4-(2-bromoethyl)oxane

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: Prepared similarly to Intermediate 223 from 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(2-bromoethyl)tetrahydro-2H-pyran but conducting the alkylation over 1 hour at 60° C. over 1 hour at 60° C.

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

Procedure: Prepared similarly to Intermediate 223 from 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(2-bromoethyl)tetrahydro-2H-pyran but conducting the alkylation over 1 hour at 60° C. over 1 hour at 60° C.

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

Procedure: Prepared similarly to Intermediate 215 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(2-bromoethyl)tetrahydro-2H-pyran.

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

Procedure: To 2-(tetrahydro-2H-pyran-4-yl)ethyl methanesulfonate (5.4 g) in dry acetone at room temperature was added lithium bromide (9 g) in one go. The reaction was heated to reflux for 4 hours, under nitrogen. The reaction was cooled to room temperature and concentrated in vacuo. The residue was taken up in dichloromethane (100 ml) and washed with water (50 ml). The organic layer was dried by passing through a hydrophobic frit, and concentrated in vacuo. The product was purified by silica chromatography (40 g) (ISCO) using a gradient elution of 0-50% cyclohexane:ethyl acetate to afford the title compound as a colourless oil (3.5 g). The reaction was heated to reflux for 4 hours, under nitrogen concentrated in vacuo washed with water (50 ml) The organic layer was dried concentrated in vacuo The product was purified by silica chromatography (40 g) (ISCO) a gradient elution of 0-50% cyclohexane

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

Procedure: 2-Butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (0.2 g) in anhydrous N,N-dimethylformamide (5 mL) was treated with anhydrous potassium carbonate (0.315 g) and then heated to 60° C. for 1 hour. On cooling to room temperature, to the above was added 4-(2-bromoethyl)tetrahydro-2H-pyran (0.110 g) and the reaction was warmed to 50° C., overnight. The reaction mixture was quenched with water (5 mL) and extracted into ethyl acetate (3 times, 100 mL combined total volume). The separated organic layers were combined and passed through a hydrophobic frit to dry. The organic phase was stripped to give a gum which was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (20-60%) to afford the title compound as a white solid (111 mg). On cooling to room temperature the reaction was warmed to 50° C., overnight The reaction mixture was quenched with water (5 mL) extracted into ethyl acetate (3 times, 100 mL combined total volume) to dry to give a gum which was purified by C18 reverse phase chromatography

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

Procedure: 2-Butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (0.2 g) in anhydrous N,N-dimethylformamide (5 mL) was treated with anhydrous potassium carbonate (0.315 g) and then heated to 60° C. for 1 hour. On cooling to room temperature, to the above was added 4-(2-bromoethyl)tetrahydro-2H-pyran (0.110 g) and the reaction was warmed to 50° C., overnight. The reaction mixture was quenched with water (5 mL) and extracted into ethyl acetate (3 times, 100 mL combined total volume). The separated organic layers were combined and passed through a hydrophobic frit to dry. The organic phase was stripped to give a gum which was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (20-60%) to afford the title compound as a white solid (111 mg). On cooling to room temperature the reaction was warmed to 50° C., overnight The reaction mixture was quenched with water (5 mL) extracted into ethyl acetate (3 times, 100 mL combined total volume) to dry to give a gum which was purified by C18 reverse phase chromatography

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

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

Procedure: Compound 206 was prepared according to Method D using 5-chloro-4-(4-(methylsulfonyl)phenyl)thiazol-2-amine instead of N-(4-(2-amino-5-chlorothiazol-4-yl)phenyl)methanesulfonamide and 3,3-diphenyl-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)propan-1-amine instead of N-methyl-3,3-diphenylpropan-1-amine. 3,3-diphenyl-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)propan-1-amine was prepared according to Method C using 3,3-diphenylpropan-1-amine instead of tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate and 4-(2-bromoethyl)-tetrahydro-2H-pyran instead of 3-bromo-1,1-diphenylpropane.

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

Procedure: Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with 4-(2-bromo-ethyl)-tetrahydro-pyran (described in US 2004220214) gave the title compound. ES-MS m/e (%): 479.5(M+H+).