4-amino-3-fluoro-2-methylphenol

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

Procedure: Potassium tert-butoxide (3.5 g, 31 mmol) was added to a solution of 4-amino-3-fluoro-2-methyl-phenol (4.2 g, 30 mmol) in dimethylacetamide. The mixture was stirred at RT for 30 min. A solution of 2,4-dichloropyridine (4.38 g, 30 mmol) in dimethylacetamide was added and the mixture was heated at 100° C. overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (200 mL) and filtered through silica gel. The filter cake was washed with ethyl acetate and the combined filtrates were concentrated in vacuo and purified by silica gel chromatography to give 4-(2-chloro-pyridin-4-yloxy)-2-fluoro-3-methyl-phenylamine (3.2 g, 42% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.21 (d, J=6.4 Hz, 1 H), 6.84 (d, J=2.0 Hz, 1 H), 6.81 (dd, J=5.6, 2.4 Hz, 1 H), 6.67-6.65 (m, 2 H), 5.13 (s, 2H), 1.91 (s, 3 H); MS (ESI): m/z 253.2 [M+H]+. the mixture was heated at 100° C. overnight The reaction mixture was concentrated in vacuo the residue was dissolved in ethyl acetate (200 mL) filtered through silica gel The filter cake was washed with ethyl acetate the combined filtrates were concentrated in vacuo purified by silica gel chromatography

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

Procedure: Potassium tert-butoxide (3.5 g, 31 mmol) was added to a solution of 4-amino-3-fluoro-2-methyl-phenol (4.2 g, 30 mmol) in dimethylacetamide. The mixture was stirred at RT for 30 min. A solution of 2,4-dichloropyridine (4.38 g, 30 mmol) in dimethylacetamide was added and the mixture was heated at 100° C. overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (200 mL) and filtered through silica gel. The filter cake was washed with ethyl acetate, the combined filtrates were concentrated in vacuo and purified by silica gel chromatography to give 4-(2-chloro-pyridin-4-yloxy)-2-fluoro-3-methyl-phenylamine (3.2 g, 42% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.21 (d, J=6.4 Hz, 1H), 6.84 (d, J=2.0 Hz, 1H), 6.81 (dd, J=5.6, 2.4 Hz, 1H), 6.67-6.65 (m, 2H), 5.13 (s, 2H), 1.91 (s, 3H); MS (ESI): m/z 253.2 [M+H]+. the mixture was heated at 100° C. overnight The reaction mixture was concentrated in vacuo the residue was dissolved in ethyl acetate (200 mL) filtered through silica gel The filter cake was washed with ethyl acetate the combined filtrates were concentrated in vacuo purified by silica gel chromatography

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

Procedure: Potassium tert-butoxide (3.5 g, 31 mmol) was added to a solution of 4-amino-3-fluoro-2-methyl-phenol (4.2 g, 30 mmol) in dimethylacetamide. The mixture was stirred at RT for 30 min. A solution of 2,4-dichloropyridine (4.38 g, 30 mmol) in dimethylacetamide was added and the mixture was heated at 100° C. overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (200 mL) and filtered through silica gel. The filter cake was washed with ethyl acetate, the combined filtrates were concentrated in vacuo and purified by silica gel chromatography to give 4-(2-chloro-pyridin-4-yloxy)-2-fluoro-3-methyl-phenylamine (3.2 g, 42% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.21 (d, J=6.4 Hz, 1H), 6.84 (d, J=2.0 Hz, 1H), 6.81 (dd, J=5.6, 2.4 Hz, 1H), 6.67-6.65 (m, 2H), 5.13 (s, 2H), 1.91 (s, 3H); MS (ESI): m/z 253.2 [M+H]+. the mixture was heated at 100° C. overnight The reaction mixture was concentrated in vacuo the residue was dissolved in ethyl acetate (200 mL) filtered through silica gel The filter cake was washed with ethyl acetate the combined filtrates were concentrated in vacuo purified by silica gel chromatography

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

Procedure: Potassium tert-butoxide (3.5 g, 31 mmol) was added to a solution of 4-amino-3-fluoro-2-methyl-phenol (4.2 g, 30 mmol) in DMA, and stirred at RT for 0.5 h. A solution of 2,4-dichloropyridine (4.38 g, 30 mmol) in DMA was added and the mixture was heated at 100° C. overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (200 mL) and filtered through silica gel. The filter cake was washed with EtOAc, and the combined filtrates were concentrated in vacuo and purified by silica gel chromatography to give 4-(2-chloro-pyridin-4-yloxy)-2-fluoro-3-methyl-phenylamine (3.2 g, 42% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.21 (d, J=6.4 Hz, 1 H), 6.84 (d, J=2.0 Hz, 1H), 6.81 (dd, J=5.6, 2.4 Hz, 1 H), 6.67-6.65 (m, 2 H), 5.13 (s, 2 H), 1.91 (s, 3H); MS (ESI): m/z 253.2 [M+H]+. the mixture was heated at 100° C. overnight The reaction mixture was concentrated in vacuo the residue was dissolved in EtOAc (200 mL) filtered through silica gel The filter cake was washed with EtOAc the combined filtrates were concentrated in vacuo purified by silica gel chromatography

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

Procedure: A solution of 1-benzyloxy-3-fluoro-2-methyl-4-nitro-benzene (8 g, 0.031 mol) in MeOH (100 mL) was treated with Pd/C (10%) and hydrogenated (30 psi) for 2 h. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to afford 4-amino-3-fluoro-2-methyl-phenol (4.2 g, 96% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.61 (s, 1 H), 6.36 (m, 2 H), 4.28 (s, 2 H), 1.96 (s, 3H); MS (ESI) m/z: 142.1 [M+H]+. The catalyst was removed by filtration the filtrate was concentrated in vacuo

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

Procedure: Potassium tert-butoxide (3.5 g, 31 mmol) was added to a solution of 4-amino-3-fluoro-2-methyl-phenol (4.2 g, 30 mmol) in dimethylacetamide. The mixture was stirred at RT for 30 min. A solution of 2,4-dichloropyridine (4.38 g, 30 mmol) in dimethylacetamide was added and the mixture was heated at 100° C. overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (200 mL) and filtered through silica gel. The filter cake was washed with ethyl acetate, the combined filtrates were concentrated in vacuo and purified by silica gel chromatography to give 4-(2-chloro-pyridin-4-yloxy)-2-fluoro-3-methyl-phenylamine (3.2 g, 42% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.21 (d, J=6.4 Hz, 1H), 6.84 (d, J=2.0 Hz, 1H), 6.81 (dd, J=5.6, 2.4 Hz, 1H), 6.67-6.65 (m, 2H), 5.13 (s, 2H), 1.91 (s, 3H); MS (ESI): m/z 253.2 [M+H]+. the mixture was heated at 100° C. overnight The reaction mixture was concentrated in vacuo the residue was dissolved in ethyl acetate (200 mL) filtered through silica gel The filter cake was washed with ethyl acetate the combined filtrates were concentrated in vacuo purified by silica gel chromatography

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

Procedure: Potassium tert-butoxide (3.5 g, 0.031 mol) was added to a solution of 4-amino-3-fluoro-2-methylphenol (4.2 g, 0.03 mol) in DMAc and the resultant mixture was stirred for 30 min at RT. To this mixture was added a solution of 2,4-dichloropyridine (4.38 g, 0.03 mol) in DMAc and the mixture was heated at 100° C. overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (200 mL) and filtered through silica gel, washing forward with EtOAc. The filtrate was concentrated and purified by silica gel chromatography to give 4-(2-chloropyridin-4-yloxy)-2-fluoro-3-methylbenzenamine (3.2 g, 42% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.21 (d, J=6.0 Hz, 1H), 6.84 (s, 1H), 6.81 (dd, J=5.6, 2.4 Hz, 1H), 6.67 (m, 2H), 5.12 (s, 2H), 1.91 (s, 3H); MS (ESI) m/z 253.1 [M+H]+. The reaction mixture was concentrated in vacuo the residue was dissolved in ethyl acetate (200 mL) filtered through silica gel washing forward with EtOAc The filtrate was concentrated purified by silica gel chromatography

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

Procedure: 1-Benzyloxy-3-fluoro-2-methyl-4-nitrobenzene (8 g, 0.031 mol) and 10% Pd—C (1 g) were combined in methanol (100 mL) and the mixture was stirred under an H2 atmosphere (1 atm) overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 4-amino-3-fluoro-2-methylphenol (4.2 g, 96% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.61 (s, 1H), 6.42 (t, J=8.4 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 4.28 (s, 2H), 1.96 (s, 3H); MS (ESI) m/z: 142.1 [M+H]+. The reaction mixture was filtered the filtrate was concentrated in vacuo

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

Procedure: Potassium tert-butoxide (3.5 g, 0.031 mol) was added to a solution of 4-amino-3-fluoro-2-methylphenol (4.2 g, 0.03 mol) in DMAc and the resultant mixture was stirred for 30 min at RT. To this mixture was added a solution of 2,4-dichloropyridine (4.38 g, 0.03 mol) in DMAc and the mixture was heated at 100° C. overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (200 mL) and filtered through silica gel, washing forward with EtOAc. The filtrate was concentrated and purified by silica gel chromatography to give 4-(2-chloropyridin-4-yloxy)-2-fluoro-3-methylbenzenamine (3.2 g, 42% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.21 (d, J=6.0 Hz, 1H), 6.84 (s, 1H), 6.81 (dd, J=5.6, 2.4 Hz, 1H), 6.67 (m, 2H), 5.12 (s, 2H), 1.91 (s, 3H); MS (ESI) m/z 253.1 [M+H]+. The reaction mixture was concentrated in vacuo the residue was dissolved in ethyl acetate (200 mL) filtered through silica gel washing forward with EtOAc The filtrate was concentrated purified by silica gel chromatography

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

Procedure: 1-Benzyloxy-3-fluoro-2-methyl-4-nitrobenzene (8 g, 0.031 mol) and 10% Pd—C (1 g) were combined in methanol (100 mL) and the mixture was stirred under an H2 atmosphere (1 atm) overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 4-amino-3-fluoro-2-methylphenol (4.2 g, 96% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.61 (s, 1H), 6.42 (t, J=8.4 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 4.28 (s, 2H), 1.96 (s, 3H); MS (ESI) m/z: 142.1 [M+H]+. The reaction mixture was filtered the filtrate was concentrated in vacuo

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

Procedure: Potassium tert-butoxide (3.5 g, 31 mmol) was added to a solution of 4-amino-3-fluoro-2-methyl-phenol (4.2 g, 30 mmol) in dimethylacetamide. The mixture was stirred at RT for 30 min. A solution of 2,4-dichloropyridine (4.38 g, 30 mmol) in dimethylacetamide was added and the mixture was heated at 100° C. overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (200 mL) and filtered through silica gel. The filter cake was washed with ethyl acetate and the combined filtrates were concentrated in vacuo and purified by silica gel chromatography to give 4-(2-chloro-pyridin-4-yloxy)-2-fluoro-3-methyl-phenylamine (3.2 g, 42% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.21 (d, J=6.4 Hz, 1 H), 6.84 (d, J=2.0 Hz, 1 H), 6.81 (dd, J=5.6, 2.4 Hz, 1 H), 6.67-6.65 (m, 2 H), 5.13 (s, 2H), 1.91 (s, 3 H); MS (ESI): m/z 253.2 [M+H]+. the mixture was heated at 100° C. overnight The reaction mixture was concentrated in vacuo the residue was dissolved in ethyl acetate (200 mL) filtered through silica gel The filter cake was washed with ethyl acetate the combined filtrates were concentrated in vacuo purified by silica gel chromatography

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

Procedure: Potassium tert-butoxide (3.5 g, 31 mmol) was added to a solution of 4-amino-3-fluoro-2-methyl-phenol (4.2 g, 30 mmol) in dimethylacetamide. The mixture was stirred at RT for 30 min. A solution of 2,4-dichloropyridine (4.38 g, 30 mmol) in dimethylacetamide was added and the mixture was heated at 100° C. overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (200 mL) and filtered through silica gel. The filter cake was washed with ethyl acetate, the combined filtrates were concentrated in vacuo and purified by silica gel chromatography to give 4-(2-chloro-pyridin-4-yloxy)-2-fluoro-3-methyl-phenylamine (3.2 g, 42% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.21 (d, J=6.4 Hz, 1H), 6.84 (d, J=2.0 Hz, 1H), 6.81 (dd, J=5.6, 2.4 Hz, 1H), 6.67-6.65 (m, 2H), 5.13 (s, 2H), 1.91 (s, 3H); MS (ESI): m/z 253.2 [M+H]+. the mixture was heated at 100° C. overnight The reaction mixture was concentrated in vacuo the residue was dissolved in ethyl acetate (200 mL) filtered through silica gel The filter cake was washed with ethyl acetate the combined filtrates were concentrated in vacuo purified by silica gel chromatography