N',N'-diethyl-N-methylpropane-1,3-diamine

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

Procedure: To a solution of 1-[4-(2-aminopyridin-4-yloxy)-3-fluorophenyl]-3-[(4-fluorophenyl)acetyl]thiourea (100 mg) in tetrahydrofuran (10 ml) was added triethylamine (0.101 ml), and then phenyl chloroformate (0.0454 ml) was added while stirring in an ice bath, followed by stirring under a nitrogen atmosphere for 10 min. The reaction mixture was concentrated under a reduced pressure to give a residue, to which N,N-dimethylformamide (2.0 ml) and N,N-diethyl-N′-methyl-1,3-propanediamine (151 mg) were then added, followed by stirring at room temperature for 2.5 hrs. The reaction mixture was diluted with ethyl acetate (150 ml), washed with a saturated aqueous solution of sodium hydrogencarbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, hexane:ethyl acetate=1:2, then ethyl acetate). Fractions containing the target compound were concentrated to give a solid, which was further purified by LC-MS. Fractions containing the target compound were concentrated to give a solid, to which a saturated aqueous solution of sodium hydrogencarbonate was then added to make it alkaline. The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated to provide the titled compound (2.7 mg, 1.9%) as a pale yellow oil. by stirring under a nitrogen atmosphere for 10 min The reaction mixture was concentrated under a reduced pressure to give a residue by stirring at room temperature for 2.5 hrs washed with a saturated aqueous solution of sodium hydrogencarbonate dried over anhydrous sodium sulfate The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, hexane Fractions containing the target compound were concentrated to give a solid, which was further purified by LC-MS Fractions containing the target compound were concentrated to give a solid The mixture was extracted with ethyl acetate the organic layer was dried over anhydrous sodium sulfate The solvent was evaporated

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

Procedure: To a solution of 1-[4-(2-aminopyridin-4-yloxy)-3-fluorophenyl]-3-[(4-fluorophenyl)acetyl]thiourea (100 mg) in tetrahydrofuran (10 ml) was added triethylamine (0.101 ml), and then phenyl chloroformate (0.0454 ml) was added while stirring in an ice bath, followed by stirring under a nitrogen atmosphere for 10 min. The reaction mixture was concentrated under a reduced pressure to give a residue, to which N,N-dimethylformamide (2.0 ml) and N,N-diethyl-N′-methyl-1,3-propanediamine (151 mg) were then added, followed by stirring at room temperature for 2.5 hrs. The reaction mixture was diluted with ethyl acetate (150 ml), washed with a saturated aqueous solution of sodium hydrogencarbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, hexane:ethyl acetate=1:2, then ethyl acetate). Fractions containing the target compound were concentrated to give a solid, which was further purified by LC-MS. Fractions containing the target compound were concentrated to give a solid, to which a saturated aqueous solution of sodium hydrogencarbonate was then added to make it alkaline. The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated to provide the titled compound (2.7 mg, 1.9%) as a pale yellow oil. by stirring under a nitrogen atmosphere for 10 min The reaction mixture was concentrated under a reduced pressure to give a residue by stirring at room temperature for 2.5 hrs washed with a saturated aqueous solution of sodium hydrogencarbonate dried over anhydrous sodium sulfate The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, hexane Fractions containing the target compound were concentrated to give a solid, which was further purified by LC-MS Fractions containing the target compound were concentrated to give a solid The mixture was extracted with ethyl acetate the organic layer was dried over anhydrous sodium sulfate The solvent was evaporated

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

Procedure: 6-(2-Fluoro-4-nitrophenoxy)pyrimidin-4-ylamine (50 mg) was dissolved in tetrahydrofuran (2 ml) under a nitrogen atmosphere, and then triethylamine (0.0697 ml) and phenyl chloroformate (0.0627 ml) were added thereto while cooling in an ice bath, followed by stirring at room temperature for 30 min. The reaction mixture was concentrated under a reduced pressure to give a residue, to which N,N-dimethylformamide (2 ml) and N,N-diethyl-N′-methylpropane-1,3-diamine (115 mg) were added, followed by stirring at room temperature for 2 hrs. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of ammonium chloride. The organic layer was washed with a saturated aqueous solution of ammonium chloride, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=2:1 to 1:1, then ethyl acetate:ethanol=19:1). Fractions containing the target compound were concentrated under a reduced pressure to give a residue, which was then dried in vacuum to provide the titled compound (55.7 mg, 66.2%) as a yellow solid. while cooling in an ice bath The reaction mixture was concentrated under a reduced pressure to give a residue by stirring at room temperature for 2 hrs The reaction mixture was partitioned between ethyl acetate The organic layer was washed with a saturated aqueous solution of ammonium chloride, water and brine in this order dried over anhydrous sodium sulfate The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent Fractions containing the target compound were concentrated under a reduced pressure to give a residue, which was then dried in vacuum

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

Procedure: To a solution of 4-(2-fluoro-4-nitrophenoxy)pyridin-2-ylamine (300 mg, 1.2 mmol) and triethylamine (0.335 ml, 2.4 mmol) in tetrahydrofuran (30 ml) was added phenyl chloroformate (0.226 ml, 1.8 mmol) dropwise while stirring in an ice bath, followed by stirring for 0.5 hr. The reaction mixture was concentrated under a reduced pressure to give a residue, to which N,N-dimethylformamide (6.0 ml) and N,N-diethyl-N′-methyl-1,3-propanediamine (606 mg, 4.2 mmol) were added, followed by stirring at room temperature for 4 hrs and 45 min. To the reaction mixture was added ethyl acetate (150 ml), washed with a saturated aqueous solution of sodium hydrogencarbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was filtered by silica gel (Fuji Silysia NH, hexane:ethyl acetate=3:1 to 1:1) to provide the titled compound (503 mg, 100%) as a yellow oil. by stirring for 0.5 hr The reaction mixture was concentrated under a reduced pressure to give a residue by stirring at room temperature for 4 hrs and 45 min washed with a saturated aqueous solution of sodium hydrogencarbonate dried over anhydrous sodium sulfate The solvent was evaporated to give a residue, which was filtered by silica gel (Fuji Silysia NH, hexane:ethyl acetate=3:1 to 1:1)

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

Procedure: To a solution of N,N-diethyl-1,3-propanediamine (10.0 ml) and triethylamine (10.0 ml) in tetrahydrofuran (150 ml) was added dropwise methyl chloroformate (5.15 ml) in an ice bath, followed by stirring at room temperature for 30 min. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate (10 ml) to partition. The organic layer was dried over anhydrous sodium sulfate, and concentrated under a reduced pressure. The residue was dissolved in ethyl acetate (200 ml) again, dried over potassium carbonate, and concentrated under a reduced pressure to provide a pale yellow oil (8.90 g, ESI-MS (m/z):189). This residue was dissolved in tetrahydrofuran (200 ml), and then lithium aluminium hydride (2.00 g, 0.826 mmol) was gradually added thereto while cooling in an ice bath and stirring, followed by stirring under a nitrogen atmosphere at room temperature for 15 min and then at 65° C. for 1.5 hrs. The reaction mixture was cooled in an ice bath, and then supplied with water (2.0 mL), an 5 N aqueous solution of sodium hydroxide (2.0 mL) and water (10.0 mL), followed by stirring in an ice bath for 1 hr. The insoluble portion was filtered and washed with tetrahydrofuran to give a filtrate, which was concentrated under a reduced pressure to provide a crude product of the titled compound (9.2 g, 72.3%) as a pale yellow oil. to partition The organic layer was dried over anhydrous sodium sulfate concentrated under a reduced pressure The residue was dissolved in ethyl acetate (200 ml) again dried over potassium carbonate concentrated under a reduced pressure to provide a pale yellow oil (8.90 g, ESI-MS (m/z):189) while cooling in an ice bath stirring by stirring under a nitrogen atmosphere at room temperature for 15 min at 65° C. for 1.5 hrs The reaction mixture was cooled in an ice bath by stirring in an ice bath for 1 hr The insoluble portion was filtered washed with tetrahydrofuran to give a filtrate, which was concentrated under a reduced pressure

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

Procedure: To a solution of N,N-diethyl-1,3-propanediamine (10.0 ml) and triethylamine (10.0 ml) in tetrahydrofuran (150 ml) was added dropwise methyl chloroformate (5.15 ml) while stirring in an ice bath. After stirring at room temperature for 30 min, a saturated aqueous solution of sodium hydrogencarbonate (10 ml) was added to the reaction mixture, and liquid-liquid separation was carried out. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved again in ethyl acetate (200 ml), dried over potassium carbonate, and concentrated under reduced pressure to provide a pale yellow oil (8.90 g, ESI-MS (m/z): 189). The residue was dissolved in tetrahydrofuran (200 ml), and lithium aluminum hydride (2.00 g) was gradually added thereto while stirring in an ice bath. The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 15 min, then at 65° C. for 1.5 hr. The reaction mixture was cooled in an ice bath, water (2.0 ml), a 5N aqueous solution of sodium hydroxide (2.0 ml) and water (10.0 ml) were added thereto in this order, followed by stirring in an ice bath for 1 hr. Insoluble matter was removed by filtration and washed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure to provide the titled compound as a pale yellow oil (9.2 g, 72%). After stirring at room temperature for 30 min The organic layer was dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was dissolved again in ethyl acetate (200 ml) dried over potassium carbonate concentrated under reduced pressure to provide a pale yellow oil (8.90 g, ESI-MS (m/z): 189) while stirring in an ice bath The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 15 min The reaction mixture was cooled in an ice bath by stirring in an ice bath for 1 hr Insoluble matter was removed by filtration washed with tetrahydrofuran the filtrate was concentrated under reduced pressure

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

Procedure: To a solution of N,N-diethyl-1,3-propanediamine (10.0 ml) and triethylamine (10.0 ml) in tetrahydrofuran (150 ml) was added dropwise methyl chloroformate (5.15 ml) while stirring in an ice bath. After stirring at room temperature for 30 min, a saturated aqueous solution of sodium hydrogencarbonate (10 ml) was added to the reaction mixture, and liquid-liquid separation was carried out. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved again in ethyl acetate (200 ml), dried over potassium carbonate, and concentrated under reduced pressure to provide a pale yellow oil (8.90 g, ESI-MS (m/z): 189). The residue was dissolved in tetrahydrofuran (200 ml), and lithium aluminum hydride (2.00 g) was gradually added thereto while stirring in an ice bath. The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 15 min, then at 65° C. for 1.5 hr. The reaction mixture was cooled in an ice bath, water (2.0 ml), a 5N aqueous solution of sodium hydroxide (2.0 ml) and water (10.0 ml) were added thereto in this order, followed by stirring in an ice bath for 1 hr. Insoluble matter was removed by filtration and washed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure to provide the titled compound as a pale yellow oil (9.2 g, 72%). After stirring at room temperature for 30 min The organic layer was dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was dissolved again in ethyl acetate (200 ml) dried over potassium carbonate concentrated under reduced pressure to provide a pale yellow oil (8.90 g, ESI-MS (m/z): 189) while stirring in an ice bath The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 15 min The reaction mixture was cooled in an ice bath by stirring in an ice bath for 1 hr Insoluble matter was removed by filtration washed with tetrahydrofuran the filtrate was concentrated under reduced pressure

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

Procedure: To a solution of N,N-diethyl-1,3-propanediamine (10.0 ml) and triethylamine (10.0 ml) in tetrahydrofuran (150 ml) was added dropwise methyl chloroformate (5.15 ml) while stirring in an ice bath. After stirring at room temperature for 30 min, a saturated aqueous solution of sodium hydrogencarbonate (10 ml) was added to the reaction mixture, and liquid-liquid separation was carried out. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved again in ethyl acetate (200 ml), dried over potassium carbonate, and concentrated under reduced pressure to provide a pale yellow oil (8.90 g, ESI-MS (m/z): 189). The residue was dissolved in tetrahydrofuran (200 ml), and lithium aluminum hydride (2.00 g) was gradually added thereto while stirring in an ice bath. The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 15 min, then at 65° C. for 1.5 hr. The reaction mixture was cooled in an ice bath, water (2.0 ml), a 5N aqueous solution of sodium hydroxide (2.0 ml) and water (10.0 ml) were added thereto in this order, followed by stirring in an ice bath for 1 hr. Insoluble matter was removed by filtration and washed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure to provide the titled compound as a pale yellow oil (9.2 g, 72%). After stirring at room temperature for 30 min The organic layer was dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was dissolved again in ethyl acetate (200 ml) dried over potassium carbonate concentrated under reduced pressure to provide a pale yellow oil (8.90 g, ESI-MS (m/z): 189) while stirring in an ice bath The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 15 min The reaction mixture was cooled in an ice bath by stirring in an ice bath for 1 hr Insoluble matter was removed by filtration washed with tetrahydrofuran the filtrate was concentrated under reduced pressure

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

Procedure: To a solution of 1-[4-(2-aminopyridin-4-yloxy)-3-fluorophenyl]-3-[(4-fluorophenyl)acetyl]thiourea (100 mg) in tetrahydrofuran (10 ml) was added triethylamine (0.101 ml), and then phenyl chloroformate (0.0454 ml) was added while stirring in an ice bath, followed by stirring under a nitrogen atmosphere for 10 min. The reaction mixture was concentrated under a reduced pressure to give a residue, to which N,N-dimethylformamide (2.0 ml) and N,N-diethyl-N′-methyl-1,3-propanediamine (151 mg) were then added, followed by stirring at room temperature for 2.5 hrs. The reaction mixture was diluted with ethyl acetate (150 ml), washed with a saturated aqueous solution of sodium hydrogencarbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, hexane:ethyl acetate=1:2, then ethyl acetate). Fractions containing the target compound were concentrated to give a solid, which was further purified by LC-MS. Fractions containing the target compound were concentrated to give a solid, to which a saturated aqueous solution of sodium hydrogencarbonate was then added to make it alkaline. The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated to provide the titled compound (2.7 mg, 1.9%) as a pale yellow oil. by stirring under a nitrogen atmosphere for 10 min The reaction mixture was concentrated under a reduced pressure to give a residue by stirring at room temperature for 2.5 hrs washed with a saturated aqueous solution of sodium hydrogencarbonate dried over anhydrous sodium sulfate The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, hexane Fractions containing the target compound were concentrated to give a solid, which was further purified by LC-MS Fractions containing the target compound were concentrated to give a solid The mixture was extracted with ethyl acetate the organic layer was dried over anhydrous sodium sulfate The solvent was evaporated

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

Procedure: 6-(2-Fluoro-4-nitrophenoxy)pyrimidin-4-ylamine (50 mg) was dissolved in tetrahydrofuran (2 ml) under a nitrogen atmosphere, and then triethylamine (0.0697 ml) and phenyl chloroformate (0.0627 ml) were added thereto while cooling in an ice bath, followed by stirring at room temperature for 30 min. The reaction mixture was concentrated under a reduced pressure to give a residue, to which N,N-dimethylformamide (2 ml) and N,N-diethyl-N′-methylpropane-1,3-diamine (115 mg) were added, followed by stirring at room temperature for 2 hrs. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of ammonium chloride. The organic layer was washed with a saturated aqueous solution of ammonium chloride, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=2:1 to 1:1, then ethyl acetate:ethanol=19:1). Fractions containing the target compound were concentrated under a reduced pressure to give a residue, which was then dried in vacuum to provide the titled compound (55.7 mg, 66.2%) as a yellow solid. while cooling in an ice bath The reaction mixture was concentrated under a reduced pressure to give a residue by stirring at room temperature for 2 hrs The reaction mixture was partitioned between ethyl acetate The organic layer was washed with a saturated aqueous solution of ammonium chloride, water and brine in this order dried over anhydrous sodium sulfate The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent Fractions containing the target compound were concentrated under a reduced pressure to give a residue, which was then dried in vacuum

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

Procedure: To a solution of 4-(2-fluoro-4-nitrophenoxy)pyridin-2-ylamine (300 mg, 1.2 mmol) and triethylamine (0.335 ml, 2.4 mmol) in tetrahydrofuran (30 ml) was added phenyl chloroformate (0.226 ml, 1.8 mmol) dropwise while stirring in an ice bath, followed by stirring for 0.5 hr. The reaction mixture was concentrated under a reduced pressure to give a residue, to which N,N-dimethylformamide (6.0 ml) and N,N-diethyl-N′-methyl-1,3-propanediamine (606 mg, 4.2 mmol) were added, followed by stirring at room temperature for 4 hrs and 45 min. To the reaction mixture was added ethyl acetate (150 ml), washed with a saturated aqueous solution of sodium hydrogencarbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was filtered by silica gel (Fuji Silysia NH, hexane:ethyl acetate=3:1 to 1:1) to provide the titled compound (503 mg, 100%) as a yellow oil. by stirring for 0.5 hr The reaction mixture was concentrated under a reduced pressure to give a residue by stirring at room temperature for 4 hrs and 45 min washed with a saturated aqueous solution of sodium hydrogencarbonate dried over anhydrous sodium sulfate The solvent was evaporated to give a residue, which was filtered by silica gel (Fuji Silysia NH, hexane:ethyl acetate=3:1 to 1:1)

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

Procedure: To a solution of N,N-diethyl-1,3-propanediamine (10.0 ml) and triethylamine (10.0 ml) in tetrahydrofuran (150 ml) was added dropwise methyl chloroformate (5.15 ml) in an ice bath, followed by stirring at room temperature for 30 min. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate (10 ml) to partition. The organic layer was dried over anhydrous sodium sulfate, and concentrated under a reduced pressure. The residue was dissolved in ethyl acetate (200 ml) again, dried over potassium carbonate, and concentrated under a reduced pressure to provide a pale yellow oil (8.90 g, ESI-MS (m/z):189). This residue was dissolved in tetrahydrofuran (200 ml), and then lithium aluminium hydride (2.00 g, 0.826 mmol) was gradually added thereto while cooling in an ice bath and stirring, followed by stirring under a nitrogen atmosphere at room temperature for 15 min and then at 65° C. for 1.5 hrs. The reaction mixture was cooled in an ice bath, and then supplied with water (2.0 mL), an 5 N aqueous solution of sodium hydroxide (2.0 mL) and water (10.0 mL), followed by stirring in an ice bath for 1 hr. The insoluble portion was filtered and washed with tetrahydrofuran to give a filtrate, which was concentrated under a reduced pressure to provide a crude product of the titled compound (9.2 g, 72.3%) as a pale yellow oil. to partition The organic layer was dried over anhydrous sodium sulfate concentrated under a reduced pressure The residue was dissolved in ethyl acetate (200 ml) again dried over potassium carbonate concentrated under a reduced pressure to provide a pale yellow oil (8.90 g, ESI-MS (m/z):189) while cooling in an ice bath stirring by stirring under a nitrogen atmosphere at room temperature for 15 min at 65° C. for 1.5 hrs The reaction mixture was cooled in an ice bath by stirring in an ice bath for 1 hr The insoluble portion was filtered washed with tetrahydrofuran to give a filtrate, which was concentrated under a reduced pressure