2,4-difluoro-N-methylaniline

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

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

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: 5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (100 mg, 0.24 mmol), (2,4-difluoro-phenyl)-methyl-amine (103 mg, 0.72 mmol), BOP (137 mg, 0.31 mmol), DIEA (265 μL, 1.44 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (2,4-difluoro-phenyl)-methyl-amide: MS m/z: (M+H) 541.0.

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

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

Procedure: To a mixture of the 2,4-Difluoro-N-methylaniline (Avacado Research Chemical, Heysham UK) (1.43 g, 10 mmole) in NMP, and K2CO3, was added methyl bromoacetate (0.945 ml, 10 mmole) and stirred at room temperature for 24 hours. The reaction mixture was added to water and extracted with ethyl acetate (3×50 ml), the organic extracts were washed 6× with water, dried (MgSO4) and evaporated to give the product as a oil. extracted with ethyl acetate (3×50 ml) the organic extracts were washed 6× with water dried (MgSO4) evaporated

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

Procedure: To a mixture of the 2,4-Difluoro-N-methylaniline (Avacado Research Chemical, Heysham UK) (1.43 g, 10 mmole) in NMP, and K2CO3, was added methyl bromoacetate (0.945 ml, 10 mmole) and stirred at room temperature for 24 hours. The reaction mixture was added to water and extracted with ethyl acetate (3×50 ml), the organic extracts were washed 6× with water, dried (MgSO4) and evaporated to give the product as a oil. extracted with ethyl acetate (3×50 ml) the organic extracts were washed 6× with water dried (MgSO4) evaporated

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

Procedure: 8-Methyl-4H-thieno[3,2-c]chromene-2-carboxylic acid was converted to the acid chloride as in Example 3, then treated with N-methyl-2,4-difluoroaniline (1.5 equiv), and triethylamine (5 equiv) in dichloromethane and N,N-dimethyl-4-aminopyridine (0.2 equiv) at 24° C. After about 24 hr, the reaction mixture was diluted with dichloromethane, and the resulting solution was washed with saturated aqueous sodium bicarbonate. The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (5:2 hexanes/ethylacetate) provided 167bp. 1H NMR (500 MHz, CDCl3) δ 7.29 (m, 1H), 6.95-6.98 (m, 4H), 6.78 (d, J=8.2 Hz, 1H), 5.04 (s, 2H), 3.39 (s, 3H), 2.27 (s, 3H). LCMS (ESI) m/z: 372.1. the resulting solution was washed with saturated aqueous sodium bicarbonate The collected organic was dried over anhydrous sodium sulfate filtered concentrated Purification by flash column chromatography (5:2 hexanes/ethylacetate) provided 167bp

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

Procedure: 8-Methyl-4H-thieno[3,2-c]chromene-2-carboxylic acid was converted to the acid chloride as in Example 3, then treated with N-methyl-2,4-difluoroaniline (1.5 equiv), and triethylamine (5 equiv) in dichloromethane and N,N-dimethyl-4-aminopyridine (0.2 equiv) at 24° C. After about 24 hr, the reaction mixture was diluted with dichloromethane, and the resulting solution was washed with saturated aqueous sodium bicarbonate. The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (5:2 hexanes/ethylacetate) provided 167bp. 1H NMR (500 MHz, CDCl3) δ 7.29 (m, 1H), 6.95-6.98 (m, 4H), 6.78 (d, J=8.2 Hz, 1H), 5.04 (s, 2H), 3.39 (s, 3H), 2.27 (s, 3H). LCMS (ESI) m/z: 372.1. the resulting solution was washed with saturated aqueous sodium bicarbonate The collected organic was dried over anhydrous sodium sulfate filtered concentrated Purification by flash column chromatography (5:2 hexanes/ethylacetate) provided 167bp

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

Procedure: Following General Procedure C, 156 is prepared from 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylic acid and 2,4-difluoro-N-methylaniline. MS: (ESI+) 371.9

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

Procedure: Following General Procedure C, 156 is prepared from 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylic acid and 2,4-difluoro-N-methylaniline. MS: (ESI+) 371.9