1-(chloromethyl)-2-methylnaphthalene

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: The parent compound was obtained as a white solid in comparable yield according to the procedure described above for the preparation of N-(3,5-bis-trifluoro-methylbenzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide (Example 16, step d) using 1-chloromethyl-2-methylnaphthalene instead of 3,5-bis-trifluoromethyl-benzyl bromide. The parent compound was obtained as a white solid in comparable yield

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

Procedure: The parent compound was obtained as a white solid in comparable yield according to the procedure described above for the preparation of N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide (Example 16, step d) using 1-chloromethyl-2-methylnaphthalene instead of 3,5-bis-trifluoromethyl-benzyl bromide. The parent compound was obtained as a white solid in comparable yield

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 solution of 1-chloromethyl-2-methylnaphthalene (9.50 g, 0.050M) in trimethylphosphite (15 mL, 15.8 g, 0.13 M) is heated at reflux temperature for 48 hours. Excess trimethylphosphite is removed under reduced pressure, giving a yellow oil which is chromatographed over silica gel (40-63 μ, 400 g, 50 mL fractions) using ethyl acetate for elution of the column. Fractions 18-21 are pooled and after concentration gave a white solid (7.78 g). Recrystallization from ether-pentane gave title compound (6.94 g) as colorless crystals, mp 54°-57° C. at reflux temperature for 48 hours Excess trimethylphosphite is removed under reduced pressure giving a yellow oil which is chromatographed over silica gel (40-63 μ, 400 g, 50 mL fractions) for elution of the column after concentration

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

Procedure: 1 M lithium bis(trimethylsilyl) amide in THF (3.07 mL, 1 eq) was added to a solution of ((S)-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid-t-butyl ester (855 mg, 3.07 mmol, 1.0 eq) in THF (10 mL) at −78° C. After 30 min. 1-(chloromethyl)-2-methylnaphthalene (586 mg, 3.07 mmol, 1 eq) and NaI (461 mg, 3.07 mmol, 1 eq) were added and the mixture warmed to RT over 2 h. The solvent was removed and the residue was suspened in EtOAc and washed with H2O. The aqueous extracts were extracted with EtOAc and the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica chromatography to afford (S)-tert-butyl 5-((2-methylnaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (1.01 g, 75%) as a yellow foam. The solvent was removed washed with H2O The aqueous extracts were extracted with EtOAc the combined organic layers were dried over Na2SO4 filtered concentrated The residue was purified by silica chromatography

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

Procedure: 1 M lithium bis(trimethylsilyl) amide in THF (3.07 mL, 1 eq) was added to a solution of ((S)-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid-t-butyl ester (855 mg, 3.07 mmol, 1.0 eq) in THF (10 mL) at −78° C. After 30 min. 1-(chloromethyl)-2-methylnaphthalene (586 mg, 3.07 mmol, 1 eq) and NaI (461 mg, 3.07 mmol, 1 eq) were added and the mixture warmed to RT over 2 h. The solvent was removed and the residue was suspened in EtOAc and washed with H2O. The aqueous extracts were extracted with EtOAc and the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica chromatography to afford (S)-tert-butyl 5-((2-methylnaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (1.01 g, 75%) as a yellow foam. The solvent was removed washed with H2O The aqueous extracts were extracted with EtOAc the combined organic layers were dried over Na2SO4 filtered concentrated The residue was purified by silica chromatography

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

Procedure: To a stirred solution of 3-Piperazin-1-ylmethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine TFA salt 5 (50 mg; 0.08 mmol; prepared in EXAMPLE 4) in dry DMF (1.0 mL) was added 1-Chloromethyl-2-methyl-Naphthalene (34 mg; 0.18 mmol) followed by potassium carbonate (55 mg; 0.40 mmol). The mixture was allowed to stir for 24 h at room temperature then taken up into CH3CN/H2O/0.1% TFA. The mixture was purified by reverse phase HPLC (Rainin C18, 0% CH3CN to 50% CH3CN gradient, CH3CN/H2O, 0.1% TFA) and the bright yellow fractions containing the product were lyophilized after removal of CH3CN in vacuo to give 23 mg of yellow colored 3-[4-(4-Ethyl-2-methyl-naphthalen-1-ylmethyl)-piperazin-1-ylmethyl]-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine as the trifluoroacetate salt. The mixture was purified by reverse phase HPLC (Rainin C18, 0% CH3CN to 50% CH3CN gradient, CH3CN/H2O, 0.1% TFA) the bright yellow fractions containing the product after removal of CH3CN in vacuo

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

Procedure: The parent compound was obtained as a white solid in comparable yield according to the procedure described above for the preparation of N-(3,5-bis-trifluoro-methylbenzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide (Example 16, step d) using 1-chloromethyl-2-methylnaphthalene instead of 3,5-bis-trifluoromethyl-benzyl bromide. The parent compound was obtained as a white solid in comparable yield

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

Procedure: The parent compound was obtained as a white solid in comparable yield according to the procedure described above for the preparation of N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide (Example 16, step d) using 1-chloromethyl-2-methylnaphthalene instead of 3,5-bis-trifluoromethyl-benzyl bromide. The parent compound was obtained as a white solid in comparable yield