4-bromo-2-fluoro-6-hydroxybenzonitrile

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

Procedure: To a 20-mL screw-cap vial was added 4-bromo-2-fluoro-6-hydroxybenzonitrile (500 mg, 2.315 mmol), bis-pinacolato diboron (705 mg, 2.78 mmol), potassium acetate (568 mg, 5.79 mmol), PdCl2(dppf).CH2Cl2 adduct (95 mg, 0.116 mmol), and 1,4-dioxane (8 mL). The vial was capped and stirred for 4 h at 100° C. on a stirrer hot-plate. The reaction mixture was allowed to cool, then was diluted with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was dried over Na2SO4 and concentrated. The residue was added to a 20 mL microwave vial and 4-chloro-N-methyl-6-[(3R)-3-methyl-4-morpholinyl]-2-pyrimidinamine (0.279 g, 1.15 mmol), PdCl2(dppf).CH2Cl2 adduct (0.047 g, 0.058 mmol), K2CO3 (2 M, 1.725 mL, 3.45 mmol), and 1,4-dioxane (6 mL) were added. The resulting mixture was heated at 140° C. for 10 minutes in a microwave reactor. The organic layer was separated and the aqueous was diluted with water (10 mL), neutralized with 0.1 N HCl (pH paper), then extracted with EtOAc (3×50 mL). The organics were combined, and then dried over Na2SO4. The dried solution was concentrated, then purified by flash chromatography 0-10% CH3OH in CH2Cl2 (24 g column, dry-loaded) to afford the title compound (0.37 g) as a brown solid. LC-MS (ES) m/z=344 [M+H]+. To a 20-mL screw-cap vial The vial was capped to cool washed with water (20 mL) The organic layer was dried over Na2SO4 concentrated The residue was added to a 20 mL microwave vial The resulting mixture was heated at 140° C. for 10 minutes in a microwave reactor The organic layer was separated the aqueous was diluted with water (10 mL) extracted with EtOAc (3×50 mL) dried over Na2SO4 The dried solution was concentrated purified by flash chromatography 0-10% CH3OH in CH2Cl2 (24 g column, dry-loaded)

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

Procedure: To a 500-mL RBF was added 4-bromo-2-fluoro-6-[(phenylmethyl)oxy]benzonitrile (5 g, 16.33 mmol) and CH2Cl2 (100 mL). The flask was cooled in an ice-water bath and BBr3 (49.0 mL, 49.0 mmol) (solution in CH2Cl2) was added dropwise via syringe. The red solution was allowed to warm to room temperature over 1 hour. The solution was poured into water (200 mL) and extracted with EtOAc (3×200 mL). The combined organics were concentrated to a yellow residue. The residue was treated with CH2Cl2, and a precipitate formed which was collected to afford the title compound (2.830 g) as a fine yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 7.03 (t, J=1.4 Hz, 1H), 7.29 (dd, J=9.0, 1.6 Hz, 1H), 12.23 (s, 1H). The flask was cooled in an ice-water bath extracted with EtOAc (3×200 mL) The combined organics were concentrated to a yellow residue The residue was treated with CH2Cl2 a precipitate formed which was collected

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

Procedure: To a 500-mL RBF was added 4-bromo-2-fluoro-6-[(phenylmethyl)oxy]benzonitrile (5 g, 16.33 mmol) and CH2Cl2 (100 mL). The flask was cooled in an ice-water bath and BBr3 (49.0 mL, 49.0 mmol) (solution in CH2Cl2) was added dropwise via syringe. The red solution was allowed to warm to room temperature over 1 hour. The solution was poured into water (200 mL) and extracted with EtOAc (3×200 mL). The combined organics were concentrated to a yellow residue. The residue was treated with CH2Cl2, and a precipitate formed which was collected to afford the title compound (2.830 g) as a fine yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 7.03 (t, J=1.4 Hz, 1H), 7.29 (dd, J=9.0, 1.6 Hz, 1H), 12.23 (s, 1H). The flask was cooled in an ice-water bath extracted with EtOAc (3×200 mL) The combined organics were concentrated to a yellow residue The residue was treated with CH2Cl2 a precipitate formed which was collected