2-bromopropanedial

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of ethyl 5-amino-1H-pyrazole-4-carboxylate (2 g, 12.89 mmol) and sodium hydroxide (19.34 mL, 38.7 mmol) (aqueous, 2M) in ethanol (30 mL) was heated at 80° C. overnight. The reaction mixture was concentrated in vacuo to give a crude mixture of carboxylate and sodium hydroxide. The crude mixture was dissolved in ethanol (4 mL) and acetic acid (14 mL, 245 mmol). Whilst stirring the mixture, bromomalonaldehyde (1.947 g, 12.90 mmol) was added and then the mixture heated to 70° C. for 1 h. The reaction mixture was allowed to cool and the precipitate was filtered and washed with ethanol. The solid product was dried in a vacuum oven to give the title compound (1.589 g). The reaction mixture was concentrated in vacuo to give a crude was added to cool the precipitate was filtered washed with ethanol The solid product was dried in a vacuum oven

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

Procedure: Bromomalonaldehyde (500 mg, 2.90 mmol) was added to a solution of 5-bromopyrimidin-2-amine (526 mg, 3.49 mmol) in acetonitrile. The reaction mixture was refluxed for 2 hours. After completion of the reaction, the reaction mixture was quenched with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The organic layer was concentrated and the product was purified by column chromatography using up to 2% methanol in chloroform gradient to obtain the title compound. Yield: 40%; 1H NMR (DMSO-d6; 300 MHz): δ 9.98(s, 1H), 9.75-9.76 (d, 1H, J=2.4 Hz), 8.97-8.98 (d, 1H, 2.4 Hz), 8.70 (s, 1H); MS (m/z): 226 (M+1)+. The reaction mixture was refluxed for 2 hours After completion of the reaction the reaction mixture was quenched with sodium bicarbonate solution extracted with ethyl acetate The organic layer was washed with brine dried over sodium sulfate The organic layer was concentrated the product was purified by column chromatography

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

Procedure: Bromomalonaldehyde (464 mg, 3.07 mmol) was added to a solution of 5-bromo-6-methylpyridin-2-amine (500 mg, 2.67 mmol) in acetonitrile. The reaction mixture was refluxed for 1 hour. After completion of the reaction, the reaction mixture was quenched with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The organic layer was concentrated and the product was purified by column chromatography using up to 0.5% methanol in chloroform gradient to obtain the title compound. Yield: 28%; 1H NMR (DMSO-d6; 300 MHz): δ 10.06 (s, 1H), 8.51 (s, 1H), 7.86-7.83 (d, 1H, J=9.3 Hz), 7.68 (d, 1H, J=9.3 Hz), 3.03 (s, 3H); MS: m/z 240.1 (M+1)+. The reaction mixture was refluxed for 1 hour After completion of the reaction the reaction mixture was quenched with sodium bicarbonate solution extracted with ethyl acetate The organic layer was washed with brine dried over sodium sulfate The organic layer was concentrated the product was purified by column chromatography

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

Procedure: Bromomalonaldehyde (5000 mg, 26.74 mmol) was added to a solution of 5-bromo-4-methylpyridin-2-amine in acetonitrile (5250 mg, 34.76 mmol). The reaction mixture was refluxed for 2 hours. After completion of the reaction, the reaction mixture was quenched with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The organic layer was concentrated in vacuum and the product was purified by column chromatography using ethyl acetate-petroleum ether gradient to obtain the title compound. Yield: 79.81%; 1H NMR (DMSO-d6; 300 MHz): δ 9.90 (s, 1H), 9.52 (s, 1H), 8.51 (s, 1H), 7.94 (s, 1H), 2.50 (s, 3H); MS (m/z): 239 (M+1)+. The reaction mixture was refluxed for 2 hours After completion of the reaction the reaction mixture was quenched with sodium bicarbonate solution extracted with ethyl acetate The organic layer was washed with brine dried over sodium sulfate The organic layer was concentrated in vacuum the product was purified by column chromatography

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

Procedure: For the synthesis of this starting compound, 1.80 g (12.3 mmol, 1.1 eq) of bromomalondialdehyde was first dissolved in 30 ml of ethanol, and 1.25 ml of m-anisidine was added. This reaction mixture is stirred over night at RT and, after the addition of acetic acid (20 ml), at 100° C. for 10 days. The solvent is subsequently removed in vacuum on a rotary evaporator, and the residual solid is partitioned between a water and an ethyl acetate phase. The aqueous phase is made alkaline with an ammonia solution, and insoluble particles were filtered off. The filtrate is extracted with ethyl acetate, and the organic phase is dried over MgSO4, filtered, and the solvent is removed in vacuum on a rotary evaporator. The product was purified by column chromatography with a mixture of hexane/ethyl acetate 8/2 as the eluent in a yield of 20% (700 mg). The solvent is subsequently removed in vacuum on a rotary evaporator the residual solid is partitioned between a water were filtered off The filtrate is extracted with ethyl acetate the organic phase is dried over MgSO4 filtered the solvent is removed in vacuum on a rotary evaporator The product was purified by column chromatography with a mixture of hexane/ethyl acetate 8/2 as the eluent in a yield of 20% (700 mg)

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

Procedure: For the synthesis of this starting compound, 1.80 g (12.3 mmol, 1.1 eq) of bromomalondialdehyde was first dissolved in 30 ml of ethanol, and 1.25 ml of m-anisidine was added. This reaction mixture is stirred over night at RT and, after the addition of acetic acid (20 ml), at 100° C. for 10 days. The solvent is subsequently removed in vacuum on a rotary evaporator, and the residual solid is partitioned between a water and an ethyl acetate phase. The aqueous phase is made alkaline with an ammonia solution, and insoluble particles were filtered off. The filtrate is extracted with ethyl acetate, and the organic phase is dried over MgSO4, filtered, and the solvent is removed in vacuum on a rotary evaporator. The product was purified by column chromatography with a mixture of hexane/ethyl acetate 8/2 as the eluent in a yield of 20% (700 mg). The solvent is subsequently removed in vacuum on a rotary evaporator the residual solid is partitioned between a water were filtered off The filtrate is extracted with ethyl acetate the organic phase is dried over MgSO4 filtered the solvent is removed in vacuum on a rotary evaporator The product was purified by column chromatography with a mixture of hexane/ethyl acetate 8/2 as the eluent in a yield of 20% (700 mg)

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

Procedure: To a solution of 4-ethyl-1H-pyrazol-3-amine (0.50 g, 4.50 mmol) and 2-bromo-malonaldehyde (1.47 g, 9.72 mmol) in ethanol (8.0 mL) was added acetic acid (1.21 mL, 21.2 mmol). The reaction mixture was refluxed for 4 h, then stored in a freezer overnight. The mixture was warmed to rt, the resulting precipitate was removed by filtration and the filtrate concentrated. The resulting residue was portioned between ethyl acetate and 1M sodium hydroxide and the organic layer was washed with brine, dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 50% EtOAc/Hex) to give product. LCMS-ESI+: calc'd for C8H9BrN3: 226.0 (M+H+); Found: 226.1 (M+H+). The reaction mixture was refluxed for 4 h the resulting precipitate was removed by filtration the filtrate concentrated the organic layer was washed with brine dried (MgSO4) filtered concentrated purified by CombiFlash (0 to 50% EtOAc/Hex) to give product

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

Procedure: To a solution of 4-ethyl-1H-pyrazol-3-amine (0.50 g, 4.50 mmol) and 2-bromo-malonaldehyde (1.47 g, 9.72 mmol) in ethanol (8.0 mL) was added acetic acid (1.21 mL, 21.2 mmol). The reaction mixture was refluxed for 4 h, then stored in a freezer overnight. The mixture was warmed to rt, the resulting precipitate was removed by filtration and the filtrate concentrated. The resulting residue was portioned between ethyl acetate and 1M sodium hydroxide and the organic layer was washed with brine, dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 50% EtOAc/Hex) to give product. LCMS-ESI+: calc'd for C8H9BrN3: 226.0 (M+H+); Found: 226.1 (M+H+). The reaction mixture was refluxed for 4 h the resulting precipitate was removed by filtration the filtrate concentrated the organic layer was washed with brine dried (MgSO4) filtered concentrated purified by CombiFlash (0 to 50% EtOAc/Hex) to give product

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

Procedure: With moderate agitation, a 20 gallon reactor system was charged with cyclohexane (29.12 L), 2-bromo-malonaldehyde (2.33 kg), p-toluenesulfonic acid monohydrate 43.94 g, and 2-propanol (4.65 L). The contents of the reactor were heated to allow for the removal of distillate under atmospheric pressure (jacket temp. 95° C. and process temp. at 66.4° C.). A total of 16 L of distillate was removed from the reaction via the cooling tower. This represents approximately 47% of the total volume of cyclohexane/2-propanol (33.77 L) being removed from the reactor. The reaction solution was cooled to near ambient temperature and transferred to a 10 gallon reactor system at 40° C. An additional 6 L of distillate was removed under vacuum (~64 torr, jacket temp. 62° C., and reaction temp. 25° C.). The mobile dark orange oil was drained from the vessel and transferred to a rotary evaporator receiver flask and further concentrated under house vacuum at ~30° C. using a rotary evaporator. About 0.2 L more of solvent was removed. Total product obtained was 3.072 kg (16 mol, 103% yield). The product was used as obtained in the next step. This material is unstable and must be kept in a freezer (<-5° C., under nitrogen). The shelve-life is about 2 weeks. The contents of the reactor were heated to allow for the removal of distillate under atmospheric pressure (jacket temp. 95° C. and process temp. at 66.4° C.) A total of 16 L of distillate was removed from the reaction via the cooling tower This represents approximately 47% of the total volume of cyclohexane/2-propanol (33.77 L) being removed from the reactor transferred to a 10 gallon reactor at 40° C An additional 6 L of distillate was removed under vacuum (~64 torr, jacket temp. 62° C., and reaction temp. 25° C.) transferred to a rotary evaporator receiver flask further concentrated under house vacuum at ~30° C. a rotary evaporator About 0.2 L more of solvent was removed Total product obtained as obtained in the next step must be kept in a freezer (<-5° C., under nitrogen) The shelve-life is about 2 weeks

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

Procedure: With moderate agitation, a 20 gallon reactor system was charged with cyclohexane (29.12 L), 2-bromo-malonaldehyde (2.33 kg), p-toluenesulfonic acid monohydrate 43.94 g, and 2-propanol (4.65 L). The contents of the reactor were heated to allow for the removal of distillate under atmospheric pressure (jacket temp. 95° C. and process temp. at 66.4° C.). A total of 16 L of distillate was removed from the reaction via the cooling tower. This represents approximately 47% of the total volume of cyclohexane/2-propanol (33.77 L) being removed from the reactor. The reaction solution was cooled to near ambient temperature and transferred to a 10 gallon reactor system at 40° C. An additional 6 L of distillate was removed under vacuum (~64 torr, jacket temp. 62° C., and reaction temp. 25° C.). The mobile dark orange oil was drained from the vessel and transferred to a rotary evaporator receiver flask and further concentrated under house vacuum at ~30° C. using a rotary evaporator. About 0.2 L more of solvent was removed. Total product obtained was 3.072 kg (16 mol, 103% yield). The product was used as obtained in the next step. This material is unstable and must be kept in a freezer (<-5° C., under nitrogen). The shelve-life is about 2 weeks. The contents of the reactor were heated to allow for the removal of distillate under atmospheric pressure (jacket temp. 95° C. and process temp. at 66.4° C.) A total of 16 L of distillate was removed from the reaction via the cooling tower This represents approximately 47% of the total volume of cyclohexane/2-propanol (33.77 L) being removed from the reactor transferred to a 10 gallon reactor at 40° C An additional 6 L of distillate was removed under vacuum (~64 torr, jacket temp. 62° C., and reaction temp. 25° C.) transferred to a rotary evaporator receiver flask further concentrated under house vacuum at ~30° C. a rotary evaporator About 0.2 L more of solvent was removed Total product obtained as obtained in the next step must be kept in a freezer (<-5° C., under nitrogen) The shelve-life is about 2 weeks

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a slurry of (5-amino-1H-[1,2,4]triazol-3-yl)-methanol (6.29 g, 33.12 mmol) in acetic acid (25 ml) was added bromomalonaldehyde (5 g, 33.12 mmol). The mixture was heated at 60° C. for hours, and then cooled to room temperature. The light yellow solid was formed. After the solid were removed by filtration followed by drying in vacuum oven provides the light yellow solid as desired product, the filtrate was concentrate by rotary evaporation to give yellow oil. The crude oil was purified by flash chromatography (2% MeOH in CH2Cl2) to give the desired product as light yellow solid (combine total 6.5 g, 86% yield). 1H NMR (300 MHz, DMSO-D6) δ ppm 4.65 (d, J=5.46 Hz, 2 H) 5.50–5.67 (m, 1 H) 8.94 (d, J=2.45 Hz, 1 H) 9.83 (d, J=2.26 Hz, 1 H). MS: (APCI) 230 (M+H) cooled to room temperature The light yellow solid was formed After the solid were removed by filtration by drying in vacuum oven