling, the mixture was extracted with dichloromethane (2×250 ml) and the combined organic layers were washed with brine (100 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to afford the product as a white solid (1.1 g), m.p. 128–130° C.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:10]=[C:9]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[S:8][C:4]=2[CH:5]=[N:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1.[O-]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:3]2[N:10]=[C:9]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[S:8][C:4]=2[CH:5]=[N+:6]([O-:27])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1cccc(Cl)c1-c1nc2c(Br)cncc2s1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1cc(Br)c2nc(-c3c(F)cccc3Cl)sc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 7-bromo-2-(2-chloro-6-fluoro-phenyl)thiazolo[5,4-c]pyridine (2.0 mmol, 690 mg) in DCM (20 mL) was added mCPBA (5. 2 mmol, 890 mg). The mixture was stirred at room temperature for 5 hours. A solution of 1 M Na2SO3 (10 mL) was then added. The mixture was then stirred at room temperature for 1 hour. A solution of sat. NaHCO3 was added. The layers were separated. The aqueous layer was extracted with DCM. Then the combined organics were dried (Na2SO4), filtered and concentrated to give the title compound as an off-white solid which was used in the next step without purification. LCMS (ESI) m/z 360.9 [M+H+].
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([F:19])=[C:12](F)[C:11]=3[F:21])[CH:5]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]([NH2:31])[CH3:30])=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>CCCCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([F:19])=[C:12]([NH:31][C@H:29]([C:26]4[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=4)[CH3:30])[C:11]=3[F:21])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1Nc1cc(C2CC2)[nH]n1
Reactant: C[C@H](N)c1ccc(F)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1c(F)cc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)c1F)c1ccc(F)cc1
Reaction time: 8 h
Yield: 71.2 %

Procedure:
A mixture of 5-cyclopropyl-N-(2,3,4-trifluoro-6-nitrophenyl)-1H-pyrazol-3-amine (Method 103, 0.300 g, 1.01 mmol), (S)-1-(4-fluorophenyl)ethylamine (0.154 g, 1.11 mmol) and DIEA (0.263 ml, 1.51 mmol) in n-BuOH (2 ml) was heated in a sealed tube placed in an oil bath set at 135° C. for 8 hours. The solvent was removed under reduced pressure and the residue was purified by chromatography (hexane-EtOAc=3:1) to give the title compound as an orange solid (0.30 g, 71%). 1H NMR (400 MHz) 11.89 (s, 1H), 8.57 (s, 1H), 7.69 (d, 1H, J=13.6 Hz), 7.35 (m, 2H), 7.14 (t, J=8.8 Hz, 2H), 6.81 (d, 1H, 7.6 Hz), 5.39 (s, 1H), 5.00 (m, 1H), 1.80 (m, 1H), 1.49 (d, J=6.8 Hz, 3H), 0.90 (m, 2H), 0.62 (m, 2H). MS: Calcd.: 417; Found: [M+H]+ 418.