4-fluoro-2-propan-2-yloxyaniline

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 round-bottom flask was charged with 4-fluoro-2-isopropoxy-1-nitrobenzene (49.3 g, 248 mmol), EtOH (600 mL), and 10% Pd/C (50% in water, Degussa type E101; 10 g, 20 wt % by weight of the starting nitro compound). The flask was sealed with a rubber septum, degassed, and back-filled with H2 (×3) from a balloon filled with H2. The reaction was stirred for 4 d using a H2 filled balloon. The reaction mixture was filtered through a pad of celite, and the pad of celite was rinsed with MeOH. The filtrate was evaporated to dryness to provide 4-fluoro-2-isopropoxybenzenamine (41.0 g, 98%) as a brown liquid that was used without further purification. 1H NMR (300 MHz; d6-DMSO) δ 6.67-6.72 (dd, 1H, J=2.7 Hz, 11 Hz), 6.55-6.60 (dd, 1H, J=6.0 Hz, 8.7 Hz), 6.43-6.49 (td, 1H, J=2.7 Hz, 8.4 Hz), 4.47-4.55 (m, 3H), 1.23-1.25 (d, 6H, J=6.0 Hz); 19F NMR (282 MHz; d6-DMSO) δ −127.4 (sextet); m/z=170 (M+H)+. The flask was sealed with a rubber septum degassed back-filled with H2 (×3) from a balloon filled with H2 The reaction mixture was filtered through a pad of celite the pad of celite was rinsed with MeOH The filtrate was evaporated to dryness

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (112 mg), 4-fluoro-2-isopropoxyaniline (77.9 mg) and p-toluenesulfonic acid monohydrate (15 mg) were dissolved in dioxane (3.0 ml). The reaction was heated at 110° C. under microwave irradiation. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in dichloromethane and extracted with water. The organic phase was dried and concentrated in vacuo. The residue was triturated with diisopropyl ether and filtered. Then the reaction mixture was concentrated in vacuo the residue was dissolved in dichloromethane extracted with water The organic phase was dried concentrated in vacuo The residue was triturated with diisopropyl ether filtered

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

Procedure: 4-Fluoro-2-iso-propoxyaniline (0.049 g, 0.28 mmol) and 4-chloro-N-(3-(dimethylamino)propyl)-5-methylthieno[2,3-d]pyrimidine-6-sulfonamide hydrochloride salt (0.1 g, 0.28 mmol) were heated at 70° C. in anhydrous 1,4-dioxane (1.5 mL) for 4 hours. The solution was cooled to ambient temperature and diluted with water (2.0 mL) and adjusted to pH 9 (4:1 water/ammonium hydroxide solution). The precipitate was collected, washed with water and diethyl ether to yield the title compound as beige solid (0.039 g, 28%). The precipitate was collected washed with water and diethyl ether

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

Procedure: Prepared from 4-fluoro-2-iso-propoxyaniline and methyl 4-chloro-5-methylthieno[2,3-d]pyrimidine-6-carboxylate in an analogous fashion to that given in general route 1. Yield (0.25 g, 53%) Yield (0.25 g, 53%)

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

Procedure: Prepared from 4-fluoro-2-iso-propoxyaniline and methyl 4-chloro-5-methylthieno[2,3-d]pyrimidine-6-carboxylate in an analogous fashion to that given in general route 1. Yield (0.25 g, 53%) Yield (0.25 g, 53%)

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

Procedure: A round-bottom flask was charged with 4-fluoro-2-isopropoxy-1-nitrobenzene (49.3 g, 248 mmol), EtOH (600 mL), and 10% Pd/C (50% in water, Degussa type E101; 10 g, 20 wt % by weight of the starting nitro compound). The flask was sealed with a rubber septum, degassed, and back-filled with H2 (×3) from a balloon filled with H2. The reaction was stirred for 4 d using a H2 filled balloon. The reaction mixture was filtered through a pad of celite, and the pad of celite was rinsed with MeOH. The filtrate was evaporated to dryness to provide 4-fluoro-2-isopropoxybenzenamine (41.0 g, 98%) as a brown liquid that was used without further purification. 1H NMR (300 MHz; d6-DMSO) δ 6.67-6.72 (dd, 1H, J=2.7 Hz, 11 Hz), 6.55-6.60 (dd, 1H, J=6.0 Hz, 8.7 Hz), 6.43-6.49 (td, 1H, J=2.7 Hz, 8.4 Hz), 4.47-4.55 (m, 3H), 1.23-1.25 (d, 6H, J=6.0 Hz); 19F NMR (282 MHz; d6-DMSO) δ −127.4 (sextet); m/z=170 (M+H)+. The flask was sealed with a rubber septum degassed back-filled with H2 (×3) from a balloon filled with H2 The reaction mixture was filtered through a pad of celite the pad of celite was rinsed with MeOH The filtrate was evaporated to dryness

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

Procedure: A round-bottom flask was charged with 4-fluoro-2-isopropoxy-1-nitrobenzene (49.3 g, 248 mmol), EtOH (600 mL), and 10% Pd/C (50% in water, Degussa type E101; 10 g, 20 wt % by weight of the starting nitro compound). The flask was sealed with a rubber septum, degassed, and back-filled with H2 (×3) from a balloon filled with H2. The reaction was stirred for 4 d using a H2 filled balloon. The reaction mixture was filtered through a pad of celite, and the pad of celite was rinsed with MeOH. The filtrate was evaporated to dryness to provide 4-fluoro-2-isopropoxybenzenamine (41.0 g, 98%) as a brown liquid that was used without further purification. 1H NMR (300 MHz; d6-DMSO) δ 6.67-6.72 (dd, 1H, J=2.7 Hz, 11 Hz), 6.55-6.60 (dd, 1H, J=6.0 Hz, 8.7 Hz), 6.43-6.49 (td, 1H, J=2.7 Hz, 8.4 Hz), 4.47-4.55 (m, 3H), 1.23-1.25 (d, 6H, J=6.0 Hz); 19F NMR (282 MHz; d6-DMSO) δ −127.4 (sextet); m/z=170 (M+H)+. The flask was sealed with a rubber septum degassed back-filled with H2 (×3) from a balloon filled with H2 The reaction mixture was filtered through a pad of celite the pad of celite was rinsed with MeOH The filtrate was evaporated to dryness

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (112 mg), 4-fluoro-2-isopropoxyaniline (77.9 mg) and p-toluenesulfonic acid monohydrate (15 mg) were dissolved in dioxane (3.0 ml). The reaction was heated at 110° C. under microwave irradiation. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in dichloromethane and extracted with water. The organic phase was dried and concentrated in vacuo. The residue was triturated with diisopropyl ether and filtered. Then the reaction mixture was concentrated in vacuo the residue was dissolved in dichloromethane extracted with water The organic phase was dried concentrated in vacuo The residue was triturated with diisopropyl ether filtered

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

Procedure: 4-Fluoro-2-iso-propoxyaniline (0.049 g, 0.28 mmol) and 4-chloro-N-(3-(dimethylamino)propyl)-5-methylthieno[2,3-d]pyrimidine-6-sulfonamide hydrochloride salt (0.1 g, 0.28 mmol) were heated at 70° C. in anhydrous 1,4-dioxane (1.5 mL) for 4 hours. The solution was cooled to ambient temperature and diluted with water (2.0 mL) and adjusted to pH 9 (4:1 water/ammonium hydroxide solution). The precipitate was collected, washed with water and diethyl ether to yield the title compound as beige solid (0.039 g, 28%). The precipitate was collected washed with water and diethyl ether

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

Procedure: Prepared from 4-fluoro-2-iso-propoxyaniline and methyl 4-chloro-5-methylthieno[2,3-d]pyrimidine-6-carboxylate in an analogous fashion to that given in general route 1. Yield (0.25 g, 53%) Yield (0.25 g, 53%)