1,1,2-trimethoxyethane

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

Procedure: Using an analogous procedure to that described in Example 43, 6-amino-4-[3-chloro-4-(2-pyridylmethoxy)anilino]quinazoline was reacted with 2-methoxyacetaldehyde dimethyl acetal to give 4-[3-chloro-4-(2-pyridylmethoxy)anilino]-6-(2-methoxyethylamino)quinazoline in 67% yield;

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

Procedure: Using an analogous procedure to that described in Example 43, 6-amino-4-[2-fluoro-4-(2-pyridylmethoxy)anilino]quinazoline was reacted with 2-methoxyacetaldehyde dimethyl acetal to give 4-[2-fluoro-4-(2-pyridylmethoxy)anilino]-6-(2-methoxyethylamino)quinazoline in 52% yield;

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A round bottom flask was charged with 2-methoxyacetaldehyde dimethyl acetal (2076 μl, 2076 μmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (299 mg, 2076 μmol). The flask was fitted with a reflux condenser and the mixture was heated at 100° C. for 2 h under nitrogen. 5,6-Dimethoxypyridin-3-amine (320 mg, 2076 μmol) was added, and within a minute a solid had precipitated out of solution. The heterogeneous mixture was heated at 100° C. for 10 min. The mixture was cooled to RT and the solids were filtered and washed with hexanes. (E)-5-((5,6-dimethoxypyridin-3-ylimino)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione was isolated as a yellow/orange solid. MS [M+H]=309. The flask was fitted with a reflux condenser within a minute a solid had precipitated out of solution The heterogeneous mixture was heated at 100° C. for 10 min The mixture was cooled to RT the solids were filtered washed with hexanes

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A round bottom flask was charged with 2-methoxyacetaldehyde dimethyl acetal (2076 μl, 2076 μmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (299 mg, 2076 μmol). The flask was fitted with a reflux condenser and the mixture was heated at 100° C. for 2 h under nitrogen. 5,6-Dimethoxypyridin-3-amine (320 mg, 2076 μmol) was added, and within a minute a solid had precipitated out of solution. The heterogeneous mixture was heated at 100° C. for 10 min. The mixture was cooled to RT and the solids were filtered and washed with hexanes. (E)-5-((5,6-dimethoxypyridin-3-ylimino)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione was isolated as a yellow/orange solid. MS [M+H]=309. The flask was fitted with a reflux condenser within a minute a solid had precipitated out of solution The heterogeneous mixture was heated at 100° C. for 10 min The mixture was cooled to RT the solids were filtered washed with hexanes

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A round bottom flask was charged with 2-methoxyacetaldehyde dimethyl acetal (2076 μl, 2076 μmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (299 mg, 2076 μmol). The flask was fitted with a reflux condenser and the mixture was heated at 100° C. for 2 h under nitrogen. 5,6-Dimethoxypyridin-3-amine (320 mg, 2076 μmol) was added, and within a minute a solid had precipitated out of solution. The heterogeneous mixture was heated at 100° C. for 10 min. The mixture was cooled to RT and the solids were filtered and washed with hexanes. (E)-5-((5,6-dimethoxypyridin-3-ylimino)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione was isolated as a yellow/orange solid. MS [M+H]=309. The flask was fitted with a reflux condenser within a minute a solid had precipitated out of solution The heterogeneous mixture was heated at 100° C. for 10 min The mixture was cooled to RT the solids were filtered washed with hexanes

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

Procedure: A solution of methoxyacetaldehyde dimethyl acetal (1.27 g, 10 mol) in water (7 ml) and 2M hydrochloric acid (76 μl) was heated at 50-60° C. for 2 hours. The mixture was allowed to cool and adjusted to pH7.5 with saturated aqueous sodium hydrogen carbonate solution. This solution was added to a suspension of 7-amino-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)quinazoline hydrochloride (400 mg, 1 mmol), (prepared as described for the starting material in Example 30), in ethanol (32 ml) and acetic acid (95 μl, 1.5 mmol). The mixture was then stirred for 5 minutes, sodium cyanoborohydride (133 mg, 2 mmol) added and the solution adjusted to pH5.5 with glacial acetic acid. The mixture was stirred for 18 hours and the organic solvents removed by evaporation and the resulting aqueous mixture partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (96/4 followed by 12/8) to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-(2-methoxyethylamino)quinazoline (308 mg, 77%) as a yellow foam. to cool (prepared The mixture was stirred for 18 hours the organic solvents removed by evaporation the resulting aqueous mixture partitioned between ethyl acetate and water The organic layer was separated washed with brine dried (MgSO4) the solvent removed by evaporation The residue was purified by column chromatography eluting with methylene chloride/methanol (96/4 followed by 12/8)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A round bottom flask was charged with 2-methoxyacetaldehyde dimethyl acetal (2076 μl, 2076 μmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (299 mg, 2076 μmol). The flask was fitted with a reflux condenser and the mixture was heated at 100° C. for 2 h under nitrogen. 5,6-Dimethoxypyridin-3-amine (320 mg, 2076 μmol) was added, and within a minute a solid had precipitated out of solution. The heterogeneous mixture was heated at 100° C. for 10 min. The mixture was cooled to RT and the solids were filtered and washed with hexanes. (E)-5-((5,6-dimethoxypyridin-3-ylimino)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione was isolated as a yellow/orange solid. MS [M+H]=309. The flask was fitted with a reflux condenser within a minute a solid had precipitated out of solution The heterogeneous mixture was heated at 100° C. for 10 min The mixture was cooled to RT the solids were filtered washed with hexanes

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A round bottom flask was charged with 2-methoxyacetaldehyde dimethyl acetal (2076 μl, 2076 μmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (299 mg, 2076 μmol). The flask was fitted with a reflux condenser and the mixture was heated at 100° C. for 2 h under nitrogen. 5,6-Dimethoxypyridin-3-amine (320 mg, 2076 μmol) was added, and within a minute a solid had precipitated out of solution. The heterogeneous mixture was heated at 100° C. for 10 min. The mixture was cooled to RT and the solids were filtered and washed with hexanes. (E)-5-((5,6-dimethoxypyridin-3-ylimino)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione was isolated as a yellow/orange solid. MS [M+H]=309. The flask was fitted with a reflux condenser within a minute a solid had precipitated out of solution The heterogeneous mixture was heated at 100° C. for 10 min The mixture was cooled to RT the solids were filtered washed with hexanes

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

Procedure: Using an analogous procedure to that described in Example 43, 6-amino-4-[3-chloro-4-(2-pyridylmethoxy)anilino]quinazoline was reacted with 2-methoxyacetaldehyde dimethyl acetal to give 4-[3-chloro-4-(2-pyridylmethoxy)anilino]-6-(2-methoxyethylamino)quinazoline in 67% yield;

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

Procedure: Using an analogous procedure to that described in Example 43, 6-amino-4-[3-chloro-4-(2-pyridylmethoxy)anilino]quinazoline was reacted with 2-methoxyacetaldehyde dimethyl acetal to give 4-[3-chloro-4-(2-pyridylmethoxy)anilino]-6-(2-methoxyethylamino)quinazoline in 67% yield;

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

Procedure: Using an analogous procedure to that described in Example 43, 6-amino-4-[2-fluoro-4-(2-pyridylmethoxy)anilino]quinazoline was reacted with 2-methoxyacetaldehyde dimethyl acetal to give 4-[2-fluoro-4-(2-pyridylmethoxy)anilino]-6-(2-methoxyethylamino)quinazoline in 52% yield;

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

Procedure: Using an analogous reductive amination procedure to that described in Example 1, 6-amino-4-(2',4'-difluoroanilino)quinazoline was reacted with 2-methoxyacetaldehyde dimethyl acetal to give 4-(2',4'-difluoroanilino)-6-(2-methoxyethylamino)quinazoline in 28% yield, m.p. 175-176° C.; NMR Spectrum: 3.31 (s, 3H), 3.38 (t, 2H), 3.61 (t, 2H), 6.19 (t, 1H), 7.07-7.18 (m, 2H), 7.27-7.38 (m, 2H), 7.48-7.6 (m, 2H), 8.2 (s, 1H), 9.3 (broad s, 1H); Elemental Analysis: Found C, 61.7; H, 4.9; N, 16.9; C17H16F2N4O requires C, 61.8; H, 4.9; N, 17.0%.