Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13]OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:25]([SH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([S:32][CH2:13][C@@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: SCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](COS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](CSCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of (3R)-1-(tert-butoxycarbonyl)-3-[(methane-sulfonyloxy)methyl]pyrrolidine (0.5071 g, 1.82 mmol) and anhydrous potassium carbonate (0.3764 g, 2.72 mmol) in DMF (13 ml), under argon, was added benzyl mercaptan (0.428 ml, 3.65 mmol) and the mixture was stirred overnight at room temperature, then at 60° C. for 4 h. The mixture was then partitioned between water (50 ml) and diethyl ether (30 ml). The aqueous layer was separated and reextracted with more diethyl ether (2×30 ml). The combined organic layers were dried (MgSO4) and evaporated in uacuo. The residue was purified by flash chromatography (silica gel, 20% EtOAc/pet. ether) to give 0.5186 (93%) of the title compound as a colourless oil. δH (360 MHz, CDCl3) 1.45 (9H, s), 1.56 (1H, m), 1.99 (1H, m), 2.32 (1H, m), 2.45 (2H, t, J=6.4 Hz), 2.97 (1H, m), 3.26 (1H, m), 3.61 (2H, m), 3.72 (2H, s), 7.22-7.40 (5H, m). m/e (ES+) 330 (M+Na)+, 308 (M+H)+, 252 (M-CMe3 +2H)+, 234, 213, 208 (M-Boc+2H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])O.[Na+].Cl.[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26]Cl>C(O)(C)C>[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26][N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CN(C)CCCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 80 °C

Procedure:
Prepared according to a slightly modified procedure from U.S. Pat. No. 3,331,845. A mixture of 4-nitrophenylpiperazine (2.1 g, 10 mmol), sodium hydrogen carbonate (2.5 g, 30 mmol), N,N-dimethyl-N-(3-chloropropyl)amine hydrochloride (1.9 g, 12 mmol) in isopropanol (80 mL) was heated at 80° C. for 18 h. The mixture was then allowed to cool, the solid filtered off and the solvent removed under reduced pressure. Ethyl acetate (ca. 200 mL) was added and the residue was washed with saturated brine twice (50 mL each time). The organic layer was dried over sodium sulphate and the solvent evaporated under reduced pressure. The crude compound was purified by column, eluting with dichloromethane/methanol 9/1 (containing 1% N,N-dimethylethylamine) to give the title compound as a yellow solid. 1H NMR (CDCl3, 400 MHz): 1.6 (2H, m); 2.15 (6H, s); 2.25 (2H, m); 2.35 (2H, m); 2.5-2.55 (4H, m); 3.35-3.4 (4H, m); 6.75 (2H, d, J 8 Hz); 8.05 (2H, d, J 8 Hz) MS: 293, 248.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:8]1[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=1>O>[N:1]1([C:8]2[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1csc(Br)n1
Solvent: O
Product: CCOC(=O)c1csc(N2CCOCC2)n1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of morpholine (1.5 mL) and ethyl 2-bromo-1,3-thiazole-4-carboxylate (200 mg) was stirred overnight at 50° C. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (193 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][OH:7].[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1F.O>CN(C=O)C>[Cl:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[O:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1
Reactant: OCc1nccs1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2nccs2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
2-(2-Chloro-4-nitro-phenoxymethyl) thiazole is prepared by adding thiazol-2-yl-methanol (2.74 g, 23.76 mmol) to a slurry of sodium hydride (1.21 g of a 60% dispersion in oil, 30.2 mmol) in DMF (10 ml) at 0° C. After several minutes, 2-chloro-1-fluoro-4-nitro-benzene (3.79 g, 21.60 mmol) is added and the reaction mixture warmed to room temperature. The reaction mixture is stirred at room temperature for 3 h, and 60° C. for 16 h. After cooling to room temperature, the reaction mixture is poured into 200 ml water. The resulting precipitate is collected by filtration, washed with water, and dried in vacuo to give 2-(2-chloro-4-nitro-phenoxymethyl)-thiazole (5.80 g, 99%) which is used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CC(=O)CC>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]#[N:15])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(OCC#N)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 97.2 %

Procedure:
4-Methyl-3-nitrophenol (5.0 g) (TCl America, Portland, Oreg.) and 4.70 g of bromoacetonitrile were dissolved in 30 ml of 2-butanone; then 13.5 g of potassium carbonate was added and the mixture was stirred and heated at 70° C. for 2 hours. The reaction mixture was cooled to room temperature, poured into ethyl acetate, washed with water, dried, and evaporated to give 6.1 g of (4-methyl-3-nitrophenoxy)-acetonitrile as a brown oil. ##STR74##
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)(Cl)Cl>[C:17]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:11]3[CH2:12][N:13]([S:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:37])=[O:36])[CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C1OC(c2ccccc2)(c2ccccc2)C2CN(S(=O)(=O)c3ccccc3)CCN12
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.6 %

Procedure:
To a solution of hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (50 mg, 0.17 mmol) in chloroform (2 mL) were sequentially added pyridine (0.5 mL) and benzenesulfonyl chloride (43 mg, 0.24 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1) and crystallized from diisopropyl ether to obtain the title compound (27 mg, yield 37%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[CH2:10]([O:12][C:13]([C:15]1([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:23](=[O:35])[C:22]3=[O:36])[CH2:18][CH2:17][CH2:16]1)=[O:14])[CH3:11]>O1CCCC1>[C:31]([O:30][C:28]([NH:24][C:25]1[CH:26]=[CH:27][C:19]([C:15]2([C:13]([O:12][CH2:10][CH3:11])=[O:14])[CH2:16][CH2:17][CH2:18]2)=[CH:20][C:21]=1[C:22](=[O:36])[C:23]([N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)=[O:35])=[O:29])([CH3:33])([CH3:32])[CH3:34]
Reactant: CCOC(=O)C1(c2ccc3c(c2)C(=O)C(=O)N3C(=O)OC(C)(C)C)CCC1
Reactant: c1ccc2c(c1)CNC2
Solvent: C1CCOC1
Product: CCOC(=O)C1(c2ccc(NC(=O)OC(C)(C)C)c(C(=O)C(=O)N3Cc4ccccc4C3)c2)CCC1
Temperature: 23 °C
Reaction time: 1 h
Yield: 27.7 %

Procedure:
1.049 g of isoindoline are added to 3.3 g of 5-(1-ethoxycarbonylcyclobutyl)-1-tert-butoxycarbonyl-2,3-dioxoindoline in 50 ml of tetrahydrofuran, and the mixture is subsequently stirred at 23° C. for 1 h. The mixture is evaporated to dryness in vacuo and purified by column chromatography, giving 1.2 g (28%) of ethyl 1-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]cyclobutanecarboxylate; LC-MS retention time: 2.75 min (“nonpolar” gradient).
Reaction SMILES: FC(C1NC(=O)C2N=CC=CC=2N=1)(F)F.O=P(Cl)(Cl)[Cl:18].[F:21][C:22]([F:35])([F:34])[C:23]1[CH:24]=[CH:25][C:26]2[N:27]=[CH:28][NH:29][C:30](=O)[C:31]=2[N:32]=1>>[Cl:18][C:30]1[C:31]2[N:32]=[C:23]([C:22]([F:35])([F:34])[F:21])[CH:24]=[CH:25][C:26]=2[N:27]=[CH:28][N:29]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2ccc(C(F)(F)F)nc12
Agent: O=c1[nH]c(C(F)(F)F)nc2cccnc12
Product: FC(F)(F)c1ccc2ncnc(Cl)c2n1
Temperature: 25 °C

Procedure:
The title compound was prepared from trifluoromethyl-3H-pyrido[3,2-d]pyrimidin-4-one using the procedure described in Example 599, Step 2. A POCl3 (9.3 ml) suspension of 6-Trifluoromethyl-3H-pyrido[3,2-d]pyrimidin-4-one (1.0 g, 4.7 mmol) was heated at reflux for 4 hours, over which time the amber suspension became a clear, deep blue solution. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue concentrated from dichloromethane 3× to remove residual POCl3. The residue was partitioned between 1:1 EtOAc and saturated sodium bicarbonate (28 ml). The mixture was stirred until visible gas evolution ceased. The suspension was filtered through a plug of celite. The layers of the filtrate were separated, and the organic phase was washed successively with saturated sodium bicarbonate and saturated sodium chloride, dried with magnesium sulfate and concentrated under reduced pressure to yield the semi-pure product as a purple solid. No further purification was carried out. The crude product was greater than 90% pure (as determined by analytical HPLC). MS: ES+234.11 (M+H, 100%
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][NH:26][N:25]=2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:26]2[CH:27]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:24]([C:21]3[CH:20]=[CH:19][C:18]([F:17])=[CH:23][CH:22]=3)=[N:25]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)c1c[nH]nc1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.8 %

Procedure:
A mixture of 4-benzyloxybenzyl chloride (11.60 g), ethyl 3-(4-fluorophenyl)-1H-pyrazole-4-carboxylate (11.70 g), potassium carbonate (13.80 g) and N,N-dimethylformamide (150 ml) was stirred at room temperature for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain ethyl 1-(4-benzyloxybenzyl)-3-(4-fluorophenyl)-1H-pyrazole-4-carboxylate (16.90 g, yield: 79%). This was recrystallized from ethyl acetate-hexane. Melting point: 103–104° C.
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9](=[O:23])[CH:10]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[F:22])[O:11][CH2:12][CH3:13])=[CH:5][CH:4]=1)#[N:2].Br[CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:23])[CH:10]([O:11][CH2:12][CH3:13])[C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([O:21][CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[C:15]=2[F:22])=[CH:24][CH:25]=1)#[N:2]
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(O)c1F
Reactant: CCC(Br)CC
Solvent: CN(C)C=O
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(OC(CC)CC)c1F
Temperature: 80 °C
Yield: 79 %

Procedure:
To a solution under Ar of (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-3-hydroxy-phenyl)-2-ethoxy-acetamide (200 mg) in DMF (10 ml) was added CSCO3 (226 mg) and 3-bromopentane (105 mg). The solution was stirred over night at 80° C. The solvent was evaporated and the residue was taken up in H2O (50 ml). The product was extracted with AcOEt (2×100 ml). The organic layers were washed with H2O (2×50 ml) and dried (NaaSO4) and the solvent was evaporated. CC (AcOEt/Hept 2:3 to AcOEt) afforded 190 mg (79%) of (RS)-N-(4-cyano-benzyl)-2-ethoxy-2-[3-(1-ethyl-propoxy)-2,6-difluoro-phenyl]-acetamide. This material was converted to (RS)-N-(4-carbamimidoyl-benzyl)-2-ethoxy-2-[3-(1-ethyl-propoxy)-2,6-difluoro-phenyl]-acetamide acetate by the sequence of procedures G and H. Off-white solid. MS 434.4 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([CH2:16][CH2:17][CH3:18])[CH:8]=2)=[CH:4][CH:3]=1.[Br:21]Br>O1CCOCC1.C(OCC)(=O)C>[Br:21][CH2:14][C:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][C:9]=1[CH2:16][CH2:17][CH3:18])=[O:15]
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1C(C)=O
Reactant: BrBr
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1C(=O)CBr
Reaction time: 2 h

Procedure:
To a solution of the product from Step 7 (1.2 g, 4.2 mmol) in dioxane (20 mL) at room temperature was added dropwise bromine (0.25 mL, 5.0 mmol). After 2 h at room temperature, the reaction mixture was diluted with ethyl acetate, washed with an aqueous solution of sodium thiosulfate and dried over magnesium sulfate. Removal of the solvent gave a residue which was purified by chromatography on silica gel to give the title product.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:17]([NH:19][CH3:20])=[O:18].CCN(C(C)C)C(C)C>C1COCC1>[Cl:10][C:6]1[N:5]=[C:4]([S:11][CH3:12])[N:3]=[C:2]([NH:13][C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:17]([NH:19][CH3:20])=[O:18])[C:7]=1[C:8]#[N:9]
Reactant: CSc1nc(Cl)c(C#N)c(Cl)n1
Reactant: CNC(=O)c1ccc(C)c(N)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(C)c(Nc2nc(SC)nc(Cl)c2C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbonitrile (2.19 g, 10 mmol), 3-amino-4,N-dimethyl-benzamide (1.64 g, 10 mmol), and DIEA (1.40 g, 18.8 mmol) were mixed in THF (20 mL). The resulting mixture was stirred at room temperature for overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was concentrated and the crude product was purified by flash chromatography to obtain 3-(6-chloro-5-cyano-2-methylsulfanyl-pyrimidin-4-ylamino)-4,N-dimethyl-benzamide (2.78 g, 80%). MS (m/z): 348 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[C:7]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:6][C:5]=1[NH2:21])([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH:30](OC)(OC)OC.CN(C=O)C>C(O)(=O)C>[N:15]1([C:7]2[C:8]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:9][C:4]3[NH:1][CH:30]=[N:21][C:5]=3[CH:6]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(OC)OC
Reactant: Nc1cc(N2CCCCC2)c(OC(F)(F)F)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1cc2[nH]cnc2cc1N1CCCCC1
Temperature: 100 °C
Yield: 70.2 %

Procedure:
A mixture of 2-nitro-5-piperidin-1-yl-4-trifluoromethoxy-phenylamine (0.900 g, 2.94 mmol), sodium dithionite (2.67 g, 15.3 mmol), trimethyl orthoformate (8.72 mL, 79.6 mmol), DMF (8.56 mL), and acetic acid (1.45 mL) was heated in a sealed tube for 15 h at 100° C. The reaction mixture was cooled to 23° C. and partitioned between EtOAc (80 mL) and saturated aqueous NaHCO3 (80 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (2×80 mL). The combined organic layers were dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (0-15% MeOH/DCM) to yield the titled compound (0.589 g, 71%). MS (ESI/CI): mass calcd. for C13H14F3N3O, 285.1; m/z found, 286.1 [M+H]+.
Reaction SMILES: Cl.[C-:2]1([C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][Br:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3]1.[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26]>C1(C)C=CC=CC=1>[C-:2]1([CH2:7][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][Br:20])[CH:6]=[CH:5][CH:4]=[CH:3]1.[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26]
Reactant: O=C(CCCCCCCCCCCBr)[c-]1cccc1
Agent: [Fe+2]
Agent: Cl
Agent: c1cc[cH-]c1
Solvent: Cc1ccccc1
Product: BrCCCCCCCCCCCC[c-]1cccc1
Temperature: 25 °C
Yield: 89.6 %

Procedure:
Following a general procedure for preparing 24 (Creager et al. (1994) J. Electroanal. Chem., 370: 203-211), to a freshly prepared zinc/mercury amalgam (6.7 g granulated Zn, 0.4 g HgCl2) in a 100 mL flask was added 10 M HCl (40 mL) with stirring. A solution of 22 (3.0 g, 6.7 mmol) in toluene (40 mL) was added in one portion. The resulting two-phase mixture was heated to reflux and stirred vigorously. After 16 h under reflux, during which two 5 mL portions of 10 M HCl were added, the reaction flask was cooled to rt. The phases were separated, and the organic layer was washed with water (3×100 mL) and dried (MgSO4). The solvent was evaporated in vacuo and the residue was purified by column chromatography (silica, petroleum ether/diethyl ether, 10:1) to afford a brown oil (2.6 g, 90%) that solidified upon standing in the freezer: mp 40-42° C.; 1H NMR δ 1.29 (s, 16H), 1.47 (m, 2H), 1.86 (m, 2H), 2.32 (m, 2H), 3.42 (m, 2H), 4.05 (s, 2H), 4.06 (s, 2H), 4.10 (s, 5H); 13C NMR δ 28.2, 28.8, 29.5, 29.6, 31.1, 32.9, 34.0, 67.0, 68.1, 68.5, 89.6; FAB-MS obsd 432.1114, calcd exact mass 432.1115 (C22H33BrFe).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][NH:11]1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]2[CH3:9])[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC1CCCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC1CCCCN1c1cncc(Cl)n1
Temperature: 80 °C
Reaction time: 22 h
Yield: 87 %

Procedure:
A mixture of 2,6-dichloropyrazine (1.49 g), 2-methylpiperidine (1.76 mL), potassium carbonate (2.07 g) and DMA (10 mL) was stirred at 80° C. for 22 hr. Water (10 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 5→20% ethyl acetate/hexane) to give the title compound (1.85 g, 87%) as a pale-yellow oil.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccccc1
Reactant: CCCCOC(=O)N1CCC(C(=O)O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCC(C(=O)OCc2ccccc2)CC1
Temperature: 60 °C

Procedure:
N-Butoxycarbonyl-4-piperidinecarboxylic acid (4.6 g) was dissolved in dimethylformamide (20 ml) and placed under an atmosphere of nitrogen. Benzyl bromide (2.9 ml) and potassium carbonate (8.3 g) were added and heated at 60° C. for 3 h. The dimethylformamide was removed in vacuo and azeotroped with toluene (three times). The residue was dispersed between ethyl acetate and water and the aqueous phase was extracted with ethyl acetate (3×100 ml). The combined organic phases were washed with brine and dried (MgSO4). The solution was filtered, evaporated to dryness and the residue was purified by chromatography on silica gel (eluting with isohexane containing increasing concentrations amounts of ethyl acetate 5-30%) to give benzyl N-butoxycarbonylpiperidine-4-carboxylate as a clear oil (7.68 g).
Reaction SMILES: [CH2:1]([N:10]1[C:15](=[O:16])[C:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:13]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:12]=[N:11]1)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.Cl.[O:35]([NH2:37])[CH3:36].C([O-])(=O)C.[Na+]>CO>[CH3:36][O:35][N:37]=[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:1][N:10]1[C:15](=[O:16])[C:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:13]([C:24]2[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=2)[CH:12]=[N:11]1
Reactant: CON
Reactant: CS(=O)(=O)c1ccc(-c2cnn(CC(=O)c3ccccc3)c(=O)c2-c2ccc(F)cc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CON=C(Cn1ncc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)c1=O)c1ccccc1

Procedure:
A mixture of the product from Example 46, 2-phenacyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (220 mg, 0.476 mmol), methoxylamine hydrochloride (318 mg, 3.8 mmol), and sodium acetate (518 mg, 3.8 mmol) in methanol (100 mL) was stirred at reflux for 48 hours. The reaction mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with brine then dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to provide a brown oil which was purified by column chromatography (silica gel, 70:30 hexanes/ethyl acetate). Fractions containing product were combined and concentrated in vacuo. The residue was crystallized from methanol/water to provide the title compound as a mixture of E and Z oximes (yield: 82 mg, 35%). mp 95-99° C. 1H NMR (300 MHz, CDCl3) δ 3.03 (s, 3H), 4.07 (s, 3H), 5.57 (s, 2H), 6.94 (t, J=9 Hz, 2H), 7.07 (dd, J=9 Hz, 3 Hz, 2H), 7.24 (d, J=9 Hz, 2H), 7.31-7.37 (m, 3H), 7.60-7.67 (m, 2H), 7.74 (s, 1H), 7.83 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 492 (M+H)+. Anal. calc. for C26H22FN3O4S: C, 63.53; H, 4.51; N, 8.54. Found: C, 63.40; H, 4.51; N, 8.31.