N-ethylidenehydroxylamine

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

Procedure: A flask was charged with water (42 ml), cooled to 0° C., and treated with concentrated hydrochloric acid (21.7 ml) and sulfuric acid (5.66 ml). To this was added 3-amino-5-bromobenzotrifluoride (8.77 ml, 62.5 mmol). The reaction was treated with a solution of sodium nitrite (5.39 g, 78 mmol) in water (10 mL). The resulting reaction mixture was stirred for 30 min at 0° C. The reaction was transferred to a solution of acetaldoxime (5.71 ml, 94 mmol) and copper(II) sulfate (0.499 g, 3.12 mmol) in water (30 mL) at room temperature. After stirring for 1 h at room temperature, the reaction was heated to reflux and held there for 3 h. The reaction was cooled and diluted with pentane. It gave an intractable suspension. The reaction mixture was filtered through a sintered glass funnel. The layers were separated. The organics were washed with water, then brine, dried over magnesium sulfate, and concentrated. The crude residue was distilled (high vacuum, 75° C.) to give 3 fractions of varying levels of purity. Total yield was 8.5 g (51%) with purity that ranged from 10:1 to 1:1. 1H NMR (500 MHz, CDCl3) δ ppm 8.25 (s, 1H), 8.11 (s, 1H), 7.95 (s, 1H), 2.63 (s, 3H). The resulting reaction mixture After stirring for 1 h at room temperature the reaction was heated to reflux held there for 3 h The reaction was cooled It gave an intractable suspension The reaction mixture was filtered through a sintered glass funnel The layers were separated The organics were washed with water brine, dried over magnesium sulfate concentrated The crude residue was distilled (high vacuum, 75° C.) to give 3 fractions of varying levels of purity

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

Procedure: To a stirring solution of the compound of Example 7241 (90 mg, 0.24 mmol; prepared in a manner similar to that of Example 2 using 6-(2,4-dichlorophenyl)-8-ethyl-9H-purine and 3-cyclopropyl-1-propyn-3-ol) in methylene chloride (2 mL) were added chloroacetaldoxime (25 mg, 0.27 mmol) and triethylamine (0.038 mL, 0.27 mmol). (The chloroacetaldoxime used was previously prepared by reacting equimolar amounts of acetaldoxime and N-chlorosuccinimide in DMF, then extracting the product into diethyl ether and washing with water.) The cycloaddition reaction was monitored by TLC and additional amounts of chloroacetaldoxime and triethylamine were added until all the starting material was consumed. The reaction mixture was purified by adding directly to 4 column packed with silica gel and eluting using a gradient of 100% hexane to 25% ethyl acetate in hexane. 72 mg of a white foam was collected. MS (NH3-CI) 428 (M+H+). HRMS: m/e=428.1037 (M+H+, C21H20Cl2N5O). Purity by reverse phase HPLC>97%. extracting the product into diethyl ether washing with water ) The cycloaddition reaction were added until all the starting material was consumed The reaction mixture was purified by adding directly to 4 column eluting 72 mg of a white foam was collected

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

Procedure: To a stirring solution of the compound of Example 7241 (90 mg, 0.24 mmol; prepared in a manner similar to that of Example 2 using 6-(2,4-dichlorophenyl)-8-ethyl-9H-purine and 3-cyclopropyl-1-propyn-3-ol) in methylene chloride (2 mL) were added chloroacetaldoxime (25 mg, 0.27 mmol) and triethylamine (0.038 mL, 0.27 mmol). (The chloroacetaldoxime used was previously prepared by reacting equimolar amounts of acetaldoxime and N-chlorosuccinimide in DMF, then extracting the product into diethyl ether and washing with water.) The cycloaddition reaction was monitored by TLC and additional amounts of chloroacetaldoxime and triethylamine were added until all the starting material was consumed. The reaction mixture was purified by adding directly to 4 column packed with silica gel and eluting using a gradient of 100% hexane to 25% ethyl acetate in hexane. 72 mg of a white foam was collected. MS (NH3-CI) 428 (M+H+). HRMS: m/e=428.1037 (M+H+, C21H20Cl2N5O). Purity by reverse phase HPLC>97%. extracting the product into diethyl ether washing with water ) The cycloaddition reaction were added until all the starting material was consumed The reaction mixture was purified by adding directly to 4 column eluting 72 mg of a white foam was collected

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

Procedure: Prepared from ethyl 3-(3-methyl-isoxazol-5-yl)-benzoate [prepared by reaction of ethyl 3-ethynylbenzoate [CAS-No. 178742-95-5] with a mixture of NCS, acetaldoxime, Et3N and cat. amount of pyridine in CHCl3 at 50° C. according to Tetrahedron 1984, 40, 2985-2988] by treatment with lithium tert.-butyl acetate according to general procedure H (method b). Obtained as a yellow solid (2.54 g). at 50° C.

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

Procedure: Prepared from ethyl 3-(3-methyl-isoxazol-5-yl)-benzoate [prepared by reaction of ethyl 3-ethynylbenzoate [CAS-No. 178742-95-5] with a mixture of NCS, acetaldoxime, Et3N and cat. amount of pyridine in CHCl3 at 50° C. according to Tetrahedron 1984, 40, 2985-2988] by treatment with lithium tert.-butyl acetate according to general procedure H (method b). Obtained as a yellow solid (2.54 g). at 50° C.

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

Procedure: A solution of N-chlorosuccinimide (0.153 g, 1.145 mmol) in DMF (1 mL) was treated with acetaldoxime (0.068 g, 1.145 mmol), stirred at RT for 30 min, then added to a solution of N-(5-((2-ethynylpyridin-4-yl)oxy)-6-methylpyridin-2-yl)acetamide (0.102 g, 0.382 mmol) and TEA (0.5 mL) in DMF (1 mL) and heated at 60° C. for 1 h. The mixture was cooled to RT, treated with H2O, extracted with EtOAc (2×) and the combined organics were washed with H2O, then brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(6-methyl-5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)acetamide (110 mg, 89%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.64 (s, 1H), 8.55 (d, J=5.7 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.35 (d, J=2.5 Hz, 1H), 6.96 (m, 2H), 2.28 (s, 3H), 2.25 (s, 3H), 2.08 (s, 3H); MS (ESI) m/z: 325.1 (M+H+). heated at 60° C. for 1 h The mixture was cooled to RT extracted with EtOAc (2×) the combined organics were washed with H2O brine, dried over Na2SO4 concentrated to dryness purified via silica gel chromatography (MeOH/DCM)

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

Procedure: A solution of N-chlorosuccinimide (0.153 g, 1.145 mmol) in DMF (1 mL) was treated with acetaldoxime (0.068 g, 1.145 mmol), stirred at RT for 30 min, then added to a solution of N-(5-((2-ethynylpyridin-4-yl)oxy)-6-methylpyridin-2-yl)acetamide (0.102 g, 0.382 mmol) and TEA (0.5 mL) in DMF (1 mL) and heated at 60° C. for 1 h. The mixture was cooled to RT, treated with H2O, extracted with EtOAc (2×) and the combined organics were washed with H2O, then brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(6-methyl-5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)acetamide (110 mg, 89%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.64 (s, 1H), 8.55 (d, J=5.7 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.35 (d, J=2.5 Hz, 1H), 6.96 (m, 2H), 2.28 (s, 3H), 2.25 (s, 3H), 2.08 (s, 3H); MS (ESI) m/z: 325.1 (M+H+). heated at 60° C. for 1 h The mixture was cooled to RT extracted with EtOAc (2×) the combined organics were washed with H2O brine, dried over Na2SO4 concentrated to dryness purified via silica gel chromatography (MeOH/DCM)

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

Procedure: A stirred solution of 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (610 mg, 783 μmol, Eq: 1.00), acetaldoxime (139 mg, 143 μl, 2.35 mmol, Eq: 3) and indium (III) chloride (8.66 mg, 39.1 μmol, Eq: 0.05) in toluene (25.2 ml) was heated to 110° C. and stirred for 3 h. The reaction mixture was poured into 15 mL EtOAc and extracted with sat NH4Cl (1×25 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. After removal of solvent and residue was separated by flash chromatography (silica gel, 12 g, 80% to 100% EtOAc in hexanes) gave 66 mgs of desired product with impurity. This material was re-purified by preparative reverphase HPLC in TFA. The desired product was neutralized with NaHCO3 (1×25 mL). The organic layers were dried over MgSO4 and concentrated in vacuo., extracted with ethyl acetate/methanol (9:1) to give 1-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid amide (43 mgs, 12%) as white solid. 1H NMR (DMSO-d6) δ: 8.64 (dd, J=7.9, 1.6 Hz, 1H), 8.60 (d, J=2.5 Hz, 1H), 8.45 (s, 1H), 8.36 (dd, J=4.8, 1.8 Hz, 1H), 7.94 (d, J=1.8 Hz, 1H), 7.82 (dd, J=13.2, 1.6 Hz, 1H), 7.66-7.78 (m, 3H), 7.63 (dd, J=7.3, 2.3 Hz, 1H), 7.36 (dd, J=8.0, 4.8 Hz, 1H), 7.18 (br. s., 1H), 4.72 (t, J=5.4 Hz, 1H), 4.11-4.34 (m, 2H), 1.44 (s, 9H). MS m/e 486.6 (M+H+). extracted with sat NH4Cl (1×25 mL) The organic layers were dried over MgSO4 concentrated in vacuo After removal of solvent and residue was separated by flash chromatography (silica gel, 12 g, 80% to 100% EtOAc in hexanes)

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

Procedure: A stirred solution of 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (610 mg, 783 μmol, Eq: 1.00), acetaldoxime (139 mg, 143 μl, 2.35 mmol, Eq: 3) and indium (III) chloride (8.66 mg, 39.1 μmol, Eq: 0.05) in toluene (25.2 ml) was heated to 110° C. and stirred for 3 h. The reaction mixture was poured into 15 mL EtOAc and extracted with sat NH4Cl (1×25 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. After removal of solvent and residue was separated by flash chromatography (silica gel, 12 g, 80% to 100% EtOAc in hexanes) gave 66 mgs of desired product with impurity. This material was re-purified by preparative reverphase HPLC in TFA. The desired product was neutralized with NaHCO3 (1×25 mL). The organic layers were dried over MgSO4 and concentrated in vacuo., extracted with ethyl acetate/methanol (9:1) to give 1-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid amide (43 mgs, 12%) as white solid. 1H NMR (DMSO-d6) δ: 8.64 (dd, J=7.9, 1.6 Hz, 1H), 8.60 (d, J=2.5 Hz, 1H), 8.45 (s, 1H), 8.36 (dd, J=4.8, 1.8 Hz, 1H), 7.94 (d, J=1.8 Hz, 1H), 7.82 (dd, J=13.2, 1.6 Hz, 1H), 7.66-7.78 (m, 3H), 7.63 (dd, J=7.3, 2.3 Hz, 1H), 7.36 (dd, J=8.0, 4.8 Hz, 1H), 7.18 (br. s., 1H), 4.72 (t, J=5.4 Hz, 1H), 4.11-4.34 (m, 2H), 1.44 (s, 9H). MS m/e 486.6 (M+H+). extracted with sat NH4Cl (1×25 mL) The organic layers were dried over MgSO4 concentrated in vacuo After removal of solvent and residue was separated by flash chromatography (silica gel, 12 g, 80% to 100% EtOAc in hexanes)