4-fluoro-2-(oxan-4-yloxy)aniline

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

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

Procedure: To a mixture of 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (8.5 g) and 4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)aniline (7.4 g) (intermediate XX) in dioxane (100 ml) was added HCl in dioxan (4M; 0.9 ml). The reaction was stirred at 100° C. overnight. The reaction mixture was allowed to warm to room temperature and water (50 ml) was added. The precipitate was isolated by filtration to warm to room temperature The precipitate was isolated by filtration

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

Procedure: To a mixture of 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (8.5 g) and 4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)aniline (7.4 g) (intermediate XX) in dioxane (100 ml) was added HCl in dioxan (4M; 0.9 ml). The reaction was stirred at 100° C. overnight. The reaction mixture was allowed to warm to room temperature and water (50 ml) was added. The precipitate was isolated by filtration to warm to room temperature The precipitate was isolated by filtration

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

Procedure: 4-(5-Fluoro-2-nitrophenoxy)tetrahydro-2-H-pyran (8.4 g) was dissolved in ethylacetate (30 ml) and Pd/C (500 mg) was added. The reaction was hydrogenated at room temperature and 50 PSI. The mixture was concentrated in vacuo to give the intended product. was hydrogenated at room temperature The mixture was concentrated in vacuo to give the intended product

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

Procedure: 4-(5-Fluoro-2-nitrophenoxy)tetrahydro-2-H-pyran (8.4 g) was dissolved in ethylacetate (30 ml) and Pd/C (500 mg) was added. The reaction was hydrogenated at room temperature and 50 PSI. The mixture was concentrated in vacuo to give the intended product. was hydrogenated at room temperature The mixture was concentrated in vacuo to give the intended product

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

Procedure: 4-Fluoro-2-(tetrahydro-2H-pyran-4-yloxy)aniline (0.057 g, 0.27 mmol), 4,6-dichloro-5-methylthieno[2,3-d]pyrimidine (0.06 g, 0.27 mmol, CA56844-14-5) and para-toluene sulfonic acid (0.005 g, 0.03 mmol) were heated at 90° C. in anhydrous 1,4-dioxane (1.5 mL) for 18 hours. The solution was cooled to ambient temperature, diluted with water (2 mL) and adjusted to pH 10 (4:1 water/ammonium hydroxide solution). The precipitate was collected, washed with water and diethyl ether to yield the title compound as yellow solid (0.012 g, 11%). The precipitate was collected washed with water and diethyl ether

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

Procedure: A solution of 4-chloro-5,7-dihydro-1H-pyrolo[3′,4′:4,5]thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester (prepared in an analogous fashion to 4-chloro-5,8-dihydro-6H-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester, WO2007/109279, 0.135 g, 0.39 mmol), 4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)aniline (0.090 g, 0.39 mmol) and para-toluene sulfonic acid (0.08 g, 0.04 mmol) in 1,4-dioxane (2 mL) was purged with nitrogen and heated at 120° C. for 21 hours. The reaction mixture was diluted with EtOAc, washed with 10% aqueous K2CO3 and brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (100% iso-hexane→100% DCM→3% MeOH/DCM→200:10:1 DCM/MeOH/NH4OH) to afford the title compound as white solid (0.015 g, 10%). was purged with nitrogen The reaction mixture was diluted with EtOAc washed with 10% aqueous K2CO3 and brine The organic phase was dried (MgSO4) filtered concentrated in vacuo The residue was purified by flash column chromatography (100% iso-hexane→100% DCM→3% MeOH/DCM→200:10:1 DCM/MeOH/NH4OH)

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

Procedure: A solution of 4-chloro-5,7-dihydro-1H-pyrolo[3′,4′:4,5]thieno[2,3-d]pyrimidine-6-carboxylic acid benzyl ester (prepared in an analogous fashion to 4-chloro-5,8-dihydro-6H-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester, WO2007/109279, 0.135 g, 0.39 mmol), 4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)aniline (0.090 g, 0.39 mmol) and para-toluene sulfonic acid (0.08 g, 0.04 mmol) in 1,4-dioxane (2 mL) was purged with nitrogen and heated at 120° C. for 21 hours. The reaction mixture was diluted with EtOAc, washed with 10% aqueous K2CO3 and brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (100% iso-hexane→100% DCM→3% MeOH/DCM→200:10:1 DCM/MeOH/NH4OH) to afford the title compound as white solid (0.015 g, 10%). was purged with nitrogen The reaction mixture was diluted with EtOAc washed with 10% aqueous K2CO3 and brine The organic phase was dried (MgSO4) filtered concentrated in vacuo The residue was purified by flash column chromatography (100% iso-hexane→100% DCM→3% MeOH/DCM→200:10:1 DCM/MeOH/NH4OH)

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

Procedure: A solution of 4-chloro-5,8-dihydro-6H-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (prepared according to WO2007/109279, 0.141 g, 0.43 mmol), 4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)aniline (0.092 g, 0.44 mmol) and para-toluene sulfonic acid (0.08 g, 0.04 mmol) in 1,4-dioxane (2 mL) was purged with nitrogen and then heated at 120° C. for 5 hours. The reaction mixture was diluted with EtOAc, washed with 10% aqueous K2CO3 and brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (100% iso-hexane→66% iso-hexane/EtOAc→100% EtOAc) followed by trituration with MeOH afforded the title compound as white solid (0.042 g, 20%). washed with 10% aqueous K2CO3 and brine The organic phase was dried (MgSO4) filtered concentrated in vacuo The residue was purified by flash column chromatography (100% iso-hexane→66% iso-hexane/EtOAc→100% EtOAc)

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

Procedure: A solution of 4-chloro-5,8-dihydro-6H-pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (prepared according to WO2007/109279, 0.141 g, 0.43 mmol), 4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)aniline (0.092 g, 0.44 mmol) and para-toluene sulfonic acid (0.08 g, 0.04 mmol) in 1,4-dioxane (2 mL) was purged with nitrogen and then heated at 120° C. for 5 hours. The reaction mixture was diluted with EtOAc, washed with 10% aqueous K2CO3 and brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (100% iso-hexane→66% iso-hexane/EtOAc→100% EtOAc) followed by trituration with MeOH afforded the title compound as white solid (0.042 g, 20%). washed with 10% aqueous K2CO3 and brine The organic phase was dried (MgSO4) filtered concentrated in vacuo The residue was purified by flash column chromatography (100% iso-hexane→66% iso-hexane/EtOAc→100% EtOAc)

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

Procedure: Methyl 4-chlorothieno[2,3-d]pyrimidine-6-carboxylate (0.256 g, 1.12 mmol), 4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)aniline (0.236 g, 1.12 mmol) and para-toluene sulfonic acid (0.021 g, 0.01 mmol) were heated at reflux in anhydrous 1,4-dioxane (6 mL) for 4 hours. The solution was cooled, concentrated in vacuo and the crude product absorbed on to silica. The sample was purified by flash column chromatography (100% DCM→10% MeOH/DCM) to yield the title compound (0.220 g, 49%) after recrystallisation from MeOH. The solution was cooled concentrated in vacuo the crude product absorbed on to silica The sample was purified by flash column chromatography (100% DCM→10% MeOH/DCM)

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

Procedure: Methyl 4-chlorothieno[2,3-d]pyrimidine-6-carboxylate (0.256 g, 1.12 mmol), 4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)aniline (0.236 g, 1.12 mmol) and para-toluene sulfonic acid (0.021 g, 0.01 mmol) were heated at reflux in anhydrous 1,4-dioxane (6 mL) for 4 hours. The solution was cooled, concentrated in vacuo and the crude product absorbed on to silica. The sample was purified by flash column chromatography (100% DCM→10% MeOH/DCM) to yield the title compound (0.220 g, 49%) after recrystallisation from MeOH. The solution was cooled concentrated in vacuo the crude product absorbed on to silica The sample was purified by flash column chromatography (100% DCM→10% MeOH/DCM)