Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.C([O-])(O)=O.[Na+].[Br:18][C:19]1[C:20]([Cl:30])=[CH:21][C:22]([F:29])=[C:23]([S:25](Cl)(=[O:27])=[O:26])[CH:24]=1>O.C(#N)C>[Br:18][C:19]1[C:20]([Cl:30])=[CH:21][C:22]([F:29])=[C:23]([S:25]([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([CH3:12])([CH3:1])[CH2:3][CH2:4]2)(=[O:27])=[O:26])[CH:24]=1
Reactant: O=S(=O)(Cl)c1cc(Br)c(Cl)cc1F
Reactant: CC1(C)CCNc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC1(C)CCN(S(=O)(=O)c2cc(Br)c(Cl)cc2F)c2ccccc21
Reaction time: 3 h
Yield: 84.6 %

Procedure:
To 4,4-dimethyl-1,2,3,4-tetrahydro-quinoline (2.2 g, 13.66 mmol) in a mixture of water (60 mL) and acetonitrile (40 mL) containing NaHCO3 (3.44 g, 41.0 mmol), was added 5-bromo-4-chloro-2-fluoro-benzenesulfonyl chloride (4.2 g, 13.66 mmol) in acetonitrile (20 mL) slowly with vigorous stirring. After addition, the mixture was stirred for 3 hrs. The resulting precipitate was filtered, washed with hexane and dried to yield 1-(5-bromo-4-chloro-2-fluoro-benzenesulfonyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline as a light brown solid (5.0 g).
Reaction SMILES: Br[C:2]1[C:3]([O:19][CH2:20][C:21]2[N:22]([CH3:26])[N:23]=[CH:24][N:25]=2)=[N:4][N:5]2[C:10]=1[C:9]([CH3:11])=[N:8][N:7]=[C:6]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18].[S:27]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:6]1[N:5]2[N:4]=[C:3]([O:19][CH2:20][C:21]3[N:22]([CH3:26])[N:23]=[CH:24][N:25]=3)[C:2]([C:29]3[CH:30]=[CH:31][S:27][CH:28]=3)=[C:10]2[C:9]([CH3:11])=[N:8][N:7]=1
Reactant: OB(O)c1ccsc1
Reactant: Cc1nnc(-c2ccccc2F)n2nc(OCc3ncnn3C)c(Br)c12
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1nnc(-c2ccccc2F)n2nc(OCc3ncnn3C)c(-c3ccsc3)c12
Temperature: 90 °C
Yield: 82.5 %

Procedure:
A mixture of 3-bromo-7-(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine (100.7 mg, 0.241 mmol), thiophene-3-boronic acid (46.8 mg, 0.366 mmol) and cesium carbonate (157.0 mg, 0.482 mmol) in anhydrous 1,4-dioxane (10 ml) was degassed by three freeze-pump-thaw cycles. Then tris(dibenzylideneacetone)dipalladium(0) (22.5 mg, 0.0246 mmol) and a 0.1M solution of tri-tert-butylphosphine in 1,4-dioxane (0.58 ml, 0.058 mmol) was added and two more freeze-pump-thaw cycles were performed. The mixture was heated at 90° C. under nitrogen for 22 h, then filtered through glass fibre paper. The solid was washed with ethyl acetate, and the filtrates were washed with saturated aqueous NaCl (15 ml). The aqueous layer was further extracted with ethyl acetate (25 ml), and the combined extracts were dried (NaSO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 2% MeOH/CH2Cl2) to give 83.8 mg (83%) of the title compound as an orange solid: mp=124-129° C. (CH2Cl2-EtOAc-isohexane); 1H NMR (360 MHz, CDCl3) δ 2.60 (3H, s), 3.71 (5H, s), 5.46 (2H, s), 7.18 (1H, d, J=4.9 Hz), 7.27 (1H, m), 7.38 (1H, m), 7.38 (1H, s), 7.44 (1H, dd, J=4.9, 3.0 Hz), 7.63 (1H, m), 7.75 (1H, t, J=7.1 Hz), 7.83 (1H, s); MS (ES+) m/e 422 [M+H]+. Anal. Found C, 56.94; H, 4.04; N, 22.49%. C20H16FN7OS.0.08 C4H8O2 requires C, 56.96; H, 3.91; N, 22.88%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].ClN1C(=O)CCC1=O.C([O-])(O)=O.[Na+].[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=1[CH2:32][O:33][CH2:34][C:35]([CH3:37])=[CH2:36]>ClCCCl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]1[CH2:36][C:35]([CH2:34][O:33][CH2:32][C:26]2[C:27]([F:31])=[CH:28][CH:29]=[CH:30][C:25]=2[F:24])([CH3:37])[O:6][N:5]=1
Reactant: C=C(C)COCc1c(F)cccc1F
Reactant: ON=Cc1ccccc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC1(COCc2c(F)cccc2F)CC(c2ccccc2Br)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
287 mg of 2-bromobenzaldehyde oxime was dissolved in 4 mL of 1,2-dichloroethane, and then, 230 mg of N-chlorosuccinimide and 0.4 mL of dimethylformamide were slowly added thereto at a temperature of 0° C. The reaction mixture was stirred at room temperature for 1 hour, and then, the reaction state was confirmed by TLC. When the oxime, which was a starting material, disappeared, the reaction mixture was cooled to a temperature 0° C., and then, 182 mg of NaHCO3, 27 mg of tetrabutylammonium iodide, and 342 mg of 1,3-difluoro-2-((2-methylallyloxy)methyl)benzene were sequentially, slowly added thereto. The reaction mixture was stirred at room temperature overnight, and then, diluted with dichloromethane, and then, washed with water, and the obtained organic layer was dried by using magnesium sulfate and concentrated, and the concentrate was separated by silicagel column chromatography to obtain 450 mg of 3-(2-bromophenyl)-5-((2,6-difluorobenzyloxy)methyl)-5-methyl-4,5-dihydroisoxazole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=2)[CH:7]=1)[CH3:2].C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26]>ClCCl>[CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][C:25](=[O:27])[CH3:26])[CH:12]=2)[CH:7]=1)[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)Nc1ccc2cc(O)ccc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Nc1ccc2cc(OC(C)=O)ccc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-(6-hydroxy-2-naphthyl)carbamic acid ethyl ester (1 g, 4.32 mmol) and triethylamine (1.80 mL, 13 mmol) in dichloromethane (20 mL) at room temperature, is added acetyl chloride (0.369 mL, 5.19 mmol) dropwise. After stirring at room temperature for 3 hours, the reaction mixture is concentrated and purified by flash chromatography on silica gel (2:1 hexane/EtOAc) to give N-(6-acetyloxy-2-naphthyl)carbamic acid ethyl ester as a white solid.
Reaction SMILES: [ClH:1].[C:2]([CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1/[CH:11]=[C:12]1\[CH2:13][N:14]([CH:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[C:20]([CH:22]2[CH2:24][CH2:23]2)=[O:21])[CH2:15][CH2:16][CH:17]\1[SH:18])([OH:4])=[O:3].C(N(CC)CC)C.[C:39](OC(=O)C)(=[O:41])[CH3:40]>ClCCl>[ClH:1].[C:39]([S:18][CH:17]1[CH2:16][CH2:15][N:14]([CH:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[C:20]([CH:22]2[CH2:23][CH2:24]2)=[O:21])[CH2:13]/[C:12]/1=[CH:11]\[C:7]1[N:6]([CH2:5][C:2]([OH:4])=[O:3])[CH:10]=[CH:9][N:8]=1)(=[O:41])[CH3:40]
Reactant: O=C(O)Cn1ccnc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1S
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1nccn1CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
To a solution of (E)-3-{[1-(carboxymethyl)-1H-imidazol-2-yl]methylidene}-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-sulfanylpiperidine hydrochloride (85.6 mg) in dichloromethane (4 ml) were added triethylamine (120 μl) and acetic anhydride (80 μl) at 0° C. After the mixture was stirred at room temperature for 3 hours, solvents were removed under reduced pressure and the residue was purified by silica gel chromatography using methanol and dichloromethane (5:95 to 25:75) as eluents to afford the free base of the title compound (57.7 mg, yield: 71%) as a colourless oil.
Reaction SMILES: [Li].CC(C)([O-])C.[K+].[CH3:8][CH:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:10][CH2:11][C:12]#[C:13][CH3:14]>>[CH3:8][CH:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:10][CH2:11][CH2:12][C:13]#[CH:14]
Reactant: CC#CCCC(C)CCCCCCCCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]
Product: C#CCCCC(C)CCCCCCCCC
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To anhydrous 1,3-diaminopropane (180 ml), which had been distilled, metallic lithium (2.8 g, 0.4 mol) was added under argon stream, and the mixture was stirred for 2 hours at 70° C. After the mixture was allowed to cool, potassium t-butoxide (27 g, 0.24 mol) was added, followed by stirring for 15 minutes. The 6-methyl-2-pentadecyne (6″) (12.1 g, 54.5 mmols) was added dropwise, and the mixture was stirred overnight at room temperature. This reaction was carefully quenched with a saturated aqueous solution of ammonium chloride, and then the mixture was extracted with ether. The resulting organic layer was washed (diluted hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of sodium chloride), dried (magnesium sulfate), and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 6-methyl-1-pentadecyne (7″) (9.90 g, 82%). IR and 1H-NMR analysis of the product showed the following results: IR (film) 3300 (m,C≡CH), 2130 cm−1 (w,C≡C). 1H-NMR (90 MHz, CDCl3) 0.84 (3H,d,J=7,6-Me), 0.88 (3H,t,J=7,15-H), 1.0-1.6 (21H,m,4˜14-H), 1.93 (1H,t,J=2.5,1-H), 2.0-2.3 (2H,m,3-H).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:30])([F:29])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([S:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=2)[CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:7][CH:6]=1>CO>[F:30][C:4]([F:3])([F:29])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([S:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)[CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(SC(Cn2ccnc2)c2ccc(C(F)(F)F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(SC(Cn2ccnc2)c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.9 %

Procedure:
8 ml of a 1N aqueous solution of sodium hydroxide were added to 792 mg of methyl 4-[1-(4-trifluoromethylphenyl)-2-(imidazol-1-yl)ethylthio]benzoate (prepared as described in Example 35) in 8 ml of methanol, and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was then treated and purified by the same method as described in Example 28, to give 481 mg of the title compound as a powder, melting at 92°-95° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[N:2]1.Cl.[CH2:12](O)[CH3:13]>C(O)C>[NH:1]1[CH:5]=[N:4][C:3]([CH2:6][CH2:7][C:8]([O:10][CH2:12][CH3:13])=[O:9])=[N:2]1
Reactant: O=C(O)CCc1nc[nH]n1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)CCc1nc[nH]n1
Temperature: 90 °C
Reaction time: 15 h
Yield: 33 %

Procedure:
A suspension of 3-(1H-1,2,4-triazol-3-yl)propanoic acid obtained in Reference Example 22 (11.6 g, 3.54 mmol) and 2N hydrogen chloride/ethanol (100 mL) in ethanol (100 mL) was stirred at 90° C. for 15 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate and water. The aqueous layer was neutralized with saturated aqueous sodium carbonate solution, and the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated to give the title compound as a yellow powder (4.36 g, 33%).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:18][C:19]2[C:28]3[O:27][CH2:26][CH2:25][O:24][C:23]=3[CH:22]=[CH:21][CH:20]=2)[S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=1)C.[OH-].[Na+]>CO.Cl>[O:24]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:18][N:13]([CH2:12][C:8]3[CH:7]=[C:6]([CH2:5][C:4]([OH:29])=[O:3])[CH:11]=[CH:10][CH:9]=3)[S:14]([CH3:17])(=[O:15])=[O:16])[C:28]=2[O:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)Cc1cccc(CN(Cc2cccc3c2OCCO3)S(C)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)N(Cc1cccc(CC(=O)O)c1)Cc1cccc2c1OCCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
To a solution of (3-{[(2,3-dihydro-benzo[1,4]dioxin-5-ylmethyl)-methanesulfonyl-amino]-methyl}-phenyl)-acetic Acid ethyl ester (210 mg, 0.5 mmol) in MeOH (3 mL) at 0° C. was added aqueous NaOH (2N, 0.5 mL). The reaction was stirred at room temperature for 16 h and was diluted with 1N HCl. The product was extracted into CH2Cl2 and the organic solution was washed with water followed by brine. The organic solution was dried over MgSO4, filtered, and concentrated to provide the title compound (165 mg). 1H NMR (400 MHz, CDCl3) δ 7.19-7.32 (m, 4H), 6.73-6.81 (m, 3H), 4.29 (s, 2H), 4.22 (s, 4H), 4.18 (s, 2H), 3.63 (s, 2H), 2.75 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH2:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].[C:16](=O)([O-])[O-].[K+].[K+].CI>CS(C)=O.O.C(OCC)C>[CH3:1][C:2]([CH3:15])([CH2:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH3:16])=[O:4]
Reactant: CC(C)(CC(=O)c1ccccc1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C(C)(C)CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred mixture of 2,2-dimethyl-4-oxo-4-phenylbutanoic acid (1.1 g, 5.3 mmol) and potassium carbonate (0.88 g, 6.4 mmol) in DMSO (6.4 mL) was added methyl iodide (0.68 g, 4.80 mmol). The resulting mixture was stirred at ambient temperature for 15 h. The reaction mixture was diluted with water (100 mL) and diethyl ether (100 mL). The organic layer was then washed successively with water, saturated sodium bicarbonate, 1 M HCl, water and finally saturated brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound which was subsequently used without further purification. MS: m/z=221 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7][C:6](=[N:23]OC(NCCC)=O)[C:5]1=[O:31]>CO.[C].[Pd]>[CH3:1][O:2][CH2:3][N:4]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[N:8]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:7][CH:6]([NH2:23])[C:5]1=[O:31]
Reactant: CCCNC(=O)ON=C1CN(c2ccccc2)c2ccc(OC)cc2N(COC)C1=O
Agent: [Pd]
Solvent: CO
Product: COCN1C(=O)C(N)CN(c2ccccc2)c2ccc(OC)cc21
Reaction time: 0.5 h
Yield: 105.2 %

Procedure:
1-Methoxymethyl-2-oxo-3-propylaminocarbonyloxyimino-5-phenyl-8-methoxy-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (0.78 g) was suspended in methanol (20 ml), 10% palladium carbon (0.20 g) was added thereto, the mixture was swung for 2 hours and 30 minutes under hydrogen atmosphere (3.5-3.0 kg/cm2). The palladium carbon was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1), to thereby obtain 0.63 g of the titled compound.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1.C([BH3-])#N.[Na+]>>[C:11]([C:8]1[CH:9]=[CH:10][C:5]([CH2:4][NH:3][O:2][CH3:1])=[CH:6][CH:7]=1)([O:13][CH3:14])=[O:12]
Reactant: CON=Cc1ccc(C(=O)OC)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccc(C(=O)OC)cc1
Yield: 53 %

Procedure:
Reduction of 4-carbomethoxybenzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of compound 3-B gave the title hydroxylamine as an oil (53% yield). The hydrochloride salt was obtained as a white solid: mp 166-169° C. 1HNMR 400 MHz (DMSO-d6) δ (ppm): 3.75 (3H, s, OCH3), 3.86 (3H, s, OCH3), 4.39 (2H, s, NCH2), 7.65 (2H, d, aromatics), 7.97 (2H, d, aromatics). Anal. calcd for C10H13NO3—HCl: C, 51.84; H, 6.09; N, 6.04. Found: C, 51.74; H, 6.01; N, 5.50.
Reaction SMILES: [F:1][C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:10]([NH2:12])[CH3:11]>C1COCC1>[CH2:10]([NH:12][CH2:8][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:11]
Reactant: CCN
Reactant: O=Cc1ncccc1F
Solvent: C1CCOC1
Product: CCNCc1ncccc1F

Procedure:
prepared by reaction of the commercially available 3-fluoro-pyridin-2-carbaldehyde with 2M ethylamine in THF.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([CH2:7][NH:8][C:9]2[C:18]([NH2:19])=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[S:24](N)(N)(=[O:26])=[O:25]>N1C=CC=CC=1>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:9]3=[CH:10][CH:11]=[C:12]4[C:17]([N:16]=[CH:15][CH:14]=[CH:13]4)=[C:18]3[NH:19][S:24]2(=[O:26])=[O:25])=[CH:5][CH:4]=1
Reactant: Nc1c(NCc2ccc(C(F)(F)F)cc2)ccc2cccnc12
Reactant: NS(N)(=O)=O
Solvent: c1ccncc1
Product: O=S1(=O)Nc2c(ccc3cccnc23)N1Cc1ccc(C(F)(F)F)cc1
Yield: 12.7 %

Procedure:
In a similar fashion using route 63 general procedure 140, N*7*-(4-trifluoromethyl-benzyl)-quinoline-7,8-diamine 577 (334 mg, 1.0 mmol), sulfamide (154 mg, 1.5 mmol) and pyridine (5 ml) gave the title compound (48 mg, 12%) after purification by preparative HPLC (acidic conditions 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16](F)=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:24]#[N:25])[CH:5]=[CH:6][C:7]=1[F:8].[OH:26][CH:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:26][CH:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:24]#[N:25])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN1CCC(O)CC1
Reactant: N#Cc1cnc2cc(F)c([N+](=O)[O-])cc2c1Nc1ccc(F)c(Cl)c1
Product: CN1CCC(Oc2cc3ncc(C#N)c(Nc4ccc(F)c(Cl)c4)c3cc2[N+](=O)[O-])CC1

Procedure:
The compound was obtained according to the process of Preparation 2 with 4-(3-chloro-4-fluorophenylamino)-7-fluoro-6-nitroquinoline-3-carbonitrile and 4-hydroxy-1-methylpiperidine as starting materials.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.CCO.Cl.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1>CCO>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:1]2[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:16][CH:17]=1)#[N:22]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: C1CNCCNC1
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc(CN2CCCNCC2)cc1

Procedure:
To a solution of homopiperazine (9.2 g, 92 mmol, 2 equiv). in EtOH (115 mL) was added 1 M HCl-EtOH (92 mL) dropwise over 1 h. The suspension was heated to 70° C. for 1 h at which point a homogeneous solution of monohydrochloride salt was obtained. α-Bromo-p-tolunitrile (9.0 g, 46 mnmol, 1 equiv) was added and the reaction mixture was heated to reflux for 5 h. After cooling, the solvent was removed by rotary evaporation and the residue was partitioned between CH2Cl2 (100 mL) and 2N aqueous KOH (100 mL). The aqueous layer was extracted with CH2Cl2 (5×50 mL) and the combined organic phase was washed with saturated aqueous NaCl (1×150 mL) and dried (MgSO4). Chromatography (SiO2, 4×20 cm, 20% CH3OH —5% Et3N—CH2Cl2) afforded the desired monoalkylated material (6.78 g, 10.1 g theoretical, 67%) as an amber oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:7][N:6]=[C:5]([CH3:8])[CH:4]=1.Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11].O.C(O)C>N1C=CC=CC=1>[C:10]([NH:2][C:3]1[S:7][N:6]=[C:5]([CH3:8])[CH:4]=1)([O:12][CH2:13][CH3:14])=[O:11]
Reactant: Cc1cc(N)sn1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cc(C)ns1
Reaction time: 0.67 h
Yield: 62.5 %

Procedure:
To a stirred solution of 6.10 g (40.5 mmole) of 5-amino-3-methylisothiazole hydrochloride in 200 ml of dry pyridine is added slowly 13.8 g (127 mmole) of ethyl chloroformate. After 2 days the reaction mixture is treated with 20 ml each of water and ethanol. After 40 min., the solution is concentrated in vacuo to a gum, which is further dried by several evaporations of aqueous ethanol. The crude product is dissolved in 75 ml of boiling ethanol to which is added water until the solution clouds. Upon cooling a crystaline solid containing some diacylated material is collected, redissolved in 100 ml of isopropyl alcohol, and treated with 40 ml of approximately 7 N HCl in isopropyl alcohol. After about 2 hours, the solution is concentrated at reduced pressure to an oily residue which is dried by multiple evaporation of ethanol. A solution of the crude solid in approximately 100 ml of water is adjusted to about pH 7 by addition of 2 N aqueous sodium hydroxide, giving the product as a precipitate. After washing with water and drying, 4.71 g (25.3 mmole) of 5-carbethoxyamino-3-methylisothiazole is obtained. Structure assignment is supported by the nmr spectrum.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][CH2:26][C@@H:25]([NH:28]C(=O)OC(C)(C)C)[C:24]4=[O:36])=[CH:19][CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>C(Cl)Cl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[NH2:28][C@@H:25]1[CH2:26][CH2:27][N:23]([C:20]2[CH:21]=[CH:22][C:17]([N:13]3[CH2:12][C@H:11]([CH2:10][NH:9][C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:8])[O:15][C:14]3=[O:16])=[CH:18][CH:19]=2)[C:24]1=[O:36]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N3C[C@H](CNC(=O)c4ccc(Cl)s4)OC3=O)cc2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CCN(c2ccc(N3C[C@H](CNC(=O)c4ccc(Cl)s4)OC3=O)cc2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
97 mg (0.181 mmol) of tert-butyl(3R)-1-{4-[(5S)-5-({[(5-chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-2-oxo-3-pyrrolidinylcarbamate are suspended in 4 ml of methylene chloride, 1.5 ml of trifluoroacetic acid are added and the mixture is stirred at room temperature for 1 hour, The mixture is then concentrated under reduced pressure and the residue is purified on an RP-HPLC (acetonitrile/water/0.1% TFA gradient). Evaporation of the appropriate fraction gives 29 mg (37% of theory) of the target compound of melting point 241° C. (decomp.).
Reaction SMILES: [N:1]#[N:2].[CH:3]1[C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[O:8][C:7]=2[CH:6]=[CH:5][C:4]=1[S:17]([NH:20][C@H:21]([C:29]([OH:31])=O)[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:28])[NH2:27])(=[O:19])=[O:18].C(OCC)C.S(Cl)([Cl:39])=O>>[N:1]#[N:2].[CH:3]1[C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[O:8][C:7]=2[CH:6]=[CH:5][C:4]=1[S:17]([NH:20][C@H:21]([C:29]([Cl:39])=[O:31])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:28])[NH2:27])(=[O:19])=[O:18]
Reactant: O=S(Cl)Cl
Reactant: N=C(N)NCCC[C@H](NS(=O)(=O)c1ccc2c(c1)Sc1ccccc1O2)C(=O)O
Agent: N#N
Solvent: CCOCC
Product: N=C(N)NCCC[C@H](NS(=O)(=O)c1ccc2c(c1)Sc1ccccc1O2)C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 4.36 g of N2 -(2-phenoxathiinylsulfonyl)-L-arginine in 20 ml of thionyl chloride was stirred for 2 hours at room temperature. Addition of cold dry diethyl ether resulted in a precipitate which was collected by filtration and washed several times with dry diethyl ether to give N2 -(2-phenoxathiinylsulfonyl)-L-arginyl chloride.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][C:14]=2[F:21])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:34][O:35][CH2:36][CH2:37][OH:38]>>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][C:14]=2[F:21])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:34][O:35][CH2:36][CH2:37][OH:38])=[O:7]
Reactant: NOCCO
Reactant: CSc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CSc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Yield: 80 %

Procedure:
The title compound was prepared from reaction of the product of Example 26, Step C, 3,4-difluoro-2-[[2-fluoro-4-(methylthio)phenyl]amino]benzoic acid, with CDI and 2-(aminooxy)ethanol by the general procedure of Example 1, Step E. Then, after workup, the crude solid triturated with Et2O and washed with pentane to afford 3,4-difluoro-2-[[2-fluoro-4-(methylthio)phenyl]amino]-N-(2-hydroxyethoxy)benzamide as a white solid (80%); m.p. (Et2O) 108–111° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.80 (br s, 1 H), 8.77 (br s, 1 H), 7.40 (ddd, J=9.0, 5.8, 2.0 Hz, 1 H), 7.18 (dd, J=12.0, 2.2 Hz, 1 H), 7.13 (ddd, J=9.9, 9.0, 7.2 Hz, 1 H), 6.99 (ddd, J=8.5, 2.4, 0.8 Hz, 1 H), 6.87 (td, J=8.9, 4.5 Hz, 1 H), 4.71 (br s, 1 H), 3.86 (t, J=4.9 Hz, 2 H), 3.57 (t, J=4.9 Hz, 2 H), 2.45 (s, 3 H). Anal. Calcd for C16H15F3N2O3S: C, 51.6; H, 4.1; N, 7.5. Found: C, 52.1; H, 4.3; N, 7.6.