sodium;hypochlorite

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

Procedure: To a solution of 2-(4-oxo-1,4-dihydropyridine-3-yloxy)acetic acid (16.9 g) in 0.5 N sodium hydroxide aqueous solution (200 ml), was added dropwise under cooling a sodium hypochlorite aqueous solution (70 ml) whose active chlorine is about 10% at 3° to 8° C. with stirring. The mixture was stirred for 30 minutes at the same temperture and adjusted to pH 3 with 10% hydrochloric acid. Precipitated crystals were collected by filtration, recrystallized from 1 N hydrochloric acid and dried at 90° to 95° C. for 4-5 hours in a stream of air to give crystals (16.7 g) of 2-(4-oxo-5-chloro-1,4-dihydropyridin-3-yloxy)acetic acid, mp 253° to 255° C. at 3° to 8° C. The mixture was stirred for 30 minutes at the same temperture Precipitated crystals were collected by filtration recrystallized from 1 N hydrochloric acid dried at 90° to 95° C. for 4-5 hours in a stream of air

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-(tert-butyl-dimethyl-silanyloxy)-pentanol (16.8 mmol, 3.66 g) in dichloromethane (30 mL) were added water (5.6 mL), potassium bromide (1.7 mmol, 202 mg), n-tetrabutylammonium hydrogensulfate (0.84 mmol, 290 mg), and TEMPO (30 mg) at room temperature. The resulting light brown solution was cooled to ˜5° C. and a solution of sodium hypochlorite (19.3 mmol, 30 mL, 5%) was added dropwise at this temperature. After addition of half of the sodium hypochlorite solution, solid potassium carbonate (300 mg) was added to maintain the reaction mixture basic. Then, the remaining sodium hypochlorite solution was added at 5-10° C. By this point, a precipitate had formed and the reaction mixture was stirred for another 1 h at ˜10-15° C. Then, water (100 mL) was added and the resulting solution was extracted into diethyl ether (2×100 mL). The combined organic extracts were washed with brine solution (150 mL) and the organic layer was dried over anhydrous magnesium sulfate. Filtration of the drying agent and the removal of the solvent gave 5-(tert-butyl-dimethyl-silanyloxy)-pentanal (3.32 g, 91%) as a light brown oil: ES(+)-HRMS m/e calculated for C11H24O2Si (M+H)+ 217.1619, found 217.1619. was added to maintain the reaction mixture basic By this point, a precipitate had formed the resulting solution was extracted into diethyl ether (2×100 mL) The combined organic extracts were washed with brine solution (150 mL) the organic layer was dried over anhydrous magnesium sulfate Filtration of the drying agent the removal of the solvent

Conditions: temp:42.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-(6,7-difluoro-1H-benzimidazol-1-yl)ethanol (2.96 g, 15 mmol) is taken into 75 ml of MeCN and sodium phosphate buffer (56 ml, 0.67 M, pH 6.8) and the mixture is heated to 42° C. TEMPO (165 mg, 1.05 mol) is added followed by the simultaneous dropwise addition of a solution of NaClO2 (3.38 g, 80% pure, 30 mmol in 15 ml water) and a solution of bleach (350 μL of 6% NaOCl in 7.5 mL water) over 1.5 hours. After 48 hrs, the same quantities of NaClO2 and bleach are added. After a further 24 hours, TEMPO (165 mg, 1.05 mol) is added and the reaction is stirred for 72 hrs. The darkened reaction is allowed to cool to room temperature followed by the dropwise addition of 30 ml of a saturated solution of Na2SO3 (exothermic). The reaction becomes almost colourless. Using 2 N NaOH, the pH is raised to 9.2 and the reaction is extracted 4 times with ethyl acetate. The pH is then lowered to 3.8 with 2 N HCl and the solution allowed to stand for 48 hours. 1.98 grams of white crystalline material is recovered. The mother liquor is reduced to half the volume and allowed to stand. A further 260 mg is collected. (Combined yield 2.23 g, 70%) After a further 24 hours The darkened reaction to cool to room temperature the pH is raised to 9.2 the reaction is extracted 4 times with ethyl acetate to stand for 48 hours 1.98 grams of white crystalline material is recovered A further 260 mg is collected

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-(tert-butyl-dimethyl-silanyloxy)-pentanol (16.8 mmol, 3.66 g) in dichloromethane (30 mL) were added water (5.6 mL), potassium bromide (1.7 mmol, 202 mg), n-tetrabutylammonium hydrogensulfate (0.84 mmol, 290 mg), and TEMPO (30 mg) at room temperature. The resulting light brown solution was cooled to ˜5° C. and a solution of sodium hypochlorite (19.3 mmol, 30 mL, 5%) was added dropwise at this temperature. After addition of half of the sodium hypochlorite solution, solid potassium carbonate (300 mg) was added to maintain the reaction mixture basic. Then, the remaining sodium hypochlorite solution was added at 5-10° C. By this point, a precipitate had formed and the reaction mixture was stirred for another 1 h at ˜10-15° C. Then, water (100 mL) was added and the resulting solution was extracted into diethyl ether (2×100 mL). The combined organic extracts were washed with brine solution (150 mL) and the organic layer was dried over anhydrous magnesium sulfate. Filtration of the drying agent and the removal of the solvent gave 5-(tert-butyl-dimethyl-silanyloxy)-pentanal (3.32 g, 91%) as a light brown oil: ES(+)-HRMS m/e calculated for C11H24O2Si (M+H)+ 217.1619, found 217.1619. was added to maintain the reaction mixture basic By this point, a precipitate had formed the resulting solution was extracted into diethyl ether (2×100 mL) The combined organic extracts were washed with brine solution (150 mL) the organic layer was dried over anhydrous magnesium sulfate Filtration of the drying agent the removal of the solvent

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-(tert-butyl-dimethyl-silanyloxy)-pentanol (16.8 mmol, 3.66 g) in dichloromethane (30 mL) were added water (5.6 mL), potassium bromide (1.7 mmol, 202 mg), n-tetrabutylammonium hydrogensulfate (0.84 mmol, 290 mg), and TEMPO (30 mg) at room temperature. The resulting light brown solution was cooled to ˜5° C. and a solution of sodium hypochlorite (19.3 mmol, 30 mL, 5%) was added dropwise at this temperature. After addition of half of the sodium hypochlorite solution, solid potassium carbonate (300 mg) was added to maintain the reaction mixture basic. Then, the remaining sodium hypochlorite solution was added at 5-10° C. By this point, a precipitate had formed and the reaction mixture was stirred for another 1 h at ˜10-15° C. Then, water (100 mL) was added and the resulting solution was extracted into diethyl ether (2×100 mL). The combined organic extracts were washed with brine solution (150 mL) and the organic layer was dried over anhydrous magnesium sulfate. Filtration of the drying agent and the removal of the solvent gave 5-(tert-butyl-dimethyl-silanyloxy)-pentanal (3.32 g, 91%) as a light brown oil: ES(+)-HRMS m/e calculated for C11H24O2Si (M+H)+ 217.1619. found 217.1619. was added to maintain the reaction mixture basic By this point, a precipitate had formed the resulting solution was extracted into diethyl ether (2×100 mL) The combined organic extracts were washed with brine solution (150 mL) the organic layer was dried over anhydrous magnesium sulfate Filtration of the drying agent the removal of the solvent

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

Procedure: To a solution of N-[2-(6-Chloro-4-formyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide (1.5 g) in a mixture of THF (25 mL), t-butanol (10 mL) and 2-methyl-2-butene was added dropwise the solution of sodium hypochlorite (0.9 g) and sodium dihydrogen phosphate (1.15 g) in water (20 mL). After 4 hour at room temperature, the mixture was concentrated under reduced pressure, diluted with water (50 mL) and acidified to pH 2 with normal HCl. The white solid was filtered and washed with water and dried under vacuum to give the title compound (1.35 g, 87%). MS (ES): M/Z [M+H]=468. 1H NMR: (400 MHz, DMSO-d6): 1.72 (s, 3H), 5.48-5.64 (m, 2H), 7.43 (d, J=8.2 Hz, 2H), 7.83 (d, J=2.0 Hz, 1H), 7.99 (d, J=8.8 Hz, 2H), 8.23 (d, J=1.8 Hz, 0H) and 9.41 (br. s, 1H). 19F NMR (376 MHz, DMSO-d6): −57.1 (s, 3F). the mixture was concentrated under reduced pressure diluted with water (50 mL) The white solid was filtered washed with water dried under vacuum

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

Procedure: Dichloromethane (25 mL), 2-[(1,5-dimethylhexyl)oxy]ethanol (5 g, 29 mmol), a solution of potassium bromide (0.34 g, 2.9 mmol) in water (4.72 g) and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO, 0.053 g, 0.34 mmol) was charged to 100 mL flask fitted with addition funnel, condenser, nitrogen, thermocouple and mechanical stirrer. A 2.8 wt % aqueous solution of sodium hypochlorite (173.5 g, 65 mmol) was added and the reaction stirred for a total of 15 hrs. The product was extracted with hexane (200 ml) and washed with water (2×200 ml). The organic phase was dried over sodium sulphate, filtered and the solvent removed by evaporation to yield a colourless oil (3.9 g). This oil (2 g) was chromatographed over silica gel (methyltert-butyl ether/hexane) to yield the product as a colourless oil (1.18 g, equating to a total chemical yield of 25%). fitted with addition funnel, condenser The product was extracted with hexane (200 ml) washed with water (2×200 ml) The organic phase was dried over sodium sulphate filtered the solvent removed by evaporation

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Benzyloxymethyl-cyclohexanecarbaldehyde (1.70 g, 2.0 mmol) is dissolved in acetic acid (0.24 mL) and 2 mL of MeOH. The reaction mixture is cooled to 0-5° C. and stirred while 10% NaOCl solution (2.5 mL, 4 mmol) is added dropwise over 20 minutes. The cooling bath is removed and the mixture is allowed to come to room temperature. After addition of saturated aqueous NaHCO3, the aqueous layer is extracted with EtOAc. The combined organic layer (dried with MgSO4) is concentrated. The desired product, 4-benzyloxymethyl-cyclohexanecarboxylic acid methyl ester, is obtained (343 mg, 65%) after purification using silica gel column chromatography (eluent: EtOAc/hexane). is added dropwise over 20 minutes The cooling bath is removed to come to room temperature After addition of saturated aqueous NaHCO3 the aqueous layer is extracted with EtOAc The combined organic layer (dried with MgSO4) is concentrated

Conditions: temp:79.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: P(OEt)3 (0.9 mL, 903 mg, 5.4 mmol) was added to a solution of bromide 93 (904 mg, 3.6 mmol) in ethanol at 79° C. The resulting mixture was stirred at 79° C. for 4 h. The mixture was then cooled in an ice bath and NaOCl (19 mL of a 10-15% sol, 1.2 g, 16 mmol) was added. The solution was cooled and concentrated under reduced pressure to provided crude 94. The mixture was then cooled in an ice bath The solution was cooled concentrated under reduced pressure to provided crude 94

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

Procedure: A solution of 2-trifluoromethylphenol (10 g, 61.7 mmol) in methanol (125 mL) at room temperature was treated with sodium hydroxide (13.87 g, 93 mmol) and stirred until homogeneous. The mixture was cooled in an ice bath and sodium iodide (2.96 g, 74 mmol) was added portionwise followed by the addition of 10% sodium hypochlorite (84 mL, 136 mmol) dropwise, dividing these reagents into 3 portions and adding them sequentially over 30 minutes. The solution was then adjusted to pH 1 by dropwise addition of concentrated hydrochloric acid and poured into brine. The product was extracted into ethyl acetate, concentrated in vacuo and purified by silica gel flash chromatography eluting with ethyl acetate/hexane (0% to 5%) to give the title compound. The mixture was cooled in an ice bath adding them sequentially over 30 minutes The product was extracted into ethyl acetate concentrated in vacuo purified by silica gel flash chromatography eluting with ethyl acetate/hexane (0% to 5%)

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

Procedure: A dichloromethane (dehydrated, 5 mL) solution of 946 mg (4.07 mmol) of the compound of the formula 3 was cooled to −5° C., 14.0 mg (0.090 mmol) of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), 102.0 mg (1.21 mmol) of sodium hydrogen carbonate, and 2.0 mL of water were added in sequence, and 3.86 g (5.19 mmol) of a 10% sodium hypochlorite aqueous solution was then added while keeping the internal temperature between −5° C. and 0° C. After stirring at −5° C. to 0° C. for 1 hour, the mixture was separated. The organic layer was washed with 1 mL of water and dried over anhydrous sodium sulfate. After concentration under reduced pressure, 899 mg of the compound of the formula 4 was obtained as an oily substance with yellow color. was then added the internal temperature between −5° C. and 0° C the mixture was separated The organic layer was washed with 1 mL of water dried over anhydrous sodium sulfate After concentration under reduced pressure, 899 mg of the compound of the formula 4 was obtained as an oily substance with yellow color

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

Procedure: Methyl 3-chloro-1-methyl-4,5-dihydro-1H-pyrazole-5-carboxylate (21 g, 119 mmol) was added drop wise to sodium hypochlorite (95 ml, 155 mmol) under ice cooling. Then, the ice bath was removed and stirring continued for 72 h. The organic phase was separated, washed with Na2S2O3 (10% aqueous solution) and water, dried over Na2SO4 and the solvent removed under reduced pressure. The resulting oil was purified by distillation (bp 35° C., 0.2 mbar) followed by column chromatography (eluent 80% hexane in EtOAc) to yield 6.0 g (29%) of the title compound. [1H-NMR (DMSO-d6, 360 MHz) δ 6.96 (s, 1H), 6.80 (s, 1H), 4.07 (s, 3H), 3.86 (s, 3H)] Then, the ice bath was removed The organic phase was separated washed with Na2S2O3 (10% aqueous solution) and water dried over Na2SO4 the solvent removed under reduced pressure The resulting oil was purified by distillation (bp 35° C., 0.2 mbar)