tert-butyl 2-oxopropanoate

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

Procedure: In the manner given in Example 1, 7-chloro-2-hydrazino-5-(2,6-difluorophenyl)-3H-1,4-benzodiazepine can be stirred with tert.-butyl pyruvate to give 7-chloro-2-[[1-(t-butyoxycarbonyl)ethylidene]hydrazino]-5-(2,6-difluorophenyl)-3H-1,4-benzodiazepine.

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

Procedure: In the manner given in Example 1, 7-chloro-2-hydrazino-5-(2,6-difluorophenyl)-3H-1,4-benzodiazepine can be stirred with tert.-butyl pyruvate to give 7-chloro-2-[[1-(t-butyoxycarbonyl)ethylidene]hydrazino]-5-(2,6-difluorophenyl)-3H-1,4-benzodiazepine.

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

Procedure: In the manner given in Example 1, 7-chloro-2-hydrazino-5-(2,6-difluorophenyl)-3H-1,4-benzodiazepine can be stirred with tert.-butyl pyruvate to give 7-chloro-2-[[1-(t-butyoxycarbonyl)ethylidene]hydrazino]-5-(2,6-difluorophenyl)-3H-1,4-benzodiazepine.

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

Procedure: tert-Butyl pyruvate was prepared as follows: tert-butyl alcohol (444 mg, 6 mmol) and pyruvic acid (528 mg, 6 mmol) were dissolved in methylene chloride (30 mL) and cooled on an ice bath. Pyridine (948 mg. 0.97 mL, 12 mmol) was added, followed by addition of 1,1-dichloromethyl methyl ether (690 mg, 0.53 mL, 6 mmol). The reaction mixture was stirred for 1 h on an ice bath, warmed to room temperature and washed with 30 mL of 5% aqueous HCl, 30 mL of saturated aqueous NaHCO3, and 30 mL of saturated aqueous NaCl. The organic layer was dried over anhydrous MgSO4, filtered and solvent removed on a rotary evaporator to give tert-butyl pyruvate in quantitative yield, slightly contaminated with methylene chloride (as 1H NMR). Aliquots used for biological analyses were cleared of methylene chloride by short path vacuum distillation. tert-Butyl pyruvate was prepared cooled on an ice bath washed with 30 mL of 5% aqueous HCl, 30 mL of saturated aqueous NaHCO3, and 30 mL of saturated aqueous NaCl The organic layer was dried over anhydrous MgSO4 filtered solvent removed on a rotary evaporator

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

Procedure: tert-Butyl pyruvate was prepared as follows: tert-butyl alcohol (444 mg, 6 mmol) and pyruvic acid (528 mg, 6 mmol) were dissolved in methylene chloride (30 mL) and cooled on an ice bath. Pyridine (948 mg. 0.97 mL, 12 mmol) was added, followed by addition of 1,1-dichloromethyl methyl ether (690 mg, 0.53 mL, 6 mmol). The reaction mixture was stirred for 1 h on an ice bath, warmed to room temperature and washed with 30 mL of 5% aqueous HCl, 30 mL of saturated aqueous NaHCO3, and 30 mL of saturated aqueous NaCl. The organic layer was dried over anhydrous MgSO4, filtered and solvent removed on a rotary evaporator to give tert-butyl pyruvate in quantitative yield, slightly contaminated with methylene chloride (as 1H NMR). Aliquots used for biological analyses were cleared of methylene chloride by short path vacuum distillation. tert-Butyl pyruvate was prepared cooled on an ice bath washed with 30 mL of 5% aqueous HCl, 30 mL of saturated aqueous NaHCO3, and 30 mL of saturated aqueous NaCl The organic layer was dried over anhydrous MgSO4 filtered solvent removed on a rotary evaporator

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

Procedure: tert-Butyl pyruvate was prepared as follows: tert-butyl alcohol (444 mg, 6 mmol) and pyruvic acid (528 mg, 6 mmol) were dissolved in methylene chloride (30 mL) and cooled on an ice bath. Pyridine (948 mg. 0.97 mL, 12 mmol) was added, followed by addition of 1,1-dichloromethyl methyl ether (690 mg, 0.53 mL, 6 mmol). The reaction mixture was stirred for 1 h on an ice bath, warmed to room temperature and washed with 30 mL of 5% aqueous HCl, 30 mL of saturated aqueous NaHCO3, and 30 mL of saturated aqueous NaCl. The organic layer was dried over anhydrous MgSO4, filtered and solvent removed on a rotary evaporator to give tert-butyl pyruvate in quantitative yield, slightly contaminated with methylene chloride (as 1H NMR). Aliquots used for biological analyses were cleared of methylene chloride by short path vacuum distillation. tert-Butyl pyruvate was prepared cooled on an ice bath washed with 30 mL of 5% aqueous HCl, 30 mL of saturated aqueous NaHCO3, and 30 mL of saturated aqueous NaCl The organic layer was dried over anhydrous MgSO4 filtered solvent removed on a rotary evaporator

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl 2-methyl-1,3-dithiane-2-carboxylate (2 g, 8.547 mmol) was dissolved in acetone (85.5 mL), and water (0.5 mL) was added. The flask was then cooled in a cold bath at −20° C. Small aliquots of N-bromosuceinimide (15.4 g, 85.47 mmol) were added over 20 minutes. The reaction mixture was stirred at the same temperature for further 30 minutes, and then quenched by adding an aqueous solution of sodium bicarbonate (7.18 g, 85.47 mmol in 90 mL of water). Insoluble material was removed by filtration. The filtrate was diluted in water (200 mL) and extracted with tert-butyl methyl ether (150 mL). The separated organic layer was washed with water and a saturated brine in order, then dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the target compound as pale yellow oil at a yield of 40%. Small aliquots of N-bromosuceinimide (15.4 g, 85.47 mmol) were added over 20 minutes quenched Insoluble material was removed by filtration The filtrate was diluted in water (200 mL) extracted with tert-butyl methyl ether (150 mL) The separated organic layer was washed with water a saturated brine in order, then dried over anhydrous sodium sulfate filtered The filtrate was concentrated The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate)

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

Procedure: To a solution of 4-methylbenzaldehyde (2.5 mL, 21.2 mmol) in 25 mL of benzene was added 1 mL each of acetic acid and piperidine. The mixture was heated to reflux with azeotropic removal of water via a Dean-Stark trap. A solution of t-butyl pyruvate (3.36 g, 23.32 mmol) in 5 mL of benzene was added over 7 h by syringe pump. The mixture was cooled, diluted with ethyl acetate and washed three times with saturated aqueous sodium bicarbonate and three times with 1N hydrochloric acid. The organics were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by MPLC on silica-gel eluting with 2.5% ethyl acetate in hexane to give the desired product as a yellow oil: 1H NMR (200 MHz, CDCl3) δ7.75 (d, 1H, J=16.19 Hz), 7.49 (d, 2H, J=8.25 Hz), 7.24 (m, 3H), 2.37 (s, 3H), 1.58 (s, 9H). The above product was dissolved in ethyl acetate and held under hydrogen in the presence of 100 mg of 10% palladium on carbon for 2 hours. The mixture was filtered and concentrated in vacuo to give 1.196 g of the title compound as a pale-yellow oil: 1H NMR (200 MHz, CDCl3) δ7.1-6.9 (m, 4H), 3.12 (t, 2H, J=6.8 Hz), 2.90 (t, 2H, J=7.3 Hz), 1.56 (s, 9H). ##STR29## N-[1(R)-Benzyloxycarbonyl-5-(1,3-dioxo-isoindolin-2-yl)pentyl]-α-(S)-(2-phenyl-ethyl)!glycine-(L)-leucine, N-phenylamide (5d') The mixture was heated The mixture was cooled washed three times with saturated aqueous sodium bicarbonate and three times with 1N hydrochloric acid The organics were dried over sodium sulfate filtered concentrated The crude product was purified by MPLC on silica-gel eluting with 2.5% ethyl acetate in hexane

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

Procedure: In the manner given in Example 1, 7-chloro-2-hydrazino-5-(2,6-difluorophenyl)-3H-1,4-benzodiazepine can be stirred with tert.-butyl pyruvate to give 7-chloro-2-[[1-(t-butyoxycarbonyl)ethylidene]hydrazino]-5-(2,6-difluorophenyl)-3H-1,4-benzodiazepine.