2-(oxan-4-yl)acetaldehyde

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

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

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

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

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

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

Procedure: A mixture of (tetrahydro-pyran-4-yl)-acetaldehyde (Pharmacore), pyrrolidine, p-toluenesulfonic acid monohydrate, sulfur and cyanamide were processed using the method described in Example 136A to obtain the title compound. MS (ESI+) m/z 185 (M+H)+.

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

Procedure: A mixture of (tetrahydro-pyran-4-yl)-acetaldehyde (Pharmacore), pyrrolidine, p-toluenesulfonic acid monohydrate, sulfur and cyanamide were processed using the method described in Example 136A to obtain the title compound. MS (ESI+) m/z 185 (M+H)+.

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

Procedure: TFA (3.66 mL, 47.5 mmol) was added to a stirred mixture of tert-butyl 1-(3,5-dibromopyrazin-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (1.04 g, 2.374 mmol) in dichloromethane (20 mL). The resulting clear yellow solution was stirred at room temperature for 3 h. All volatiles were removed under reduced pressure and the residue dried under high vacuum to give a yellow semi-solid. MS (ESI) m/z 339.1 [M+1]+. Sodium sulfate (1.686 g, 11.87 mmol) was added followed by 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde (0.396 g, 3.09 mmol) and 1,2-dichloroethane (20 mL). The resulting mixture was stirred vigorously and heated at 80° C. under a reflux condenser under nitrogen for 2.5 h. More 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde (0.100 g, 0.780 mmol) and sodium sulfate (1.00 g, 7.04 mmol) were added and heating at 80° C. continued for another 2 h. The resulting yellow solution was removed by pipette from the solid sodium sulfate into a dry 250 mL round bottom flask equipped with a stirbar. The resulting mixture was stirred vigorously and cooled to 0° C. under nitrogen. Sodium triacetoxyborohydride (0.553 g, 2.61 mmol) was added slowly. The resulting mixture was stirred vigorously at 0° C. under nitrogen for 30 min. The cold bath was removed and the resulting mixture stirred at room temperature under nitrogen for 2 h. The mixture was cooled to 0° C. and more sodium triacetoxyborohydride (0.250 g, 1.180 mmol) was added. The cold bath was removed and the resulting mixture stirred at room temperature under nitrogen for 1.5 h. More sodium triacetoxyborohydride (0.055 g, 0.260 mmol) was added. The resulting mixture was stirred vigorously at room temperature under nitrogen for 1 h and then stirred overnight at 0° C. The resulting mixture was diluted with methanol and the volatiles removed under reduced pressure. The residue was taken up in methanol, filtered and purified using reverse-phase preparatory HPLC (10-40% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min). Fractions containing the desired product were combined and the solvent removed under reduced pressure. The residue was dried under vacuum to give the desired product (0.890 g, 1.978 mmol, 67% yield) as a slightly yellow foam-solid. MS (ESI) m/z 451.3 [M+1]+. All volatiles were removed under reduced pressure the residue dried under high vacuum to give a yellow semi-solid The resulting mixture was stirred vigorously heated at 80° C. under a reflux condenser under nitrogen for 2.5 h heating at 80° C. continued for another 2 h The resulting yellow solution was removed by pipette from the solid sodium sulfate into a dry 250 mL round bottom flask equipped with a stirbar The resulting mixture was stirred vigorously cooled to 0° C. under nitrogen The resulting mixture was stirred vigorously at 0° C. under nitrogen for 30 min The cold bath was removed the resulting mixture stirred at room temperature under nitrogen for 2 h The mixture was cooled to 0° C. The cold bath was removed the resulting mixture stirred at room temperature under nitrogen for 1.5 h The resulting mixture was stirred vigorously at room temperature under nitrogen for 1 h stirred overnight at 0° C the volatiles removed under reduced pressure filtered purified reverse-phase preparatory HPLC (10-40% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min) Fractions containing the desired product the solvent removed under reduced pressure The residue was dried under vacuum

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

Procedure: TFA (3.66 mL, 47.5 mmol) was added to a stirred mixture of tert-butyl 1-(3,5-dibromopyrazin-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (1.04 g, 2.374 mmol) in dichloromethane (20 mL). The resulting clear yellow solution was stirred at room temperature for 3 h. All volatiles were removed under reduced pressure and the residue dried under high vacuum to give a yellow semi-solid. MS (ESI) m/z 339.1 [M+1]+. Sodium sulfate (1.686 g, 11.87 mmol) was added followed by 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde (0.396 g, 3.09 mmol) and 1,2-dichloroethane (20 mL). The resulting mixture was stirred vigorously and heated at 80° C. under a reflux condenser under nitrogen for 2.5 h. More 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde (0.100 g, 0.780 mmol) and sodium sulfate (1.00 g, 7.04 mmol) were added and heating at 80° C. continued for another 2 h. The resulting yellow solution was removed by pipette from the solid sodium sulfate into a dry 250 mL round bottom flask equipped with a stirbar. The resulting mixture was stirred vigorously and cooled to 0° C. under nitrogen. Sodium triacetoxyborohydride (0.553 g, 2.61 mmol) was added slowly. The resulting mixture was stirred vigorously at 0° C. under nitrogen for 30 min. The cold bath was removed and the resulting mixture stirred at room temperature under nitrogen for 2 h. The mixture was cooled to 0° C. and more sodium triacetoxyborohydride (0.250 g, 1.180 mmol) was added. The cold bath was removed and the resulting mixture stirred at room temperature under nitrogen for 1.5 h. More sodium triacetoxyborohydride (0.055 g, 0.260 mmol) was added. The resulting mixture was stirred vigorously at room temperature under nitrogen for 1 h and then stirred overnight at 0° C. The resulting mixture was diluted with methanol and the volatiles removed under reduced pressure. The residue was taken up in methanol, filtered and purified using reverse-phase preparatory HPLC (10-40% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min). Fractions containing the desired product were combined and the solvent removed under reduced pressure. The residue was dried under vacuum to give the desired product (0.890 g, 1.978 mmol, 67% yield) as a slightly yellow foam-solid. MS (ESI) m/z 451.3 [M+1]+. All volatiles were removed under reduced pressure the residue dried under high vacuum to give a yellow semi-solid The resulting mixture was stirred vigorously heated at 80° C. under a reflux condenser under nitrogen for 2.5 h heating at 80° C. continued for another 2 h The resulting yellow solution was removed by pipette from the solid sodium sulfate into a dry 250 mL round bottom flask equipped with a stirbar The resulting mixture was stirred vigorously cooled to 0° C. under nitrogen The resulting mixture was stirred vigorously at 0° C. under nitrogen for 30 min The cold bath was removed the resulting mixture stirred at room temperature under nitrogen for 2 h The mixture was cooled to 0° C. The cold bath was removed the resulting mixture stirred at room temperature under nitrogen for 1.5 h The resulting mixture was stirred vigorously at room temperature under nitrogen for 1 h stirred overnight at 0° C the volatiles removed under reduced pressure filtered purified reverse-phase preparatory HPLC (10-40% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min) Fractions containing the desired product the solvent removed under reduced pressure The residue was dried under vacuum

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

Procedure: TFA (3.66 mL, 47.5 mmol) was added to a stirred mixture of tert-butyl 1-(3,5-dibromopyrazin-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (1.04 g, 2.374 mmol) in dichloromethane (20 mL). The resulting clear yellow solution was stirred at room temperature for 3 h. All volatiles were removed under reduced pressure and the residue dried under high vacuum to give a yellow semi-solid. MS (ESI) m/z 339.1 [M+1]+. Sodium sulfate (1.686 g, 11.87 mmol) was added followed by 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde (0.396 g, 3.09 mmol) and 1,2-dichloroethane (20 mL). The resulting mixture was stirred vigorously and heated at 80° C. under a reflux condenser under nitrogen for 2.5 h. More 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde (0.100 g, 0.780 mmol) and sodium sulfate (1.00 g, 7.04 mmol) were added and heating at 80° C. continued for another 2 h. The resulting yellow solution was removed by pipette from the solid sodium sulfate into a dry 250 mL round bottom flask equipped with a stirbar. The resulting mixture was stirred vigorously and cooled to 0° C. under nitrogen. Sodium triacetoxyborohydride (0.553 g, 2.61 mmol) was added slowly. The resulting mixture was stirred vigorously at 0° C. under nitrogen for 30 min. The cold bath was removed and the resulting mixture stirred at room temperature under nitrogen for 2 h. The mixture was cooled to 0° C. and more sodium triacetoxyborohydride (0.250 g, 1.180 mmol) was added. The cold bath was removed and the resulting mixture stirred at room temperature under nitrogen for 1.5 h. More sodium triacetoxyborohydride (0.055 g, 0.260 mmol) was added. The resulting mixture was stirred vigorously at room temperature under nitrogen for 1 h and then stirred overnight at 0° C. The resulting mixture was diluted with methanol and the volatiles removed under reduced pressure. The residue was taken up in methanol, filtered and purified using reverse-phase preparatory HPLC (10-40% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min). Fractions containing the desired product were combined and the solvent removed under reduced pressure. The residue was dried under vacuum to give the desired product (0.890 g, 1.978 mmol, 67% yield) as a slightly yellow foam-solid. MS (ESI) m/z 451.3 [M+1]+. All volatiles were removed under reduced pressure the residue dried under high vacuum to give a yellow semi-solid The resulting mixture was stirred vigorously heated at 80° C. under a reflux condenser under nitrogen for 2.5 h heating at 80° C. continued for another 2 h The resulting yellow solution was removed by pipette from the solid sodium sulfate into a dry 250 mL round bottom flask equipped with a stirbar The resulting mixture was stirred vigorously cooled to 0° C. under nitrogen The resulting mixture was stirred vigorously at 0° C. under nitrogen for 30 min The cold bath was removed the resulting mixture stirred at room temperature under nitrogen for 2 h The mixture was cooled to 0° C. The cold bath was removed the resulting mixture stirred at room temperature under nitrogen for 1.5 h The resulting mixture was stirred vigorously at room temperature under nitrogen for 1 h stirred overnight at 0° C the volatiles removed under reduced pressure filtered purified reverse-phase preparatory HPLC (10-40% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min) Fractions containing the desired product the solvent removed under reduced pressure The residue was dried under vacuum

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Chloro-3-aminopyridine (200 mg, 1.56 mmol) was dissolved in DMA (4 mL) and Pd2(dba)3 (71.2 mg, 0.08 mmol), X-Phos (74.2 mg, 0.16 mmol), potassium acetate (458 mg, 4.67 mmol) and (tetrahydro-pyran-4-yl)-acetaldehyde (598 mg, 4.67 mmol) were added under nitrogen. The reaction mixture was heated at 120° C. overnight, cooled to r.t. and partitioned between water (100 mL) and DCM (100 mL). The aqueous fraction was concentrated in vacuo and the residue was dissolved in DCM (100 mL), dried (MgSO4) and concentrated in vacuo to give the crude title compound as an orange/brown solid (314 mg, 99.8%). LCMS (ES+): 203.1 (M+H)+. cooled to r.t. partitioned between water (100 mL) and DCM (100 mL) The aqueous fraction was concentrated in vacuo the residue was dissolved in DCM (100 mL) dried (MgSO4) concentrated in vacuo

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Chloro-3-aminopyridine (200 mg, 1.56 mmol) was dissolved in DMA (4 mL) and Pd2(dba)3 (71.2 mg, 0.08 mmol), X-Phos (74.2 mg, 0.16 mmol), potassium acetate (458 mg, 4.67 mmol) and (tetrahydro-pyran-4-yl)-acetaldehyde (598 mg, 4.67 mmol) were added under nitrogen. The reaction mixture was heated at 120° C. overnight, cooled to r.t. and partitioned between water (100 mL) and DCM (100 mL). The aqueous fraction was concentrated in vacuo and the residue was dissolved in DCM (100 mL), dried (MgSO4) and concentrated in vacuo to give the crude title compound as an orange/brown solid (314 mg, 99.8%). LCMS (ES+): 203.1 (M+H)+. cooled to r.t. partitioned between water (100 mL) and DCM (100 mL) The aqueous fraction was concentrated in vacuo the residue was dissolved in DCM (100 mL) dried (MgSO4) concentrated in vacuo