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Product Details of [ 1301214-71-0 ]

CAS No. :	1301214-71-0	MDL No. :	MFCD19689083
Formula :	C₈H₉BrN₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	229.07	Pubchem ID :	-
Synonyms :

Safety of [ 1301214-71-0 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1301214-71-0 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 1301214-71-0 ]
Downstream synthetic route of [ 1301214-71-0 ]

[ 1301214-71-0 ] Synthesis Path-Upstream 1~2

1
[ 1301214-71-0 ]
[ 1150617-54-1 ]

Yield	Reaction Conditions	Operation in experiment
77%	Stage #1: With potassium acetate; acetic anhydride; acetic acid In chloroform at 20℃; for 0.25 h; Stage #2: With isopentyl nitrite In chloroform at 40 - 60℃; Stage #3: With sodium hydroxide In methanol; water at 0 - 20℃;	To a solution of N-(5-bromo-2-methylpyridin-3-yl)acetamide (8.28 g, 36 mmol) in chloroform (550 mL) at ambient temperature was added potassium acetate (4.32 g, 43.6 mmol), acetic acid (2.5 mL, 43.6 mmol) and followed by acetic anhydride (6.86 mL, 72.6 mmol). The mixture was stirred at ambient temperature for 15 minutes before being heated to 40° C. IsoamyInitrite was then added dropwise. The reaction was then stirred at 60° C. for 48 hours. The reaction mixture was poured slowly into a saturated solution of sodium bicarbonate (500 mL) at 0° C. The organic phase was retained and the aqueous phase extracted with dichloromethane (500 mL). The combined organics were then concentrated to a brown oil which was dissolved in methanol (500 mL). Aqueous sodium hydroxide (2 M, 500 mL) was added at 0° C. and the mixture stirred at ambient temperature for 1 hour before the methanol was removed in vacuo. The aqueous mixture was then extracted with ethyl acetate (3*500 mL). The combined organics dried over magnesium sulfate, and the solvent removed in vacuo to give 6-bromo-1H-pyrazolo[4,3-b]pyridine as a light brown solid (5.5 g, 27.9 mmol, 77percent). ¹HNMR (400, CD₃OD): δ ppm 8.55 (s, 1H), 8.24 (s, 1H), 8.21 (s, 1H).
77%	With potassium acetate; acetic anhydride; isopentyl nitrite In chloroform; acetic acid at 20 - 60℃;	To a solution of N-(5-bromo-2-methylpyridin-3-yl)acetamide (8.28 g, 36 mmol) in chloroform (550 mL) at ambient temperature was added potassium acetate (4.32 g, 43.6 mmol), acetic acid (2.5 mL, 43.6 mmol) and followed by acetic anhydride (6.86 mL, 72.6 mmol). The mixture was stirred at ambient temperature for 15 minutes before being heated to 40 °C. Isoamylnitrite was then added dropwise. The reaction was then stirred at 60 °C for 48 hours. The reaction mixture was poured slowly into a saturated solution of sodium bicarbonate (500 mL) at 0 °C. The organic phase was retained and the aqueous phase extracted with dichloromethane (500 mL). The combined organics were then concentrated to a brown oil which was dissolved in methanol (500 mL). Aqueous sodium hydroxide (2 M, 500 mL) was added at 0 °C and the mixture stirred at ambient temperature for 1 hour before the methanol was removed in vacuo. The aqueous mixture was then extracted with ethyl acetate (3 x 500 mL). The combined organics dried over magnesium sulfate, and the solvent removed in vacuo to give 6-bromo-1H-pyrazolo[4,3-b]pyridine as a light brown solid (5.5 g, 27.9 mmol, 77 percent). ¹HNMR (400, CD₃OD): ppm 8.55 (s, 1 H), 8.24 (s, 1 H), 8.21 (s, 1 H).
77%	Stage #1: With potassium acetate; acetic anhydride; acetic acid In chloroform at 20 - 60℃; for 48.25 h; Stage #2: With water; sodium hydroxide In methanol at 0 - 20℃;	To a solution of N-(5-bromo-2-methylpyridin-3-yl)acetamide (8.28 g, 36 mmol) in chloroform (550 mL) at ambient temperature was added potassium acetate (4.32 g, 43.6 mmol), acetic acid (2.5 mL, 43.6 mmol) and followed by acetic anhydride (6.86 mL, 72.6 mmol). The mixture was stirred at ambient temperature for 15 minutes before being heated to 40° C. Isoamylnitrite was then added dropwise. The reaction was then stirred at 60° C. for 48 hours. The reaction mixture was poured slowly into a saturated solution of sodium bicarbonate (500 mL) at 0° C. The organic phase was retained and the aqueous phase extracted with dichloromethane (500 mL). The combined organics were then concentrated to a brown oil which was dissolved in methanol (500 mL). Aqueous sodium hydroxide (2 M, 500 mL) was added at 0° C. and the mixture stirred at ambient temperature for 1 hour before the methanol was removed in vacuo. The aqueous mixture was then extracted with ethyl acetate (3.x.500 mL). The combined organics were dried over magnesium sulfate, filtered, and the solvent removed in vacuo to give 6-bromo-1H-pyrazolo[4,3-b]pyridine as a light brown solid (5.5 g, 77percent). ¹HNMR (400 MHz, CD₃OD, δ): 8.55 (s, 1H), 8.24 (s, 1H), 8.21 (s, 1H).

77%	Stage #1: With potassium acetate; acetic anhydride; acetic acid In chloroform at 20 - 40℃; Stage #2: With tert.-butylnitrite In chloroform at 60℃; for 48 h; Stage #3: With water; sodium hydroxide In methanol at 0 - 20℃;	To a solution of N-(5- bromo-2-methylpyridin-3-yl)acetamide (M-3) (8.3 g, 36 mmol) in chloroform (550 mL) at ambient temperature was added potassium acetate (4.3 g, 43.6 mmol), acetic acid (2.5 mL, 43.6 mmol) and followed by acetic anhydride (6.9 mL, 72.6 mmol). The mixture was stirred at ambient temperature for 15 minutes before being heated to 40 °C. Jert-butyl nitrite (6.5 mL, 54 mmol) was then added dropwise. The reaction was then stirred at 60 °C for 48 hours. The reaction mixture was poured slowly into a saturated solution of sodium bicarbonate (500 mL) at 0 °C. The organic phase was retained and the aqueous phase extracted with dichloromethane (500 mL). The combined organics were then concentrated to a brown oil which was dissolved in methanol (500 mL). Aqueous sodium hydroxide (2 M, 500 mL) was added at 0 °C and the mixture stirred at ambient temperature for 1 hour before the methanol was removed in vacuo. The aqueous mixture was then extracted with ethyl acetate (3 ^χ 500 mL). The combined organics dried over magnesium sulfate, and the solvent removed in vacuo to give the title compound as a light brown solid (5.5 g, 27.9 mmol, 77percent). ¹HNMR (400, CD₃OD): δ ppm 8.55 (s, 1H), 8.24 (s, 1H), 8.21 (s, 1H). LCMS (ESI) calc'd for C₆H₄BrN₃ [M+H]⁺: 197.96, found: 198, 199.
77%	Stage #1: With potassium acetate; acetic anhydride; acetic acid In chloroform at 20℃; for 0.25 h; Stage #2: With tert.-butylnitrite In chloroform at 40 - 60℃; for 48 h;	To a solution of N-(5-bromo-2-methylpyridin-3-yl)acetamide (M-3) (8.3 g, 36 mmol) in chloroform (550 mL) atambient temperature was added potassium acetate (4.3 g, 43.6 mmol), acetic acid (2.5 mL, 43.6 mmol) and followed by acetic anhydride (6.9 mL, 72.6 mmol). The mixture was stirred at ambient temperature for 15 minutes before being heated to 40 °C. Tert-butyl nitrite (6.5 mL, 54 mmol) was then added dropwise. The reaction was then stirred at 60 °C for 48 hours.The reaction mixture was poured slowly into a saturated solution of sodium bicarbonate (500 mL) at 0 °C. The organic phase was retained and the aqueous phase extracted with dichloromethane (500 mL). The combined organics were then concentrated to a brown oil which was dissolved in methanol (500 mL). Aqueous sodium hydroxide (2 M, 500 mL) was added at 0 °C and the mixture stirred at ambient temperature for 1 hour before the methanolwas removed in vacuo. The aqueous mixture was then extracted with ethyl acetate (3 x 500 mL). The combined organics were dried over magnesium sulfate, and the solvent removed in vacuo to give the title compound as a light brown solid (5.5 g, 27.9 mmol, 77percent). ‘HNMR (400, CD3OD): ö ppm 8.55 (s, 1H), 8.24 (s, 1H), 8.21 (s, 1H). LCMS (ESI) calc’d for C6H4BrN3 [M+H]: 197.96, found: 198, 199.

Reference： [1] Patent: US2011/111046, 2011, A1, . Location in patent: Page/Page column 16
[2] Patent: WO2011/58473, 2011, A1, . Location in patent: Page/Page column 33; 34
[3] Patent: US2012/108619, 2012, A1, . Location in patent: Page/Page column 30
[4] Patent: WO2014/26327, 2014, A1, . Location in patent: Page/Page column 89
[5] Patent: WO2014/28589, 2014, A2, . Location in patent: Page/Page column 108; 109
[6] Patent: WO2012/87782, 2012, A1,
[7] Patent: WO2015/91889, 2015, A1,
[8] Patent: US2015/175619, 2015, A1,
[9] Patent: WO2016/57834, 2016, A1,

2
[ 1301214-71-0 ]
[ 1150617-56-3 ]

Reference： [1] Patent: WO2016/57834, 2016, A1,

[ 1301214-71-0 ] Synthesis Path-Downstream 1~11

1
[ 1301214-71-0 ]
[ 1150617-54-1 ]

Yield	Reaction Conditions	Operation in experiment
77%		To a solution of N-(5-bromo-2-methylpyridin-3-yl)acetamide (8.28 g, 36 mmol) in chloroform (550 mL) at ambient temperature was added potassium acetate (4.32 g, 43.6 mmol), acetic acid (2.5 mL, 43.6 mmol) and followed by acetic anhydride (6.86 mL, 72.6 mmol). The mixture was stirred at ambient temperature for 15 minutes before being heated to 40 C. IsoamyInitrite was then added dropwise. The reaction was then stirred at 60 C. for 48 hours. The reaction mixture was poured slowly into a saturated solution of sodium bicarbonate (500 mL) at 0 C. The organic phase was retained and the aqueous phase extracted with dichloromethane (500 mL). The combined organics were then concentrated to a brown oil which was dissolved in methanol (500 mL). Aqueous sodium hydroxide (2 M, 500 mL) was added at 0 C. and the mixture stirred at ambient temperature for 1 hour before the methanol was removed in vacuo. The aqueous mixture was then extracted with ethyl acetate (3*500 mL). The combined organics dried over magnesium sulfate, and the solvent removed in vacuo to give 6-bromo-1H-pyrazolo[4,3-b]pyridine as a light brown solid (5.5 g, 27.9 mmol, 77%). 1HNMR (400, CD3OD): delta ppm 8.55 (s, 1H), 8.24 (s, 1H), 8.21 (s, 1H).
77%	With potassium acetate; acetic anhydride; isopentyl nitrite; In chloroform; acetic acid; at 20 - 60℃;	To a solution of N-(5-bromo-2-methylpyridin-3-yl)acetamide (8.28 g, 36 mmol) in chloroform (550 mL) at ambient temperature was added potassium acetate (4.32 g, 43.6 mmol), acetic acid (2.5 mL, 43.6 mmol) and followed by acetic anhydride (6.86 mL, 72.6 mmol). The mixture was stirred at ambient temperature for 15 minutes before being heated to 40 C. Isoamylnitrite was then added dropwise. The reaction was then stirred at 60 C for 48 hours. The reaction mixture was poured slowly into a saturated solution of sodium bicarbonate (500 mL) at 0 C. The organic phase was retained and the aqueous phase extracted with dichloromethane (500 mL). The combined organics were then concentrated to a brown oil which was dissolved in methanol (500 mL). Aqueous sodium hydroxide (2 M, 500 mL) was added at 0 C and the mixture stirred at ambient temperature for 1 hour before the methanol was removed in vacuo. The aqueous mixture was then extracted with ethyl acetate (3 x 500 mL). The combined organics dried over magnesium sulfate, and the solvent removed in vacuo to give 6-bromo-1H-pyrazolo[4,3-b]pyridine as a light brown solid (5.5 g, 27.9 mmol, 77 %). 1HNMR (400, CD3OD): ppm 8.55 (s, 1 H), 8.24 (s, 1 H), 8.21 (s, 1 H).
77%		To a solution of N-(5-bromo-2-methylpyridin-3-yl)acetamide (8.28 g, 36 mmol) in chloroform (550 mL) at ambient temperature was added potassium acetate (4.32 g, 43.6 mmol), acetic acid (2.5 mL, 43.6 mmol) and followed by acetic anhydride (6.86 mL, 72.6 mmol). The mixture was stirred at ambient temperature for 15 minutes before being heated to 40 C. Isoamylnitrite was then added dropwise. The reaction was then stirred at 60 C. for 48 hours. The reaction mixture was poured slowly into a saturated solution of sodium bicarbonate (500 mL) at 0 C. The organic phase was retained and the aqueous phase extracted with dichloromethane (500 mL). The combined organics were then concentrated to a brown oil which was dissolved in methanol (500 mL). Aqueous sodium hydroxide (2 M, 500 mL) was added at 0 C. and the mixture stirred at ambient temperature for 1 hour before the methanol was removed in vacuo. The aqueous mixture was then extracted with ethyl acetate (3×500 mL). The combined organics were dried over magnesium sulfate, filtered, and the solvent removed in vacuo to give 6-bromo-1H-pyrazolo[4,3-b]pyridine as a light brown solid (5.5 g, 77%). 1HNMR (400 MHz, CD3OD, delta): 8.55 (s, 1H), 8.24 (s, 1H), 8.21 (s, 1H).

77%		To a solution of N-(5- bromo-2-methylpyridin-3-yl)acetamide (M-3) (8.3 g, 36 mmol) in chloroform (550 mL) at ambient temperature was added potassium acetate (4.3 g, 43.6 mmol), acetic acid (2.5 mL, 43.6 mmol) and followed by acetic anhydride (6.9 mL, 72.6 mmol). The mixture was stirred at ambient temperature for 15 minutes before being heated to 40 C. Jert-butyl nitrite (6.5 mL, 54 mmol) was then added dropwise. The reaction was then stirred at 60 C for 48 hours. The reaction mixture was poured slowly into a saturated solution of sodium bicarbonate (500 mL) at 0 C. The organic phase was retained and the aqueous phase extracted with dichloromethane (500 mL). The combined organics were then concentrated to a brown oil which was dissolved in methanol (500 mL). Aqueous sodium hydroxide (2 M, 500 mL) was added at 0 C and the mixture stirred at ambient temperature for 1 hour before the methanol was removed in vacuo. The aqueous mixture was then extracted with ethyl acetate (3 chi 500 mL). The combined organics dried over magnesium sulfate, and the solvent removed in vacuo to give the title compound as a light brown solid (5.5 g, 27.9 mmol, 77%). 1HNMR (400, CD3OD): delta ppm 8.55 (s, 1H), 8.24 (s, 1H), 8.21 (s, 1H). LCMS (ESI) calc'd for C6H4BrN3 [M+H]+: 197.96, found: 198, 199.
77%		To a solution of N-(5-bromo-2-methylpyridin-3-yl)acetamide (M-3) (8.3 g, 36 mmol) in chloroform (550 mL) atambient temperature was added potassium acetate (4.3 g, 43.6 mmol), acetic acid (2.5 mL, 43.6 mmol) and followed by acetic anhydride (6.9 mL, 72.6 mmol). The mixture was stirred at ambient temperature for 15 minutes before being heated to 40 C. Tert-butyl nitrite (6.5 mL, 54 mmol) was then added dropwise. The reaction was then stirred at 60 C for 48 hours.The reaction mixture was poured slowly into a saturated solution of sodium bicarbonate (500 mL) at 0 C. The organic phase was retained and the aqueous phase extracted with dichloromethane (500 mL). The combined organics were then concentrated to a brown oil which was dissolved in methanol (500 mL). Aqueous sodium hydroxide (2 M, 500 mL) was added at 0 C and the mixture stirred at ambient temperature for 1 hour before the methanolwas removed in vacuo. The aqueous mixture was then extracted with ethyl acetate (3 x 500 mL). The combined organics were dried over magnesium sulfate, and the solvent removed in vacuo to give the title compound as a light brown solid (5.5 g, 27.9 mmol, 77%). ?HNMR (400, CD3OD): oe ppm 8.55 (s, 1H), 8.24 (s, 1H), 8.21 (s, 1H). LCMS (ESI) calc?d for C6H4BrN3 [M+H]: 197.96, found: 198, 199.

Reference： [1]Patent: US2011/111046,2011,A1 .Location in patent: Page/Page column 16
[2]Patent: WO2011/58473,2011,A1 .Location in patent: Page/Page column 33; 34
[3]Patent: US2012/108619,2012,A1 .Location in patent: Page/Page column 30
[4]Patent: WO2014/26327,2014,A1 .Location in patent: Page/Page column 89
[5]Patent: WO2014/28589,2014,A2 .Location in patent: Page/Page column 108; 109
[6]Patent: WO2012/87782,2012,A1
[7]Patent: WO2015/91889,2015,A1
[8]Patent: US2015/175619,2015,A1
[9]Patent: WO2016/57834,2016,A1

2
[ 1301214-71-0 ]
[ 1301214-72-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: acetic anhydride; potassium acetate; acetic acid / chloroform / 0.25 h / 20 °C 1.2: 40 - 60 °C 1.3: 0 - 20 °C 2.1: triethylamine / 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; palladium dichloride / acetonitrile / 18 h / 100 °C / 15001.5 Torr
	Multi-step reaction with 2 steps 1: acetic anhydride; potassium acetate; isopentyl nitrite / chloroform; acetic acid / 20 - 60 °C 2: triethylamine / (S)-(1,1'-binaphthalene)-2,2'-diylbis(diphenylphosphine); palladium dichloride / acetonitrile / 18 h / 100 °C / 15001.5 Torr
	Multi-step reaction with 2 steps 1: acetic anhydride; isopentyl nitrite; potassium acetate / toluene / 90 °C / Inert atmosphere 2: triethylamine; bis-triphenylphosphine-palladium(II) chloride / 100 °C / 7600.51 Torr

	Multi-step reaction with 2 steps 1: acetic anhydride; isopentyl nitrite; potassium acetate / toluene / 90 °C / Inert atmosphere 2: triethylamine; bis-triphenylphosphine-palladium(II) chloride / 100 °C / 7600.51 Torr / Sealed tube
	Multi-step reaction with 2 steps 1: isopentyl nitrite; potassium acetate; acetic anhydride / toluene / 90 °C / Inert atmosphere 2: triethylamine; bis-triphenylphosphine-palladium(II) chloride / 100 °C / 7600.51 Torr
	Multi-step reaction with 2 steps 1: potassium acetate; isopentyl nitrite / toluene / 90 °C / Inert atmosphere 2: bis-triphenylphosphine-palladium(II) chloride; methanol; triethylamine / 100 °C / 7600.51 Torr
	Multi-step reaction with 2 steps 1.1: acetic anhydride; acetic acid; potassium acetate / chloroform / 20 - 40 °C 1.2: 48 h / 60 °C 1.3: 0 - 20 °C 2.1: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; palladium dichloride; triethylamine / acetonitrile / 18 h / 100 °C / 15001.5 Torr
	Multi-step reaction with 2 steps 1.1: potassium acetate; acetic acid; acetic anhydride / chloroform / 0.25 h / 20 °C 1.2: 48 h / 40 - 60 °C 2.1: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; palladium dichloride; triethylamine / acetonitrile / 18 h / 100 °C / 15001.5 Torr
	Multi-step reaction with 2 steps 1.1: potassium acetate; acetic anhydride; acetic acid / chloroform / 48.25 h / 20 - 60 °C 1.2: 0 - 20 °C 2.1: triethylamine / 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; palladium dichloride / acetonitrile / 18 h / 100 °C / 15001.5 Torr

Reference： [1]Current Patent Assignee: PFIZER INC - US2011/111046, 2011, A1
[2]Current Patent Assignee: PFIZER INC - WO2011/58473, 2011, A1
[3]Current Patent Assignee: VALO HEALTH INC - WO2013/127266, 2013, A1
[4]Current Patent Assignee: VALO HEALTH INC - WO2013/127267, 2013, A1
[5]Current Patent Assignee: FORMA THERAPEUTICS, INC.; ROCHE HOLDING AG - WO2013/130935, 2013, A1
[6]Current Patent Assignee: FORMA THERAPEUTICS, INC.; ROCHE HOLDING AG - WO2013/130943, 2013, A1
[7]Current Patent Assignee: MERCK & CO INC - WO2014/26327, 2014, A1
[8]Current Patent Assignee: MERCK & CO INC - WO2014/28589, 2014, A2
[9]Current Patent Assignee: PFIZER INC - US2012/108619, 2012, A1

3
[ 914358-73-9 ]
[ 108-24-7 ]
[ 1301214-71-0 ]

Yield	Reaction Conditions	Operation in experiment
85%	With sulfuric acid; In acetonitrile; at 60℃; for 0.5h;Inert atmosphere;	Under a nitrogen atmosphere, a solution of <strong>[914358-73-9]5-bromo-2-methylpyridine-3-amine</strong> (1, 2 g), aceticanhydride (1.95 g) and acetonitrile (20 mL) was stirred at 60 C and treated with 96% H2SO4 (a fewdrops). Stirring was continued for another half an hour while the reaction was monitored by TLC.The reaction mixture was evaporated and allowed to cool to room temperature. After cooling, waterwas added dropwise to form a precipitate. Then the mixture was stirred near one hour around roomtemperature and then filtered. The impure solid was washed with deionized water and later dried inan oven [44]. N-[5-Bromo-2-methylpyridine-3-yl]acetamide (3). Yield: 85 %; m.p.: 256 C. 1H-NMR (CDCl3) delta 7.8 (s, 1Hpyridine),7.38 (s, 1H-pyridine), 2.6 (s, 3H, methyl), 2.45 (s, 3H, COCH3). 13C-NMR (CDCl3 + CD3OD) delta16.5, 24.1, 112.3, 127.9, 147.2, 150, 169.1. EI-MS m/z (+ion mode): 229 [M + H]+: [M - CH3]+ = 207: [M -Br]+ = 150. Anal. calcd for C8H9BrN2O (229.07): C, 41.95; H, 4.01. Found: C, 41.93; H, 3.97%.
71%	With acetic acid; at 20℃;	A solution of 5- bromo-2-methyl-pyridin-3-ylamine (3 g, 1 6 04 mmol, 1 .00 equiv) in acetic anhydride (20 mL) and acetic acid ( 10 mL) was stirred overnight at rt. The resulting mixture was concentrated under vacuum to give 2.6 g (71 %) of the title compound as a light yellow solid. LC/MS (Method 1, ESI): RT= 1 .05 min, m/z = 229.0; 231.0 [M+H]
71%	With acetic acid; at 20℃;	A solution of 5- bromo-2-methyl-pyridin-3-ylamine (3 g, 1 6 04 mmol, 1 .00 equiv) in acetic anhydride (20 mL) and acetic acid ( 10 mL) was stirred overnight at rt. The resulting mixture was concentrated under vacuum to give 2 6 g (71 %) of the title compound as a light yellow solid. LC MS (Method 1, ESI): RT= 1 .05 min, m/z = 229.0; 23 1 0 [M+H]

71%	With acetic acid; at 20℃;	[0201] Step 2. N-(5-Bromo-2-methyl-pyridin-3-yl)-acetamide. A solution of 5-bromo-2- methyl-pyridin-3-ylamine (3 g, 16.04 mmol, 1.00 equiv) in acetic anhydride (20 mL) and acetic acid (10 mL) was stirred overnight at rt. The resulting mixture was concentrated under vacuum to give 2.6 g (7 1%) of the title compound as a light yellow solid. LC/MS (Method I, ESI): RT= 1.05 mm, m/z = 229.0; 231.0 [M+Hf?.
71%	In acetic acid; at 20℃;	[0209] Step 2. N-(5-Bromo-2-methyl-pyridin-3-yl)-acetamide. A solution of 5-bromo-2- methyl-pyridin-3-ylamine (3 g, 16.04 mmol, 1.00 equiv) in acetic anhydride (20 mL) and acetic acid (10 mL) was stirred overnight at rt. The resulting mixture was concentrated under vacuum to give 2.6 g (71 ) of the title compound as a light yellow solid. LC/MS (Method I, ESI): RT= 1.05 min, m/z = 229.0; 231.0 [M+H]+.
63%	With triethylamine; In dichloromethane; at 0 - 20℃;	To a solution of 5-bromo-2-methylpyridin-3-amine (10.7 g, 57.5 mmol) in dichloromethane (575 mL) was added acetic anhydride (12 mL, 126.5 mmol) at 0 C. followed by triethylamine (22 mL, 158 mmol). The mixture was allowed to warm to ambient temperature and stirred for 18 hours at which point a further equivalent of acetic anhydride (6 mL, 63 mmol) was added. The mixture was stirred at ambient temperature for a further 72 hours. The reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate (500 mL) and the organic phase washed with saturated aqueous sodium chloride (500 mL), dried over magnesium sulfate and concentrated in vacuo to give a brown solid. This solid was triturated with 30% ethyl acetate in hexanes to yield N-(5-bromo-2-methylpyridin-3-yl)acetamide as an off-white solid, (8.28 g, 36 mmol, 63%). 1HNMR (400 MHz, CD3OD): delta ppm 8.31 (s, 1H), 8.18 (s, 1H), 2.43 (s, 3H), 2.18 (s, 3H).
63%	With triethylamine; In dichloromethane; at 20℃; for 90h;	To a solution of 5-bromo-2-methylpyridin-3-amine (10.7 g, 57.5 mmol) in dichloromethane (575 mL) was added acetic anhydride (12 mL, 126.5 mmol) at 0 C followed by triethylamine (22 mL, 158 mmol). The mixture was allowed to warm to ambient temperature and stirred for 18 hours at which point a further equivalent of acetic anhydride (6 mL, 63 mmol) was added. The mixture was stirred at ambient temperature for a further 72 hours. The reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate (500 mL) and the organic phase washed with saturated aqueous sodium chloride (500 mL), dried over magnesium sulfate and concentrated in vacuo to give a brown solid. This solid was triturated with 30 % ethyl acetate in hexanes to yield N-(5-bromo-2-methylpyridin-3-yl)acetamide as an off-white solid, (8.28 g, 36 mmol, 63 %). 1HNMR (400 MHz, CD3OD): ppm 8.31 (s, 1 H), 8.18 (s, 1 H), 2.43 (s, 3H), 2.18 (s, 3H).
63%	With triethylamine; In dichloromethane; at 0 - 20℃;	To a solution of 5-bromo-2-methylpyridin-3-amine (10.7 g, 57.5 mmol) in dichloromethane (575 mL) was added acetic anhydride (12 mL, 126.5 mmol) at 0 C. followed by triethylamine (22 mL, 158 mmol). The mixture was allowed to warm to ambient temperature and stirred for 18 hours at which point a further equivalent of acetic anhydride (6 mL, 63 mmol) was added. The mixture was stirred at ambient temperature for a further 72 hours. The reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate (500 mL) and the organic phase washed with saturated aqueous sodium chloride (500 mL), dried over magnesium sulfate and concentrated in vacuo to give a brown solid. This solid was triturated with 30% ethyl acetate in hexanes to yield N-(5-bromo-2-methylpyridin-3-yl)acetamide as an off-white solid (8.28 g, 63%). 1HNMR (400 MHz, CD3OD, delta): 8.31 (s, 1H), 8.18 (s, 1H), 2.43 (s, 3H), 2.18 (s, 3H).
63%	With triethylamine; In dichloromethane; at 0 - 20℃;	To a solution of 5-bromo-2-methylpyridin-3-amine (M-2) (10.7 g, 57.5 mmol) in dichloromethane (575 mL) was added acetic anhydride (12 mL, 126.5 mmol) at 0 C, followed by triethylamine (22 mL, 158 mmol). The mixture was allowed to warm to ambient temperature and stirred for 18 hours at which point a further equivalent of acetic anhydride (6 mL, 63 mmol) was added. The mixture was stirred at ambient temperature for a further 18 hours. The reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate (500 mL) and the organic phase washed with saturated aqueous sodium chloride (500 mL), dried over magnesium sulfate and concentrated in vacuo to give a brown solid. This solid was triturated with 30% ethyl acetate in hexanes to yield the title compound as an off-white solid, (8.28 g, 36 mmol, 63%). 1HNMR (400 MHz, CD3OD): delta ppm 8.31 (s, 1H), 8.18 (s, 1H), 2.43 (s, 3H), 2.18 (s, 3H). LCMS (ESI) calc'd for C8H9BrN20 [M+H]+: 228.99, found: 229, 230.
63%	With triethylamine; In dichloromethane; at 0 - 20℃; for 36h;	To a solutionof 5-bromo-2-methylpyridin-3-amine (M-2) (10.7 g, 57.5 mmol) in dichioromethane (575mL) was added acetic anhydride (12 mL, 126.5 mmol) at 0 C, followed by triethylamine (22mL, 158 mmol). The mixture was allowed to warm to ambient temperature and stirred for 18hours at which point a further equivalent of acetic anhydride (6 mL, 63 mmol) was added.The mixture was stirred at ambient temperature for a further 18 hours. The reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate (500 mL) and the organic phase washed with saturated aqueous sodium chloride (500 mL), dried over magnesium sulfate and concentrated in vacuo to give a brown solid. This solid was trituratedwith 30% ethyl acetate in hexanes to yield the title compound as an off-white solid, (8.28 g,36 mmol, 63%). ?HNMR (400 MHz, CD3OD): oe ppm 8.31 (s, 1H), 8.18 (s, 1H), 2.43 (s, 3H),2.18 (s, 3H). LCMS (ESI) calc?d for C8H9BrN2O [M+H]: 228.99, found: 229, 230.
		To a solution of T-4 (12.1 g, 64.6 mmol) in DCM (50 mL) is added acetic anhydride (9.50 mL, 98.5 mmol) followed by Et3N (20.0 mL, 143.7 mmol). After 18 hours, the reaction is concentrated and the residue is diluted with methanol (200 mL) and K2CO3 (35 g) is added. After 1 hour, the mixture is concentrated and diluted with water and the solid is collected by filtration to provide T-5.
3.1 g	With pyridine; In dichloromethane; at 80℃; for 16h;	To a solution of 5-bromo-2-methylpyridin-3-amine (3.2 g, 17. mmol) in dichloromethane (100 mL) was added pyridine (2.03 g, 25.7 mmol) and acetic anhydride (2.63 g, 25.7 mmol). The mixture was stirred at 80 C for 16 h. The mixture was poured intowater (80 mL) and extracted with dichloromethane (3 x 150 mL). The organic layer was concentrated in vacuo, and the resultant residue was purified by flash column chromatography (15 -30% ethyl acetate in petroleum ether) to afford N-(5-bromo-2-methylpyridin-3-yl)acetamide (3.1 g, 80% yield). 1H NMR (400 MHz, Chloroform-d) oe: 8.48 (s, 1 H), 8.32 (s, 1 H), 7.09 (br s. 1 H), 2.45 (s, 3 H), 2.23 (s, 3 H).
3.1 g	With pyridine; In dichloromethane; at 80℃; for 16h;Inert atmosphere;	To a solution of 5-bromo-2-methylpyridin-3-amine (3.2 g, 17 mmol) in dichloromethane (100 mL) was added pyridine (2.03 g, 25.7 mmol) and acetic anhydride (2.63 g, 25.7 mmol). The mixture was stirred at 80 C. for 16 h. The mixture was poured into water (80 mL) and extracted with dichloromethane (3*150 mL). The organic layer was concentrated in vacuo, and the resultant residue was purified by flash column chromatography (15?30% ethyl acetate in petroleum ether) to afford N-(5-bromo-2-methylpyridin-3-yl)acetamide (3.1 g, 80% yield). 1H NMR (400 MHz, Chloroform-d) delta 8.48 (s, 1H), 8.32 (s, 1H), 7.09 (br s. 1H), 2.45 (s, 3H), 2.23 (s, 3H).
	With triethylamine; In dichloromethane; at 20℃; for 24h;	[0005701 To a stirred solution ofcompound4 (1.15 g, 1 eq) in DCM (10 mL), acetic anhydride (0.99 mL,1.7 eq) and TEA (1 mL, 2.3 eq) were added and stirred at room temperature for 24 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (3 X 25 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 5. LCMS (mlz):231.00 (M+2).
	With triethylamine; In dichloromethane; at 150℃; for 12h;	[0260] [0261] [A] N- (5-Bromo-2-methylpyridin-3-yl) acetamide [0262] [0263] To a solution of 5-bromo-2-methylpyridin-3-amine (20 g, 106 mmol) and Et3N (11.7 g, 116 mmol) in DCM (200mL) was added Ac2O (14.1 g, 139 mmol) and the resulting reaction mixture was stirred at 150 for 12 h. Afterwards, the mixture solution was concentrated under reduced pressure. The residule was diluted with water, basified with aq. NaHCO3 solution (10 mL), and then extracted with EtOAc (10 mL x 3). The combined organic layers were dried over anhy. Na2SO4, filtered, and concentrated in vacuo to giv a crude title compound (14 g, 66.3yield) as a solid. MS 231.7 [M+H] +.

Reference： [1]Molecules,2017,vol. 22
[2]Patent: WO2013/127266,2013,A1 .Location in patent: Page/Page column 91
[3]Patent: WO2013/127267,2013,A1 .Location in patent: Page/Page column 90; 91
[4]Patent: WO2013/130935,2013,A1 .Location in patent: Paragraph 0201
[5]Patent: WO2013/130943,2013,A1 .Location in patent: Paragraph 0209
[6]Patent: US2011/111046,2011,A1 .Location in patent: Page/Page column 16
[7]Patent: WO2011/58473,2011,A1 .Location in patent: Page/Page column 33
[8]Patent: US2012/108619,2012,A1 .Location in patent: Page/Page column 30
[9]Patent: WO2014/26327,2014,A1 .Location in patent: Page/Page column 89
[10]Patent: WO2014/28589,2014,A2 .Location in patent: Page/Page column 108; 109
[11]Patent: WO2012/87782,2012,A1 .Location in patent: Page/Page column 75
[12]Patent: WO2015/91889,2015,A1 .Location in patent: Page/Page column 77
[13]Patent: US2015/175619,2015,A1 .Location in patent: Paragraph 0237; 0238
[14]Patent: WO2016/57834,2016,A1 .Location in patent: Paragraph 000570
[15]Patent: WO2017/133657,2017,A1 .Location in patent: Page/Page column 62
[16]Patent: WO2017/133667,2017,A1 .Location in patent: Page/Page column 174

4
[ 1301214-71-0 ]
[ 1256807-59-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: acetic anhydride; potassium acetate; acetic acid / chloroform / 0.25 h / 20 °C 1.2: 40 - 60 °C 1.3: 0 - 20 °C 2.1: triethylamine / 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; palladium dichloride / acetonitrile / 18 h / 100 °C / 15001.5 Torr 3.1: sodium hydroxide; water / methanol / 0 - 20 °C 3.2: pH 5 - 6
	Multi-step reaction with 3 steps 1.1: acetic anhydride; potassium acetate; isopentyl nitrite / chloroform; acetic acid / 20 - 60 °C 2.1: triethylamine / (S)-(1,1'-binaphthalene)-2,2'-diylbis(diphenylphosphine); palladium dichloride / acetonitrile / 18 h / 100 °C / 15001.5 Torr 3.1: sodium hydroxide; water / methanol / 18 h / 20 °C 3.2: pH 5 - 6
	Multi-step reaction with 3 steps 1: acetic anhydride; isopentyl nitrite; potassium acetate / toluene / 90 °C / Inert atmosphere 2: triethylamine; bis-triphenylphosphine-palladium(II) chloride / 100 °C / 7600.51 Torr 3: water; sodium hydroxide / 20 °C

	Multi-step reaction with 3 steps 1: acetic anhydride; isopentyl nitrite; potassium acetate / toluene / 90 °C / Inert atmosphere 2: triethylamine; bis-triphenylphosphine-palladium(II) chloride / 100 °C / 7600.51 Torr / Sealed tube 3: water; sodium hydroxide / 20 °C
	Multi-step reaction with 3 steps 1: isopentyl nitrite; potassium acetate; acetic anhydride / toluene / 90 °C / Inert atmosphere 2: triethylamine; bis-triphenylphosphine-palladium(II) chloride / 100 °C / 7600.51 Torr 3: sodium hydroxide; water / 20 °C
	Multi-step reaction with 3 steps 1: potassium acetate; isopentyl nitrite / toluene / 90 °C / Inert atmosphere 2: bis-triphenylphosphine-palladium(II) chloride; methanol; triethylamine / 100 °C / 7600.51 Torr 3: sodium hydroxide / 20 °C
	Multi-step reaction with 3 steps 1.1: potassium acetate; acetic anhydride; acetic acid / chloroform / 48.25 h / 20 - 60 °C 1.2: 0 - 20 °C 2.1: triethylamine / 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; palladium dichloride / acetonitrile / 18 h / 100 °C / 15001.5 Torr 3.1: water; sodium hydroxide / methanol / 0 - 20 °C 3.2: pH 5 - 6

5
[ 1301214-71-0 ]
[ 1383735-65-6 ]

Yield	Reaction Conditions	Operation in experiment
75%	With 18-crown-6 ether; potassium carbonate; isopentyl nitrite In chloroform at 60℃; for 12h;	4.1.18. 1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one (18) Intermediate 17 (56.7 mmol, 1.0 equiv) was added to 100 mLchloroform, followed by isoamyl nitrite (9.2 mL, 68.0 mmol, 1.2 equiv),18-crown-6 (1.5 g, 56.7 mmol, 0.1 equiv), potassium carbonate (19.5 g,141.8 mmol, 2.5 equiv), and the reaction was stirred at 60 C for 12 h.After the reaction was completed, the reaction liquid was concentratedunder reduced pressure, and the crude silica gel was stirred for sample.Pooled sample was separated on a 100 g flashmaster personal + column(mobile phase system PE/EA = 80:20). The target product 18 (10.2 g)was obtained, yield 75%. 1H NMR (400 MHz, DMSO-d6) δ: 8.67 (d, J =1.9 Hz, 1H), 8.45 (d, J = 1.6 Hz, 2H), 2.74 (s, 3H).
75%	With 18-crown-6 ether; potassium carbonate; isopentyl nitrite In chloroform at 60℃; for 12h;	4.1.18. 1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-one (18) Intermediate 17 (56.7 mmol, 1.0 equiv) was added to 100 mLchloroform, followed by isoamyl nitrite (9.2 mL, 68.0 mmol, 1.2 equiv),18-crown-6 (1.5 g, 56.7 mmol, 0.1 equiv), potassium carbonate (19.5 g,141.8 mmol, 2.5 equiv), and the reaction was stirred at 60 C for 12 h.After the reaction was completed, the reaction liquid was concentratedunder reduced pressure, and the crude silica gel was stirred for sample.Pooled sample was separated on a 100 g flashmaster personal + column(mobile phase system PE/EA = 80:20). The target product 18 (10.2 g)was obtained, yield 75%. 1H NMR (400 MHz, DMSO-d6) δ: 8.67 (d, J =1.9 Hz, 1H), 8.45 (d, J = 1.6 Hz, 2H), 2.74 (s, 3H).
55%	With anhydrous potassium acetate; acetic anhydride; isopentyl nitrite In toluene at 90℃; Inert atmosphere;	9.3 Step 3. 1-(6-bromopyrazolo[4,3-b]pyridin-1-yl)-ethanone A mixture of N- (5-bromo-2-methyl-pyridin-3-yl)-acetamide (3.5 g, 1 5.28 mmol, 1 .00 equiv), isopentyl nitrite (4 g, 34.73 mmol, 2.27 equiv ), potassium acetate (20 g), and acetic anhydride (30 mL) in toluene ( 1 0 mL) was stirred under nitrogen overnight at 90 °C. The reaction mixture was cooled to rt and the solid material was removed by filtration. The filtrate was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether ( 1 :5) to give in 2 g (55%) of the title compound as a light yellow solid. LC/MS (Method I, ESI): RT= 1 .44 min, m/z = 240.0; 242.0 [M · H]-.

55%	With anhydrous potassium acetate; acetic anhydride; isopentyl nitrite In toluene at 90℃; Inert atmosphere;	9.3 Step 3. 1-(6-bromopyrazolo[4,3-b]pyridin-1-yl)-ethanone A mixture of N- (5-bromo-2-methyl-pyridin-3-yl)-acetamide (3.5 g, 1 5.28 mmol, 1 .00 equiv), isopentyl nitrite (4 g, 34.73 mmol, 2.27 equiv ), potassium acetate (20 g), and acetic anhydride (30 mL) in toluene ( 1 0 mL) was stirred under nitrogen overnight at 90 °C. The reaction mixture was cooled to rt and the solid material was removed by filtration. The filtrate was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether ( 1 :5) to give in 2 g (55%) of the title compound as a light yellow solid. LC MS (Method I, ESI): RT= 1 .44 min, m z = 240.0; 242.0 [M · H]*.
55%	With anhydrous potassium acetate; acetic anhydride; isopentyl nitrite In toluene at 90℃; Inert atmosphere;	9.3 Step 3. 1-(6-Bromo-pyrazolo[4,3-blpyridin-1-yl)-ethanone. [0202] Step 3. 1-(6-Bromo-pyrazolo[4,3-blpyridin-1-yl)-ethanone. A mixture of N-(5- bromo-2-methyl-pyridin-3-yl)-acetamide (3.5 g, 15.28 mmol, 1.00 equiv), isopentyl nitrite (4 g, 34.73 mmol, 2.27 equiv), potassium acetate (20 g), and acetic anhydride (30 mL) in toluene (150 mL) was stirred under nitrogen overnight at 90 °C. The reaction mixture was cooled to rt and the solid material was removed by filtration. The filtrate was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1:5) to give in 2 g (55%) of the title compound as a light yellow solid. LC/MS (Method I, ESI): RT= 1.44 mm, m/z = 240.0; 242.0 [M+H].
55%	With anhydrous potassium acetate; isopentyl nitrite In toluene at 90℃; Inert atmosphere;	Step 3. l-(6-Bromo-pyrazolor4,3-blpyridin-l-yl)-ethanone 0210] Step 3. l-(6-Bromo-pyrazolor4,3-blpyridin-l-yl)-ethanone. A mixture of N-(5- bromo-2-methyl-pyridin-3-yl)-acetamide (3.5 g, 15.28 mmol, 1.00 equiv), isopentyl nitrite (4 g, 34.73 mmol, 2.27 equiv), potassium acetate (20 g), and acetic anhydride (30 mL) in toluene (150 mL) was stirred under nitrogen overnight at 90 °C. The reaction mixture was cooled to rt and the solid material was removed by filtration. The filtrate was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1:5) to give in 2 g (55%) of the title compound as a light yellow solid. LC/MS (Method I, ESI): RT= 1.44 min, m/z = 240.0; 242.0 [M+H]+.
48%	Stage #1: N-(5-bromo-2-methylpyridin-3-yl)acetamide With anhydrous potassium acetate In toluene at 80℃; for 0.5h; Inert atmosphere; Stage #2: With 2-Methyl-2-nitropropane; acetic anhydride In toluene at 80℃; for 18h; Inert atmosphere;	1.3 Synthesis of 1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethanone A solution of N-(5-bromo-2-methylpyridin-3-yl)acetamide (2.8 g, 12 mmol) and potassium acetate (3.59 g, 36.6 mmol) in toluene (50 mL) was heated at 80° C. under nitrogen. After 30 min, 2-methyl-2-nitropropane (3.77 g, 36.6 mmol) and acetic anhydride (3.73 g, 36.6 mmol) were added, and the resulting mixture was stirred at 80° C. for another 18 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with water (50 mL). The aqueous mixture was extracted with ethyl acetate (3*60 mL). The collected organic extractions were concentrated in vacuo. Purification by flash column chromatography (5→10% ethyl acetate in petroleum ether) afforded 1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethanone (1.4 g, 48.% yield). 1H NMR (400 MHz, Chloroform-d) δ 8.90 (s, 1H), 8.75 (s, 1H), 8.32 (s, 1H), 2.79 (s, 3H).
	With anhydrous potassium acetate; acetic anhydride; glacial acetic acid; isopentyl nitrite In toluene for 3h; Reflux;	To a solution of T-5 (13.14 g, 57.36 mmol) in toluene (200 mL) is added acetic anhydride (16.50 mL, 174.5 mmol), acetic acid (16.50 mL, 288.2 mmol) and potassium acetate (12.30 g, 125.3 mmol). The mixture is warmed at reflux and isoamyl nitrite (10.0 mL, 71.5 mmol) is added. After 3 hours, the reaction is concentrated to provide without isolation T-6. The residue is diluted with methanol (250 mL) and K2CO3 (32.0 g, 188 mmol) is added and the mixture is warmed at reflux. After 1 hour, the reaction is poured into water and extracted with EtOAc (3 x 150 mL). The combined organic layers are washed with brine (2 x 50 mL), dried over magnesium sulfate, filtered through a pad of silica gel and filter agent and concentrated. The solid is triturated with Et2O to provide T-7. The filtrate is purified on silica gel using a gradient of 25-100% EtOAc in hexanes and then 5% methanol in ethyl acetate. The material from the column is triturated with ether-heptane to provide T-7.
	Stage #1: N-(5-bromo-2-methylpyridin-3-yl)acetamide With anhydrous potassium acetate; acetic anhydride; glacial acetic acid In toluene Reflux; Stage #2: With isopentyl nitrite In toluene for 2h; Reflux;	172.5 [0005711 Step 5: Synthesis of 1-(6-bromo-1H-pyrazolo [4,3-bi pyridin-1-yl)ethanone (6): [0005721 To a stirred solution of compoundS (1.35 g,1 eq) in toluene (15 mE), potassiumacetate (1.27 g, 2.2 eq), acetic anhydride (1.67 mL, 3 eq) and acetic acid (1.68 mL, 5 eq) was heated to reflux followed by the addition of isoamyl nitrite (1 mL, 1.25 eq) and refluxed for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (2 X 50 mL). Combined organic extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound 6. LCMS (mlz): 242.15 (M + 2).
	With 3-methyl-1-nitrobutane; anhydrous potassium acetate; acetic anhydride; glacial acetic acid In toluene at 90℃; for 5h;	B [B] 1- (6-Bromo-1H-pyrazolo [4 3-b] pyridin-1-yl) ethanone [B] 1- (6-Bromo-1H-pyrazolo [4 3-b] pyridin-1-yl) ethanone[0265][0266]To a solution of N- (5-bromo-2-methylpyridin-3-yl) acetamide (14 g 61.1 mmol) in toluene (200 mL) was added Ac2O (21 mL 183 mmol) AcOH (21 mL 300 mmol) and KOAc (11.7 g 120 mmol) . The resulting reaction mixture was warmed up to 90 added CHMe2CH2CH2NO2(110 mL) and stirred at 90 for 5 h. After cooling to room temperature the mixture was poured into water basified with aq. NaHCO3solution and extracted with EtOAc (50 mL x 6) . The combined organic layers were dried over anhy. MgSO4 filtered and concentrated in vacuo to give a crude title compound (6.5 g 44.5yield) as a solid. MS 241.06 [M+H]+.
50 mg	Stage #1: N-(5-bromo-2-methylpyridin-3-yl)acetamide With anhydrous potassium acetate; acetic anhydride In toluene at 120℃; for 0.333333h; Inert atmosphere; Stage #2: With isopentyl nitrite In toluene	11.2 Step 2: 1-(6-bromopyrazolo[4,3-b]pyridin-1-yl)ethanone (C11-3) Intermediate C11-2 (100 mg, 0.44 mmol), KOAc (94 mg, 0.96 mmol) and Ac2O (265 mg, 1.31 mmol) were dissolved in toluene (10 mL) under N2, and the mixture was refluxed at 120 °C for 20 min. Isopentyl nitrite (64 mg, 0.55 mmol) was added via a syringe. The reaction continued overnight. TLC was used to monitor the reaction and the reaction was incomplete. The mixture was extracted with EtOAc (20 mL). The organic layer was collected, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 5:1) to afford the title compound as a yellow solid (50 mg, 48%). NMR (400 MHz, CDCl3) d 8.91 (s, 1H), 8.75 (s, 1H), 8.32 (s, 1H), 2.80 (s, 3H).

Reference： [1]Chen, Lijuan; Chen, Yong; Deng, Dexin; Fu, Suhong; Guo, Yong; Hu, Mengshi; Li, Xiandeng; Liu, Kongjun; Peng, Bin; Si, Wenting; Tan, Yan; Tang, Minghai; Wang, Huan; Yang, Tao; Yang, Yingxue; Yang, Zhuang; Zhang, Chufeng [Bioorganic Chemistry, 2022, vol. 121]
[2]Chen, Lijuan; Chen, Yong; Deng, Dexin; Fu, Suhong; Guo, Yong; Hu, Mengshi; Li, Xiandeng; Liu, Kongjun; Peng, Bin; Si, Wenting; Tan, Yan; Tang, Minghai; Wang, Huan; Yang, Tao; Yang, Yingxue; Yang, Zhuang; Zhang, Chufeng [Bioorganic Chemistry, 2022, vol. 121]
[3]Current Patent Assignee: VALO HEALTH INC - WO2013/127266, 2013, A1 Location in patent: Page/Page column 139; 140
[4]Current Patent Assignee: VALO HEALTH INC - WO2013/127267, 2013, A1 Location in patent: Page/Page column 90; 91
[5]Current Patent Assignee: FORMA THERAPEUTICS, INC.; ROCHE HOLDING AG - WO2013/130935, 2013, A1 Location in patent: Paragraph 0202
[6]Current Patent Assignee: FORMA THERAPEUTICS, INC.; ROCHE HOLDING AG - WO2013/130943, 2013, A1 Location in patent: Paragraph 0210
[7]Current Patent Assignee: ROCHE HOLDING AG - US2015/175619, 2015, A1 Location in patent: Paragraph 0239; 0240
[8]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2012/87782, 2012, A1 Location in patent: Page/Page column 75
[9]Current Patent Assignee: BIOMARIN PHARMACEUTICAL INC - WO2016/57834, 2016, A1 Location in patent: Paragraph 000571; 000572
[10]Current Patent Assignee: SAVIRA PHARMACEUTICALS GMBH; EUROPEAN MOLECULAR BIOLOGY LABORATORY - WO2017/133657, 2017, A1 Location in patent: Page/Page column 63
[11]Current Patent Assignee: ACCRO BIOSCIENCE; ZHANG - WO2020/146858, 2020, A1 Location in patent: Paragraph 00160; 00163-00164

6
[ 594-70-7 ]
[ 1301214-71-0 ]
[ 1383735-65-6 ]

Yield	Reaction Conditions	Operation in experiment
48%	Stage #1: N-(5-bromo-2-methyl-pyridin-3-yl)-acetamide With potassium acetate In toluene at 80℃; for 0.5h; Inert atmosphere; Stage #2: 2-Methyl-2-nitropropane With acetic anhydride In toluene at 80℃; for 18h;	1.3 Step 3: Synthesis of 1- (6-bromo- 1 H-pyrazolo [4,3-b]pyridin- 1 -yl)ethanone. A solution of N-(5-bromo-2-methylpyridin-3-yl)acetamide (2.8 g, 12 mmol) and potassium acetate (3.59 g, 36.6 mmol) in toluene (50 mL) was heated at 80 °C under nitrogen. After 30 mi 2-methyl-2-nitropropane (3.77 g, 36.6 mmol) and acetic anhydride (3.73 g,36.6 mmol) were added, and the resulting mixture was stirred at 80 °C for another 18 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with water (50 mL). The aqueous mixture was extracted with ethyl acetate (3 x 60 mL). The collected organic extractions were concentrated in vacuo. Purification by flash column chromatography (5-* 10% ethyl acetate in petroleum ether) afforded1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethanone (1.4 g, 48.% yield). 1H NMR (400MHz, Chloroform-d) ö: 8.90 (s, 1 H), 8.75 (s, 1 H), 8.32 (s, 1 H), 2.79 (s, 3 H).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2015/91889, 2015, A1 Location in patent: Page/Page column 77; 78

7
[ 1301214-71-0 ]
[ 1150617-56-3 ]

Reference： [1]Patent: WO2016/57834,2016,A1

8
[ 1301214-71-0 ]
[ 5122-99-6 ]
N-[5-(4-iodophenyl)-2-methylpyridin-3-yl]acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%		General procedure: All compounds were synthesized by reported method [28]. N-[5-bromo-2-methylpyridine-3-yl]acetamide (3, 0.1 g), tetrakis(triphenylphosphine)-palladium (5 mol %) and 1,4-dioxane (2 mL) wereplaced in the Schlenk flask at room temperature and the mixture was stirred for 30 min . Then theappropriate arylboronic acid (1.1 mmol), potassium phosphate (1.5 mmol) and H2O (0.5 mL) were addedto the mixture, which was stirred and kept at 85-95 C for more than 15 h. After reaching roomtemperature, the mixture was filtered and then diluted with ethyl acetate (50 mL). The excess solvent wasevaporated by rotary evaporator in order to obtain a concentrated solution. Column chromatography(silica gel, n-hexane and ethyl acetate?) was applied to obtain the desired pure products. The finalproduct was dried and recrystallized and further analyzed using different spectroscopic techniques.

Reference： [1]Molecules,2017,vol. 22

9
[ 1301214-71-0 ]
[ 98546-51-1 ]
N-[2-methyl-5-(4-methylsulfanyl)phenylpyridin-3-yl]acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	Stage #1: N-(5-bromo-2-methyl-pyridin-3-yl)-acetamide With tetrakis(triphenylphosphine) palladium⁽⁰⁾ In 1,4-dioxane at 20℃; for 0.5h; Schlenk technique; Stage #2: (4-thiomethoxyphenyl)boronic acid With potassium phosphate In 1,4-dioxane; water at 90℃; for 18h; Schlenk technique;	3.4. General Procedure for the Synthesis of Compounds 4a-4i General procedure: All compounds were synthesized by reported method [28]. N-[5-bromo-2-methylpyridine-3-yl]acetamide (3, 0.1 g), tetrakis(triphenylphosphine)-palladium (5 mol %) and 1,4-dioxane (2 mL) wereplaced in the Schlenk flask at room temperature and the mixture was stirred for 30 min . Then theappropriate arylboronic acid (1.1 mmol), potassium phosphate (1.5 mmol) and H2O (0.5 mL) were addedto the mixture, which was stirred and kept at 85-95 °C for more than 15 h. After reaching roomtemperature, the mixture was filtered and then diluted with ethyl acetate (50 mL). The excess solvent wasevaporated by rotary evaporator in order to obtain a concentrated solution. Column chromatography(silica gel, n-hexane and ethyl acetate?) was applied to obtain the desired pure products. The finalproduct was dried and recrystallized and further analyzed using different spectroscopic techniques.

Reference： [1]Ahmad, Gulraiz; Rasool, Nasir; Ikram, Hafiz Mansoor; Khan, Samreen Gul; Mahmood, Tariq; Ayub, Khurshid; Zubair, Muhammad; Al-Zahrani, Eman; Rana, Usman Ali; Akhtar, Muhammad Nadeem; Alitheen, Noorjahan Banu [Molecules, 2017, vol. 22, # 2]

10
[ 1301214-71-0 ]
[ 144432-85-9 ]
N-[5-(3-chloro-4-fluorophenyl)-2-methylpyridin-3-yl]acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%		General procedure: All compounds were synthesized by reported method [28]. N-[5-bromo-2-methylpyridine-3-yl]acetamide (3, 0.1 g), tetrakis(triphenylphosphine)-palladium (5 mol %) and 1,4-dioxane (2 mL) wereplaced in the Schlenk flask at room temperature and the mixture was stirred for 30 min . Then theappropriate arylboronic acid (1.1 mmol), potassium phosphate (1.5 mmol) and H2O (0.5 mL) were addedto the mixture, which was stirred and kept at 85-95 C for more than 15 h. After reaching roomtemperature, the mixture was filtered and then diluted with ethyl acetate (50 mL). The excess solvent wasevaporated by rotary evaporator in order to obtain a concentrated solution. Column chromatography(silica gel, n-hexane and ethyl acetate?) was applied to obtain the desired pure products. The finalproduct was dried and recrystallized and further analyzed using different spectroscopic techniques.

Reference： [1]Molecules,2017,vol. 22

11
[ 1301214-71-0 ]
[ 110-46-3 ]
[ 1383735-65-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium acetate; acetic anhydride; acetic acid In toluene at 90℃; for 5h;

Reference： [1]Current Patent Assignee: SAVIRA PHARMACEUTICALS GMBH; EUROPEAN MOLECULAR BIOLOGY LABORATORY - WO2017/133667, 2017, A1 Location in patent: Page/Page column 174; 175

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P321
P322
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P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
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P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
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P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
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P401
P402	Store in a dry place.
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Disposal
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P501	Dispose of contents/container to ...
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Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
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H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
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H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
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H351	Suspected of causing cancer
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H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 1301214-71-0 ] {[proInfo.proName]}

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[ 1301214-71-0 ] Synthesis Path-Upstream 1~2

[ 1301214-71-0 ] Synthesis Path-Downstream 1~11

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