Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:19][C:20]2[CH:25]=[N:24][C:23]([CH2:26][OH:27])=[CH:22][N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C1C([N+]([O-])=O)=CC=C([Cl-][C:39]([O-:41])=O)C=1.C([N:44](CC)CC)C.N>C1COCC1.CN(C=O)C.C(O)CC.CC#N.O>[C:39](=[O:41])([O:27][CH2:26][C:23]1[CH:22]=[N:21][C:20]([CH2:19][N:4]2[C:5]([CH3:18])=[CH:6][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[C:2]([Br:1])[C:3]2=[O:28])=[CH:25][N:24]=1)[NH2:44]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cnc(CO)cn1
Reactant: CCN(CC)CC
Agent: N
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cnc(COC(N)=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
To a suspension of 3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-{[5-(hydroxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(1H)-one (0.21 g, 0.00055 mol) in THF (5.0 mL) and DMF (2.0 mL), was added 4-nitrophenylchloroformate (0.1 g, 0.0005 mol) and cooled to 0° C. triethylamine (0.052 g, 0.0005 mol) was then added, stirred at room temperature for 1 h, and at 65° C. for an additional 1 h. It was cooled in an ice bath and added 2M ammonia in propanol (1.0 mL) and stirred at room temperature for 2 h. After the removal of the solvents under reduced pressure, the residue was partitioned between 5% sod. bicarbonate, and EtOAc (25 mL). The organic phase was washed with 5% sod. bicarbonate, (3×25 mL), water (3×25 mL), dried (Na2SO4) and concentrated under reduced pressure. The resulting substance was purified by isolated by reverse-phase HPLC using 10-90% CH3CN/Water (30 min gradient) at a flow rate of 100 mL/min. The appropriate fractions (m/z=495 M+H) were combined and freeze-dried, and the residue was partitioned between 5% sod. bicarbonate (20 mL) and EtOAc (25 mL). The organic phase was washed with water, dried (Na2SO4) and concentrated to dryness under reduced pressure, to afford the title compound as a white powder (0.065 g):
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:2].[CH2:9](O)[CH3:10]>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH3:10])[CH3:2]
Reactant: CCc1ccccc1
Reactant: CCO
Product: CCc1ccccc1CC

Procedure:
Argon gas is then flowed over the coked zeolite catalyst, and a reaction mixture of ethylbenzene and ethanol is injected into the reaction chamber to produce diethylbenzene, which is then removed from within the reaction chamber. The reaction temperature is preferably between approximately 250° C. and approximately 400° C. at a gas pressure between approximately 1.0 atmospheres and approximately 5.0 atmospheres. The ethylbenzene and ethanol are preferably provided in a molar ratio of between 1 to 1 and 1 to 6.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([S:18][CH3:19])[N:13]=3)=[CH:10][NH:9][N:8]=2)=[CH:4][CH:3]=1.I[CH:21]([CH3:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([S:18][CH3:19])[N:13]=3)=[CH:10][N:9]([CH:21]([CH3:23])[CH3:22])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CSc1nccc(-c2c[nH]nc2-c2ccc(Cl)s2)n1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CSc1nccc(-c2cn(C(C)C)nc2-c2ccc(Cl)s2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.9 %

Procedure:
To a solution of 4-[3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]-2-(methylsulfanyl)pyrimidin (1 eq, 16.2 mmol) in 120 mL N,N-dimethylformamide were added 2-iodopropane (1.5 eq, 24.3 mmol) and cesium carbonate (1.1 eq, 17.8 mmol). The reaction mixture was stirred at room temperature for 4 h and the solvent was then evaporated. The residue was diluted with water and dichloromethane. The layers were separated and the aqueous layer was extracted three times with dichloromethane. The combined organic extracts were dried over MgSO4 filtered and concentrated. The residue was purified by chromatography on silica gel (dichloromethane) to afford 4.2 g of 4-[3-(5-chloro-2-thienyl)-1-isopropyl-1H-pyrazol-4-yl]-2-(methylsulfanyl)pyrimidin (70% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[CH:5][C:4]=1[S:11]([NH:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[C:17]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:16]=1[CH3:29])(=[O:13])=[O:12].[H-].[Na+].Cl.[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36]Cl.[O-][Si]([O-])=O.[Mg+2]>CN(C=O)C>[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36][N:14]([C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[C:17]([N:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[C:16]=1[CH3:29])[S:11]([C:4]1[CH:5]=[C:6]([CH3:10])[CH:7]=[C:8]([CH3:9])[C:3]=1[O:2][CH3:1])(=[O:12])=[O:13]
Reactant: CN(C)CCCl
Reactant: COc1c(C)cc(C)cc1S(=O)(=O)Nc1c(C)cc(C)c(N2CCCCC2)c1C
Agent: Cl
Agent: O=[Si]([O-])[O-]
Agent: [H-]
Solvent: CN(C)C=O
Product: COc1c(C)cc(C)cc1S(=O)(=O)N(CCN(C)C)c1c(C)cc(C)c(N2CCCCC2)c1C
Temperature: 85 °C
Yield: 65.6 %

Procedure:
To a solution of 32 (103 mg, 0.25 mmol) in anhydrous DMF (5 mL) was added NaH (60% dispersion in mineral oil, 22 mg, 0.54 mmol). The mixture was stirred for 10 min at room temperature before the addition of 2-(dimethylamino)-ethyl chloride hydrochloride (39.2 mg, 0.27 mmol). The resulting mixture was heated overnight at 85° C. After a usual workup, the residue was loaded onto column (Florisil) and the column eluted with EtOAc/CH3OH (10:1) to give 80 mg of the title compound as an off-white solid. ESI [M+H+]=488.27.
Reaction SMILES: [F:1][CH2:2][CH:3]([O:6][C:7]1[CH:8]=[C:9]([CH:19]=[C:20]([OH:22])[CH:21]=1)[C:10]([NH:12][C:13]1[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=1)=[O:11])[CH2:4][F:5].CC([Si](C)(C)[O:28][CH2:29][CH2:30][N:31]([CH3:43])[C:32](=[O:42])[C:33]1[CH:38]=[CH:37][C:36](F)=[C:35]([F:40])[C:34]=1F)(C)C.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[F:5][CH2:4][CH:3]([O:6][C:7]1[CH:8]=[C:9]([CH:19]=[C:20]([O:22][C:36]2[CH:37]=[CH:38][C:33]3[C:32](=[O:42])[N:31]([CH3:43])[CH2:30][CH2:29][O:28][C:34]=3[C:35]=2[F:40])[CH:21]=1)[C:10]([NH:12][C:13]1[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=1)=[O:11])[CH2:2][F:1]
Reactant: Cn1ccc(NC(=O)c2cc(O)cc(OC(CF)CF)c2)n1
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1ccc(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN1CCOc2c(ccc(Oc3cc(OC(CF)CF)cc(C(=O)Nc4ccn(C)n4)c3)c2F)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.1 %

Procedure:
A solution of 3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (100 mg, 0.32 mmol), N-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-2,3,4-trifluoro-N-methylbenzamide (112 mg, 0.32 mmol) and potassium carbonate (89 mg, 0.64 mmol) in DMA (2 mL) was heated in a microwave reactor for 2 hours. Water (20 mL) was added and the solution extracted with ethyl acetate. The ethyl acetate layer was washed with brine (20 mL), dried (MgSO4) and evaporated to a residue which was taken up in DCM (10 mL) and TFA (5 drops) added. The mixture was stirred at RT for 2 hours. The solvent was evaporated to a residue, which was chromatographed by preparative HPLC on C18 reversed phase, eluting with 5-95% acetonitrile (+0.2% TFA) in water (+0.2% TFA), to give the required product (5 mg).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.Br[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O>CN(C)C=O>[Br:3][C:4]1[C:9]([O:10][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: BrC1CCCCC1
Reactant: Oc1cccnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ncccc1OC1CCCCC1
Yield: 30 %

Procedure:
Sodium hydride (160 mg) was dissolved in dimethylformamide (5 ml) and 2-bromo-3-pyridinol (500 mg) dissolved in dimethylformamide is slowly added dropwise. Then, bromocyclohexane (0.7 ml) was added to the solution and reacted for 5 hours at room temperature. Water was added to the suspension to dilute and extracted with ethyl acetate to separate an organic layer. The separated organic layer was dried with anhydrous magnesium sulfate and distilled under reduced pressure. As a result, 2-bromo-3-cyclohexyloxy pyridine (220 mg, yield: 30%) was obtained as an oil phase.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[OH:11])[C:7](=[O:12])[O:6][CH2:5]2.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:13]([O-:15])=[O:14])[C:10]=1[OH:11])[C:7](=[O:12])[O:6][CH2:5]2
Reactant: O=C1OCc2cc(O)c(O)cc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1OCc2cc(O)c(O)c([N+](=O)[O-])c21
Temperature: 25 °C

Procedure:
To a solution of 5,6-dihydroxy-3H-isobenzofuran-1-one (0.4 g) in sulfuric acid at −30° C. was added 5 M nitric acid in sulfuric acid (0.55 ml). The reaction mixture was let to warm up to room temperature and then poured into ice water. The product was filtered and recrystallized from acetic acid.
Reaction SMILES: [CH:1](OCC)=[O:2].[CH3:6][C:7]([CH3:23])([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1)[C:8](=[O:10])[CH3:9].C[O-].[Na+]>C(OCC)C>[CH3:6][C:7]([CH3:23])([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:19]([F:21])([F:22])[F:20])=[CH:14][CH:13]=1)[C:8](=[O:10])[CH:9]=[CH:1][OH:2]
Reactant: CC(=O)C(C)(C)Cc1ccc(SC(F)(F)F)cc1
Reactant: CCOC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(Cc1ccc(SC(F)(F)F)cc1)C(=O)C=CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.4 %

Procedure:
34.7 g (0.469 mole) of ethyl formate are added dropwise with stirring to 129.4 g (0.469 mole) of 3,3-dimethyl-4-(4-trifluoromethylthiophenyl)-butan-2-one and 25.3 g (0.469 mole) of sodium methylate in 1 liter of diethyl ether at room temperature, and the mixture is stirred at room temperature for 4 hours after the addition is complete. For work-up, the mixture is extracted with 1 liter of water, and the combined aqueous extracts are washed once with diethyl ether, acidified to pH 1-2 with dilute aqueous hydrochloric acid and extracted with dichloromethane. The dichloromethane phase is dried over sodium sulphate and concentrated in vacuo. 90.5 g of 4,4-dimethyl-5-(4-trifluoromethylthiophenyl)-penten-1-ol-3-one are obtained; these are dissolved in 200 ml of methanol and 17.0 g (0.315 mol) of sodium methylate are added. Concentrating the solution in vacuo gives 97.1 g (75% of theory) of the sodium salt of 4,4-dimethyl-5-(4-trifluoromethylthiophenyl)-1 -penten-1-ol-3-one as a resin, which is further reacted without purification. ##STR875##
Reaction SMILES: [CH2:1]([CH:3]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([CH2:19][CH3:20])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:8][CH:7]=1)[CH3:2].[N+:25]([O-])([OH:27])=[O:26].O>C(Cl)(Cl)Cl>[CH2:19]([CH:14]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13][O:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:11][C:10]=1[N+:25]([O-:27])=[O:26])[CH3:20]
Reactant: O=[N+]([O-])O
Reactant: CCCCC(CC)COc1ccc(OCC(CC)CCCC)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCC(CC)COc1ccc(OCC(CC)CCCC)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
1,4-Bis(2-ethylhexyloxy)benzene (50.2 g, 0.150 mol) is dissolved in chloroform (150 ml) and cooled to 0° C. Nitric acid (70%, 17.0 g, 0.190 mol) is added dropwise at 0-3° C. and the reaction stirred whilst monitoring progress by HPLC. After 60 minutes, water (50 ml) is added and the organic layer separated, dried (MgSO4) and evaporated to give the title compound as a yellow oil (56.9 g, 100%). The material is used without further purification.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:8][C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.OO>>[CH:1]1([NH:7][S:8][C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: Sc1nc2ccccc2s1
Agent: OO
Product: c1ccc2sc(SNC3CCCCC3)nc2c1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
Example 1 of DE-A-31 27 193 was reworked: in a 250 ml glass reactor, 59.9 g of 50% strength aqueous cyclohexylamine and 0.1 mol of 2-mercaptobenzothiazole were heated to 85° C. with vigorous stirring, with the resulting cyclohexylamine salt of 2-mercaptobenzothiazole going largely into solution. After the mixture had been cooled to 45° C., 92 g of 5% strength hydrogen peroxide (0.135 mol) were metered in over the course of 60 min with vigorous stirring. Stirring was continued for 30 min at the same temperature, and then the reaction mixture was cooled to room temperature, and the precipitate was filtered off, washed with 10% strength cyclohexylamine solution and water, and dried. Cyclohexylbenzothiazolylsulphenamide was obtained in a yield of 75.6% of theory (melting point 99°-100° C.; purity (Lichty titration) 97.6%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:18])[C:6]([F:17])([F:16])[CH2:7][C:8]1[N:9]=[C:10]([N+:13]([O-:15])=[O:14])[NH:11][CH:12]=1.N1C=CC=CC=1.Cl[C:26]([O:28][CH3:29])=[O:27]>C(Cl)(Cl)Cl>[N+:13]([C:10]1[NH:11][CH:12]=[C:8]([CH2:7][C:6]([F:17])([F:16])[C:5]([NH:4][CH2:3][CH2:2][O:1][C:26]([O:28][CH3:29])=[O:27])=[O:18])[N:9]=1)([O-:15])=[O:14]
Reactant: COC(=O)Cl
Reactant: O=C(NCCO)C(F)(F)Cc1c[nH]c([N+](=O)[O-])n1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)OCCNC(=O)C(F)(F)Cc1c[nH]c([N+](=O)[O-])n1

Procedure:
3-(2'-Nitroimidazolyl)-2,2-difluoropropionic acid hydroxyethylamide (6.0 g, 22.7 mmol) was dissolved in a solvent mixture of methyl chloroformate (30 ml) and chloroform (30 ml) and cooled by ice. To the solution, a solution of pyridine (6.0 ml) in chloroform (30 ml) was dropwise added over 2 hours. The completion of the reaction was confirmed by thin-layer chromatography. Then, the reaction solution was washed with dilute hydrochloric acid and water, dried over magnesium sulfate, concentrated and subjected to silica gel column chromatography to obtain methyl 3-(2'-nitroimidazolyl)-2,2-difluoropropionamidoethoxyformate (6.89 g). m.p. 50.5°-52.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O.C(Cl)Cl>C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Reactant: Br[Mg]c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccccc1
Solvent: ClCCl
Product: COc1ccc(-c2cc(-c3ccccc3)nnc2-c2ccc(OC)cc2)cc1
Temperature: 60 °C
Reaction time: 1.25 h
Yield: 36.9 %

Procedure:
3,4-Bis(4-methoxyphenyl)-6-chloropyridazine [Eur. J. Med. Chem.-Chimica Therapeutica, 14, 53-60 (1979)] (309.3 mg, 0.95 mmol) was dissolved in benzene (2 ml). Tetrakis(triphenylphosphine)palladium [Pd(Ph3P)4] (90.6 mg, 0.08 mmol) and phenylmagnesium bromide (1.0 M tetrahydrofuran solution) (1.5 ml) were then added successively, followed by stirring at 60° C. for 75 minutes. After water-methylene chloride was added to the reaction mixture, the mixture was extracted with methylene chloride and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was then separated and purified by chromatography on a silica gel column [silica gel (40 g), hexane/ethyl acetate (2/1)], whereby the title compound was obtained as a pale yellow amorphous solid (129 mg, 36.9%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:3]=1.[CH3:19][C:20]1[N:25]=[C:24]([CH2:26][OH:27])[CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[C:5]([C:11]#[N:12])=[C:6]([O:27][CH2:26][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:19])[N:25]=2)[N:7]=1
Reactant: Cc1ccc(-c2nc(N)nc(S(C)=O)c2C#N)o1
Reactant: Cc1cccc(CO)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1cccc(COc2nc(N)nc(-c3ccc(C)o3)c2C#N)n1

Procedure:
From 2-amino-4-methanesulfinyl-6-(5-methyl-furan-2-yl)-pyrimidine-5-carbonitrile, 6-methyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 322 (M+H+, 100).
Reaction SMILES: [C:1]1([CH2:7][O:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:22][N:9]([O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NOCc1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN(OCc1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.9 %

Procedure:
A mixture of 110.6 g of the product of Example 32, 49.8 g of anhydrous potassium carbonate, 55.8 g of methyliodide and 500 ml of acetone was stirred at ambient temperature for 20 hours. The solvent was evaporated and the residue partitioned between methylene chloride and water. Concentration of the organic extract afforded 88.9 g of N-methyl-N-(phenylmethoxy)-2-nitrobenzenesulfonamide as a yellow oil. [NMR: δ 2.8 (s, 3H, NCH3)].
Reaction SMILES: CC1C=CC=CC=1S(Cl)(=O)=O.[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([N:22]1[C:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:25][C:24]([C:33](OCC)=[O:34])=[CH:23]1)(=[O:21])=[O:20]>>[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([N:22]1[C:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:25][C:24]([CH:33]=[O:34])=[CH:23]1)(=[O:21])=[O:20]
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2ccccc2C)c1
Agent: Cc1ccccc1S(=O)(=O)Cl
Product: Cc1ccccc1S(=O)(=O)n1cc(C=O)cc1-c1ccccc1

Procedure:
Using 2-methylbenzenesulfonyl chloride instead of tosyl chloride, a procedure as in Reference Example 4 was performed to synthesize ethyl 1-[(2-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate, and procedures as in Reference Examples 5 and 6 were sequentially performed to give the title compound as a colorless oil.
Reaction SMILES: BrC1C=CC(OC)=C(C)C=1.Br[C:12]1[C:17]([F:18])=[CH:16][C:15]([O:19][CH3:20])=[C:14]([F:21])[CH:13]=1.[C:22]1([CH2:28][CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[F:18][C:17]1[CH:16]=[C:15]([O:19][CH3:20])[C:14]([F:21])=[CH:13][C:12]=1[N:34]1[CH2:35][CH2:36][CH:31]([CH2:30][CH2:29][CH2:28][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:32][CH2:33]1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Reactant: COc1cc(F)c(Br)cc1F
Agent: COc1ccc(Br)cc1C
Product: COc1cc(F)c(N2CCC(CCCc3ccccc3)CC2)cc1F
Yield: 33.7 %

Procedure:
Production Example 9 was repeated except that 5-bromo-2-methoxytoluene and 1-(2-phenethyl)piperazine were replaced with 4-bromo-2,5-difluoroanisole (446 mg) and 4-(3-phenylpropyl)-piperidine (1.220 g), respectively. The resulting crude product was purified on silica gel column chromatography (eluent, hexane: ethyl acetate=8:1) to provide 1-(2,5-difluoro-4-methoxyphenyl)-4-(3-phenylpropyl)piperidine (233 mg).
Reaction SMILES: [CH:1]([O:4][C:5]1[NH:9][N:8]=[C:7]([NH2:10])[CH:6]=1)(C)[CH3:2].NC1C=C(O)NN=1>>[CH2:1]([O:4][C:5]1[NH:9][N:8]=[C:7]([NH2:10])[CH:6]=1)[CH3:2]
Reactant: CC(C)Oc1cc(N)n[nH]1
Agent: Nc1cc(O)[nH]n1
Product: CCOc1cc(N)n[nH]1

Procedure:
The title compound was prepared using a procedure similar to the one described for the synthesis of Intermediate 6, using 3-amino-5-hydroxypyrazole as the starting material. (400 MHz, CD3OD) □ ppm 4.85 (br s, 3H), 4.02 (m, 2H), 1.30 (t, J=8 Hz, 3H)
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:22])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][N:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.[H-].[Na+].CS(O[CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1)(=O)=O.N>CN(C=O)C>[CH:1]1([NH:4][C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)[N:17]=[CH:16]4)[CH:7]=2)=[O:22])[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2[nH]ncc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2C2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 18 h
Yield: 4.4 %

Procedure:
A solution of N-cyclopropyl-3-(1H-indazol-5-yl)-4-methylbenzamide (Example 17) (0.07 g) in dry DMF (3 ml) was treated with sodium hydride (60% oil dispersion, 0.014 g) under nitrogen. After 5 min 1,1-dimethylethyl 4-[(methylsulfonyl)oxy]-1-piperidinecarboxylate (0.08 g) was added and the mixture was stirred at room temp. for 18 h. 0.88 Ammonia (1 ml) was added and the mixture was concentrated under vacuum. The residue was purified by column chromatography on silica eluting with cyclohexane:ethyl acetate (1:1) followed by reverse phase preparative Hplc to give the title compound (0.005 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:28]3[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=3[O:26][N:25]=2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[ClH:42]>O.C(Cl)(Cl)Cl.CCOCC.C(#N)C>[ClH:42].[F:33][C:31]1[CH:30]=[CH:29][C:28]2[C:24]([C:21]3[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][N:11]4[CH2:10][CH2:9][CH:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)[CH2:13][CH2:12]4)=[CH:23][CH:22]=3)=[N:25][O:26][C:27]=2[CH:32]=1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: Fc1ccc2c(-c3ccc(OCCBr)cc3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: CCOCC
Product: Fc1ccc(C2CCN(CCOc3ccc(-c4noc5cc(F)ccc45)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 48 %

Procedure:
Add 4-(4-fluoro-phenyl)-piperidine (133 mg, 0.744 mol) (See Table No.1, SM 2) to a suspension of 3-[4-(2-bromo-ethoxy)-phenyl]-6-fluoro-benzo[d]isoxazole (250 mg, 0.744 mol) in a mixture of water:acetonitrile (0.1 mL:2.5 mL). Then add potassium carbonate (164 mg, 1.63 mmol) and potassium iodide (12 mg, 1.07 mmol) and heat at reflux for 8 hours. Stir at room temperature for 72 hours, filter the suspension and wash the solid thoroughly with dichloromethane. Dilute the resulting solution with dichloromethane (5 mL) and wash with water (5 mL), 10% HCl (5 mL), water (5 mL), saturated sodium chloride (5 mL), dry (MgSO4), filter and evaporate to give a white solid. Dissolve the solid in a minimum amount of chloroform and add 1.0 M HCl in ether and stir under a nitrogen atmosphere for 1 hour. Collect the solid by vacuum filtration, wash thoroughly with ether and dry to give the title compound (168 mg, 48% Yield). Microanalysis (C, H, N) is consistent with the final, desired compound. mp-235-239° C.
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10](OCC)=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[C:7]([CH:22]=[CH:23][CH2:24][CH2:25][CH3:26])=[C:6]([CH:27]([CH3:29])[CH3:28])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[C:7]([CH:22]=[CH:23][CH2:24][CH2:25][CH3:26])=[C:6]([CH:27]([CH3:28])[CH3:29])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccccc1C

Procedure:
The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. 1H NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): δ 0.70 (t, J=7.5 Hz, 3 H), 1.10-1.40 (m, 15 H), 1.87 (tdd, J=7.5, 7.5, 1.5, 2 H), 1.95 (s, 3 H), 3.30-3.50 (m, 2 H), 4.20 (m, 1 H), 4.45 (m, 1 H), 5.30 (m, 1 H), 5.93 (m, 2 H), 6.90-7.30 (m, 4 H). FAB-MS: calculated for C24H33NO 352; found 352 (M+H, 100%). Rf=0.32 (10% ethyl acetate/n-hexane). mp 76-79° C.