azane;hydrate

Conditions: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 2-(1-(benzyloxycarbonyl)azetidin-3-yl)benzo[d]oxazole-7-carboxylate (280 mg, 0.76 mmol) was added to ammonia water (10 ml) and the mixture was stirred at 35° C. for overnight. Then the solid was filtered. 160 mg of benzyl 3-(7-carbamoylbenzo[d]oxazol-2-yl)azetidine-1-carboxylate was obtained, yield 60%. LC-MS (ESI) m/z: 352 (M+1)+. (M+1)+, Then the solid was filtered

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

Procedure: Methyl 2-(1-(benzyloxycarbonyl)piperidin-4-yl)benzo[d]oxazole-7-carboxylate (102 mg, 0.26 mmol) was added to a mixture of methanol (5 mL) and ammonia water (10 mL) and the mixture was stirred at room temperature for overnight. Then the solid was filtered. 98 mg of solid of benzyl 4-(7-carbamoylbenzo[d]oxazol-2-yl)piperidine-1-carboxylate was obtained. LC-MS (ESI) m/z: 380 (M+1)+. Then the solid was filtered

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

Procedure: To a stirred solution of methyl 2-(1-(benzyloxycarbonyl)pyrrolidin-2-yl)benzo[d]oxazole-7-carboxylate (150 mg, 0.394 mmol) in methanol (8 mL) was added ammonia water (6 mL) at 0° C. After the addition, the mixture was allowed to stir at room temperature overnight. Methanol was removed in vacuum. The residue was diluted with water (100 mL), extracted with ethyl acetate (50 mL×3). The combined organic layers washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=20:1 to 1:1) to give benzyl 2-(7-carbamoylbenzo[d]oxazol-2-yl)pyrrolidine-1-carboxylate (68 mg, yield 42%). LC-MS (ESI) m/z: 366 (M+1)+. After the addition Methanol was removed in vacuum The residue was diluted with water (100 mL) extracted with ethyl acetate (50 mL×3) The combined organic layers washed with brine dried over anhydrous sodium sulfate concentrated to give crude product The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=20:1 to 1:1)

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 2-(4-((dimethylamino)methyl)phenyl)benzo[d]oxazole-4-carboxylate (40 mg, 0.13 mmol) and ammonia water (17.2 mg, 0.52 mmol) were added and the mixture was stirred at 30° C. for 1 h. The resulting mixture was evaporated under reduced pressure and purified by pre-HPLC. 2-(4-((dimethylamino)methyl)phenyl)benzo[d]oxazole-4-carboxamide (16 mg) was obtained, yield 41%. LC-MS (ESI) m/z: 296 (M+1)+. 1H-NMR (400 MHz, DMSO-d6): δ 2.94 (s, 6H), 4.46 (s, 2H), 7.57-7.58 (m, 1H), 7.75-7.77 (m, 2H), 7.93 (brs, 1H), 8.09 (brs, 1H), 8.43-8.44 (m, 2H). The resulting mixture was evaporated under reduced pressure purified by pre-HPLC

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Oxalyl chloride (0.04 g, 0.3 mmol) was slowly added to a solution of 2-p-tolylbenzo[d]oxazole-4-carboxylic acid (0.064 g, 0.25 mmol) in dichloromethane (10 mL) with stirring. The reaction mixture was warmed to 50° C. for 4 hr and then cooled to 25° C. The solution was condensed in vacuum and then slowly added to 28% ammonia water (10 mL) and a solid precipitated out immediately. The mixture was warmed to 50° C. and stirred for another 2 hr. Water (20 mL) was added to the mixture and the slurry was cooled to 25° C. The product was filtered and the cake was washed with water, dried to afford 44 mg 2-p-tolylbenzo[d]oxazole-4-carboxamide as a solid (yield 69.8%). 1H-NMR (400 MHz, DMSO-d6) δ 2.46 (s, 3H), 6.01 (s, 1H), 7.34-7.36 (d, J=7.6 Hz, 2H), 7.43-7.47 (t, J=8.0 Hz, 1H), 7.71-7.73 (d, J=8.0 Hz, 1H), 8.15-8.18 (m, 3H), 9.02 (s, 1H); LC-MS (ESI) m/z 253 [M+1]+. cooled to 25° C condensed in vacuum a solid precipitated out immediately The mixture was warmed to 50° C. stirred for another 2 hr Water (20 mL) was added to the mixture the slurry was cooled to 25° C The product was filtered the cake was washed with water dried

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

Procedure: In 10 ml of 85% phosphoric acid was refluxed 1 g of 1,2-dihydro-6-methyl-5-(imidazo[1,2-a]pyridin-6-yl)-2-oxo-3-pyridinecarbonitrile for 18 hours. After cooling, water was added and then conc. ammonia water was further added to the reaction mixture to render the mixture alkaline. The mixture was extracted with chloroform. After washing with water and drying over magnesium sulfate, chloroform was removed by distillation under reduced pressure. The residue was recrystallized from ethanol-ether to obtain 0.4 g of 1,2-dihydro-6-methyl-5-(imidazo[1,2-a]pyridin-6-yl)-2-oxo-pyridine. After cooling The mixture was extracted with chloroform After washing with water drying over magnesium sulfate, chloroform was removed by distillation under reduced pressure The residue was recrystallized from ethanol-ether

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

Procedure: In 15 ml of conc. sulfuric acid, 3 g of 1,2-dihydro-6-methyl-5-(imidazo[1,2-a]pyridin-6-yl)-2-oxo-3-pyridinecarbonitrile was stirred at 90° C. for 40 minutes. After cooling, the reaction mixture was poured into ice and conc. ammonia water was added thereto to render the mixture alkaline. Crystals prepcipitated were taken by filtration. After washing with water and drying, the crystals were recrystallized from N,N-dimethylformamide to obtain 2.5 g of 1,2-dihydro-6-methyl-5-(imidazo[1,2-a]pyridin-6-yl)-2-oxo-3-pyridinecarboxamide. After cooling was added Crystals prepcipitated were taken by filtration After washing with water drying the crystals were recrystallized from N,N-dimethylformamide

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

Procedure: In 10 ml of 85% phosphoric acid was refluxed 1 g of 1,2-dihydro-6-methyl-5-(imidazo[1,2-a]pyridin-6-yl)-2-oxo-3-pyridinecarbonitrile for 18 hours. After cooling, water was added and then conc. ammonia water was further added to the reaction mixture to render the mixture alkaline. The mixture was extracted with chloroform. After washing with water and drying over magnesium sulfate, chloroform was removed by distillation under reduced pressure. The residue was recrystallized from ethanol-ether to obtain 0.4 g of 1,2-dihydro-6-methyl-5-(imidazo[1,2-a]pyridin-6-yl)-2-oxo-pyridine. After cooling The mixture was extracted with chloroform After washing with water drying over magnesium sulfate, chloroform was removed by distillation under reduced pressure The residue was recrystallized from ethanol-ether

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

Procedure: In 15 ml of conc. sulfuric acid, 3 g of 1,2-dihydro-6-methyl-5-(imidazo[1,2-a]pyridin-6-yl)-2-oxo-3-pyridinecarbonitrile was stirred at 90° C. for 40 minutes. After cooling, the reaction mixture was poured into ice and conc. ammonia water was added thereto to render the mixture alkaline. Crystals prepcipitated were taken by filtration. After washing with water and drying, the crystals were recrystallized from N,N-dimethylformamide to obtain 2.5 g of 1,2-dihydro-6-methyl-5-(imidazo[1,2-a]pyridin-6-yl)-2-oxo-3-pyridinecarboxamide. After cooling was added Crystals prepcipitated were taken by filtration After washing with water drying the crystals were recrystallized from N,N-dimethylformamide

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

Procedure: 48.0 g of phenol and 82.6 g of 37%-formalin were placed in a separable flask equipped with a Dimroth condenser, and stirred for mixing therein, followed further by addition of 3.8 g of 29% ammonia water and stirring for mixing. The resultant solution was reacted at a temperature of 70-80° C. for 6.5 hours on a mantle heater. After the reaction, the reaction product was cooled to room temperature to obtain 78 g of phenol-formaldehyde initial condensate. The initial condensate was placed in a vessel formed by a copper foil and cured at 150° C. for 12 hours in a drier to obtain 60 g of a phenolic resin. Then, the phenolic resin was crushed to diameters of ca. 1-2 cm, heated to 600° C. at a rate of 200° C./h in a nitrogen gas atmosphere (normal pressure) and held at 600° C. for 1 hour for pre-calcination to obtain a carbon precursor. The carbon precursor was pulverized to form a powdery carbon precursor having an average particle size of 25 μm. Then, the powdery carbon precursor was charged in a vacuum calcination furnace, heated to 1200° C. at a rate of 5° C./min and held at 1200° C. for 1 hour for main calcination under a reduced pressure maintained at 1 kPa or below, followed by cooling to obtain a powdery carbonaceous material. equipped with a Dimroth condenser for mixing stirring for mixing After the reaction

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

Procedure: To chlorosulfonic acid (3.1 mL) was added dropwise a solution of 1-acetyl-4-benzylpiperidine (2.0 g) in chloroform (5 mL) under ice cooling, and the mixture was stirred at, the same temperature for 1 hour and at room temperature for 30 minutes. The reaction mixture was poured into ice-water, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give chlorosulfone derivatives (1.87 g). A solution of the above chlorosulfone derivatives (1.04 g), 10% ammonia water (12 mL) and triethylamine (0.92 mL) in THF (20 mL) was heated for 1.5 hour under ref lux. The organic solvent was distilled off, and the residue was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to silica gel column chromatography (ethyl acetate/methanol=8/1), and the desired fraction was concentrated under reduced pressure to give the titled compound (0.755 g, 2.55 mmol, Yield 78%) as a colorless oily substance. was heated for 1.5 hour under ref lux The organic solvent was distilled off the residue was extracted with ethyl acetate The organic layer was washed with saturated sodium chloride solution dried over magnesium sulfate concentrated under reduced pressure the desired fraction was concentrated under reduced pressure

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

Procedure: A 25 ml round-bottom tube is charged with (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (480 mg, 0.8 mmol), imidazole (82 mg, 1.2 mmol), CuI (152 mg, 0.8 mmol), K2CO3 (221 mg, 1.3 mmol), N,N-dimethyl glycine (82 mg, 0.8 mmol), and DMSO (4 ml). Then the tube is sealed and heated to 110 degree for 18 hours. After cooling to rt, saturated NH3/H2O and EtOAc are added and then filtered through Celite pad. The solution is extracted with EtOAc and organic layer is dried over MgSO4. Removal of solvent under reduced pressure and purification with reverse phase column give product (163 mg, 0.27 mmol, 35%). ESI-MS m/z: 585 [M]+, Retention time 2.07 min (condition A). Then the tube is sealed heated to 110 degree for 18 hours filtered through Celite pad The solution is extracted with EtOAc and organic layer is dried over MgSO4 Removal of solvent under reduced pressure and purification with reverse phase column