N,N-dimethylhydroxylamine;hydrochloride

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-tert-butoxycarbonyl-N-methyl-L-leucine (5.0 g, 20.4 mmol) was dissolved in DMF (100 mL), treated with treated with N,N-diisopropylethylamine (28 mL, 163 mmol), N,N-dimethylhydroxylamine hydrochloride salt (2.0 g, 20.4 mmol), and HBTU (7.73 g, 20.4 mmol), then stirred overnight at room temperature. The reaction was diluted with EtOAc (500 mL), washed with saturated bicarbonate solution and brine, dried over Na2SO4, and concentrated to give the desired product as an oil; MS: 289.2 (M+1 for C14H28N2O4); TLC (SiO2) Rf 0.39 (8% MeOH/CH2Cl2), visualized with ninhydrin. treated washed with saturated bicarbonate solution and brine dried over Na2SO4 concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1.73 Grams of 6-chlorosalicylic acid was dissolved in 20 ml of tetrahydrofuran, and 1.95 g of N,N'-carbonyldiimidazole was added. After stirring at room temperature for 30 minutes, 1.47 g of N,N-dimethylhydroxylamine hydrochloride and 1.52 g of triethylamine were added, and the resulting mixed solution was stirred at room temperature for 7 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue obtained was subjected to column chromatography to obtain 1.1 g of 3-chloro-2-(N,N-dimethylaminooxycarbonyl)phenol. the resulting mixed solution was stirred at room temperature for 7 hours extracted with ethyl acetate The organic layer was washed with a saturated aqueous sodium chloride solution dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure the residue obtained

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1.73 Grams of 6-chlorosalicylic acid was dissolved in 20 ml of tetrahydrofuran, and 1.95 g of N,N'-carbonyldiimidazole was added. After stirring at room temperature for 30 minutes, 1.47 g of N,N-dimethylhydroxylamine hydrochloride and 1.52 g of triethylamine were added, and the resulting mixed solution was stirred at room temperature for 7 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue obtained was subjected to column chromatography to obtain 1.1 g of 3-chloro-2-(N,N-dimethylaminooxycarbonyl)phenol. the resulting mixed solution was stirred at room temperature for 7 hours extracted with ethyl acetate The organic layer was washed with a saturated aqueous sodium chloride solution dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure the residue obtained

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1.56 Grams of 6-fluorosalicylic acid was dissolved in 20 ml of tetrahydrofuran, and 1.94 g of N,N'-carbonyldiimidazole was added. After stirring at room temperature for 30 minutes, 1.47 g of N,N-dimethylhydroxylamine hydrochloride and 1.52 g of triethylamine were added, and the resulting mixed solution was stirred at room temperature for 7 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue obtained was subjected to column chromatography to obtain 0.6 g of 3-fluoro-2-(N,N-dimethylaminooxycarbonyl)phenol. the resulting mixed solution was stirred at room temperature for 7 hours extracted with ethyl acetate The organic layer was washed with a saturated aqueous sodium chloride solution dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure the residue obtained

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 7.0 Grams of 3-hydroxypicolinic acid was dissolved in 10 ml of N,N-dimethylformamide, and the resulting solution was cooled to 0° to 5° C. 5.9 Grams of thionyl chloride was then added dropwise to the solution which was then stirred at 0° to 5° C. for further 30 minutes. Thereafter, 30 ml of chloroform was added to the solution which was then stirred at 0° to 5° C. for further 15 minutes. To the resulting mixed solution was added dropwise a dichloromethane solution of N,N-dimethylhydroxylamine prepared from 7.4 g of N,N-dimethylhydroxylamine hydrochloride and 7.6 g of triethylamine. After stirring at 0° to 5° C. for 30 minutes, 7.9 g of pyridine was added, and stirring was continued at 0° to 5° C. for further 1 hour. After stirring at room temperature for 8 hours, the reaction solution was poured into water, and insoluble matters were removed by filtration on celite. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue obtained was subjected to chromatography to obtain 1.0 g of 3-hydroxy-2-(N,N-dimethylaminooxycarbonyl)pyridine. the resulting solution was cooled to 0° to 5° C was then stirred at 0° to 5° C. for further 15 minutes To the resulting mixed solution After stirring at 0° to 5° C. for 30 minutes stirring was continued at 0° to 5° C. for further 1 hour After stirring at room temperature for 8 hours were removed by filtration on celite The organic layer was washed with water dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure the residue obtained

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 7.0 Grams of 3-hydroxypicolinic acid was dissolved in 10 ml of N,N-dimethylformamide, and the resulting solution was cooled to 0° to 5° C. 5.9 Grams of thionyl chloride was then added dropwise to the solution which was then stirred at 0° to 5° C. for further 30 minutes. Thereafter, 30 ml of chloroform was added to the solution which was then stirred at 0° to 5° C. for further 15 minutes. To the resulting mixed solution was added dropwise a dichloromethane solution of N,N-dimethylhydroxylamine prepared from 7.4 g of N,N-dimethylhydroxylamine hydrochloride and 7.6 g of triethylamine. After stirring at 0° to 5° C. for 30 minutes, 7.9 g of pyridine was added, and stirring was continued at 0° to 5° C. for further 1 hour. After stirring at room temperature for 8 hours, the reaction solution was poured into water, and insoluble matters were removed by filtration on celite. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue obtained was subjected to chromatography to obtain 1.0 g of 3-hydroxy-2-(N,N-dimethylaminooxycarbonyl)pyridine. the resulting solution was cooled to 0° to 5° C was then stirred at 0° to 5° C. for further 15 minutes To the resulting mixed solution After stirring at 0° to 5° C. for 30 minutes stirring was continued at 0° to 5° C. for further 1 hour After stirring at room temperature for 8 hours were removed by filtration on celite The organic layer was washed with water dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure the residue obtained

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6.00 Grams of acetylsalicylic acid chloride was dissolved in 70 ml of methylene chloride, and 7.37 g of N,N-dimethylhydroxylamine hydrochloride was added. Then, 9.16 of triethylamine was added dropwise thereto with stirring at room temperature. After completion of addition, stirring was carried out at room temperature for further 6 hours. The reaction mixture was washed with a 0.5N hydrochloric acid and then twice with water, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue obtained was subjected to column chromatography to obtain 3.10 g of 2-(N,N-dimethylaminooxycarbonyl)phenol. After completion of addition stirring The reaction mixture was washed with a 0.5N hydrochloric acid twice with water, and dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure the residue obtained

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (2S,4S)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (Example 53; 0.100 g, 0.204 mmol), EDCI (0.0548 g, 0.286 mmol) and HOBT (0.0359 g, 0.266 mmol) were mixed in CH2Cl2 (2.5 mL) and the mixture was cooled to 0° C. Triethylamine (0.0712 mL, 0.511 mmol) was added and the mixture was stirred for 15 minutes. Dimethyl hydroxylamine HCl (0.0299 g, 0.306 mmol) was added, and the mixture was warmed to ambient temperature and stirred for 4.5 hours. The mixture was diluted with EtOAc (20 mL) and washed with 1N KHSO4 (2×10 mL), followed by a saturated aqueous NaHCO3 solution and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by column chromatography (1 to 5% MeOH/CH2Cl2) to provide 0.076 g (70%) of the product as a white foam. the mixture was warmed to ambient temperature stirred for 4.5 hours washed with 1N KHSO4 (2×10 mL) The organic layer was dried over Na2SO4 filtered concentrated The crude material was purified by column chromatography (1 to 5% MeOH/CH2Cl2)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (2S,4S)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (Example 53; 0.100 g, 0.204 mmol), EDCI (0.0548 g, 0.286 mmol) and HOBT (0.0359 g, 0.266 mmol) were mixed in CH2Cl2 (2.5 mL) and the mixture was cooled to 0° C. Triethylamine (0.0712 mL, 0.511 mmol) was added and the mixture was stirred for 15 minutes. Dimethyl hydroxylamine HCl (0.0299 g, 0.306 mmol) was added, and the mixture was warmed to ambient temperature and stirred for 4.5 hours. The mixture was diluted with EtOAc (20 mL) and washed with 1N KHSO4 (2×10 mL), followed by a saturated aqueous NaHCO3 solution and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by column chromatography (1 to 5% MeOH/CH2Cl2) to provide 0.076 g (70%) of the product as a white foam. the mixture was warmed to ambient temperature stirred for 4.5 hours washed with 1N KHSO4 (2×10 mL) The organic layer was dried over Na2SO4 filtered concentrated The crude material was purified by column chromatography (1 to 5% MeOH/CH2Cl2)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of dimethylhydroxylamine HCl (510 mg, 5.18 mmol) and triethylamine (2.16 mL, 15.5 mmol) in anhydrous THF (9.41 mL) and acetonitrile (2.35 mL) was added 4-chloropyridine-2-carbonyl chloride hydrochloride (1.00 g, 4.71 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h then at RT for 16 h. The solvent was removed under reduced pressure and partitioned between EtOAc and water. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by MPLC (biotage) eluted with 30% EtOAc/Hex to afford 925 mg (98%) of 4-chloro-N-methoxy-N-methylpyridine-2-carboxamide as an orange oil: TLC (50% EtOAc/Hex), Rf=0.31. at RT for 16 h The solvent was removed under reduced pressure partitioned between EtOAc and water The organic layer was washed with H2O and brine dried over Na2SO4 concentrated under reduced pressure The crude product was purified by MPLC (biotage) eluted with 30% EtOAc/Hex

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This intermediate (2.5 g, 9.28 mmol) was treated with oxalyl chloride (4.1 mL, 46.4 mmol), DMF (2 drops) in methylene chloride (70 mL) and stirred at room temperature for 2 hours to give 1-ethyl-4-(3-methoxy-phenylethynyl)-1H-pyrrole-2-carboxylic acid chloride (2.7 g, 9.38 mmol) after a usual workup. 1-Ethyl-4-(3-methoxy-phenylethynyl)-1H-pyrrole-2-carboxylic acid chloride (2.7 g, 9.38 mmol) was diluted with methylene chloride (35 mL) and added to a prepared solution of N,O, dimethyl-hydroxylamine hydrochloride (4.6 g, 46.4 mmol) and diisopropyl-ethyl amine (13 mL, 74.3 mmol) in methylene chloride (35 mL) over 5 minutes. The reaction was complete after 4 hours. Solvent was removed in vacuo and the residue was taken back in a mixture of saturated aqueous NH4Cl:H2O (1:1, 150 mL) solution and extracted with ether. Combined ether extracts were washed with brine dried (MgSO4) and filtered. Evaporation and purification by flash chromatography (hexane/ethyl acetate 9/1) gave the title compound as a light yellow oil (2.48 g g, 82% yield), 1H NMR (400 MHZ, CDCl3) □ 1.35-1.37 (t, 3H), 3.31 (s, 3H), 3.67 (s, 3H), 3.78 (s, 3H), 4.29-4.30 (q, 2H), 6.83 (m, 1H), 6.99 (m, 2H), 7.01 (m, 2H), 7.19 (m, 1H), MS m/e (M+H)+ 313.1. Solvent was removed in vacuo the residue was taken back in a mixture of saturated aqueous NH4Cl:H2O (1:1, 150 mL) solution extracted with ether Combined ether extracts were washed with brine dried (MgSO4) filtered Evaporation and purification by flash chromatography (hexane/ethyl acetate 9/1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl acetate (50.0 mL) was added to [(4R,6S)-6-methanesulfonyloxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl]-acetic acid (10.0 g) prepared in Preparation 8. The reaction mixture was cooled to 0˜5° C. and then 1,1′-carbonyldiimidazole (7.6 g) was slowly added thereto. The temperature of the reaction mixture was raised to 20˜30° C. The reaction mixture was stirred for 3 hours. Dimethylhydroxyamine hydrochloride (5.6 g) and sodium bicarbonate (3.2 g) were added to the reaction mixture, which was then stirred for over 3 hours while maintaining the temperature of 20˜25° C. Water (40.0 mL) was added to the reaction mixture under stirring. The separated organic layer was concentrated under reduced pressure to obtain 2-[(4R,6S)-6-methanesulfonyloxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl]-N-methoxy-N-methyl-acetamide (10.0 g, yield 87%). prepared in Preparation 8 The reaction mixture was cooled to 0˜5° C. The temperature of the reaction mixture was raised to 20˜30° C was then stirred for over 3 hours while maintaining the temperature of 20˜25° C under stirring The separated organic layer was concentrated under reduced pressure