[ CAS No. 1124382-72-4 ] {[proInfo.proName]}

Name: 1124382-72-4|2-Amino-8-bromo[1,2,4]triazolo[1,5-a]pyridine|97%
Brand: Ambeed
SKU: A193385
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Quality Control of [ 1124382-72-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 1124382-72-4 ]

Product Details of [ 1124382-72-4 ]

CAS No. :	1124382-72-4	MDL No. :	MFCD16658939
Formula :	C₆H₅BrN₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SUFKKFLJJMKVJJ-UHFFFAOYSA-N
M.W :	213.04	Pubchem ID :	46864069
Synonyms :

Calculated chemistry of [ 1124382-72-4 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	45.09
TPSA :	56.21 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.83 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.73
Log Po/w (XLOGP3) :	1.09
Log Po/w (WLOGP) :	1.08
Log Po/w (MLOGP) :	1.58
Log Po/w (SILICOS-IT) :	0.45
Consensus Log Po/w :	1.18

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.45
Solubility :	0.751 mg/ml ; 0.00352 mol/l
Class :	Soluble
Log S (Ali) :	-1.86
Solubility :	2.92 mg/ml ; 0.0137 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.21
Solubility :	1.3 mg/ml ; 0.00612 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.94

Safety of [ 1124382-72-4 ]

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 [ 1124382-72-4 ]

* 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 [ 1124382-72-4 ]
Downstream synthetic route of [ 1124382-72-4 ]

[ 1124382-72-4 ] Synthesis Path-Upstream 1~4

1
[ 1124383-00-1 ]
[ 1124382-72-4 ]

Yield	Reaction Conditions	Operation in experiment
96%	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine In methanol; ethanol at 20℃; for 6 h;	To a sol. of intermediate 50 (55 g, 181 mmol) in EtOH (300 mL) were added MeOH (300 mL), hydroxylamine hydrochloride (62.83 g, 904 mmol) and DIPEA (694 mL, 543 mmol). The r.m. was stirred at r.t. for 6 h. The mixture was concentrated in vacuo and the residue was suspended in DIPE. The precipitate was filtered off. Yield: 37 g of intermediate 51 (96percent yield).
82%	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine In methanol; ethanol for 4 h; Reflux	Hydroxylamine hydrochloride 180.5 g (2.60 mol) in EtOH / MeOH (1: 1, 1.5 L) was added to the mixed solvent. It was added to N, N-Diisopropylethylamine 271 mL (1.56 mol) the reaction mixture was stirred for 1 hour. 1- (3-Bromo-pyridine-2-yl) -3-carboethoxy-thiourea 158 g was added (0.52 mol) and gradually raise the temperature given by heating under reflux for 3 hours. It cooled to room temperature and the resulting solids were filtered. The filtrate was distilled under reduced pressure and the resulting solids were filtered. Summing the thus obtained solid product washed with purified water, EtOH / MeOH mixture and the solvent n-hexane and dried to give the title compound hunpung 91 g (82percent yield).
82%	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine In methanol; ethanol for 3 h; Reflux	Hydroxylamine hydrochloride 180.5 g (2.60 mol) in EtOH / MeOH (1:1, 1.5 L) was mixed solvent.It was added to N, N-Diisopropylethylamine 271 mL (1.56 mol) the reaction mixture was stirred for 1 hour.Given the addition of 1- (3-bromo-pyridine-2-yl) -3-carboethoxy-thiourea 158 g (0.52 mol) synthesized in the above and the temperature gradually raised and the mixture was heated under reflux for 3 hours.It cooled to room temperature and the resulting solids were filtered.The filtrate was distilled under reduced pressure and the resulting solids were filtered.Summing the thus obtained solid product washed with purified water, EtOH / MeOH mixture and the solvent n-hexane and dried to give the title compound hunpung 91 g (82percent yield).

78%	With hydroxylamine In methanol; ethanol at 20 - 60℃; for 4 h;	b) 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine; Hydroxyl amine (58.5 g, 842 mmol) and N,N-diisopropylethylamine (65.3 g, 86.3 ml, 505 mmol) were dissolved in methanol (200 ml) and ethanol (200 ml). N-(3-bromo-pyridin-2-yl)-N'-ethoxycarbonyl-thiourea (51.2 g, 168 mmol) was added and the reaction mixture was stirred at rt for 1 hour and then at 60° C. for 3 hours.The white precipitate was filtered off and triturated with water for 25 min, filtered and triturated two times with diethylether. The solid was dried by co-evaporation with toluene and dried in vacuum. The title compound was obtained as a white solid (27.9 g, 78percent).MS ISP (m/e): 213.0/215.1 (86/95) [(M+H)⁺].¹H NMR (CDCl₃, 300 MHz): δ (ppm)=8.28 (dd, 1H) 7.62 (dd, 1H), 6.73 (t, 1H), 4.66 (bs, 2H).
78%	With hydroxylamine; N-ethyl-N,N-diisopropylamine In methanol; ethanol at 20 - 60℃; for 4 h;	Hydroxyl amine (58.5 g, 842 mmol) and N,N-diisopropylethylamine (65.3 g, 86.3 ml, 505 mmol) were dissolved in methanol (200 ml) and ethanol (200 ml). N-(3-bromo-pyridin-2-yl)-N'- ethoxycarbonyl-thiourea (51.2 g, 168 mmol) was added and the reaction mixture was stirred at rt for 1 hour and then at 60°C for 3 hours. The white precipitate was filtered off and triturated with water for 25 min, filtered and triturated two times with diethylether. The solid was dried by co-evaporation with toluene and dried in vacuum. The title compound was obtained as a white solid (27.9 g, 78percent).MS ISP (m/e): 213.0/ 215.1 (86/ 95) [(M+H)⁺].1H NMR (CDCI3, 300 MHz): δ (ppm) = 8.28 (dd, 1H) 7.62 (dd, 1H), 6.73 (t, 1H), 4.66 (bs, 2H).
78%	With hydroxylamine; N-ethyl-N,N-diisopropylamine In methanol; ethanol at 20 - 60℃; for 4 h;	b) 8-Bromo-[1,2,4]-triazolo[1,5-a]pyridin-2-amine; Hydroxylamine (58.5 g, 842 mmol) and N,N-diisopropylethylamine (65.3 g, 86.3 mL, 505 mmol) were dissolved in methanol (200 mL) and ethanol (200 mL). N-(3-Bromo-pyridin-2-yl)-N'-ethoxycarbonyl-thiourea (51.2 g, 168 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour and then at 60° C. for 3 hours. The white precipitate was filtered off and triturated with water for 25 minutes, filtered and triturated two times with diethylether. The solid was dried by co-evaporation with toluene and dried in vacuum. The title compound was obtained as a white solid (27.9 g, 78percent).MS ISP (m/e): 213.0/215.1 (86/95) [(M+H)⁺].¹H NMR (CDCl₃, 300 MHz): δ (ppm)=8.28 (dd, 1H) 7.62 (dd, 1H), 6.73 (t, 1H), 4.66 (bs, 2H).
78%	With hydroxylamine; N-ethyl-N,N-diisopropylamine In methanol; ethanol at 20 - 60℃; for 4 h;	c) 8-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine Hydroxylamine (58.5 g, 842 mmol) and N,N-diisopropylethylamine (65.3 g, 86.3 mL, 505 mmol) were dissolved in methanol (200 mL) and ethanol (200 mL). N-(3-Bromo-pyridin-2-yl)-N'-ethoxycarbonyl-thiourea (51.2 g, 168 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour and then at 60° C. for 3 hours. The white precipitate was filtered off and triturated with water for 25 minutes, filtered and triturated two times with diethyl ether. The solid was dried by co-evaporation with toluene and dried in vacuum. The title compound was obtained as a white solid (27.9 g, 78percent). MS ISP (m/e): 213.0/215.1 (86/95) [(M+H)⁺]. ¹H NMR (CDCl₃, 300 MHz): δ (ppm)=8.28 (dd, 1H) 7.62 (dd, 1H), 6.73 (t, 1H), 4.66 (bs, 2H).
75%	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine In methanol; ethanol at 20℃; for 20 h; Reflux	To a suspension of DIPEA (128.2 g, 984 mmol) and hydroxylamine hydrochloride (115.1 g, 1.64 mol) in a mixture of ethanol/methanol (400 mL/400 mL) is added 1-(3-bromo-pyridin-2-yl)-3-carboethoxy-thiourea (34a) (105.0 g, 328 mmol). After stirring for 2 h at RT, the reaction mixture is heated under reflux for 18 h. After cooling to RT the precipitate is collected, washed with water and EE and dried to give the product (35a). Yield: 55 g (75percent). LCMS (ESI⁺) calculated for C₆H₅BrN₄ [M+H]⁺ m/z 212.9776, found 213.1. ¹H NMR (400 MHz, (CD₃)₂SO) δ 8.58 (dd, J = 6.6, 0.7 Hz, 1H), 7.73 (dd, J = 7.6, 0.7 Hz, 1H), 6.81 (dd, J = 7.5, 6.7 Hz, 1H), 6.24 (br s, 2H). TLC (silica gel, DCM/MeOH 10:1): R_f = 0.5.fx9
70%	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine In methanol; ethanol at 20 - 60℃; for 20 h;	To a stirred suspension of hydroxylamine hydrochloride (17.4 g, 25.0 mmol) and N ,N- diisopropylethylamine (26.0 rnL, 14.9 mmol) in a mixture of methanol (70 mL) and ethanol (70 mL) was added N-(3-bromo-2-pyridinyl)-N'-carboethoxy-thiourea. The mixture was stirred for 2 hours at room temperature then heated to 60⁰C for 18 hours. The suspension was cooled to room temperature, filtered and rinsed with methanol, water then methanol. 8-Bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine was isolated as an off-white solid (8.41 g, 70percent). ¹H NMR (400 MHz, (D₃C)₂SO, δ, ppm): 8.58 (d, J=6.4 Hz, IH), 7.73 (d, J=7.6 Hz, IH), 6.80 (t, J=7.0 Hz, IH), 6.25 (s, 2H). MS = 213, 215 (MH)+.
40%	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine In methanol; ethanol at 20 - 60℃;	To a solution of hydroxylamine hydrochloride (0.10 kg, 1.4 mol, 5.0 equiv) and JV,./V-diisopropylethylamine (112 g, 0.867 mol, 3.00 eq ) in 1 :1 methanol / ethanol (1.5 L) was added ethyl [(3-bromopyridin-2- yl)carbamothioyl] carbamate (88 g, 0.29 mmol, 1 equiv) in one portion at room temperature. After 2 h, the reaction mixture was warmed to 60 ⁰C for overnight. The reaction mixture was concentrated in vacuo, and water was added to the resulting residue. The solids were filtered and rinsed sequentially with 4:1 methanol / diethyl ether and diethyl ether to provide product as an off-white solid (25 g, 40percent). LCMS (ESI) m/z: 212.8; ¹U NMR (400 MHz, DMSO-J₆) δ: 8.55 (m 1 H), 7.70 (m, 1 H), 6.75 (m, 1 H), 6.20 (br s, 2 H).
8 g	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine In methanol; ethanol at 20 - 60℃; for 20 h;	To a stirred suspension of hydroxylamine hydrochloride (about 17 g) and N,N-diisopropylethylamine (about26 mL) in a mixture of methanol (about 70 mL) and ethanol (about 70 mL) is added N-(3-bromo-2-pyridinyl)-N’-carboethoxy-thiourea. The mixture is stirred for about 2 hours at room temperature then heated to about 60°C forabout 18 hours. The suspension is cooled to room temperature, filtered and rinsed with methanol, water thenmethanol. 8-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine is isolated as an off-white solid (about 8 g). 1H NMR (400MHz, (D3C)2SO, δ, ppm): 8.58 (d, J=6.4 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 6.80 (t, J=7.0 Hz, 1H), 6.25 (s, 2H). MS =213, 215 (MH)+.

Reference： [1] Patent: WO2013/10904, 2013, A1, . Location in patent: Page/Page column 76
[2] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 17, p. 4794 - 4800
[3] Patent: KR2015/77599, 2015, A, . Location in patent: Paragraph 0096; 0099-0101
[4] Patent: KR101601354, 2016, B1, . Location in patent: Paragraph 0110 - 0112
[5] Patent: US2011/190269, 2011, A1, . Location in patent: Page/Page column 66
[6] Patent: WO2011/92272, 2011, A1, . Location in patent: Page/Page column 139; 140
[7] Patent: US2011/201605, 2011, A1, . Location in patent: Page/Page column 51
[8] Patent: US2012/225884, 2012, A1, . Location in patent: Page/Page column 17
[9] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 12, p. 3227 - 3241
[10] Patent: WO2010/141796, 2010, A2, . Location in patent: Page/Page column 133
[11] Patent: WO2009/155551, 2009, A1, . Location in patent: Page/Page column 86
[12] Patent: WO2010/10186, 2010, A1, . Location in patent: Page/Page column 52-53
[13] Patent: WO2011/101304, 2011, A2, . Location in patent: Page/Page column 105
[14] Patent: WO2012/116965, 2012, A1, . Location in patent: Page/Page column 34
[15] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 17, p. 5014 - 5021
[16] Organic Process Research and Development, 2016, vol. 20, # 12, p. 2085 - 2091
[17] Patent: EP2648728, 2016, B1, . Location in patent: Paragraph 0047

2
[ 13534-99-1 ]
[ 16182-04-0 ]
[ 1124382-72-4 ]

Reference： [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 11, p. 5243 - 5254

3
[ 13534-99-1 ]
[ 1124382-72-4 ]

Reference： [1] Patent: US2011/190269, 2011, A1,
[2] Patent: WO2011/92272, 2011, A1,
[3] Patent: US2011/201605, 2011, A1,
[4] Patent: US2012/225884, 2012, A1,
[5] Patent: WO2011/101304, 2011, A2,
[6] Patent: WO2012/116965, 2012, A1,
[7] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 17, p. 4794 - 4800
[8] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 17, p. 5014 - 5021
[9] Patent: KR2015/77599, 2015, A,
[10] Patent: KR101601354, 2016, B1,
[11] Organic Process Research and Development, 2016, vol. 20, # 12, p. 2085 - 2091
[12] Patent: EP2648728, 2016, B1,
[13] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 12, p. 3227 - 3241
[14] Patent: WO2013/10904, 2013, A1,
[15] Patent: WO2009/155551, 2009, A1,

4
[ 1124382-72-4 ]
[ 1257704-57-6 ]

Reference： [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 11, p. 5243 - 5254
[2] Organic Process Research and Development, 2016, vol. 20, # 12, p. 2085 - 2091
[3] Organic Process Research and Development, 2016, vol. 20, # 12, p. 2085 - 2091
[4] Organic Process Research and Development, 2016, vol. 20, # 12, p. 2085 - 2091
[5] Organic Process Research and Development, 2016, vol. 20, # 12, p. 2085 - 2091

[ 1124382-72-4 ] Synthesis Path-Downstream 1~88

Yield	Reaction Conditions	Operation in experiment
90%	With hydroxylamine hydrochloride; triethylamine; In methanol; ethanol; for 3h;Reflux;	General procedure: A mixed solvent of EtOH / MeOH (1: 1, 2.15 L) was added to 298 g (4.29 mol) of hydroxylamine hydrochloride.399 mL (2.86 mol) of triethylamine was added to the reaction solution, which was stirred for 1 hour.215 g (0.95 mol) of [(2-pyridinylamino) thioxomethyl] -, ethyl ester (9CI) was added and the temperature was gradually raised, and the mixture was refluxed for 3 hours.The temperature was cooled to room temperature and the resulting solid was filtered.The resulting solid product was combined, washed with purified water, EtOH / MeOH mixed solvent and n-hexane, and dried under a warm air stream to obtain 115 g of the title compound (yield 90%).

2
[ 1124382-72-4 ]
[ 75-36-5 ]
[ 1205683-44-8 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of the 8-bromo-2-amino-triazolopyridine (1 eq.) in dry CH3CN at 5 0C was addedEt3N (2.5 eq.) followed by acetyl chloride (2.5 eq.). The reaction mixture was then allowed to warm to ambient temperature and stirred until all starting material was consumed. If required, further Et3N (1 eq.) and acid chloride (1 eq.) were added to ensure complete reaction. Following solvent evaporation in vacuo the resultant residue was treated with 7 N methanolic ammonia solution and stirred at ambient temp, (for 16 h) to hydrolyse any bis-acylated product. Product isolation was made by removal of volatiles in vacuo followed by addition of water and extraction with ethyl acetate. The organic phase was then dried over MgSO4, evaporated in vacuo The compound was used without further purification.

Reference： [1]Patent: WO2010/10186,2010,A1 .Location in patent: Page/Page column 73

3
[ 1124382-72-4 ]
[ 4023-34-1 ]
[ 1205683-27-7 ]

Yield	Reaction Conditions	Operation in experiment
47.8%	With triethylamine; In acetonitrile; at 26℃; for 12h;	To <strong>[1124382-72-4]8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine</strong>(1.0 g, 4.7 mmol) and triethylamine (1.4 g, 14.1 mmol), dissolved in acetonitrile(15.0 mL), was added dropwise cyclopropanecarboxylic acid chloride(1.5 g, 14.1 mmol). Then the mixture is stirred at 26C for reacting for 12 hours. LC-MC showed that the reaction was completed. The reaction mixture was distilled under reduced pressure to remove acetonitrile. The residue was added to H2O(5 mL) and water layer was extracted with DCM(15 mL*3). The organic phase was combined, washed with saturated salt water(15 mL), dried with anhydrous sodium sulfate, filtered, and distilled under reduced pressure to remove the filtrate. The residue was purified through silica gel column chromatography(DCM/MeOH= 20/1) to give a yellow solid(700 mg, 47.8% yield). MS (ESI) Calcd. for C10H9N4OBr [M+H]+ 282, Found 282.
		To a solution of the 2-amino-triazolopyridine (3) (7.10 g, 33.3 mmol) in dry CH3CN (150 mL) at 5C is added Et3N (11.6 mL, 83.3 mmol) followed by the appropriate acid chloride (83.3 mmol). The reaction mixture is then allowed to warm to ambient temperature and stirred until all starting material (3) is consumed. If required, further Et3N (4.64 mL, 33.3 mmol) and acid chloride (33 3 mmol) may be added to ensure complete reaction. Following solvent evaporation in vacuo the resultant residue is treated with 7 N methanolic ammonia solution (50 mL) and stirred at ambient temp, (for 1-16 h) to hydrolyse any bis-acylated product. Product isolation is made by removal of volatiles in vacuo followed by trituration with Et2O (50 mL). The solids may be collected by filtration, washed with H2O (2x50 mL), acetone (50 mL) and Et2O (50 mL), then dried in vacuo to give the required intermediate (4). In some cases column chromatography (petrol/EtOAc) may be required to obtain pure compounds.

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 9323 - 9342
[2]Patent: EP3290418,2018,A1 .Location in patent: Paragraph 0127; 0128
[3]Patent: WO2010/10186,2010,A1 .Location in patent: Page/Page column 53

4
[ 1124383-00-1 ]
[ 1124382-72-4 ]

Yield	Reaction Conditions	Operation in experiment
96%	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine; In methanol; ethanol; at 20℃; for 6h;	To a sol. of intermediate 50 (55 g, 181 mmol) in EtOH (300 mL) were added MeOH (300 mL), hydroxylamine hydrochloride (62.83 g, 904 mmol) and DIPEA (694 mL, 543 mmol). The r.m. was stirred at r.t. for 6 h. The mixture was concentrated in vacuo and the residue was suspended in DIPE. The precipitate was filtered off. Yield: 37 g of intermediate 51 (96% yield).
82%	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine; In methanol; ethanol; for 4h;Reflux;	Hydroxylamine hydrochloride 180.5 g (2.60 mol) in EtOH / MeOH (1: 1, 1.5 L) was added to the mixed solvent. It was added to N, N-Diisopropylethylamine 271 mL (1.56 mol) the reaction mixture was stirred for 1 hour. 1- (3-Bromo-pyridine-2-yl) -3-carboethoxy-thiourea 158 g was added (0.52 mol) and gradually raise the temperature given by heating under reflux for 3 hours. It cooled to room temperature and the resulting solids were filtered. The filtrate was distilled under reduced pressure and the resulting solids were filtered. Summing the thus obtained solid product washed with purified water, EtOH / MeOH mixture and the solvent n-hexane and dried to give the title compound hunpung 91 g (82% yield).
82%	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine; In methanol; ethanol; for 3h;Reflux;	Hydroxylamine hydrochloride 180.5 g (2.60 mol) in EtOH / MeOH (1:1, 1.5 L) was mixed solvent.It was added to N, N-Diisopropylethylamine 271 mL (1.56 mol) the reaction mixture was stirred for 1 hour.Given the addition of 1- (3-bromo-pyridine-2-yl) -3-carboethoxy-thiourea 158 g (0.52 mol) synthesized in the above and the temperature gradually raised and the mixture was heated under reflux for 3 hours.It cooled to room temperature and the resulting solids were filtered.The filtrate was distilled under reduced pressure and the resulting solids were filtered.Summing the thus obtained solid product washed with purified water, EtOH / MeOH mixture and the solvent n-hexane and dried to give the title compound hunpung 91 g (82% yield).

78%	With hydroxylamine; In methanol; ethanol; at 20 - 60℃; for 4h;	b) 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine; Hydroxyl amine (58.5 g, 842 mmol) and N,N-diisopropylethylamine (65.3 g, 86.3 ml, 505 mmol) were dissolved in methanol (200 ml) and ethanol (200 ml). N-(3-bromo-pyridin-2-yl)-N'-ethoxycarbonyl-thiourea (51.2 g, 168 mmol) was added and the reaction mixture was stirred at rt for 1 hour and then at 60 C. for 3 hours.The white precipitate was filtered off and triturated with water for 25 min, filtered and triturated two times with diethylether. The solid was dried by co-evaporation with toluene and dried in vacuum. The title compound was obtained as a white solid (27.9 g, 78%).MS ISP (m/e): 213.0/215.1 (86/95) [(M+H)+].1H NMR (CDCl3, 300 MHz): delta (ppm)=8.28 (dd, 1H) 7.62 (dd, 1H), 6.73 (t, 1H), 4.66 (bs, 2H).
78%	With hydroxylamine; N-ethyl-N,N-diisopropylamine; In methanol; ethanol; at 20 - 60℃; for 4h;	Hydroxyl amine (58.5 g, 842 mmol) and N,N-diisopropylethylamine (65.3 g, 86.3 ml, 505 mmol) were dissolved in methanol (200 ml) and ethanol (200 ml). N-(3-bromo-pyridin-2-yl)-N'- ethoxycarbonyl-thiourea (51.2 g, 168 mmol) was added and the reaction mixture was stirred at rt for 1 hour and then at 60C for 3 hours. The white precipitate was filtered off and triturated with water for 25 min, filtered and triturated two times with diethylether. The solid was dried by co-evaporation with toluene and dried in vacuum. The title compound was obtained as a white solid (27.9 g, 78%).MS ISP (m/e): 213.0/ 215.1 (86/ 95) [(M+H)+].1H NMR (CDCI3, 300 MHz): delta (ppm) = 8.28 (dd, 1H) 7.62 (dd, 1H), 6.73 (t, 1H), 4.66 (bs, 2H).
78%	With hydroxylamine; N-ethyl-N,N-diisopropylamine; In methanol; ethanol; at 20 - 60℃; for 4h;	b) 8-Bromo-[1,2,4]-triazolo[1,5-a]pyridin-2-amine; Hydroxylamine (58.5 g, 842 mmol) and N,N-diisopropylethylamine (65.3 g, 86.3 mL, 505 mmol) were dissolved in methanol (200 mL) and ethanol (200 mL). N-(3-Bromo-pyridin-2-yl)-N'-ethoxycarbonyl-thiourea (51.2 g, 168 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour and then at 60 C. for 3 hours. The white precipitate was filtered off and triturated with water for 25 minutes, filtered and triturated two times with diethylether. The solid was dried by co-evaporation with toluene and dried in vacuum. The title compound was obtained as a white solid (27.9 g, 78%).MS ISP (m/e): 213.0/215.1 (86/95) [(M+H)+].1H NMR (CDCl3, 300 MHz): delta (ppm)=8.28 (dd, 1H) 7.62 (dd, 1H), 6.73 (t, 1H), 4.66 (bs, 2H).
78%	With hydroxylamine; N-ethyl-N,N-diisopropylamine; In methanol; ethanol; at 20 - 60℃; for 4h;	c) 8-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine Hydroxylamine (58.5 g, 842 mmol) and N,N-diisopropylethylamine (65.3 g, 86.3 mL, 505 mmol) were dissolved in methanol (200 mL) and ethanol (200 mL). N-(3-Bromo-pyridin-2-yl)-N'-ethoxycarbonyl-thiourea (51.2 g, 168 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour and then at 60 C. for 3 hours. The white precipitate was filtered off and triturated with water for 25 minutes, filtered and triturated two times with diethyl ether. The solid was dried by co-evaporation with toluene and dried in vacuum. The title compound was obtained as a white solid (27.9 g, 78%). MS ISP (m/e): 213.0/215.1 (86/95) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): delta (ppm)=8.28 (dd, 1H) 7.62 (dd, 1H), 6.73 (t, 1H), 4.66 (bs, 2H).
75%	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine; In methanol; ethanol; at 20℃; for 20h;Reflux;	To a suspension of DIPEA (128.2?g, 984?mmol) and hydroxylamine hydrochloride (115.1?g, 1.64?mol) in a mixture of ethanol/methanol (400?mL/400?mL) is added 1-(3-bromo-pyridin-2-yl)-3-carboethoxy-thiourea (34a) (105.0?g, 328?mmol). After stirring for 2?h at RT, the reaction mixture is heated under reflux for 18?h. After cooling to RT the precipitate is collected, washed with water and EE and dried to give the product (35a). Yield: 55?g (75%). LCMS (ESI+) calculated for C6H5BrN4 [M+H]+ m/z 212.9776, found 213.1. 1H NMR (400?MHz, (CD3)2SO) delta 8.58 (dd, J?=?6.6, 0.7?Hz, 1H), 7.73 (dd, J?=?7.6, 0.7?Hz, 1H), 6.81 (dd, J?=?7.5, 6.7?Hz, 1H), 6.24 (br s, 2H). TLC (silica gel, DCM/MeOH 10:1): Rf?=?0.5.fx9
75%	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine; In methanol; ethanol; at 20℃; for 20h;Reflux;	8-Bromo-[l,2,4]triazolo[l,5-a]pyridine-2-ylamine (35a). To a suspension of DIPEA (128.2 g, 984 mmol) and hydroxylamine hydrochloride (115.1 g, 1.64 mol) in a mixture of ethanol/methanol (400 mL/400 mL) is added l-(3-bromo-pyridin-2-yl)-3-carboethoxy-thiourea (34a) (105.0 g, 328 mmol). After stirring for 2h at RT, the reaction mixture is heated under reflux for 18h. After cooling to RT the precipitate is collected, washed with water and EE and dried to give the product (35a). Yield: 55 g (75%). LCMS (ESI+) calculated for C6H5BrN4 [M + H]+ m/z 212.9776, found 213.1. XH NMR (400 MHz, (CD3)2SO) <5 8.58 (dd, J = 6.6, 0.7 Hz, 1H), 7.73 (dd, J = 7.6, 0.7 Hz, 1H), 6.81 (dd, J = 7.5, 6.7 Hz, 1H), 6.24 (br s, 2H). TLC (silica gel, DCM/MeOH 10:1): Rf = 0.5.
70%	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine; In methanol; ethanol; at 20 - 60℃; for 20h;	To a stirred suspension of hydroxylamine hydrochloride (17.4 g, 25.0 mmol) and N ,N- diisopropylethylamine (26.0 rnL, 14.9 mmol) in a mixture of methanol (70 mL) and ethanol (70 mL) was added N-(3-bromo-2-pyridinyl)-N'-carboethoxy-thiourea. The mixture was stirred for 2 hours at room temperature then heated to 600C for 18 hours. The suspension was cooled to room temperature, filtered and rinsed with methanol, water then methanol. 8-Bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine was isolated as an off-white solid (8.41 g, 70%). 1H NMR (400 MHz, (D3C)2SO, delta, ppm): 8.58 (d, J=6.4 Hz, IH), 7.73 (d, J=7.6 Hz, IH), 6.80 (t, J=7.0 Hz, IH), 6.25 (s, 2H). MS = 213, 215 (MH)+.
40%	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine; In methanol; ethanol; at 20 - 60℃;	To a solution of hydroxylamine hydrochloride (0.10 kg, 1.4 mol, 5.0 equiv) and JV,./V-diisopropylethylamine (112 g, 0.867 mol, 3.00 eq ) in 1 :1 methanol / ethanol (1.5 L) was added ethyl [(3-bromopyridin-2- yl)carbamothioyl] carbamate (88 g, 0.29 mmol, 1 equiv) in one portion at room temperature. After 2 h, the reaction mixture was warmed to 60 0C for overnight. The reaction mixture was concentrated in vacuo, and water was added to the resulting residue. The solids were filtered and rinsed sequentially with 4:1 methanol / diethyl ether and diethyl ether to provide product as an off-white solid (25 g, 40%). LCMS (ESI) m/z: 212.8; 1U NMR (400 MHz, DMSO-J6) delta: 8.55 (m 1 H), 7.70 (m, 1 H), 6.75 (m, 1 H), 6.20 (br s, 2 H).
	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine; In methanol; ethanol; at 20℃; for 4h;Reflux;	To a suspension of hydroxylamine hydrochloride (101.8 g, 1.465 mol) in EtOH/MeOH (1 :1,900 mL) was added tauV,JV-diisopropylethylamine (145.3 mL, 0.879 mol) and the mixture was stirred at room temp. (200C) for 1 h. l-(3-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2) (89.0 g, 0.293 mol) was then added and the mixture slowly heated to reflux (Note: bleach scrubber is required to quench H2S evolved). After 3 h at reflux, the mixture was allowed to cool and filtered to collect the precipitated solid. Further product was collected by evaporation in vacuo of the filtrate, addition of H2O (250 mL) and filtration. The combined solids were washed successively with H2O (250 mL), EtOH/MeOH (1 :1, 250 mL) and Et2O (250 mL) then dried in vacuo to afford (3) as a solid. No further purification was required. NMR (1H, DMSO) 8.57 (IH, d, ArH); 7.72 (IH, d, ArH), 6.79 (IH, m, ArH), 6.27 (2H, s, NH2).
	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine; In methanol; ethanol; at 20 - 60℃; for 4h;	Hydroxyl amine (58.5 g, 842 mmol) and N,N-diisopropylethylamine (65.3 g, 86.3 mL, 505 mmol) were dissolved in methanol (200 mL) and ethanol (200 mL). N-(3-Bromo-pyridin-2-yl)-N'-ethoxycarbonyl-thiourea (51.2 g, 168 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour and then at 60 C for 3 hours. The white precipitate was filtered off and triturated with water for 25 minutes, filtered and triturated two times with diethylether.The solid was dried by co-evaporation with toluene and dried in vacuum. The title compound was obtained as a white solid (27.9 g, 78%).MS ISP (m/e): 213.0/ 215.1 (86/ 95) [(M+H)+].1H NMR (CDC13, 300 MHz): delta (ppm) = 8.28 (dd, 1H) 7.62 (dd, 1H), 6.73 (t, 1H), 4.66 (bs, 2H).
	With hydroxylamine; N-ethyl-N,N-diisopropylamine; In methanol; ethanol; at 20 - 60℃; for 4h;	c) 8-Bromo-[ 1 ,2,4]triazolo[ 1 , 5-a]pyridin-2-amineHydroxyl amine (58.5 g, 842 mmol) and N,N-diisopropylethylamine (65.3 g, 86.3 mL, 505 mmol) were dissolved in methanol (200 mL) and ethanol (200 mL). N-(3-Bromo-pyridin-2-yl)- N' -ethoxycarbonyl-thiourea (51.2 g, 168 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour and then at 60 C for 3 hours. The white precipitate was filtered off and triturated with water for 25 minutes, filtered and triturated two times with diethyl ether. The solid was dried by co-evaporation with toluene and dried in vacuum. The title compound was obtained as a white solid (27.9 g, 78%).MS ISP (m/e): 213.0/ 215.1 (86/ 95) [(M+H)+].1H MR (CDCI3, 300 MHz): delta (ppm) = 8.28 (dd, 1H) 7.62 (dd, 1H), 6.73 (t, 1H), 4.66 (bs, 2H).
8 g	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine; In methanol; ethanol; at 20 - 60℃; for 20h;	To a stirred suspension of hydroxylamine hydrochloride (about 17 g) and N,N-diisopropylethylamine (about26 mL) in a mixture of methanol (about 70 mL) and ethanol (about 70 mL) is added N-(3-bromo-2-pyridinyl)-N?-carboethoxy-thiourea. The mixture is stirred for about 2 hours at room temperature then heated to about 60C forabout 18 hours. The suspension is cooled to room temperature, filtered and rinsed with methanol, water thenmethanol. 8-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine is isolated as an off-white solid (about 8 g). 1H NMR (400MHz, (D3C)2SO, delta, ppm): 8.58 (d, J=6.4 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 6.80 (t, J=7.0 Hz, 1H), 6.25 (s, 2H). MS =213, 215 (MH)+.

Reference： [1]Patent: WO2013/10904,2013,A1 .Location in patent: Page/Page column 76
[2]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 4794 - 4800
[3]Patent: KR2015/77599,2015,A .Location in patent: Paragraph 0096; 0099-0101
[4]Patent: KR101601354,2016,B1 .Location in patent: Paragraph 0110 - 0112
[5]Patent: US2011/190269,2011,A1 .Location in patent: Page/Page column 66
[6]Patent: WO2011/92272,2011,A1 .Location in patent: Page/Page column 139; 140
[7]Patent: US2011/201605,2011,A1 .Location in patent: Page/Page column 51
[8]Patent: US2012/225884,2012,A1 .Location in patent: Page/Page column 17
[9]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 3227 - 3241
[10]Patent: WO2019/121596,2019,A1 .Location in patent: Page/Page column 29
[11]Patent: WO2010/141796,2010,A2 .Location in patent: Page/Page column 133
[12]Patent: WO2009/155551,2009,A1 .Location in patent: Page/Page column 86
[13]Patent: WO2010/10186,2010,A1 .Location in patent: Page/Page column 52-53
[14]Patent: WO2011/101304,2011,A2 .Location in patent: Page/Page column 105
[15]Patent: WO2012/116965,2012,A1 .Location in patent: Page/Page column 34
[16]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 5014 - 5021
[17]Organic Process Research and Development,2016,vol. 20,p. 2085 - 2091
[18]Patent: EP2648728,2016,B1 .Location in patent: Paragraph 0047

5
[ 1124382-72-4 ]
[ 5720-07-0 ]
[ 1202616-64-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;Product distribution / selectivity;	[00264] An appropriate aryl substituted boronic acid derivative (2eq.) is added to a solution of -8-bromo-triazolopyridine derivative in 1,4-dioxane/water (5:1) (or EtOH). K2CO3 (2 eq.) and PdCl2dppf (5%) (or Pd(Ph3^) are added to the mixture. The resulting mixture is heated in a microwave oven at 110 to 1400C for 10-45 min or heated in an oil bath at 900C for 4 to 16 h until the reaction goes to completion (monitored by LCMS). Water is added and the mixture is extracted with ethyl acetate. The organic layers are combined, dried over anhydrous MgSO4 and evaporated in vacuo to yield the crude product. The crude product is then purified by flash chromatography to give the corresponding 2-amino- 8-Ar-triazolopyridine derivative (2). (The compounds may be purified by preparative HPLC). If the compound is not soluble in EtOAc, after cooling to room temperature, the reaction mixture is diluted with CH2Cl2/MeOH/H2O and the mixture filtered through Celite. The organic layer is separated and concentrated in vacuo. (The compounds may be further purified by preparative HPLC).; This compound was prepared via Method C using 4-methoxyphenyl boronic acid in step a then4-amino-phenyl)-acetamide in step c

Reference： [1]Patent: WO2010/10184,2010,A1 .Location in patent: Page/Page column 51; 52; 64

6
[ 13329-40-3 ]
[ 1124382-72-4 ]
[ 1206641-00-0 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 16h;Inert atmosphere;	To a solution of l-(4-Iodo-phenyl)-ethanone (1.2 eq) and 8-Bromo-[l,2,4]triazolo[l,5- a]pyridin-2-ylamine ( 1 eq) in 1 ,4-dioxane were added Pd2(dba)3 (0.01 eq), Xantphos (0.01 eq) and Cs2CO3 (2 eq). The reaction mixture was degassed by sonication under a stream of N2 for 10 min and then stirred at 90 0C for 16 h. The reaction mixture was diluted with CH2Cl2MeOH (1 :1) filtered through Celite and the filtrate was concentrated in vacuo. Purification by flash column chromatography yielded the target compound.

Reference： [1]Patent: WO2010/10184,2010,A1 .Location in patent: Page/Page column 116

7
[ 1124382-72-4 ]
[ 1206640-83-6 ]

Yield	Reaction Conditions	Operation in experiment
63%	With toluene-4-sulfonic acid; potassium iodide; sodium nitrite; In water; acetonitrile; at 20 - 40℃;	A solution of potassium iodide (90.9 g, 549 mmol) and sodium nitrite (29.2 g, 420 mmol) in water (180 mL) over a period of 60 min was added dropwise to the cooled 13-15 C8-bromo - [1,2,4] triazolo [1,5-a] pyridin-2-yl-amine (30.0g, 141mmol)And p-toluenesulfonic acid monohydrate (123.3 g, 648 mmol) in acetonitrile (900 mL).Upon completion of the addition, the mixture was warmed to ambient temperature and stirred for 30 min. The reaction mixture was heated to 40 C in a water bath and then cooled to ambient temperature.The reaction was quenched by addition of saturated aqueous sodium bicarbonate solution (600 mL) and extracted with EtOAc (2 x 500 mL).The combined organic phases were washed with 10% w / w aqueous sodium metabisulfite (500 mL), water (500 mL) and brine (500 mL), dried over anhydrous sodium sulfate, filtered and evaporated to give a yellow solid.The crude solid was purified by flash chromatography on silica gel, eluting with a gradient of MeOH (0-2%) in DCM.Appropriate fractions were collected and evaporated to give 8-bromo-2-iodo- [1,2,4] triazolo [1,5-a] pyridine as a white solid (28.6 g, 63%).
	With hydrogen iodide; sodium nitrite; In water; dimethyl sulfoxide; at 35℃;	Method C:Step a. Preparation of 8-R-2-iodo-triazolopyridine derivatives[00271] A mixture of the above 2-amino-8-Br-triazolopyridine derivative (1) (1 eq.) and NaNO2 in DMSO (2eq. in DMSO) is treated dropwise with a solution of 57% aqueous HI (5 eq.) in DMSO at 35 CC with agitation. The mixture is stirred at 35 0C for 10 minutes or until the reaction goes to completion (monitored by LCMS), and then it is transferred to a saturated solution of K2Ctheta3. The reaction mixture is extracted with ethyl acetate and the extracts are combined, washed with water and dried over anhydrous magnesium sulfate. The organic solvent is removed under high vacuum to yield the crude product. The crude product is then purified by flash chromatography to give the corresponding8-Br-2-iodo-triazolopyridine derivative (2).

Reference： [1]Patent: CN107428750,2017,A .Location in patent: Paragraph 0548; 0551; 0564; 0565; 0566
[2]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 3227 - 3241
[3]Patent: WO2010/10184,2010,A1 .Location in patent: Page/Page column 53; 54

8
[ 1124382-72-4 ]
[ 5720-06-9 ]
[ 1257704-10-1 ]

Yield	Reaction Conditions	Operation in experiment
89%	With sodium carbonate;palladium diacetate; triphenylphosphine; In 1,4-dioxane; water; N,N-dimethyl-formamide; at 80℃; for 18h;Inert atmosphere; Sealed tube;Product distribution / selectivity;	An oven dried tube was charged with palladium acetate (0.20 g, 0.89 mmol) and triphenylphosphine (0.60 g, 2.3 mmol). The tube was evacuated under high vacuum and backflushed under a stream of nitrogen for 5 minutes. 1,4-Dioxane (10 mL) was added and the mixture was stirred under nitrogen for 10 minutes. 8-Bromo-[l,2,4]triazolo[l,5- a]pyridin-2-ylamine (1.0 g, 4.7 mmol), 2-methoxybenzeneboronic acid (1.1 g, 7.0 mmol), N,N-dimethylformamide (10 mL) and 1.50 M of sodium carbonate in water (10 mL) were added. The mixture was stirred for 2 minutes at room temperature under nitrogen then the tube was sealed and heated at 800C for 18 hours. The mixture was transferred to a round bottom flask and the volatiles were evaporated under reduced pressure. Water (100 mL) was added and the mixture was stirred when a precipitate was formed. The solid was collected by filtration, rinsed with water, air dried, triturated with ether/dichloromethane (4:1; 10 mL), filtered and rinsed with ether. 8-(2-Methoxy-phenyl)-[l,2,4]triazolo[l,5- a]pyridin-2-ylamine was isolated (1.0 g, 89%). 1H NMR (400 MHz, CDCl3, delta, ppm): 8.50 (d, J=6.5 Hz, IH), 7.51 (dd, J=I .6, 1.5 Hz, IH), 7.43-7.36 (m, 2H), 7.13 (d, J=8.1 Hz, IH), 7.02 (t, J=7.3 Hz, IH), 6.91 (t, J=7.0 Hz, IH), 5.96 (br s, 2H), 3.73 (s, 3H). MS = 241 (MH)+.

Reference： [1]Patent: WO2010/141796,2010,A2 .Location in patent: Page/Page column 133
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 5243 - 5254

9
[ 1124382-72-4 ]
[ 1257705-04-6 ]

Yield	Reaction Conditions	Operation in experiment
90%	With hydrogenchloride; copper(II) choride dihydrate; sodium nitrite; In water; at 5 - 20℃; for 18.5h;	To a cooled, stirred suspension of 8-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine (0.961 g, 4.51 mmol) and copper(II)chloride dihydrate (0.20 g, 1.2 mmol) in 12 M of hydrochloric acid (10.0 rnL) at 5C was added dropwise a solution of sodium nitrite (0.37 g, 5.4 mmol) in water (2 mL). Gentle gas evolution was noted. The mixture was stirred for 30 minutes at 5C then at room temperature for 18 hours. The yellow mixture was diluted with water (80 mL) and the resulting precipitate was filtered, rinsed with water and dried in-the-air. 8-Bromo-2-chloro-[l,2,4]triazolo[l,5-a]pyridine was isolated as a pale yellow solid (0.947 g, 90%) and was used without further purification. 1H NMR (400 MHz, (D3C)2SO, delta, ppm): 8.98 (d, J=6.9 Hz, IH), 8.10 (d, J=7.8 Hz, IH), 7.22 (t, J=7.0 Hz, IH). MS = 232, 234, 236 (MH)+.

Reference： [1]Patent: WO2010/141796,2010,A2 .Location in patent: Page/Page column 177; 178

10
[ 1124382-72-4 ]
[ 24424-99-5 ]
[ 1202616-56-5 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; dmap; at 50℃;	A solution of 8-bromo-[l,2,4]triazolo[l,5-alpha]pyridin-2-amine (10.6 g,49.7 mmol, 1 equiv), di-tert-butyl dicarbonate (43.6 g, 0.200 mol, 4.01 equiv), and 4-dimethylaminopyridine (0.61 g, 5.0 mmol, 0.10 equiv) in pyridine (200 mL) was heated at 50 0C overnight. The reaction mixture was concentrated in vacuo. The resulting residue was partitioned between water <n="88"/>and diethyl ether. The organic layer was separated and washed with water (3x). Filtration of the organic through a plug of silica gel (4:1 petroleum ether / ethyl acetate) afforded crude product. (14.8 g, 72%). 1H NMR (400 MHz), DMSO-J6) delta: 9.0 (m, 1 H), 8.1 (m, 1 H), 7.2 (m, 1 H), 1.4 (s, 18 H).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 5014 - 5021
[2]Patent: WO2009/155551,2009,A1 .Location in patent: Page/Page column 86-87

11
[ 1124382-72-4 ]
[ 619-44-3 ]
[ 1202616-61-2 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃; for 1h;	A suspension of 8-bromo-[l,2,4]triazolo[l,5-alpha]pyridin-2-amine (2.8 g,13.2 mmol, 1 equiv), methyl 4-iodobenzoate (3.4 g, 13 mmol, 1.0 equiv), cesium carbonate (8.4 g, 26 mmol, 2.0 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (763 mg, 1.32 mmol, 0.10 equiv), and palladium (II) acetate (300 mg, 1.32 mmol, 0.10 equiv) in dioxane (100 mL) was heated at <n="112"/>80 0C for 1 h. The reaction mixture was cooled to room temperature and diluted with dichloromethane (100 mL). The resulting solids were filtered and sequentially rinsed with water (3 x 50 mL) and methanol (2 X 20 mL). The solids were dried in vacuo to afford methyl 4-(8-bromo-[l,2,4]triazolo[l,5- a]pyridin-2-ylamino)benzoate (3.1 g). 1H NMR (400 MHz, DMSO-J6), delta:10.42 (s, 1 H), 8.87 (m, 1 H), 7.93 (m, 1 H), 7.92 (d, J= 8.8 Hz, 2 H), 7.77 (d, J= 8.8 Hz, 2 H), 7.00 (dd, J= 7.4, 6.9 Hz, 1 H), 3.81 (s, 3 H).

Reference： [1]Patent: WO2009/155551,2009,A1 .Location in patent: Page/Page column 110-111

12
[ 1124382-72-4 ]
[ 1679-18-1 ]
[ 1319068-99-9 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 110℃; for 2h;	c) 8-(4-Chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine; A mixture of <strong>[1124382-72-4]8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine</strong> (500 mg, 2.35 mmol), 4-chlorophenyl boronic acid (757 mg, 4.69 mmol), dichloro[1,1'-bis(diphenylphosphino)-ferrocene]palladium(II) dichloromethane adduct (153 mg, 0.188 mmol) and an aqueous solution of Na2CO3 (2 N, 2.35 mL, 4.69 mmol) in dioxane (10 mL) was stirred at 110 C. for 2 hours. The reaction mixture was diluted with a 2N aqueous solution of sodium carbonate and extracted with diethyl ether, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using pentane/diethyl ether as eluent. The title compound was obtained as a white solid (572 mg, 99%).MS ISP (m/e): 245.3/247.2 (100/38) [(M+H)+].1H NMR (CDCl3, 300 MHz): delta (ppm)=8.30 (dd, 1H) 7.93-7.88 (m, 2H), 7.52-7.45 (m, 3H), 6.92 (t, 1H), 4.51 (bs, 2H).
99%	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 110℃; for 2h;	A mixture of 8-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-amine (500 mg, 2.35 mmol), 4- chlorophenyl boronic acid (757 mg, 4.69 mmol), dichloro[l,l'-bis(diphenylphosphino)- ferrocene]palladium(II) dichloromethane adduct (153 mg, 0.188 mmol) and an aqueous solution of Na2CC"3 (2 N, 2.35 mL, 4.69 mmol) in dioxane (10 mL) was stirred at 110 C for 2 hours. The reaction mixture was diluted with a 2N aqueous solution of sodium carbonate and extracted with diethyl ether, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using pentane/diethyl ether as eluent. The title compound was obtained as a white solid (572 mg, 99%).MS ISP (m/e): 245.3/ 247.2 (100/ 38) [(M+H)+].1H NMR (CDCI3, 300 MHz): delta (ppm) = 8.30 (dd, 1H) 7.93-7.88 (m, 2H), 7.52-7.45 (m, 3H), 6.92 (t, 1H), 4.51 (bs, 2H).
99%	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 110℃; for 2h;	c) 8-(4-Chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine; A mixture of <strong>[1124382-72-4]8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine</strong> (500 mg, 2.35 mmol), 4-chlorophenyl boronic acid (757 mg, 4.69 mmol), dichloro[1,1'-bis(diphenylphosphino)-ferrocene]palladium(II) dichloromethane adduct (153 mg, 0.188 mmol) and an aqueous solution of Na2CO3 (2 N, 2.35 mL, 4.69 mmol) in dioxane (10 mL) was stirred at 110 C. for 2 hours. The reaction mixture was diluted with a 2 N aqueous solution of sodium carbonate and extracted with diethyl ether, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using pentane/diethyl ether as eluent. The title compound was obtained as a white solid (572 mg, 99%).MS ISP (m/e): 245.3/247.2 (100/38) [(M+H)+].1H NMR (CDCl3, 300 MHz): delta (ppm)=8.30 (dd, 1H) 7.93-7.88 (m, 2H), 7.52-7.45 (m, 3H), 6.92 (t, 1H), 4.51 (bs, 2H).

99%

With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 110℃; for 2h;

A mixture of 8-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-amine (500 mg, 2.35 mmol), 4- chlorophenyl boronic acid (757 mg, 4.69 mmol), dichloro[l,l'-bis(diphenylphosphino)- ferrocene]palladium(II) dichloromethane adduct (153 mg, 0.188 mmol) and an aqueous solution of Na2C03 (2 N, 2.35 mL, 4.69 mmol) in dioxane (10 mL) was stirred at 110 C for 2 hours. The reaction mixture was diluted with a 2 N aqueous solution of sodium carbonate and extracted with diethyl ether, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using pentane/diethyl ether as eluent. The title compound was obtained as a white solid (572 mg, 99%).MS ISP (m/e): 245.3/ 247.2 (100/ 38) [(M+H)+].1H NMR (CDC13, 300 MHz): delta (ppm) = 8.30 (dd, 1H) 7.93-7.88 (m, 2H), 7.52-7.45 (m, 3H), 6.92 (t, 1H), 4.51 (bs, 2H).

Reference： [1]Patent: US2011/190269,2011,A1 .Location in patent: Page/Page column 66
[2]Patent: WO2011/92272,2011,A1 .Location in patent: Page/Page column 140
[3]Patent: US2011/201605,2011,A1 .Location in patent: Page/Page column 51
[4]Patent: WO2011/101304,2011,A2 .Location in patent: Page/Page column 105

13
[ 13534-99-1 ]
[ 1124382-72-4 ]

Reference： [1]Patent: US2011/190269,2011,A1
[2]Patent: WO2011/92272,2011,A1
[3]Patent: US2011/201605,2011,A1
[4]Patent: WO2011/101304,2011,A2
[5]Patent: WO2012/116965,2012,A1
[6]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 4794 - 4800
[7]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 5014 - 5021
[8]Patent: KR2015/77599,2015,A
[9]Patent: KR101601354,2016,B1
[10]Organic Process Research and Development,2016,vol. 20,p. 2085 - 2091
[11]Patent: EP2648728,2016,B1
[12]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 3227 - 3241
[13]Patent: WO2013/10904,2013,A1
[14]Patent: WO2009/155551,2009,A1
[15]Patent: WO2019/121596,2019,A1

14
[ 1124382-72-4 ]
[ 108-95-2 ]
[ 1319069-01-6 ]

Yield	Reaction Conditions	Operation in experiment
38%	With potassium phosphate;2-Picolinic acid; copper(l) iodide; In dimethyl sulfoxide; at 120℃; for 30h;	a) 8-phenoxy-[1,2,4]triazolo[1,5-a]pyridin-2-amine; A suspension of <strong>[1124382-72-4]8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine</strong> (500 mg, 2.35 mmol), phenol (442 mg, 4.69 mmol), copper (I) iodide (44.7 mg, 235 mumol), picolinic acid (57.8 mg, 469 mumol) and potassium phosphate tribasic (1.49 g, 7.04 mmol) in DMSO (10 ml) was heated to 120 C. for 12 h. Further phenol (442 mg, 4.69 mmol), copper (I) iodide (44.7 mg, 235 mumol), picolinic acid (57.8 mg, 469 mumol) and potassium phosphate tribasic (1.49 g, 7.04 mmol) were added and heated to 120 C. for 18 h. The reaction mixture was cooled to rt and water was added. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by preparative HPLC (Gemini 5mu, 30×100 mm) using MeOH/H2O (with 0.1% NEt3) as eluent. The title compound was obtained as a off-white solid (200 mg; 38%).MS ISP (m/e): 227.2 (100) [(M+H)+].1H NMR (CDCl3, 300 MHz): delta (ppm)=8.10-8.07 (m, 1H), 7.42-7.37 (m, 2H), 7.22-7.11 (m, 3H), 6.78-6.67 (m, 2H), 4.53 (bs, 2H).
38%	With potassium phosphate;2-Picolinic acid; copper(l) iodide; In dimethyl sulfoxide; at 120℃; for 30h;	A suspension of 8-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-amine (500 mg, 2.35 mmol), phenol (442 mg, 4.69 mmol), copper (I) iodide (44.7 mg, 235 muiotaetaomicron), picolinic acid (57.8 mg, 469 muiotaetaomicron) and potassium phosphate tribasic (1.49 g, 7.04 mmol) in DMSO (10 ml) was heated to 120 C for 12 h. Further phenol (442 mg, 4.69 mmol), copper (I) iodide (44.7 mg, 235 muiotaetaomicron), picolinic acid (57.8 mg, 469 muiotaetaomicron) and potassium phosphate tribasic (1.49 g, 7.04 mmol) were added and heated to 120 C for 18 h. The reaction mixture was cooled to rt and water was added. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by preparative HPLC (Gemini 5mu, 30x100mm) using MeOH/ H20 (with 0.1% NEt3) as eluent. The title compound was obtained as a off-white solid (200 mg; 38%).MS ISP (m/e): 227.2 (100) [(M+H)+].1H NMR (CDC13, 300 MHz): delta (ppm) = 8.10-8.07 (m, 1H), 7.42-7.37 (m, 2H), 7.22-7.11 (m, 3H), 6.78-6.67 (m, 2H), 4.53 (bs, 2H).
38%	With potassium phosphate;2-Picolinic acid; copper(l) iodide; In dimethyl sulfoxide; at 120℃; for 30h;	a) 8-Phenoxy-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine; A mixture of <strong>[1124382-72-4]8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine</strong> (see example 66b, 500 mg, 2.35 mmol), phenol (442 mg, 4.69 mmol), copper(I) iodide (44.7 mg, 235 mumol), picolinic acid (57.8 mg, 469 mumol) and potassium phosphate tribasic (1.49 g, 7.04 mmol) in DMSO (10 mL) was heated to 120 C. After 12 hours further phenol (442 mg, 4.69 mmol), copper(I) iodide (44.7 mg, 235 mumol), picolinic acid (57.8 mg, 469 mumol) and potassium phosphate tribasic (1.49 g, 7.04 mmol) were added and stirred at 120 C. for another 18 hours. Water was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was evaporated. The crude material was purified by prep. HPLC. The title compound was obtained as off-white solid (200 mg, 38%).MS ISP (m/e): 227.2 (100) [(M+H)+].1H NMR (CDCl3, 300 MHz): delta (ppm)=8.10-8.07 (m, 1H), 7.42-7.37 (m, 2H), 7.22-7.17 (m, 1H), 7.14-7.11 (2H), 6.78-6.67 (m, 2H), 4.53 (bs, 2H).

38%

With 2-Picolinic acid; potassium phosphate; copper(l) iodide; In dimethyl sulfoxide; at 120℃; for 30h;

A mixture of 8-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-amine (see example 66b, 500 mg, 2.35 mmol), phenol (442 mg, 4.69 mmol), copper(I) iodide (44.7 mg, 235 muiotaetaomicron), picolinic acid (57.8 mg, 469 muiotaetaomicron) and potassium phosphate tribasic (1.49 g, 7.04 mmol) in DMSO (10 mL) was heated to 120 C. After 12 hours further phenol (442 mg, 4.69 mmol), copper(I) iodide (44.7 mg, 235 muiotaetaomicron), picolinic acid (57.8 mg, 469 muiotaetaomicron) and potassium phosphate tribasic (1.49 g, 7.04 mmol) were added and stirred at 120 C for another 18 hours. Water was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was evaporated. The crude material was purified by prep. HPLC. The title compound was obtained as off-white solid (200 mg, 38%).MS ISP (m/e): 227.2 (100) [(M+H)+].1H NMR (CDCls, 300 MHz): delta (ppm) = 8.10-8.07 (m, 1H), 7.42-7.37 (m, 2H), 7.22-7.17 (m, 1H), 7.14-7.11 (2H), 6.78-6.67 (m, 2H), 4.53 (bs, 2H).

Reference： [1]Patent: US2011/190269,2011,A1 .Location in patent: Page/Page column 69
[2]Patent: WO2011/92272,2011,A1 .Location in patent: Page/Page column 146
[3]Patent: US2011/201605,2011,A1 .Location in patent: Page/Page column 66-67
[4]Patent: WO2011/101304,2011,A2 .Location in patent: Page/Page column 137-138

15
[ 1124382-72-4 ]
[ 1329670-05-4 ]

Reference： [1]Patent: US2011/201605,2011,A1
[2]Patent: WO2011/101304,2011,A2

16
[ 1124382-72-4 ]
[ 1329672-70-9 ]

Reference： [1]Patent: US2011/201605,2011,A1
[2]Patent: WO2011/101304,2011,A2

17
[ 1124382-72-4 ]
[ 1329670-64-5 ]

Reference： [1]Patent: US2011/201605,2011,A1
[2]Patent: WO2011/101304,2011,A2

18
[ 13534-99-1 ]
[ 16182-04-0 ]
[ 1124382-72-4 ]