2-chloro-1,1,1-triethoxyethane

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

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

Procedure: 2-Fluoro-5-methyl-benzoic acid hydrazide (320 mg, 1.9 mmol) and 2-chloro-1,1,1-triethoxy-ethane (1.9 ml) were heated in a sealed vial at 120° C. for 30 min. The reaction mixture was place directly onto a flash column (silica gel) and purified by using 0-5% ethyl acetate in hexanes to afford 2-chloromethyl-5-(2-fluoro-5-methyl-phenyl)-[1,3,4]oxadiazole (284.5 mg, 66%). 1H NMR (CDCl3) d (ppm): 7.89 (q, 1H), 7.36 (m, 1H), 7.16 (t, 1H), 4.81 (s, 2H), 2.43 (s, 3H). purified

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

Procedure: 2-Fluoro-5-methyl-benzoic acid hydrazide (320 mg, 1.9 mmol) and 2-chloro-1,1,1-triethoxy-ethane (1.9 ml) were heated in a sealed vial at 120° C. for 30 min. The reaction mixture was place directly onto a flash column (silica gel) and purified by using 0-5% ethyl acetate in hexanes to afford 2-chloromethyl-5-(2-fluoro-5-methyl-phenyl)-[1,3,4]oxadiazole (284.5 mg, 66%). 1H NMR (CDCl3) d (ppm): 7.89 (q, 1H), 7.36 (m, 1H), 7.16 (t, 1H), 4.81 (s, 2H), 2.43 (s, 3H). purified

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

Procedure: To a RT solution of 2-amino-3-nitrophenol (14.7 g, 95 mmol, 1.0 equiv) in 2-methoxyethylether (136 mL) was added 2-chloro-1,1,1-triethoxyethane (19.1 g, 97.3 mmol, 1.02 equiv) and p-toluene sulfonic acid hydrate (25 mg, 0.13 mmol, 0.2 equiv). The resulting mixture was heate to reflux overnight. After the reaction was cooled to RT, the solvent was removed in vacuo. The solid was suspended in methanol (40 mL), stirred and filtered to provide the desired product as a red solid (3.61 g). The filtrate provided an additional 9.8 g of the title compound through an additional methanol treatment (13.4 g, 98% combined). to reflux overnight the solvent was removed in vacuo filtered

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

Procedure: To a RT solution of 2-amino-3-nitrophenol (14.7 g, 95 mmol, 1.0 equiv) in 2-methoxyethylether (136 mL) was added 2-chloro-1,1,1-triethoxyethane (19.1 g, 97.3 mmol, 1.02 equiv) and p-toluene sulfonic acid hydrate (25 mg, 0.13 mmol, 0.2 equiv). The resulting mixture was heate to reflux overnight. After the reaction was cooled to RT, the solvent was removed in vacuo. The solid was suspended in methanol (40 mL), stirred and filtered to provide the desired product as a red solid (3.61 g). The filtrate provided an additional 9.8 g of the title compound through an additional methanol treatment (13.4 g, 98% combined). to reflux overnight the solvent was removed in vacuo filtered

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

Procedure: The mixture of the above obtained methyl [1-(2-chlorophenyl)-5-hydroxy-1H-pyrazol-3-yl]acetate (Compound of Formula (IV), 0.60 g), was suspended in acetonitrile (5 mL) and glacial acetic acid (14 mg, 0.1 eq.) and 2-chloro-1,1,1-triethoxyethane (1.5 g) under nitrogen, was heated at 70° C. for 45-60 minutes. The resulting red solution was concentrated in vacuo to afford a red syrup that was washed with cyclohexane and then dried in vacuo. Due to its relative instability, no further purification of methyl [4-(chloroacetyl)-1-(2-chlorophenyl)-5-hydroxy-1H-pyrazol-3-yl]acetate was conducted (0.77 g, quantitative yield). MS (ESL): 344.3; MS (ESI−): 342.2. The mixture of the The resulting red solution was concentrated in vacuo to afford a red syrup that was washed with cyclohexane dried in vacuo Due to its relative instability, no further purification of methyl [4-(chloroacetyl)-1-(2-chlorophenyl)-5-hydroxy-1H-pyrazol-3-yl]acetate

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

Procedure: 2-Fluoro-5-methyl-benzoic acid hydrazide (320 mg, 1.9 mmol) and 2-chloro-1,1,1-triethoxy-ethane (1.9 ml) were heated in a sealed vial at 120° C. for 30 min. The reaction mixture was place directly onto a flash column (silica gel) and purified by using 0-5% ethyl acetate in hexanes to afford 2-chloromethyl-5-(2-fluoro-5-methyl-phenyl)-[1,3,4]oxadiazole (284.5 mg, 66%). 1H NMR (CDCl3) d (ppm): 7.89 (q, 1H), 7.36 (m, 1H), 7.16 (t, 1H), 4.81 (s, 2H), 2.43 (s, 3H). purified

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

Procedure: 2-Fluoro-5-methyl-benzoic acid hydrazide (320 mg, 1.9 mmol) and 2-chloro-1,1,1-triethoxy-ethane (1.9 ml) were heated in a sealed vial at 120° C. for 30 min. The reaction mixture was place directly onto a flash column (silica gel) and purified by using 0-5% ethyl acetate in hexanes to afford 2-chloromethyl-5-(2-fluoro-5-methyl-phenyl)-[1,3,4]oxadiazole (284.5 mg, 66%). 1H NMR (CDCl3) d (ppm): 7.89 (q, 1H), 7.36 (m, 1H), 7.16 (t, 1H), 4.81 (s, 2H), 2.43 (s, 3H). purified

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N7-[(2S)-bicyclo[2.2.1]hept-2-yl]thieno[3,2-b]pyridine-6,7-diamine (0.060 g, 0.23 mmol) and 2-chloro-1,1,1-triethoxyethane (0.134 mL, 0.700 mmol) in acetic acid (0.2 mL) was stirred at 120° C. for 30 min. The solvent was removed and the resultant residue was dissolved in dichloromethane and purified on silica gel (eluting with 0-5% MeOH in dichloromethane) to give the desired product. LCMS calculated for C16H17ClN3S (M+H)+: m/z=318.1. Found: 318.0. The solvent was removed the resultant residue was dissolved in dichloromethane purified on silica gel (eluting with 0-5% MeOH in dichloromethane)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N7-[(2S)-bicyclo[2.2.1]hept-2-yl]thieno[3,2-b]pyridine-6,7-diamine (0.060 g, 0.23 mmol) and 2-chloro-1,1,1-triethoxyethane (0.134 mL, 0.700 mmol) in acetic acid (0.2 mL) was stirred at 120° C. for 30 min. The solvent was removed and the resultant residue was dissolved in dichloromethane and purified on silica gel (eluting with 0-5% MeOH in dichloromethane) to give the desired product. LCMS calculated for C16H17ClN3S (M+H)+: m/z=318.1. Found: 318.0. The solvent was removed the resultant residue was dissolved in dichloromethane purified on silica gel (eluting with 0-5% MeOH in dichloromethane)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of {trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}acetonitrile (51.9 mg, 0.181 mmol) (Example 2, Step 4) and 2-chloro-1,1,1-triethoxyethane (from Aldrich, 0.105 mL, 0.549 mmol) in acetic acid (0.5 mL) was stirred at 120° C. for 30 min. The solvent was removed and the resultant residue dissolved in dichloromethane and purified on silica gel (eluting with 0-5% MeOH in dichloromethane) to give 22 mg (35.5%) of {trans-4-[2-(Chloromethyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl]cyclohexyl}acetonitrile. LCMS calculated for C17H18ClN4S (M+H)+: m/z=345.1. Found: 345.0. Also eluted was 8 mg (12%) of {1-[trans-4-(cyanomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}methyl acetate, LCMS calculated for C19H21N4O2S (M+H)+: m/z=369.1. Found: 369.0. The acetate compound was treated with lithium hydroxide to give compound the desired product after HPLC purification (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min). LCMS calculated for C17H19N4OS (M+H)+: m/z=327.1. Found: 327.1. 1H NMR (500 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.01 (d, J=5.5 Hz, 1H), 7.67 (d, J=5.5 Hz, 1H), 5.80 (t, J=5.6 Hz, 1H), 4.85 (d, J=5.3 Hz, 2H), 4.74 (m, 1H), 2.61 (d, J=6.1 Hz, 2H), 2.42 (m, 2H), 2.09-1.99 (m, 5H), 1.41 (m, 2H) ppm. The solvent was removed the resultant residue dissolved in dichloromethane purified on silica gel (eluting with 0-5% MeOH in dichloromethane)

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

Procedure: 2-Fluoro-5-methyl-benzoic acid hydrazide (320 mg, 1.9 mmol) and 2-chloro-1,1,1-triethoxy-ethane (1.9 ml) were heated in a sealed vial at 120° C. for 30 min. The reaction mixture was place directly onto a flash column (silica gel) and purified by using 0-5% ethyl acetate in hexanes to afford 2-chloromethyl-5-(2-fluoro-5-methyl-phenyl)-[1,3,4]oxadiazole (284.5 mg, 66%). 1H NMR (CDCl3) d (ppm): 7.89 (q, 1H), 7.36 (m, 1H), 7.16 (t, 1H), 4.81 (s, 2H), 2.43 (s, 3H). purified