O-phenylhydroxylamine;hydrochloride

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

Procedure: A mixture of 2-(3-chloro-propyl)-[1,3]-dioxolane (5.7 g; 0.038 mol), THF (50 ml) and aqueous acid chloride (1/1) was stirred at room temperature for 24 hours. O-phenyl-hydroxylamine hydrochloride (5 g; 0.034 mol) was then added and the resulting mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated under vacuum. Then the product was extracted with methylene chloride. The organic extract was dried (Mg SO4) and evaporated under vacuum. After purification by Flash Chromatography on silica gel using as eluent hexane/ethyl acetate (95/5), the desired compound was obtained. the resulting mixture was stirred at room temperature for 48 hours The reaction mixture was concentrated under vacuum Then the product was extracted with methylene chloride The organic extract was dried (Mg SO4) evaporated under vacuum After purification by Flash Chromatography on silica gel using as eluent hexane/ethyl acetate (95/5)

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of O-phenylhydroxylamine hydrochloride (1:1) (0.625 mol) and 4,4-piperidinediol hydrochloride (1:1) (0.682 mol) in 2-propanol (615 ml) was stirred at 20° C. HCl (353 ml) was added dropwise at 20 ° C. The reaction mixture was gently heated to reflux temperature. The reaction mixture was stirred and refluxed for 3 hours, then cooled to room temperature. The precipitate was filtered off, washed with diisopropyl ether, and dried. This fraction was crystallized from water (1600 ml). The desired compound was allowed to crystallize out while stirring. The precipitate was filtered off, washed with 2-propanol and diisopropyl ether, then dried, yielding 84 g (64%) of 1,2,3,4-tetrahydrobenzo-furo[3,2-c]pyridine hydrochloride (1:1) (interm. 1). The reaction mixture was gently heated to reflux temperature The reaction mixture was stirred refluxed for 3 hours cooled to room temperature The precipitate was filtered off washed with diisopropyl ether dried This fraction was crystallized from water (1600 ml) to crystallize out while stirring The precipitate was filtered off washed with 2-propanol and diisopropyl ether dried

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of O-phenylhydroxylamine hydrochloride (1:1) (0.625 mol) and 4,4-piperidinediol hydrochloride (1:1) (0.682 mol) in 2-propanol (615 ml) was stirred at 20° C. HCl (353 ml) was added dropwise at 20 ° C. The reaction mixture was gently heated to reflux temperature. The reaction mixture was stirred and refluxed for 3 hours, then cooled to room temperature. The precipitate was filtered off, washed with diisopropyl ether, and dried. This fraction was crystallized from water (1600 ml). The desired compound was allowed to crystallize out while stirring. The precipitate was filtered off, washed with 2-propanol and diisopropyl ether, then dried, yielding 84 g (64%) of 1,2,3,4-tetrahydrobenzo-furo[3,2-c]pyridine hydrochloride (1:1) (interm. 1). The reaction mixture was gently heated to reflux temperature The reaction mixture was stirred refluxed for 3 hours cooled to room temperature The precipitate was filtered off washed with diisopropyl ether dried This fraction was crystallized from water (1600 ml) to crystallize out while stirring The precipitate was filtered off washed with 2-propanol and diisopropyl ether dried

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

Procedure: This compound prepared from methyl Z-2-(carboxycyclopent-1-yloxyimino)-2-(fur-2-yl)acetate and phenoxyamine hydrochloride as described in Preparation 7(c), was purified by chromatography on silica gel plates in ethyl acetate-light petroleum b.p. 40°-60° (3:1 v/v). τ(DMSO d6) 2.5-3.1 (phenyl), 7.7-8.1, 8.1-8.5 (cyclopentyl), 2.0, 3.28, 3.02 (furyl), 6.03 (methyl). Yield 44% was purified by chromatography on silica gel plates in ethyl acetate-light petroleum b.p. 40°-60° (3:1 v/v)

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

Procedure: This compound prepared from methyl Z-2-(carboxycyclopent-1-yloxyimino)-2-(fur-2-yl)acetate and phenoxyamine hydrochloride as described in Preparation 7(c), was purified by chromatography on silica gel plates in ethyl acetate-light petroleum b.p. 40°-60° (3:1 v/v). τ(DMSO d6) 2.5-3.1 (phenyl), 7.7-8.1, 8.1-8.5 (cyclopentyl), 2.0, 3.28, 3.02 (furyl), 6.03 (methyl). Yield 44% was purified by chromatography on silica gel plates in ethyl acetate-light petroleum b.p. 40°-60° (3:1 v/v)

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

Procedure: This compound was prepared from phenoxyamine hydrochloride and chloroacetyl chloride by the method described in Preparation 1, m.p. 126°-128° (decomp.), λmax (EtOH) 266.5 nm (ε15,400), νmax (Nujol) 3340, 3260, 3140 (--NH--), 1720, 1710, 1690 cm-1 (--CONH--), τ(DMSO d6) 5.79 (ClCH2CO--), -2.2 (--NH--), 2.3-3.2 (phenyl). Yield 67%

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

Procedure: This compound was prepared from phenoxyamine hydrochloride and chloroacetyl chloride by the method described in Preparation 1, m.p. 126°-128° (decomp.), λmax (EtOH) 266.5 nm (ε15,400), νmax (Nujol) 3340, 3260, 3140 (--NH--), 1720, 1710, 1690 cm-1 (--CONH--), τ(DMSO d6) 5.79 (ClCH2CO--), -2.2 (--NH--), 2.3-3.2 (phenyl). Yield 67%

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

Procedure: The title compound was prepared by coupling of 3-(4-fluoro-benzyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid and N-phenoxyamine hydrochloride under the same conditions as those in step (c) of example 1. 1H NMR (300 MHz, MeOH-d4) δ; 8.82 (s, 1H), 8.53 (s, 1H), 8.43 (s, 1H), 8.24 (d, 2H, J=7.9 Hz), 7.38–7.33 (m, 2H), 7.07–7.01 (m, 2H), 6.88–6.74 (m, 3H), 5.57 (s, 2H). LCMS (API-ES, M+H+): 363.1. HRMS calcd for C20H16FN4O2 (M+H) 363.1257. found 363.1256. HPLC: >85% purity.

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

Procedure: A mixture of 2-(3-chloro-propyl)-[1,3]-dioxolane (5.7 g; 0.038 mol), THF (50 ml) and aqueous acid chloride (1/1) was stirred at room temperature for 24 hours. O-phenyl-hydroxylamine hydrochloride (5 g; 0.034 mol) was then added and the resulting mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated under vacuum. Then the product was extracted with methylene chloride. The organic extract was dried (Mg SO4) and evaporated under vacuum. After purification by Flash Chromatography on silica gel using as eluent hexane/ethyl acetate (95/5), the desired compound was obtained. the resulting mixture was stirred at room temperature for 48 hours The reaction mixture was concentrated under vacuum Then the product was extracted with methylene chloride The organic extract was dried (Mg SO4) evaporated under vacuum After purification by Flash Chromatography on silica gel using as eluent hexane/ethyl acetate (95/5)

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

Procedure: A mixture of 2-(3-chloro-propyl)-[1,3]-dioxolane (5.7 g; 0.038 mol), THF (50 ml) and aqueous acid chloride (1/1) was stirred at room temperature for 24 hours. O-phenyl-hydroxylamine hydrochloride (5 g; 0.034 mol) was then added and the resulting mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated under vacuum. Then the product was extracted with methylene chloride. The organic extract was dried (Mg SO4) and evaporated under vacuum. After purification by Flash Chromatography on silica gel using as eluent hexane/ethyl acetate (95/5), the desired compound was obtained. the resulting mixture was stirred at room temperature for 48 hours The reaction mixture was concentrated under vacuum Then the product was extracted with methylene chloride The organic extract was dried (Mg SO4) evaporated under vacuum After purification by Flash Chromatography on silica gel using as eluent hexane/ethyl acetate (95/5)

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of O-phenylhydroxylamine hydrochloride (1:1) (0.625 mol) and 4,4-piperidinediol hydrochloride (1:1) (0.682 mol) in 2-propanol (615 ml) was stirred at 20° C. HCl (353 ml) was added dropwise at 20 ° C. The reaction mixture was gently heated to reflux temperature. The reaction mixture was stirred and refluxed for 3 hours, then cooled to room temperature. The precipitate was filtered off, washed with diisopropyl ether, and dried. This fraction was crystallized from water (1600 ml). The desired compound was allowed to crystallize out while stirring. The precipitate was filtered off, washed with 2-propanol and diisopropyl ether, then dried, yielding 84 g (64%) of 1,2,3,4-tetrahydrobenzo-furo[3,2-c]pyridine hydrochloride (1:1) (interm. 1). The reaction mixture was gently heated to reflux temperature The reaction mixture was stirred refluxed for 3 hours cooled to room temperature The precipitate was filtered off washed with diisopropyl ether dried This fraction was crystallized from water (1600 ml) to crystallize out while stirring The precipitate was filtered off washed with 2-propanol and diisopropyl ether dried

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

Procedure: O-phenylhydroxylamine hydrochloride (6.9 mmol, 1.0 g), 4-methoxybenzenesulfonyl chloride (6.2 mmol, 1.29 g), diisopropylethylamine (13.1 mmol, 2.28 mL) and andhydrous THF (15 mL) were combined under nitrogen. After stirring for 2 hours at room temperature, a few crystals of 4-dimethylaminopyridine were added and the flask was re-sealed. After another 2 hours, 4 mL of N,N-dimethylformamide was injected and the reaction stirred for an additional 15 hours. The resulting red solution was concentrated to an oil and partitioned between ethyl acetate and 1N HCl. The organic layer was separated and washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated under vacuum. The resulting dark brown residue was purified by silica gel chromatography (3:1 hexanes/ethyl acetate) providing 360 mg (21%) of a redish solid. H1-NMR (CDCl3): δ 7.89 (2H,d), 7.30-7.20 (3H,m), 7.11 (2H,d), 7.02 (1H,s), 7.00 (2H,d), 3.88 (3H,s). the flask was re-sealed After another 2 hours the reaction stirred for an additional 15 hours The resulting red solution was concentrated to an oil partitioned between ethyl acetate and 1N HCl The organic layer was separated washed with saturated aqueous sodium bicarbonate and brine dried over magnesium sulfate concentrated under vacuum The resulting dark brown residue was purified by silica gel chromatography (3:1 hexanes/ethyl acetate) providing 360 mg (21%) of a redish solid