2-chloro-5-fluorobenzoyl chloride

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 24.4 g of 2-chloro-5-fluoro-benzoyl chloride in 100 ml of dichloromethane was added dropwise to a solution of 26.8 g of aminomalonic acid diethyl ester hydrochloride and 38.6 ml of triethylamine in 50 ml of dichloromethane with cooling in an ice bath. The reaction mixture was stirred for 2 h while the temperature was maintained at 0-5° C. Then 100 ml of water were added slowly. The phases were separated, and the aqueous phase was extracted twice with 100 ml of dichloromethane. The combined organic phases were dried with sodium sulfate, filtered and evaporated to give 39.3 g of the crude title compound. with cooling in an ice bath The phases were separated the aqueous phase was extracted twice with 100 ml of dichloromethane The combined organic phases were dried with sodium sulfate filtered evaporated

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

Procedure: Following the procedure as describe in Example 6, making variations as required to replace 2-fluorobenzoyl chloride with 2-chloro-5-fluorobenzoyl chloride to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(2-chloro-5-fluorobenzamido)-isonicotinamide was obtained as a colorless solid in 57% yield: mp 180-181° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) (9.15 (d, J=13.8 Hz, 1H), 8.60 (s, 1H), 8.44 (d, J=5.0 Hz, 1H), 8.07 (dd, J=6.6, 2.8 Hz, 1H), 7.58 (d, J=4.2 Hz, 1H), 7.52-7.46 (m, 1H), 7.36-7.12 (m, 6H), 6.67 (s, 1H), 4.65 (d, J=5.7 Hz, 2H); MS (ES+) m/z 384.5 (M+1).

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

Procedure: Following the procedure of Example 3, making variations only as required to use 2-chloro-5-fluorobenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (94% yield). m.p. 194-196° C. 1H NMR (300 MHz, CDCl3) δ 8.05, 7.96, 7.41-7.37, 7.11-7.03, 7.00, 4.07-3.34, 1.55-1.46, 0.79-0.68, 0.48-0.42, 0.11-0.06. 13C NMR (75 MHz, CDCl3) δ 165.7, 163.0, 160.0, 159.7, 145.5, 136.7, 131.5, 127.1, 125.3, 117.8, 115.2, 112.5, 46.0, 44.8, 44.6, 41.2, 39.6, 34.5, 8.6, 4.2. MS (ES+) m/z 432.2 (M+1).

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

Procedure: Following the procedure of Example 3, making variations only as required to use 2-chloro-5-fluorobenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (94% yield). m.p. 194-196° C. 1H NMR (300 MHz, CDCl3) δ 8.05, 7.96, 7.41-7.37, 7.11-7.03, 7.00, 4.07-3.34, 1.55-1.46, 0.79-0.68, 0.48-0.42, 0.11-0.06. 13C NMR (75 MHz, CDCl3) δ 165.7, 163.0, 160.0, 159.7, 145.5, 136.7, 131.5, 127.1, 125.3, 117.8, 115.2, 112.5, 46.0, 44.8, 44.6, 41.2, 39.6, 34.5, 8.6, 4.2. MS (ES+) m/z 432.2 (M+1).

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

Procedure: Following the procedure of Example 3, making variations only as required to use 2-chloro-5-fluorobenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (94% yield). m.p. 194-196° C. 1H NMR (300 MHz, CDCl3) δ 8.05, 7.96, 7.41-7.37, 7.11-7.03, 7.00, 4.07-3.34, 1.55-1.46, 0.79-0.68, 0.48-0.42, 0.11-0.06. 13C NMR (75 MHz, CDCl3) 6165.7, 163.0, 160.0, 159.7, 145.5, 136.7, 131.5, 127.1, 125.3, 117.8, 115.2, 112.5, 46.0, 44.8, 44.6, 41.2, 39.6, 34.5, 8.6, 4.2. MS (ES+) m/z 432.2 (M+1).

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

Procedure: Following the procedure of Example 3, making variations only as required to use 2-chloro-5-fluorobenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (94% yield). m.p. 194-196° C. 1H NMR (300 MHz, CDCl3) δ 8.05, 7.96, 7.41-7.37, 7.11-7.03, 7.00, 4.07-3.34, 1.55-1.46, 0.79-0.68, 0.48-0.42, 0.11-0.06. 13C NMR (75 MHz, CDCl3) 6165.7, 163.0, 160.0, 159.7, 145.5, 136.7, 131.5, 127.1, 125.3, 117.8, 115.2, 112.5, 46.0, 44.8, 44.6, 41.2, 39.6, 34.5, 8.6, 4.2. MS (ES+) m/z 432.2 (M+1).

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

Procedure: Following the procedure of Example 3, making variations only as required to use 2-chloro-5-fluorobenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (94% yield). m.p. 194-196° C. 1H NMR (300 MHz, CDCl3) δ 8.05, 7.96, 7.41-7.37, 7.11-7.03, 7.00, 4.07-3.34, 1.55-1.46, 0.79-0.68, 0.48-0.42, 0.11-0.06. 13C NMR (75 MHz, CDCl3) 6165.7, 163.0, 160.0, 159.7, 145.5, 136.7, 131.5, 127.1, 125.3, 117.8, 115.2, 112.5, 46.0, 44.8, 44.6, 41.2, 39.6, 34.5, 8.6, 4.2. MS (ES+) m/z 432.2 (M+1).

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A dry, 3-L, 3-necked, round-bottomed flask equipped with a thermometer and addition funnel was charged a solution of 33 (96 g, 0.53 mol, 1.0 equiv.) and Et3N (88 ml, 0.64 mol, 1.2 equiv.) in dichloromethane (1.2 L). The solution was cooled to 0° C. by an ice bath and 2-chloro-5-fluoro-benzoyl chloride (110 g, 0.57 mol, 1.05 equiv.) was added drop-wise over 40 min at 0° C. After the addition, the reaction mixture was stirred at 0° C. for further 1.5 h. The organic layer was washed with brine three times, dried over MgSO4, filtered, and evaporated to yield 4-(2-chloro-5-fluoro-benzoylamino)-3-methoxy-benzoic acid methyl ester 34 as a white solid. 1H NMR (400 MHz, CDCl3) δ: 8.84 (s, 1H), 8.61 (d, 1H), 7.75 (dd, 1H), 7.60 (d, 1H), 7.55 (dd, 1H), 7.45 (dd, 1H), 7.20-7.13 (m, 1H), 3.97 (s, 3H), 3.93 (s, 3H). MS (ES) m/z 338.0 (MH)+. After the addition The organic layer was washed with brine three times dried over MgSO4 filtered evaporated

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

Procedure: Following the procedure of Example 3, making variations only as required to use 2-chloro-5-fluorobenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (94% yield). m.p. 194-196° C. 1H NMR (300 MHz, CDCl3) δ 8.05, 7.96, 7.41-7.37, 7.11-7.03, 7.00, 4.07-3.34, 1.55-1.46, 0.79-0.68, 0.48-0.42, 0.11-0.06. 13C NMR (75 MHz, CDCl3) δ 165.7, 163.0, 160.0, 159.7, 145.5, 136.7, 131.5, 127.1, 125.3, 117.8, 115.2, 112.5, 46.0, 44.8, 44.6, 41.2, 39.6, 34.5, 8.6, 4.2. MS (ES+) m/z 432.2 (M+1).

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

Procedure: To a solution of {4-[2-(3-amino-phenyl)-pyrazolo[1,5-a]pyridin-3-yl]-pyrimidin-2-yl}-(3-fluoro-phenyl)-amine (80 mg, 0.20 mmol) in 2 mL THF was added 2-chloro-5-fluorobenzoyl chloride (26 μL, 0.22 mmol). When LC/MS indicated the reaction was complete, several equivalents of PS-trisamine were added and the mixture was stirred for 16 h. Et3N was added if necessary to get the reaction into solution. The mixture was filtered and the resin washed well with THF. The filtrate was concentrated and triturated with DCM to give the title compound (51 mg, 46%). 1H NMR (400 MHz, d6-DMSO) δ 10.66 (s, 1H), 9.78 (s, 1H), 8.84 (d, J=6.8 Hz, 1H), 8.45 (d, J=8.8 Hz, 1H), 8.30 (d, J=5.2 Hz, 1H), 8.01 (s, 1H), 7.80-7.74 (m, 2H), 7.61-7.42 (m, 5H), 7.39-7.32 (m, 2H), 7.26-7.20 (m, 1H), 7.11 (t, J=6.4 Hz, 1H), 6.72-6.67 (m, 1H), 6.57 (d, J=5.2 Hz, 1H) ppm. MS (ESI) m/z=553 [M+H]+. to get the reaction into solution The mixture was filtered the resin washed well with THF The filtrate was concentrated triturated with DCM

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 24.4 g of 2-chloro-5-fluoro-benzoyl chloride in 100 ml of dichloromethane was added dropwise to a solution of 26.8 g of aminomalonic acid diethyl ester hydrochloride and 38.6 ml of triethylamine in 50 ml of dichloromethane with cooling in an ice bath. The reaction mixture was stirred for 2 h while the temperature was maintained at 0-5° C. Then 100 ml of water were added slowly. The phases were separated, and the aqueous phase was extracted twice with 100 ml of dichloromethane. The combined organic phases were dried with sodium sulfate, filtered and evaporated to give 39.3 g of the crude title compound. with cooling in an ice bath The phases were separated the aqueous phase was extracted twice with 100 ml of dichloromethane The combined organic phases were dried with sodium sulfate filtered evaporated

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

Procedure: Following the procedure as describe in Example 6, making variations as required to replace 2-fluorobenzoyl chloride with 2-chloro-5-fluorobenzoyl chloride to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(2-chloro-5-fluorobenzamido)-isonicotinamide was obtained as a colorless solid in 57% yield: mp 180-181° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) (9.15 (d, J=13.8 Hz, 1H), 8.60 (s, 1H), 8.44 (d, J=5.0 Hz, 1H), 8.07 (dd, J=6.6, 2.8 Hz, 1H), 7.58 (d, J=4.2 Hz, 1H), 7.52-7.46 (m, 1H), 7.36-7.12 (m, 6H), 6.67 (s, 1H), 4.65 (d, J=5.7 Hz, 2H); MS (ES+) m/z 384.5 (M+1).