azetidin-3-ol;hydrochloride

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

Procedure: A solution of (R)-2-(5-(2-(3-fluoro-4-(trifluoromethyl)phenyl)acetamido)-6-methyl-1-oxoisoquinolin-2(1H)-yl)propyl methanesulfonate (100 mg, 0.2 mmol), 3-hydroxyazetidine hydrochloride (120 mg, 1.1 mmol), triethylamine (200 mg, 2 mmol) and methylene chloride (1 mL, 20 mmol) was stirred at room temperature overnight. The volatiles were removed and the residue was purified by reverse phase preparative HPLC to afford the desired product as a white solid. The volatiles were removed the residue was purified by reverse phase preparative HPLC

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

Procedure: The title compound was synthesized from compound 2A and 3-hydroxyazetidine hydrochloride in 52% yield following a similar procedure described in the synthesis of Example 5. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.83 (s, 1H) 7.65 (d, J=9.85 Hz, 1H) 7.52 (d, J=9.60 Hz, 1H) 6.90-6.99 (m, 1H) 5.64 (d, J=5.31 Hz, 1H) 4.25-4.34 (m, 1H) 3.96-4.04 (m, 1H) 3.69-3.75 (m, 1H) 3.39-3.47 (m, 1H) 3.35 (s, 3H) 3.17-3.23 (m, 1 H) 3.16 (s, 3H). [M+H] calc'd for C16H16FIN4O4, 475; found, 475. described in the synthesis of Example 5

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

Procedure: A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with acetonitrile (50 mL), 5-fluoro-2-nitropyridine (1.2 g, 7.9 mmol), K2CO3 (2.1 g, 15.8 mmol), and azetidin-3-ol hydrochloride (1.3 g, 11.9 mmol). The mixture was heated at 60° C. for 1 h. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (50:1 to 20:1) to afford 147a (1.1 g, 73%) as a yellow solid. MS-ESI: [M+H]+ 196.0. A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser After this time the reaction was cooled to room temperature It was then filtered the filtrate was evaporated under reduced pressure The residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (50:1 to 20:1)

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

Procedure: This compound was prepared by using procedure analogous to those described for the synthesis of Example 98, Step 9 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}phenyl)propanoic acid and azetidin-3-ol hydrochloride (Oakwood, Cat. No. 013898). LCMS (M+H)+: m/z=539.3 This compound was prepared

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

Procedure: This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and azetidin-3-ol hydrochloride (Oakwood and Cat. No. 013898). LCMS (M+H)+: m/z=529.2. This compound was prepared

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 azetidin-3-ol hydrochloride and isolated as white solid (10.3 mg, 56%). MS (m/e): 387.4 (MH+).

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 azetidin-3-ol hydrochloride and isolated as light-yellow solid (8.0 mg, 46%). MS (m/e): 373.4 (MH+).

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

Procedure: Triethylamine (0.100 ml) was added to a mixture of benzyl 1-({[4-({2-[(phenoxycarbonyl)amino]pyridin-4-yl}oxy)-2,5-difluorophenyl]amino}carbonyl)cyclopropanecarboxylate (200 mg), 3-hydroxyazetidine hydrochloride (39.1 mg) and N,N-dimethylformamide (4.0 ml) at room temperature under a nitrogen atmosphere, and the mixture was stirred for 6 hours and 10 minutes. 3-Hydroxyazetidine hydrochloride (10.0 mg) and triethylamine (0.025 ml) were added at room temperature, and the mixture was stirred for 1 hour and 20 minutes. A saturated aqueous solution of sodium hydrogencarbonate (16 ml) and hexane (5 ml) were added to the mixture, and the precipitated solid was collected by filtration. The solid was washed with water (2 ml, three times), and dried under aeration. The resultant solid was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=10:1). The fractions containing the target compound was concentrated under reduced pressure to give the title compound (86.7 mg, 45%) as a white solid. the mixture was stirred for 1 hour and 20 minutes the precipitated solid was collected by filtration The solid was washed with water (2 ml, three times) dried under aeration The resultant solid was purified by silica gel column chromatography (Fuji Silysia NH, eluent The fractions containing the target compound was concentrated under reduced pressure

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

Procedure: To 280 mg of N,N-dimethylformamide were added 125 mg 1-(6-amino-3,5-difluoropyridine-2-yl)-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 60 mg of 3-hydroxyazetidine hydrochloride, and 120 mg of N-methylpyrrolidine together with 3 drops of ethanol, and the mixture was stirred at 85 C for 10 minutes. After adding 0.8 ml of ethanol, the solution was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 90 mg of the title compound as a pale yellow powder. to cool the precipitate was collected by filtration washed with ethanol and diisopropylether successively

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 3.5 g of N,N-dimethylformamide were added 2.00 g of 1-(6-amino-3,5-difluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 1.00 g of 3-hydroxyazetidine hydrochloride, and 2.00 g of N-methylpyrrolidine together with 0.2 ml of ethanol, and the mixture was stirred at 85° C. for 10 minutes. The solvent and the like were distilled off under reduced pressure. After adding 10 ml. of ethanol to the residue, the mixture was heated under reflux for 10 minutes and allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 2.10 g of the title compound as a pale yellow powder. The solvent and the like were distilled off under reduced pressure After adding 10 ml of ethanol to the residue, the mixture was heated under reflux for 10 minutes to cool the precipitate was collected by filtration washed with ethanol and diisopropylether successively

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 270 mg of N,N-dimethylformamide were added 110 mg of 1-(6-amino-3,5-difluoropyridine-2-yl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 50 mg of 3-hydroxyazetidine hydrochloride, and 100 mg of N-methy-lpyrrolidine together with 3 drops of ethanol, and the mixture was stirred at 85° C. for 25 minutes. After adding 0.5 ml of ethanol, the solution was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 101 mg of the title compound as a pale yellow powder. to cool the precipitate was collected by filtration washed with ethanol and diisopropylether successively

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

Procedure: To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) and azetidin-3-ol hydrochloride (70.7 mg, 0.65 mmol) in THF (6 mL) at 0° C. were added 1-hydroxybenzotriazole hydrate (100.8 mg, 0.65 mmol), N-ethyldiisopropylamine (281.7 μl, 1.613 mmol) and N-(3-dimethylaminopropy)-N′-ethylcarbodiimidazole hydrochloride (126.2 mg, 0.65 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=3:1 to 1:4) afforded the title compound (215 mg, 91%) as a colourless oil. MS: m/e=366.2 [M+H]+. The resulting reaction mixture Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=3:1 to 1:4)