2-methylcyclohexane-1-carbonyl chloride

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

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

Procedure: In analogy to the procedure for Example 36A, 150 mg (0.67 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 120 mg (0.74 mmol) 2-methylcyclohexanecarbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification. The crude product is used in the next step without further purification

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

Procedure: In analogy to the procedure for Example 36A, 150 mg (0.67 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 120 mg (0.74 mmol) 2-methylcyclohexanecarbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification. The crude product is used in the next step without further purification

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

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

Procedure: To a solution of 5-(4-tert-butylphenylsulfonyl)-2-hydrazinyl-5H-pyrrolo[2,3-b]pyrazine (0.40 g, 1.2 mmol, Preparation #3) and DIEA (0.20 mL, 1.2 mmol) in 1,4-dioxane (12 mL) at about 0° C. was added 2-methylcyclohexanecarbonyl chloride (0.19 g, 1.2 mmol, Preparation #4). After the complete addition, the ice bath was removed and the reaction was allowed to warm to ambient temperature. After about 1 h, SOCl2 (0.42 mL, 5.8 mmol) was added and the reaction was heated at about 90° C. for about 1 h. The reaction was allowed to cool to ambient temperature and then aqueous Na2CO3 (2 M, 11.6 mL, 23.2 mmol) and MeOH (12 mL) were added. The reaction was heated at about 90° C. for about 3 days. The reaction was concentrated under reduced pressure to remove MeOH and then partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (40 mL). The organic layer was separated and dried over anhydrous Na2SO4 and the solvent was concentrated under reduced pressure. The residue was purified over silica gel (12 g) using EtOAc as the eluent and then further purified by RP-HPLC (Table 2, Method b). The combined product-containing fractions were concentrated under reduced pressure to remove the MeCN and the resulting precipitate was collected by vacuum filtration to afford 1-(2-methylcyclohexyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine as a white solid (0.10 g, 35%): LC/MS (Table 2, Method a) Rt=1.84 min; MS m/z: 256 (M+H)+. After the complete addition the ice bath was removed the reaction was heated at about 90° C. for about 1 h to cool to ambient temperature The reaction was heated at about 90° C. for about 3 days The reaction was concentrated under reduced pressure to remove MeOH partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (40 mL) The organic layer was separated dried over anhydrous Na2SO4 the solvent was concentrated under reduced pressure The residue was purified over silica gel (12 g) further purified by RP-HPLC (Table 2, Method b) The combined product-containing fractions were concentrated under reduced pressure to remove the MeCN the resulting precipitate was collected by vacuum filtration

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

Procedure: To a flask containing an amine or an amine salt (preferably 1 equiv) is added CDI (1-2 equiv, preferably 1.10 equiv) and an organic solvent (such as 1,4-dioxane, THF, DCM, DMF, or pyridine, preferably pyridine). If an amine salt is used, pyridine is used as the solvent. The reaction mixture is stirred at ambient temperature for about 2-24 h (preferably about 16 h). A second amine (1-3 equiv, preferably 1.10 equiv) is then added to the mixture which is stirred at ambient temperature for about 2-24 h (preferably about 16 h). The organic solvent is optionally removed under reduced pressure. The crude material can be partitioned between an organic solvent (such as EtOAc or DCM) and water, an aqueous base (such as saturated aqueous NaHCO3) or brine. The layers are separated and the organic solution is optionally washed with water, an aqueous base (such as saturated aqueous NaHCO3) and/or brine, dried over anhydrous Na2SO4 or MgSO4, filtered, and concentrated under reduced pressure to give the target compound. The crude material is optionally purified by precipitation, crystallization, or trituration from an appropriate solvent or solvents or by chromatography to give the target compound. is stirred at ambient temperature for about 2-24 h (preferably about 16 h) The organic solvent is optionally removed under reduced pressure The crude material can be partitioned between an organic solvent (such as EtOAc or DCM) and water The layers are separated the organic solution is optionally washed with water an aqueous base (such as saturated aqueous NaHCO3) and/or brine, dried over anhydrous Na2SO4 or MgSO4 filtered concentrated under reduced pressure to give the target compound The crude material is optionally purified by precipitation, crystallization, or trituration from an appropriate solvent or solvents or by chromatography to give the target compound

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

Procedure: To a solution of 2-methylcyclohexanecarboxylic acid (6.00 mL, 42.6 mmol, mixture of cis and trans) in DCM (60 mL) was added oxalyl chloride (4.80 mL, 55.3 mmol) followed by DMF (0.03 mL, 0.4 mmol). The reaction was stirred at ambient temperature for about 4 h before it was concentrated under reduced pressure to a constant weight to afford 2-methylcyclohexanecarbonyl chloride (mixture of diastereomers) as a yellow oil (7.0 g, 97%): 1H NMR (400 MHz, CDCl3) δ 2.98-2.94 (m, 1H), 2.39-2.35 (m, 1H), 1.91-1.82 (m, 1H), 1.79-1.72 (m, 1H), 1.69-1.60 (m, 2H), 1.57-1.47 (m, 2H), 1.42-1.36 (m, 1H), 1.34-1.26 (m, 1H), 1.04-0.96 (m, 3H). was concentrated under reduced pressure to a constant weight

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

Procedure: To a solution of 2-methylcyclohexanecarboxylic acid (6.00 mL, 42.6 mmol, mixture of cis and trans) in DCM (60 mL) was added oxalyl chloride (4.80 mL, 55.3 mmol) followed by DMF (0.03 mL, 0.4 mmol). The reaction was stirred at ambient temperature for about 4 h before it was concentrated under reduced pressure to a constant weight to afford 2-methylcyclohexanecarbonyl chloride (mixture of diastereomers) as a yellow oil (7.0 g, 97%): 1H NMR (400 MHz, CDCl3) δ 2.98-2.94 (m, 1H), 2.39-2.35 (m, 1H), 1.91-1.82 (m, 1H), 1.79-1.72 (m, 1H), 1.69-1.60 (m, 2H), 1.57-1.47 (m, 2H), 1.42-1.36 (m, 1H), 1.34-1.26 (m, 1H), 1.04-0.96 (m, 3H). was concentrated under reduced pressure to a constant weight

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

Procedure: To a solution of 5-(4-tert-butylphenylsulfonyl)-2-hydrazinyl-5H-pyrrolo[2,3-b]pyrazine (0.40 g, 1.2 mmol, Preparation #3) and DIEA (0.20 mL, 1.2 mmol) in 1,4-dioxane (12 mL) at about 0° C. was added 2-methylcyclohexanecarbonyl chloride (0.19 g, 1.2 mmol, Preparation #4). After the complete addition, the ice bath was removed and the reaction was allowed to warm to ambient temperature. After about 1 h, SOCl2 (0.42 mL, 5.8 mmol) was added and the reaction was heated at about 90° C. for about 1 h. The reaction was allowed to cool to ambient temperature and then 2 M aqueous Na2CO3 (2N, 11.6 mL, 23.2 mmol) and MeOH (12 mL) were added. The reaction was heated at about 90° C. for about 3 days. The reaction was concentrated under reduced pressure and then partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (40 mL). The organic layer was separated and dried over anhydrous Na2SO4, filtered and the solvent was concentrated under reduced pressure. The residue was purified over silica gel (12 g) using EtOAc as the eluent and then further purified by RP-HPLC (Table 2, Method b). The combined product-containing fractions were concentrated under reduced pressure to remove the MeCN and the resulting precipitate was collected by vacuum filtration to afford 1-(2-methylcyclohexyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine as a white solid (0.10 g, 35%): LC/MS (Table 2, Method a) Rt=1.84 min; MS m/z: 256 (M+H)+. After the complete addition the ice bath was removed the reaction was heated at about 90° C. for about 1 h to cool to ambient temperature The reaction was heated at about 90° C. for about 3 days The reaction was concentrated under reduced pressure partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (40 mL) The organic layer was separated dried over anhydrous Na2SO4 filtered the solvent was concentrated under reduced pressure The residue was purified over silica gel (12 g) further purified by RP-HPLC (Table 2, Method b) The combined product-containing fractions were concentrated under reduced pressure to remove the MeCN the resulting precipitate was collected by vacuum filtration

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

Procedure: To a solution of 5-(4-tert-butylphenylsulfonyl)-2-hydrazinyl-5H-pyrrolo[2,3-b]pyrazine (0.40 g, 1.2 mmol, Preparation #3) and DIEA (0.20 mL, 1.2 mmol) in 1,4-dioxane (12 mL) at about 0° C. was added 2-methylcyclohexanecarbonyl chloride (0.19 g, 1.2 mmol, Preparation #4). After the complete addition, the ice bath was removed and the reaction was allowed to warm to ambient temperature. After about 1 h, SOCl2 (0.42 mL, 5.8 mmol) was added and the reaction was heated at about 90° C. for about 1 h. The reaction was allowed to cool to ambient temperature and then 2 M aqueous Na2CO3 (2N, 11.6 mL, 23.2 mmol) and MeOH (12 mL) were added. The reaction was heated at about 90° C. for about 3 days. The reaction was concentrated under reduced pressure and then partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (40 mL). The organic layer was separated and dried over anhydrous Na2SO4, filtered and the solvent was concentrated under reduced pressure. The residue was purified over silica gel (12 g) using EtOAc as the eluent and then further purified by RP-HPLC (Table 2, Method b). The combined product-containing fractions were concentrated under reduced pressure to remove the MeCN and the resulting precipitate was collected by vacuum filtration to afford 1-(2-methylcyclohexyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine as a white solid (0.10 g, 35%): LC/MS (Table 2, Method a) Rt=1.84 min; MS m/z: 256 (M+H)+. After the complete addition the ice bath was removed the reaction was heated at about 90° C. for about 1 h to cool to ambient temperature The reaction was heated at about 90° C. for about 3 days The reaction was concentrated under reduced pressure partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (40 mL) The organic layer was separated dried over anhydrous Na2SO4 filtered the solvent was concentrated under reduced pressure The residue was purified over silica gel (12 g) further purified by RP-HPLC (Table 2, Method b) The combined product-containing fractions were concentrated under reduced pressure to remove the MeCN the resulting precipitate was collected by vacuum filtration

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

Procedure: To a solution of 2-methylcyclohexanecarboxylic acid (6.00 mL, 42.6 mmol, mixture of cis and trans) in DCM (60 mL) was added oxalyl chloride (4.80 mL, 55.3 mmol) followed by DMF (0.03 mL, 0.4 mmol). The reaction mixture was stirred at ambient temperature for about 4 h before it was concentrated under reduced pressure to constant weight to afford 2-methylcyclohexanecarbonyl chloride (mixture of diastereomers) as a yellow oil (7.0 g, 97%): 1H NMR (400 MHz, CDCl3) δ 2.98-2.94 (m, 1H), 2.39-2.35 (m, 1H), 1.91-1.82 (m, 1H), 1.79-1.72 (m, 1H), 1.69-1.60 (m, 2H), 1.57-1.47 (m, 2H), 1.42-1.36 (m, 1H), 1.34-1.26 (m, 1H), 1.04-0.96 (m, 3H). was concentrated under reduced pressure to constant weight

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

Procedure: In analogy to the procedure for Example 36A, 150 mg (0.67 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 120 mg (0.74 mmol) 2-methylcyclohexanecarbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification. The crude product is used in the next step without further purification