Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6](=[O:23])[CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[C:17]2[C:18]([NH2:22])=[N:19][O:20][N:21]=2)=[CH:4][CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[CH3:26][NH:22][C:18]1[C:17]([C:9]2[N:8]([CH2:7][C:6]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:25][CH:24]=3)=[O:23])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)=[N:21][O:20][N:19]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(Cl)cc1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CNc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 4-[1-(4-chlorophenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine (0.10 g, 0.282 mmol, prepared according to Example 1), potassium carbonate (0.233 g, 1.69 mmol) and dimethylsulfate (0.142 g, 1.12 mmol) in acetone (5 ml) is stirred at room temperature for 16 hours. Filtration of the solids, concentration of the filtrate under reduced pressure and chromatography of the residue on silicagel using hexane-ethyl acetate as eluent gives the title compound as a colorless solid, m.p. 210-214° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.O.[OH-].[Li+]>CO>[CH:15]1([N:9]2[C:10]([C:11]([F:12])([F:13])[F:14])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCOC(=O)c1cnn(C2CCCC2)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnn(C2CCCC2)c1C(F)(F)F
Temperature: 80 °C
Yield: 62.9 %

Procedure:
Cyclopentyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.237 g, 0.858 mmol) was dissolved in methanol (2.0 mL). Water (2.0 mL) and lithium hydroxide (0.027 g, 1.127 mmol) were added and the mixture was heated at 80° C. for 2 hours. After cooling to room temperature, the methanol was removed in vacuo. THF was added to the residue and then removed in vacuo to insure complete removal of the methanol. 6N HCl (0.2 mL) was added to the aqueous residue to pH 2-3 resulting in precipitation of a white solid. The solid was collected by filtration, washed with water and dried under high vacuum at 100° C. to give 1-cyclopentyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (0.134 g, 63%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]2[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:25](O)=[O:26])[CH:19]=3)[NH:14]2)[CH:5]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[CH:28]1([S:31]([NH2:34])(=[O:33])=[O:32])[CH2:30][CH2:29]1>CN(C)C1C=CN=CC=1.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:13]2[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:25]([NH:34][S:31]([CH:28]4[CH2:30][CH2:29]4)(=[O:33])=[O:32])=[O:26])[CH:19]=3)[NH:14]2)[CH:5]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(F)cc(N2CCCC2)c1
Reactant: NS(=O)(=O)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)Cc2cc(C(=O)NS(=O)(=O)C3CC3)ccc2NC1c1cc(F)cc(N2CCCC2)c1
Temperature: 60 °C
Yield: 19.7 %

Procedure:
A mixture of 2-(3-fluoro-5-pyrrolidin-1-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (50 mg, 0.14 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (39 mg, 0.20 mmol), 4-dimethylaminopyridine (24.4 mg, 0.20 mmol), cyclopropanesulfonic acid amide (51 mg, 0.42 mmol) in dichloromethane (3 mL) was heated for 12 hours at 60° C. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded cyclopropanesulfonic acid [2-(3-fluoro-5-pyrrolidin-1-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (13 mg, 20%) as a light yellow solid: LC/MS m/e calcd for C25H30FN3O3S (M+H)+: 472.6, observed: 472.2.
Reaction SMILES: [N+:1]([N:4]=[C:5]1[NH:9][CH2:8][CH2:7][NH:6]1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)=O.[CH:15](=O)[CH2:16][CH3:17]>O>[CH:15]([N:6]1[CH2:7][CH2:8][NH:9][C:5]1=[N:4][N+:1]([O-:3])=[O:2])=[CH:16][CH3:17]
Reactant: O=[N+]([O-])N=C1NCCN1
Reactant: CCC=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC=CN1CCNC1=N[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.5 %

Procedure:
A mixture comprising 4.0 g of 2-nitroiminoimidazolidine, 20 ml of 1,3-dimethyl-2imidazolidine, 7.5 g of phosphorus oxychloride and 2.7 g of propionaldehyde was stirred for 30 minutes at room temperature. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried (with anhydrous MgSO4) and concentrated. The crystals thus precipitated out were sludged with ethyl acetate, filtrated and dried to give 1.7 g of 1-(1-propenyl)-2-nitroiminoimidazolidine.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Br:35][C:36]1[C:37]([F:46])=[C:38]2[C:44]([NH2:45])=[CH:43][NH:42][C:39]2=[N:40][CH:41]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:35][C:36]1[C:37]([F:46])=[C:38]2[C:44]([NH:45][C:10]([C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:12])=[CH:43][NH:42][C:39]2=[N:40][CH:41]=1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C([O-])[O-]
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
trans-2-Phenylcyclopropanecarboxylic acid (705 mg, 4.35 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (1107 mg, 4.35 mmol) and triethylamine (1100 mg, 10.9 mmol) were added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (500 mg, 2.17 mmol) in DCM (100 mL). The reaction was stirred at room temperature for 1 hour, and then 2N aqueous Na2CO3 was added (50 mL). The resulting suspension was filtered and the solid rinsed with DCM and water. After drying, trans-N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylcyclopropanecarboxamide (503 mg, 61.8% yield) was obtained as a solid.
Reaction SMILES: [NH3:1].[O:2]=[C:3]1[CH2:7][C@H:6]([CH2:8][CH2:9][CH3:10])[CH2:5][N:4]1[C@@H:11]([CH2:16][CH3:17])[C:12](OC)=[O:13]>O>[O:2]=[C:3]1[CH2:7][C@H:6]([CH2:8][CH2:9][CH3:10])[CH2:5][N:4]1[C@@H:11]([CH2:16][CH3:17])[C:12]([NH2:1])=[O:13]
Reactant: CCC[C@H]1CC(=O)N([C@@H](CC)C(=O)OC)C1
Reactant: N
Solvent: O
Product: CCC[C@H]1CC(=O)N([C@@H](CC)C(N)=O)C1
Reaction time: 6 h

Procedure:
Ammonia gas was condensed in 2 ml water at 0–5° C. and the temperature of the system was maintained at 0–5° C. 0.68 g of methyl (2S)-2-[2-oxo-(4S)-4-propyl-1-pyrrolidinyl]butanoate obtained such as described above was then added dropwise, maintaining the reaction mixture at 0–5° C. The system was then stirred for 6 hrs, with TLC indicating completion of reaction. After standing overnight at ambient temperature the reaction mixture was concentrated at 40° C. under vacuum and further dried by azyeotropic distillation with toluene to give 150 mg of crude (2S)-2-[2-oxo-(4S)-4-propyl-1-pyrrolidinyl]butanamide.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([CH:19]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:8].[C:21]1(=[O:27])[NH:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.O1CCOCC1>[Cl:20][C:5]1[CH:4]=[CH:3][C:2]([N:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]2=[O:27])=[CH:19][C:6]=1[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:8]
Reactant: O=C1CCCCN1
Reactant: O=C(NCCc1ccccc1Cl)c1cc(Br)ccc1Cl
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(NCCc1ccccc1Cl)c1cc(N2CCCCC2=O)ccc1Cl
Temperature: 25 °C
Yield: 1.2 %

Procedure:
A mixture of 5-bromo-2-chloro-N-[2-(2-chloro-phenyl)-ethyl]-benzamide (200 mg, 0.536 mmol), δ-valerolactam (106 mg, 1.07 mmol), potassium carbonate (156 mg, 1.13 mmol), dioxane (1 ml, purged with nitrogen), and copper (I) iodide (5 mg) in an oven-dried round bottom flask equipped with a reflux condenser under a nitrogen atmosphere was heated in an oil bath at 120–125° C. After 21 hours the mixture was cooled to room temperature, filtered through a pad of silica gel and concentrated under reduced pressure to give 50 mg of crude product. Purification by preparative HPLC (Shimadsu LC-8A preparative liquid chromatograph) eluting with a gradient of 0.1% aqueous formic acid in acetonitrile provided 2.5 mg of the title compound as a colorless amorphous solid. Mass Spectrum (ES+) 391.6; LC retention time=2.3 minutes (using the LC/MS and method outlined for the examples in Table 1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[C:22]([NH:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([O:33][CH3:34])=[O:32])[CH2:26]2)=[O:23])=[CH:4][CH:3]=1.Br[CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1>>[Cl:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][CH2:37][CH2:36][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=3[C:22]([NH:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([O:33][CH3:34])=[O:32])[CH2:26]3)=[O:23])=[CH:4][CH:3]=2)=[CH:40][CH:41]=1
Reactant: Clc1ccc(CCCBr)cc1
Reactant: COC(=O)c1ccc(OCCCc2ccc(O)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Product: COC(=O)c1ccc(OCCCc2ccc(OCCCc3ccc(Cl)cc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Methyl 4-(3-{4-[3-(4-chlorophenyl)propoxy]phenyl}propoxy)-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate is prepared in analogy to the process described in Example 34 from methyl 4-[3-(4-hydroxyphenyl)propoxy]-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate and 1-(3-bromopropyl)-4-chlorobenzene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21](O)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.[CH3:24][S:25]([NH2:28])(=[O:27])=[O:26].Cl.C(N=C=NCCCN(C)C)C.CN(C1C=CC=CN=1)C>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([CH2:24][S:25]([NH2:28])(=[O:27])=[O:26])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)c(F)c1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: NS(=O)(=O)CC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(F)c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
6 g (0.019 mol) of the compound from Example XV, 1.9 g (0.019 mol) of dried methanesulphonamide, 3.8 g (0.019 mol) of N-ethyl-N'-dimethylaminopropylcarbodiimide hydrochloride and 2.4 g (0.019 mol) of dimethylaminopyridine are dissolved in 40 ml of dichloromethane and the mixture is stirred at room temperature for 60 h. It is then evaporated to dryness in vacuo, the residue is taken up in 40 ml of dichloromethane and the solution is washed twice with 20 ml of water. After drying the organic phase using Na2SO4, it is evaporated in vacuo and the residue is separated by column chromatography (silica gel 60, eluent dichloromethane/ethyl acetate/glacial acetic acid=10:1:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=[O:14])=[N:6][C:7]=1[S:8][CH2:9][CH:10]([CH3:12])[CH3:11].S(=O)(=O)(O)O.[CH3:21]O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([O:15][CH3:21])=[O:14])=[N:6][C:7]=1[S:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: CO
Reactant: CC(C)CSc1nc(C(=O)O)ccc1Br
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Br)c(SCC(C)C)n1
Temperature: 80 °C
Reaction time: 24 h
Yield: 39 %

Procedure:
5-Bromo-6-(isobutylthio)picolinic acid (500 mg, 1.72 mmol) was dissolved in methanol (5 mL) to give a yellow solution. Sulfuric acid (169 mg, 92.3 μL, 1.72 mmol) was added. The reaction mixture was heated to 80° C. and stirred for 1 d. The reaction mixture was cooled to 0° C. and poured onto ice-water/brine (25 mL). The aqueous layer was extracted with EtOAc (2×40 mL) and washed with ice-water/brine (20 mL). The organic layers were combined, dried over Na2SO4 and concentrated in vacuo to give crude title compound as a yellow oil. The oil was purified by flash chromatography (silica gel, 5 g, 0% to 15% EtOAc in heptane) to give the title product (205 mg, 39%) as a colorless oil. MS (EI): m/e=306.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:13]3([C:20](=[O:21])[C:4]=2[CH:3]=1)[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3.[N:24]#CBr.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:19]([N:16]1[CH2:17][CH2:18][C:13]2([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[S:6][C:5]3[CH:22]=[CH:23][C:2]([F:1])=[CH:3][C:4]=3[C:20]2=[O:21])[CH2:14][CH2:15]1)#[N:24]
Reactant: N#CBr
Reactant: CN1CCC2(CC1)C(=O)c1cc(F)ccc1Sc1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: N#CN1CCC2(CC1)C(=O)c1cc(F)ccc1Sc1ccccc12
Temperature: 25 °C

Procedure:
A mixture of 3.0 g of 2-fluoro-10,11-dihydro-1'-methyl-11-oxospiro[dibenz(b,f)thiepin-10,4'-piperidine], free base of Example 26, in 10 ml of methylene chloride is added portionwise to a mixture of 1.3 g of cyanogen bromide and 6.4 g of potassium carbonate in 17 ml of methylene chloride. After total addition, the mixture is stirred at reflux for 2 hours and then permitted to cool to ambient temperature. Thereafter, the mixture is filtered and then evaporated to dryness and the residue is taken up in methyl alcohol. The alcoholic solution is refluxed before the addition of acetone and ether, effecting a precipitate. The mixture is filtered and the supernatant liquid is evaporated. The residue is chromatographed through a silica gel column and eluted with an ether-methylene chloride (1:1) mixture, to provide 1'-cyano-2-fluoro-10,11-dihydro-11-oxospiro[dibenz(b,f)thiepin-10,4'-piperidine].
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[CH:5][NH:6][CH:7]=1.Cl[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[F:1][C:2]([F:9])([F:8])[C:3]1[N:4]=[CH:5][N:6]([C:11]2[N:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH:7]=1
Reactant: FC(F)(F)c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Nc1ccc(-n2cnc(C(F)(F)F)c2)nc1
Temperature: 85 °C
Reaction time: 5 h

Procedure:
A mixture of 4-(trifluoromethyl)-1H-imidazole (2000 mg, 14.70 mmol), 2-chloro-5-nitropyridine (2330 mg, 14.70 mmol), and potassium carbonate (4060 mg, 29.4 mmol) in acetonitrile (14.7 mL) was heated at 85° C. overnight. The reaction was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was dissolved in ethanol (20 mL) and ethyl acetate (15 mL). 10 wt % Palladium on carbon (500 mg) was added to the solution. The mixture was pressurized to 50 psi hydrogen and was shaken for 5 hours. The reaction was filtered through celite, rinsing with methanol. The filtrate was concentrated to give 6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-amine. 1H NMR (400 MHz, CDCl3, δ): 8.15 (s, 1H), 7.93 (d, J=2.73 Hz, 1H), 7.85 (s, 1H), 7.20-7.15 (m, 1H), 7.14-7.09 (m, 1H), 3.13-2.30 (m, 2H). MS (M+HCO2−): 273.0.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1)=[O:12])=[O:4].O.[OH-].[Li+]>C1COCC1>[C:13]1([C:11]([N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C@H:5]2[C:3]([OH:4])=[O:2])=[O:12])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1
Reactant: COC(=O)[C@@H]1CCCCN1C(=O)c1nccc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H]1CCCCN1C(=O)c1nccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of (S)-1-(isoquinoline-1-carbonyl)-2-piperidinecarboxylic acid methyl ester (1.05 g, 3.52 mmol) in THF (20 ml) at room temperature was treated with water (10 ml). Lithium hydroxide (84 mg, 3.51 mmol) was then added and the resulting mixture was stirred at room temperature for 16 hrs. The resulting mixture was concentrated to remove the organic solvent. The resulting solution was then washed with diethyl ether and the remaining aqueous layer was made acid with 2 N HCl. The resulting solution was extracted with ethyl acetate and the organic layer was separated, dried (Na2SO4), filtered and concentrated to reveal a white solid (902 mg, 90%): 1H NMR (400 MHz, d4-MeOH) δ 1.20-2.52 (6H, m), 3.10-3.39 (2H, m), 4.10-4.90 (1H, m), 7.68-8.55 (5H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]2[NH:8][C:9](=[O:18])/[C:10](=[CH:12]/[C:13]3[NH:14][CH:15]=[CH:16][CH:17]=3)/[S:11][C:6]=2[CH:5]=1)([O-])=O.O.NN>[Ni].C(O)C>[NH2:1][C:4]1[CH:20]=[CH:19][C:7]2[NH:8][C:9](=[O:18])/[C:10](=[CH:12]/[C:13]3[NH:14][CH:15]=[CH:16][CH:17]=3)/[S:11][C:6]=2[CH:5]=1
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2S/C1=C\c1ccc[nH]1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)S/C(=C\c1ccc[nH]1)C(=O)N2

Procedure:
A catalytic amount of Raney nickel was added portionwise with stirring to a mixture of (Z)-7-nitro-2-[(pyrrol-2-yl)methylene]-2H-1,4-benzothiazin-3(4H)-one (Example 5) (0.43 g, 1.5 mmol) and hydrazine hydrate (98%) (0.8 ml) in ethanol (20 ml). The reaction mixture heated under reflux for 5.5 hours, then filtered and the solvent removed in vacuo. The product was purified by silica gel chromatography using a gradient of (98:2) to (95:5) toluene:ethanol as the mobile phase.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[Cl:17].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[Cl:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[O:9][C:3]1[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=1[C:22]1[CH:21]=[CH:20][C:19]([F:18])=[CH:24][C:23]=1[F:25]
Reactant: Cc1nn(C)c(Br)c1Oc1ccc(F)cc1Cl
Reactant: OB(O)c1ccc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1nn(C)c(-c2ccc(F)cc2F)c1Oc1ccc(F)cc1Cl
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-4-(2-chloro-4-fluorophenoxy)-1,3-dimethyl-1H-pyrazole (i.e. the product of Step C) (250 mg, 0.78 mmol) in 1,2-dimethoxyethane/water (5 mL, 2:1) was sparged with a subsurface stream of argon for 30 minutes, and then 2,4-difluorophenylboronic acid (371 mg, 2.34 mmol), potassium carbonate (1.08g, 7.82 mmol) and tetrakis(triphenylphosphine)palladium (90 mg, 0.078 mmol) were added. The reaction mixture was heated to 80° C. for 15 h, and then cooled and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by silica gel column chromatography (5 to 30% gradient of ethyl acetate in hexanes as eluant) to provide the title compound, a compound of the present invention, as a pale yellow solid (150 mg) melting at 70-72° C.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])=[N:9][CH:10]=1.[CH2:25]([O:27][C:28]1[C:32]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:31][NH:30][N:29]=1)[CH3:26].O>CN(C)C=O>[CH2:25]([O:27][C:28]1[C:32]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:31][N:30]([CH2:4][C:5]2[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]3[N:14]=[C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[O:16][C:17]=3[CH3:18])=[CH:7][CH:6]=2)[N:29]=1)[CH3:26]
Reactant: CCOC(=O)Cc1c[nH]nc1OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)nc2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
Sodium hydride (60%, oily, 70.0 mg) was added to a solution of 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (551 mg), ethyl 3-ethoxy-1H-pyrazol-4-ylacetate (347 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. 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 residue was subjected to silica gel column chromatography to obtain ethyl 3-ethoxy-1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-ylacetate (608 mg, yield: 73%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: C([O:5]C1C=CC(SC(C2C=CC(C3SC=CC=3)=CC=2)C(NO)=O)=CC=1)C#CC.[CH2:29]([O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([CH:42]([C:47]2[CH:52]=[CH:51][C:50]([C:53]3[S:54][CH:55]=[CH:56][CH:57]=3)=[CH:49][CH:48]=2)[C:43]([NH:45][OH:46])=[O:44])=[O:41])=[CH:36][CH:35]=1)[C:30]#[C:31][CH3:32]>>[CH2:29]([O:33][C:34]1[CH:35]=[CH:36][C:37]([S:40]([CH:42]([C:47]2[CH:52]=[CH:51][C:50]([C:53]3[S:54][CH:55]=[CH:56][CH:57]=3)=[CH:49][CH:48]=2)[C:43]([NH:45][OH:46])=[O:44])(=[O:5])=[O:41])=[CH:38][CH:39]=1)[C:30]#[C:31][CH3:32]
Reactant: CC#CCOc1ccc(SC(C(=O)NO)c2ccc(-c3cccs3)cc2)cc1
Reactant: CC#CCOc1ccc(S(=O)C(C(=O)NO)c2ccc(-c3cccs3)cc2)cc1
Product: CC#CCOc1ccc(S(=O)(=O)C(C(=O)NO)c2ccc(-c3cccs3)cc2)cc1
Yield: 26 %

Procedure:
Starting from a mixture of 2{[4-(2-butynyloxy)phenyl]sulfanyl}-N-hydroxy-2-[4-(2-thienyl)phenyl]acetamide and 2-{[4-(2-butynyloxy)phenyl]sulfinyl}-N-hydroxy-2-[4-(2-thienyl)phenyl]ethanamide (410 mg, 0.96 mmol), and following the procedure as outlined in Example 75, 110 mg of 2-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-2-[4-(2-thienyl)phenyl]acetamide was isolated as a gray solid. mp: 175° C.; Yield: 26%; MS: 442.2 (M+W)+; 1H NMR (300 MHz, DMSO-d6): δ 1.83 (t, 3H), 4.85 (d, J=2.01 Hz, 2H), 5.04 (s, 1H), 7.11 (m, 4H), 7.39 (d, 7.49-7.63 (band, 5H), 9.30 (s, 1H), 10.9 (s, 1H).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH3:15])=[O:13])(OCC)=O)C.[Si:16]([O:23][CH:24]([C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=O)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C1COCC1>[Si:16]([O:23][CH:24]([C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:11][C:12]([O:14][CH3:15])=[O:13])([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17]
Reactant: CCOP(=O)(CC(=O)OC)OCC
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCC=O)c1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C=CCCCCC(O[Si](C)(C)C(C)(C)C)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 177 mg, 4.42 mmol) in THF (25 mL) at room temperature under nitrogen atmosphere was added dropwise neat methyl diethylphosphonoacetate (811 μL, 4.42 mmol). The resulting solution was stirred for 10 minutes while cooling down to 0° C. A solution of crude aldehyde 183 (1.05 g, 2.94 mmol) in THF (10 mL) was transferred via cannula. The resulting solution was stirred for 15 minutes at 0° C. and quenched with a saturated aqueous solution of ammonium chloride. The THF was evaporated in vacuo and the aqueous residue was partitioned between diethyl ether and water. The aqueous layer was extracted with diethyl ether and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude residue was purified by flash chromatography (5% ethyl acetate/hexane), affording the title compound 184 in 63% yield (1.30 g). 1H NMR: (300 MHz, CDCl3) δ: 7.83-7.78 (m, 3H), 7.69 (s, 1H), 7.49-7.41 (m, 3H), 6.94 (dt, J=15.4, 7.1 Hz, 1H), 5.79 (dt, J=15.7, 1.1 Hz, 1H), 4.79 (dd, J=7.1, 5.2 Hz, 1H), 3.71 (s, 3H), 2.16 (q, J=7.4 Hz, 2H), 1.81-1.62 (m, 2H), 1.48-1.29 (m, 4H), 0.90 (s, 9H), 0.04 (s, 3H), −0.15 (s, 3H). MS (ESI)=413 (MH+).