1,4-oxazepane;hydrochloride

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

Procedure: In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1,4-oxazepane hydrochloride and isolated as white gum (12.0 mg, 63%). MS (m/e): 401.5 (MH+).

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Pyrrolo[2,1-f][1,2,4]triazin-4-amine (4000 mg, 29.8 mmol) was dissolved in acetic acid (160 mL). 37% wt formaldehyde in water is added (2.90 mL, 35.8 mmol) followed by 1,4-oxazepane hydrochloride (4.92 g, 35.8 mmol) and potassium acetate (5.27 g, 53.7 mmol). The reaction was heated at 60° C. under a nitrogen atmosphere overnight then cooled to room temperature. The reaction was concentrated under vacuum. The residue was partitioned between EtOAc (300 mL) and saturated aqueous bicarbonate (150 mL). The aqueous layer is extracted with EtOAc (5×100 mL). The combined organics were washed with brine (100 mL) then dried with Na2SO4 to yield 6.78 g (92%) of desired product. is added (2.90 mL, 35.8 mmol) then cooled to room temperature The reaction was concentrated under vacuum The residue was partitioned between EtOAc (300 mL) and saturated aqueous bicarbonate (150 mL) The aqueous layer is extracted with EtOAc (5×100 mL) The combined organics were washed with brine (100 mL) then dried with Na2SO4

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

Procedure: A solution of formaldehyde (0.61 mL, 8.10 mmol, 37% in H2O) and homomorpholine hydrochloride (1.11 g, 8.10 mmol) in AcOH (5 mL) was added to a stirring solution of 6-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (1.00 g, 6.75 mmol) in AcOH (5 mL) at 60° C. The reaction was allowed to stir until all starting material had been consumed as shown by HPLC (1 hr). The reaction mixture was worked up by diluting with EtOAc and washing 3× with saturated sodium carbonate solution. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was triturated with Et2O to obtain 1.37 g (78%) of a light brown powder. 1H-NMR (DMSO-d6) δ 7.76 (s, 1H), 7.47 (br s, 2H), 6.65 (s, 1H), 3.85 (s, 2H), 3.62 (t, J=5.7 Hz, 2H), 3.55-3.51 (m, 2H), 2.61-2.55 (m, 4H), 2.21 (s, 3H), 1.77-1.74 (m, 2H); MS [M+H]+=262.0; LCMS RT=1.02. had been consumed as shown by HPLC (1 hr) by diluting with EtOAc washing 3× with saturated sodium carbonate solution The organic layer was dried over Na2SO4 concentrated under reduced pressure The crude product was triturated with Et2O

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

Procedure: A suspension of 1,4-oxazepane hydrochloride (24.80 g, 180 mmol), sodium acetate (29.60 g, 360 mmol) and acetic acid (20.6 ml, 360 mmol) in tetrahydrofuran (400 ml) was stirred for 1 hr, a solution of chloroacetyl chloride (14.3 ml, 180 mmol) in tetrahydrofuran (100 ml) was added dropwise under ice-cooling, and the mixture was stirred overnight at room temperature. To the reaction mixture was added, sodium hydrogen carbonate (65.7 g, 792 μmmol), and the mixture was stirred for 1 hr. The insoluble material was filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:2) to give N-chloroacetyl-1,4-oxazepane (29.8 g, yield 93%). cooling the mixture was stirred overnight at room temperature To the reaction mixture was added The insoluble material was filtered the filtrate was concentrated The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:2)

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

Procedure: A suspension of 1,4-oxazepane hydrochloride (24.80 g, 180 mmol), sodium acetate (29.60 g, 360 mmol) and acetic acid (20.6 ml, 360 mmol) in tetrahydrofuran (400 ml) was stirred for 1 hr, a solution of chloroacetyl chloride (14.3 ml, 180 mmol) in tetrahydrofuran (100 ml) was added dropwise under ice-cooling, and the mixture was stirred overnight at room temperature. To the reaction mixture was added, sodium hydrogen carbonate (65.7 g, 792 μmmol), and the mixture was stirred for 1 hr. The insoluble material was filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:2) to give N-chloroacetyl-1,4-oxazepane (29.8 g, yield 93%). cooling the mixture was stirred overnight at room temperature To the reaction mixture was added The insoluble material was filtered the filtrate was concentrated The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:2)

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

Procedure: Homomorpholine hydrochloride (28.2 g, 200 mol) was added to a mixture of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (21.68 g, 0.1368 mol, Example B(45), Step 2), HMPA (30 mL), water (50 mL), and potassium carbonate (59 g, 0.6 mol) at constant stirring and room temperature. The reaction mixture was heated at 80° C. for 50 h, diluted with water, and extracted with ethyl acetate (3×100 mL). The organic extracts were washed with water to weakly alkaline pH and dried with sodium sulfate. The product was purified chromatographically using hexane/ethyl acetate mixture as eluent to afford the title product (18.7 g, 61%). Satisfactory C,H,N-analysis was obtained. The reaction mixture was heated at 80° C. for 50 h extracted with ethyl acetate (3×100 mL) The organic extracts were washed with water to weakly alkaline pH dried with sodium sulfate The product was purified chromatographically using hexane/ethyl acetate mixture as eluent

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 27 mg (74 μmol) of tetrabutylammonium iodide, 153 mg (1.11 mmol) of homomorpholine hydrochloride and 153 mg (1.11 mmol) of potassium carbonate are successively added to a solution of 200 mg (0.37 mmol) of an approximately 70:30 mixture of tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-methyl-N′-phenylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate and tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-(4-chlorophenyl)-N′-methylhydrazinocarbonyl)-thieno[2,3-c]pyrazole-1-carboxylate in 6 mL of dimethylformamide under argon. The reaction mixture is stirred at a temperature in the region of 25° C. for 16 hours, and then poured onto ice. It is then extracted twice with a 50/50 mixture of ethyl acetate and heptane. The organic extracts are combined, dried over magnesium sulfate and then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is dissolved in 4 mL of methanol and the solution is introduced into a microwave oven tube. The tube is stoppered and the reaction mixture is irradiated at a temperature in the region of 100° C. for 30 minutes. The reaction mixture is then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is purified by preparative LC/MS (conditions B). 34 mg of N-[5-(N′-methyl-N′-phenylhydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]-4-perhydro-1,4-oxazepin-4-ylmethylbenzamide are thus obtained in the form of a yellow powder melting from 174 to 179° C. LC-MS-DAD-ELSD: 505(+)=(M+H)(+). 38 mg of N-{5-[N′-(4-chlorophenyl)-N′-methylhydrazinocarbonyl]-1H-thieno[2,3-c]pyrazol-3-yl}-4-perhydro-1,4-oxazepin-4-ylmethylbenzamide are isolated in the same manner, in the form of a yellow powder. 1H NMR (400 MHz, (CD3)2SO-d6, δ in ppm): This is the salt of the expected structure, with 2.08 (m, 2H); from 3.13 to 4.07 (m, 8H); 3.18 (s, 3H); 4.50 (broad s, 2H); 6.82 (d, J=9.0 Hz, 2H); 7.25 (d, J=9.0 Hz, 2H); 7.70 (broad d, J=8.0 Hz, 2H); 8.17 (partially masked d, J=8.0 Hz, 2H); 8.18 (s, 1H); 9.75 (broad multiplet, 1H); 10.85 (s, 1H); 11.3 (s, 1H); 12.95 (very broad m, 1H). poured onto ice It is then extracted twice with a 50/50 mixture of ethyl acetate and heptane dried over magnesium sulfate concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C The residue is dissolved in 4 mL of methanol the solution is introduced into a microwave oven tube the reaction mixture is irradiated at a temperature in the region of 100° C. for 30 minutes The reaction mixture is then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C The residue is purified by preparative LC/MS (conditions B)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 27 mg (74 μmol) of tetrabutylammonium iodide, 153 mg (1.11 mmol) of homomorpholine hydrochloride and 153 mg (1.11 mmol) of potassium carbonate are successively added to a solution of 200 mg (0.37 mmol) of an approximately 70:30 mixture of tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-methyl-N′-phenylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate and tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-(4-chlorophenyl)-N′-methylhydrazinocarbonyl)-thieno[2,3-c]pyrazole-1-carboxylate in 6 mL of dimethylformamide under argon. The reaction mixture is stirred at a temperature in the region of 25° C. for 16 hours, and then poured onto ice. It is then extracted twice with a 50/50 mixture of ethyl acetate and heptane. The organic extracts are combined, dried over magnesium sulfate and then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is dissolved in 4 mL of methanol and the solution is introduced into a microwave oven tube. The tube is stoppered and the reaction mixture is irradiated at a temperature in the region of 100° C. for 30 minutes. The reaction mixture is then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is purified by preparative LC/MS (conditions B). 34 mg of N-[5-(N′-methyl-N′-phenylhydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]-4-perhydro-1,4-oxazepin-4-ylmethylbenzamide are thus obtained in the form of a yellow powder melting from 174 to 179° C. LC-MS-DAD-ELSD: 505(+)=(M+H)(+). 38 mg of N-{5-[N′-(4-chlorophenyl)-N′-methylhydrazinocarbonyl]-1H-thieno[2,3-c]pyrazol-3-yl}-4-perhydro-1,4-oxazepin-4-ylmethylbenzamide are isolated in the same manner, in the form of a yellow powder. 1H NMR (400 MHz, (CD3)2SO-d6, δ in ppm): This is the salt of the expected structure, with 2.08 (m, 2H); from 3.13 to 4.07 (m, 8H); 3.18 (s, 3H); 4.50 (broad s, 2H); 6.82 (d, J=9.0 Hz, 2H); 7.25 (d, J=9.0 Hz, 2H); 7.70 (broad d, J=8.0 Hz, 2H); 8.17 (partially masked d, J=8.0 Hz, 2H); 8.18 (s, 1H); 9.75 (broad multiplet, 1H); 10.85 (s, 1H); 11.3 (s, 1H); 12.95 (very broad m, 1H). poured onto ice It is then extracted twice with a 50/50 mixture of ethyl acetate and heptane dried over magnesium sulfate concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C The residue is dissolved in 4 mL of methanol the solution is introduced into a microwave oven tube the reaction mixture is irradiated at a temperature in the region of 100° C. for 30 minutes The reaction mixture is then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C The residue is purified by preparative LC/MS (conditions B)

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

Procedure: 8-((1,4-oxazepan-4-yOmethyl)-6-(4-methoxybenzyl)thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (29). To a mixture of 6-(4-methoxybenzyl)-5-oxo-5,6-dihydrothieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine-8-carbaldehyde (50 mg, 0.15 mmol) and 1,4-oxazepane hydrochloride (30 mg, 0.22 mmol) in dichloromethane (2 ml) was added triethylamine (25 μl, 0.18 mmol). After 5 minutes of stifling, sodium triacetoxyhydroborate (47 mg, 0.22 mmol) was added. The resulting mixture was stirred at room temperature. After 4 hours, the mixture was concentrated under reduced pressure. The resulting residue was taken up in DMSO (2 mL), filtered and purified directly by reverse phase chromatography to yield the above product (33 mg, 41%) as a white solid. the mixture was concentrated under reduced pressure filtered purified directly by reverse phase chromatography

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

Procedure: To a stirred solution of 3-[6-(2-chloroethoxy)-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid (0.50 g), 1,4-oxazepane hydrochloride (0.77 g), N,N-diisopropylethylamine (0.98 ml) and KI (0.47 g) in DMA (2 ml) was heated to 120° C. for 30 minutes in a microwave (Personal Chemistry Emrys Optimizer with 300 W magnetron). The reaction mixture was diluted with methylene chloride (20 ml), CombiZorb isocyanate resin (loading 1.03 mmol/g from Agilent) (6 g) added and stirred at room temperature for 16 hours. The resin was removed by filtration and the filtrate washed with water (50 ml). The aqueous phase was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give 4-methyl-3-[6-[2-(1,4-oxazepan-4-yl)ethoxy]-4-oxoquinazolin-3(4H)-yl]benzoic acid (0.31 g); NMR Spectrum: (DMSOd6) 1.87 (m, 2H), 2.10 (s, 3H), 2.91 (m, 2H), 3.02 (m, 4H), 3.66 (m, 4H), 4.20 (m, 2H), 7.46 (m, 2H), 7.58 (s, 1H), 7.69 (d, 1H), 7.81 (s, 1H), 7.93 (d, 1H), 8.16 (s, 1H); Mass Spectrum: M+H+ 424. added The resin was removed by filtration the filtrate washed with water (50 ml) The aqueous phase was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) a 99:1 mixture of methanol and aqueous ammonia solution

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

Procedure: A mixture of 3.0 g (20.1 mmol) of 4,6-dichloropyrimidine, 2.8 g (20.1 mmol) of 1,4-oxazepane hydrochloride and 6.4 g (60.4 mmol) of sodium carbonate in 45 ml of water is stirred under reflux for 16 h. After cooling to RT, the reaction mixture is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate and filtered. Under reduced pressure, the filtrate is concentrated to dryness. The product is obtained as an oil. Yield: 3.9 g (86% of theory) under reflux for 16 h the reaction mixture is extracted with ethyl acetate The organic phase is washed with saturated sodium chloride solution dried over sodium sulphate filtered Under reduced pressure, the filtrate is concentrated to dryness The product is obtained as an oil

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

Procedure: Et3N (96.9 mL, 0.695 mol) was added in one portion to a stirred suspension of homomorpholine hydrochloride (79.76 g, 0.579 mol) and ketone 1 (90.5 g, 0.579 mol) in 1,2-dichloroethane (1.81 L). Then glacial acetic acid (34.8 mL, 0.607 mol) was added in one portion followed by solid NaBH(OAc)3 (154 g, 0.727 mol) in one portion as well. This was accompanied by 5° C. increase in the temperature of the reaction mixture. After 2 h 45 min the reaction was quenched by addition of 10% aqueous NaOH (800 mL). The mixture was stirred for 10 min. The organic layer was separated, washed with brine (100 mL), dried (MgSO4) and concentrated to afford an oil (142.36 g) with some suspended solid, which was filtered off (3.00 g). The aqueous part of the reaction mixture was combined with the brine washings and extracted with AcOEt (4×500 mL). Combined extracts were washed with brine (100 mL), dried (MgSO4) and concentrated to afford additional portion of oil (16.82 g). The two oily products were combined and distilled in vacuum to give 3 (101.07 g, 72%) as colorless liquid, b.p. 122° C./8.9·10−3 mbar. 1H NMR (400 MHz, CDCl3) δ 1.48-1.64 (m, 4H), 1.70-1.88 (m, 6H), 2.50-2.63 (m, 1H), 2.71-2.81 (m, 4H), 3.66-3.72 (m, 2H), 3.78 (t, J=6.0 Hz, 2H), 3.93 (s, 4H). This was accompanied by 5° C. increase in the temperature of the reaction mixture After 2 h 45 min the reaction was quenched by addition of 10% aqueous NaOH (800 mL) The organic layer was separated washed with brine (100 mL) dried (MgSO4) concentrated