[ CAS No. 947248-68-2 ]

Name: 947248-68-2|6-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine|97%
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SKU: A209273
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Quality Control of [ 947248-68-2 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 947248-68-2 ]

SDS Specification

Alternatived Products of [ 947248-68-2 ]

Product Details of [ 947248-68-2 ]

CAS No. :	947248-68-2	MDL No. :	MFCD11656619
Formula :	C₆H₅BrN₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XHBQNLHFUPSZNL-UHFFFAOYSA-N
M.W :	213.04	Pubchem ID :	25215940
Synonyms :

Calculated chemistry of [ 947248-68-2 ]

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) :	1.75
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 :	1.19

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 :	1.87

Safety of [ 947248-68-2 ]

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

Application In Synthesis of [ 947248-68-2 ]

* 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 [ 947248-68-2 ]
Downstream synthetic route of [ 947248-68-2 ]

[ 947248-68-2 ] Synthesis Path-Upstream 1~3

1
[ 1010120-60-1 ]
[ 947248-68-2 ]

Yield	Reaction Conditions	Operation in experiment
99%	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine In methanol; ethanol at 20 - 70℃; for 5 h;	Step b) Formation of 6-bromo[1 ,2,4]triazolo[1 ,5-a]pyridin-2-amine A suspension of ethyl [(5-bromopyridin-2-yl)amino]carbonothioyl}carbamate (12.3 g,40.4 mmol), hydroxylamine hydrochloride (14.1 g, 202 mmol) and DIEA (15.7 g, 122 mmol) in a mixture of MeOH and EtOH (ratio 1 :1 , 200 ml.) was stirred at RT for 2 hours and then at 70⁰C for 3 hours. The solvents were removed under reduced pressure. The residue was taken up in dioxane/water (1 :1 ) and filtered to give the title compound as an off-white powder (42.6 g, 99percent). HPLC, Rt: 1.1 min (purity 99.8percent). LC/MS, M⁺(ESI): 215.3.
99%	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine In methanol; ethanol at 20 - 70℃;	A suspension of ethyl [(5-bromopyridin-2-yl)amino]carbonothioyl}carbamate (12.3 g, 40.4 mmol), hydroxylamine hydrochloride (14.1 g, 202 mmol) and DIEA (15.7 g, 122 mmol) in a mixture of MeOH and EtOH (ratio 1 :1 , 200 ml_) was stirred at RT for 2 hours and then at 70⁰C for 3 hours. The solvents were removed under reduced pressure. The residue was taken up in dioxane/water (1 :1 ) and filtered to give the title compound as an off-white powder (42.6 g, 99percent). HPLC, Rt: 1.1 min (purity 99.8percent). LC/MS, M⁺(ESI): 215.3.
96%	With hydroxylamine hydrochloride; diisopropylamine In methanol; ethanol at 20 - 60℃; for 5 h;	12.83 g (184.632 mmol) of hydroxylamine hydrochloride and 14.32 g (110.779 mmol) N,N- diisopropylamine were dissolved in 70 ml methanol/ethanol (v/v = 1:1). .sect.0.4 g of the compound from example 105 A was added and the mixture was stirred at room temperature for 2 h and at 60°C for 3 h. After cooling, water and ethyl acetate were added, the organic phase was removed and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated in a rotary evaporator and the residue was dried under high vacuum. We obtained 7.02 g (96percent of theor.) of the target compound.GC-MS (method 6): R, = 6.11 min; MS (EIpos): m/z = 212 [M]⁺. 1H-NMR (400 MHz, DMSO-D₆): δ [ppm] = 6.13 (s, 2H), 7.33 (d, IH), 7.55 (dd, IH), 8.92 (d, IH).

85%	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine In ethanol at 25℃; Reflux	b) 6-Bromo-[ 1 ,2,4] triazolo[ 1 ,5-a]pyridin-2-ylamineA mixture of hydroxylamine hydrochloride (40.0 g, 575 mmol) and N- ethyldiisopropylamine (44.6 g, 60.3 ml, 345 mmol) in ethanol (734 ml) was stirred for a few minutes at 25 °C, then the mixture was added to l-ethoxycarbonyl-3-(5-bromo-pyridin-2-yl)- thiourea (35 g, 115 mmol) and the resulting mixture was refluxed for 1 day. The solvent was evaporated under reduced pressure and the white solid was treated with 400 ml water. The suspension was stirred for 1 hour, the solid was filtered off, washed with water 3 times and dried under reduced pressure, affording 6-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine (21 g, 85percent) as white solid. Mp.: 185°C. MS: m/z=213.0/215.1 (M+H+).
69%	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine In methanol; ethanol for 2 h; Heating / reflux	2.2 6-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (3) To a suspension of hydroxylamine hydrochloride (409.2 g, 5.888 mol) in EtOH/MeOH (1 :1, 2.5 L) was added JV,jV-diisopropylethylamine (606.1 mL, 3.480 mol), the mixture was stirred at room temperature (20 ⁰C) for 1 h. l-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2) (352.8 g, 1.160 mol) was then added and the mixture slowly heated to reflux (Note: bleach scrubber required to quench H₂S evolved). After 2 h at reflux the mixture was allowed to cool and filtered to collect the precipitated solid. The collected solid was washed successively with <n="45"/>water (1.0 L), EtOH/MeOH (1 :1, 1.0 L) and diethyl ether (500 niL) then air-dried to afford the title compound as a white solid (169.2 g, 69 percent). No further purification was required.¹H NMR (de-DMSO) δ 8.94 (d, IH), 7.58 (dd, IH), 7.36 (d, IH), 6.16 (br s, 2H). m/z 213/215 (1 :1, M+H⁺, 100percent).
60.9%	at 20 - 60℃; for 4.5 h;	6-Bromo-[1 ,2,4]triazolo[1 ,5-a]pyridln-2-amine (PZ972-2): DMAP (2.82 g, 23.1 mmol) was added to a mixture of PZ972-1 (2.34 g, 7.7 mmol), hydroxylamine HCl salt (2.67 g, 38.5 mmol) in methanol/ethanol (20 mL 20 mL). The reaction was stirred at rt for 1.5 h, then at 60 °C for 3 h. The solvent was removed under vacuum, and the resulting residue was partitioned between dichloromethane (30 mL) and water (30 mL). The water phase was extracted with dichloromthane (30 mLx2). The organic phases were collected, dried over anhydrous sodium sulfate, and concentrated. The crude product was washed with petroleum ether to get PZ972-2 (1 g, 60.9percent). LC-MS: 213.2, 215.2 (M+l).
19.3 g	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine In methanol; ethanol at 60℃; for 2 h;	Hydroxylammoniumchlorid (39.8 g) was suspended in methanol (200 mL) and ethanol (190 mL) and Hiinig Base (59 mL) was added at r.t. The mixture was heated to 60°C, Int01.01 (30 g) was added portionwise, and the mixture was stirred at 60 °C for 2h. The solvent was removed in vacuum and water (150 mL) was added. A solid was collected by filtration and was washed with water and dried in vacuum. Yield: 19.3 g of the title compound. ¹H-NMR (300MHz, DMSO-d₆): δ [ppm]= 6.10 (s, 2H), 7.28 (dd, 1H), 7.51 (dd, 1H), 8.88 (dd, 1H).
19.3 g	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine In methanol; ethanol at 60℃; for 2 h;	Hydroxylammonium chloride (39.8 g) was suspended in methanol (200 mL) and ethanol (190 mL) and Hiinig Base (59 mL) was added at r.t. The mixture was heated to 60°C, Int01.01 (30 g) was added portionwise, and the mixture was stirred at 60° C for 2h. The solvent was removed in vacuum and water (150 mL) was added. A solid was collected by filtration and was washed with water and dried in vacuum. Yield: 19.3 g of the title compound. ¹H-NMR (300MHz, DMSO-d₆): δ [ppm] = 6.10 (s, 2H), 7.28 (dd, 1 H), 7.51 (dd, 1 H), 8.88 (dd, 1 H).
19.3 g	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine In methanol; ethanol at 60℃; for 2 h; Inert atmosphere	Hydroxylammoniumchlorid (39.8 g) was suspended in methanol (200 mL) and ethanol (190 mL) and Hunig Base (59 mL) was added at r.t. The mixture was heated to 60°C, Int01 .01 (30 g) was added portionwise, and the mixture was stirred at 60 °C for 2h. The solvent was removed in vacuum and water (150 mL) was added. A solid was collected by filtration and was washed with water and dried in vacuum. Yield: 19.3 g of the title compound. ¹H-NMR (300MHz, DMSO-d₆): δ [ppm]= 6.10 (s, 2H), 7.28 (dd, 1 H), 7.51 (dd, 1 H), 8.88 (dd, 1 H).
19.3 g	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine In methanol at 60℃; for 2 h;	Hydroxylammonium chloride (39.8 g) was suspended in methanol (200 mL), and ethanol (190 mL) and Hiinig Base (59 mL) were added at r.t. The mixture was heated to 60°C, Int01.01 (30 g) was added portionwise, and the mixture was stirred at 60 °C for 2h. The solvent was removed in vacuum, and water (150 mL) was added. A solid was collected by filtration and was washed with water and dried in vacuum. Yield: 19.3 g of the title compound.1H-NMR (300MHz, DMSO-d6): δ [ppm] = 6.10 (s, 2H), 7.28 (dd, 1 H), 7.51 (dd,1 H), 8.88 (dd, 1 H).
19.3 g	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine In methanol; ethanol at 60℃; for 2 h;	Hydroxylammonium chloride (39.8 g) was suspended in methanol (200 mL) and ethanol (190 mL) and Hünig Base (59 mL) was added at r.t. The mixture was heated to 60°C, IntOl.01 (30 g) was added portionwise, and the mixture was stirred at 60°C for 2h. The solvent was removed in vacuum and water (150 mL)was added. A solid was collected by filtration and was washed with water and dried in vacuum.Yield: 19.3 g of the title compound.1H-NMR (300MHz, DMSO-d6): 6 [ppm] = 6.10 (5, 2H), 7.28 (dd, 1H), 7.51 (dd, 1H), 8.88 (dd, 1H).
19.3 g	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine In methanol; ethanol at 60℃; for 2 h;	Hydroxylammonium chloride (39.8 g) was suspended in methanol (200 mL) and ethanol (190 mL) and Hünig Base (59 mL) was added at r.t. The mixture was heated to 60° C., Int01.01 (30 g) was added portionwise, and the mixture was stirred at 60° C. for 2 h. The solvent was removed in vacuum and water (150 mL) was added. A solid was collected by filtration and was washed with water and dried in vacuum. Yield: 19.3 g of the title compound. ¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=6.10 (s, 2H), 7.28 (dd, 1H), 7.51 (dd, 1H), 8.88 (dd, 1H).

Reference： [1] Patent: WO2010/100144, 2010, A1, . Location in patent: Page/Page column 102-103
[2] Patent: WO2009/133127, 2009, A1, . Location in patent: Page/Page column 85
[3] Patent: WO2010/20363, 2010, A1, . Location in patent: Page/Page column 126-127
[4] Patent: WO2013/41472, 2013, A1, . Location in patent: Page/Page column 36
[5] Patent: WO2009/68482, 2009, A1, . Location in patent: Page/Page column 43-44
[6] Patent: WO2012/130299, 2012, A1, . Location in patent: Page/Page column 130
[7] Patent: WO2011/64328, 2011, A1, . Location in patent: Page/Page column 63-64
[8] Patent: WO2011/63908, 2011, A1, . Location in patent: Page/Page column 53-54
[9] Patent: EP2343295, 2011, A1, . Location in patent: Page/Page column 23
[10] Patent: EP2343297, 2011, A1, . Location in patent: Page/Page column 25
[11] Patent: WO2011/157688, 2011, A1, . Location in patent: Page/Page column 92
[12] ChemMedChem, 2011, vol. 6, # 12, p. 2214 - 2224
[13] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 16, p. 5257 - 5263
[14] Patent: WO2012/143329, 2012, A1, . Location in patent: Page/Page column 73
[15] Patent: WO2012/160029, 2012, A1, . Location in patent: Page/Page column 69-70
[16] Patent: WO2013/87579, 2013, A1, . Location in patent: Page/Page column 93; 94
[17] Patent: WO2014/9219, 2014, A1, . Location in patent: Page/Page column 68
[18] Patent: WO2014/20041, 2014, A1, . Location in patent: Page/Page column 125
[19] Patent: WO2014/195276, 2014, A1, . Location in patent: Page/Page column 96
[20] Patent: WO2014/198647, 2014, A2, . Location in patent: Page/Page column 71
[21] Patent: US2015/148542, 2015, A1, . Location in patent: Paragraph 0325-0328
[22] Bioorganic and Medicinal Chemistry Letters, 2019, vol. 29, # 2, p. 257 - 261

2
[ 1010120-60-1 ]
[ 5470-11-1 ]
[ 947248-68-2 ]

Yield	Reaction Conditions	Operation in experiment
51%	Stage #1: With N-ethyl-N,N-diisopropylamine In methanol; ethanol at 20℃; for 1 h; Stage #2: Reflux	Step 2; To a solution of hydroxylamine hydrochloride (345 mg) in ethanol-methanol (1:1) (10 mL), diisopropylethylamine (0.5 mL) was added. The solution was then stirred at room temperature for 1 hour. To the solution, 55 (303 mg, 1 mmol) was added, followed by reflux. After the starting material was consumed, the reaction mixture was cooled. The precipitate was collected by filtration, and then washed sequentially with water, ethanol-methanol (1:1), and diethyl ether to yield target compound 56 (100 mg, y. 51percent). ¹H-NMR (300 Mz) (DMSO): 6.13 (s, 2H), 7.02 (d, J = 9 Hz, 1H), 7.54 (d, J = 9 Hz, 1H), 8.92 (s, 1H).

Reference： [1] Patent: EP2426135, 2012, A1, . Location in patent: Page/Page column 113

3
[ 1072-97-5 ]
[ 947248-68-2 ]

Reference： [1] Patent: WO2011/63908, 2011, A1,
[2] Patent: WO2012/143329, 2012, A1,
[3] Patent: EP2343295, 2011, A1,
[4] Patent: WO2011/64328, 2011, A1,
[5] Patent: EP2343297, 2011, A1,
[6] Patent: WO2012/160029, 2012, A1,
[7] Patent: WO2011/157688, 2011, A1,
[8] Patent: EP2426135, 2012, A1,
[9] ChemMedChem, 2011, vol. 6, # 12, p. 2214 - 2224
[10] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 16, p. 5257 - 5263
[11] Patent: WO2012/130299, 2012, A1,
[12] Patent: WO2013/87579, 2013, A1,
[13] Patent: WO2014/9219, 2014, A1,
[14] Patent: WO2014/20041, 2014, A1,
[15] Patent: WO2014/195276, 2014, A1,
[16] Patent: WO2014/198647, 2014, A2,
[17] Patent: US2015/148542, 2015, A1,
[18] Patent: WO2013/41472, 2013, A1,
[19] Patent: WO2009/133127, 2009, A1,
[20] Bioorganic and Medicinal Chemistry Letters, 2019, vol. 29, # 2, p. 257 - 261

[ 947248-68-2 ] Synthesis Path-Downstream 1~16

1
[ 947248-68-2 ]
[ 243990-53-6 ]
[ 1124383-09-0 ]

Yield	Reaction Conditions	Operation in experiment
86%	With cesium fluoride In water; N,N-dimethyl-formamide at 80℃; for 18h;	144.a Step a) Formation of 6-{3-(methyloxy)-4-[(phenylmethyl)oxy] phenyl} [1,2, 4] triazolo [1,5- aJpyridin-2-amine; To a reaction vessel containing 6-bromo[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A5), 3.44 g, 16.1 mmol, 1 eq.), 4-benzyloxy-3-methoxy boronic acid (5.0 g, 19.3 mmol, 1.2 eq., Synthonix) and cesium fluoride (7.34 g, 48.3 mmol, 3 eq.) in dimethylformamide (60 mL) and water (24 mL) was added δ-triphenylphosphine palladium dichloride (0.3 g, 0.4 mmol, 3%). The vessel was purged with nitrogen, capped and heated at 80 0C for approximately 18 hours. After this time, the crude mixture was filtered through celite washing the celite with ethyl acetate and water. The resulting filtrate was extracted with ethyl acetate (3 x 150 mL) and the combined organic layers dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by flash column chromatography (ethyl acetate: petroleum ether; 1 :1) to give the title compound as a brown solid (4.82 g, 86%). HPLC, Rt: 2.55 min (purity 96%). LC/MS M+(ESI): 347, M (ESI) 345.

Reference： [1]Current Patent Assignee: MERCK KGAA - WO2009/27283, 2009, A1 Location in patent: Page/Page column 134-135

2
[ 947248-68-2 ]
[ 89694-46-2 ]
[ 1239954-94-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; N,N-dimethyl-formamide; for 2h;Reflux; Inert atmosphere;	To a solution of 2-Ch.oro-5-methoxy-phenylboronic acid (3.38g, 22.5 mmol, 1.5eq), 6- Bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine (3.2g, 15 mmol, leq) and Na2CO3 (6.36g, 60 mmol, 4eq) in a mixture of 40ml DMF/10ml EtOH/lOml H2O, was added 1.733g (1.5 mmol, 0.1 eq) of tetrakis(triphenylphospine) palladium. The reaction was refluxed for 2 hours under argon. It was then cooled off to room temperature and the product was precipitated by water, filtered, rinsed with water, ether and pentane to give a pale yellow powder (3.21 g, 13 mmol, 90percent yield).
90%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; N,N-dimethyl-formamide; for 2h;Reflux; Inert atmosphere;	Method 1 :Synthesis of intermediate 1 : 6-(2-Chloro-5-methoxy-phenyl)-[1 ,2,4]triazolo[1 ,5- a]pyridin-2-ylamineTo a solution of 2-Chloro-5-methoxy-phenylboronic acid (3.38g, 22.5 mmol, 1 .5eq), 6- Bromo-[1 ,2,4]triazolo[1 ,5-a]pyridin-2-ylamine (3.2g, 15 mmol, 1 eq) and Na2C03 (6.36g, 60 mmol, 4eq) in a mixture of 40ml DMF/10ml EtOH/10ml H20, was added 1 .733g (1 .5 mmol, 0.1 eq) of tetrakis(triphenylphospine) palladium. The reaction was refluxed for 2 hours under argon. It was then cooled off to room temperature and the product was precipitated by water, filtered, rinsed with water, ether and pentane to give a pale yellow powder (3.21 g, 13 mmol, 90percent yield).

Reference： [1]Patent: WO2010/92041,2010,A1 .Location in patent: Page/Page column 20
[2]Patent: WO2011/161159,2011,A1 .Location in patent: Page/Page column 26

3
[ 445264-61-9 ]
[ 947248-68-2 ]
[ 1244059-54-8 ]

Yield	Reaction Conditions	Operation in experiment
48%	With cesium fluoride;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 85℃; for 48h;	Step 3) Formation of6-(5-methoxypyridin-3-yl)[1,2,4]triazolo[1,5-a]pyridin-2-amine A mixture of 6-bromo[1 ,2,4]triazolo[1 ,5-a]pyridin-2-amine (200 mg; 0.94 mmol), 3- methoxypyridine-5-boronic acid pinacol ester (287 mg; 1.22 mmol), PdCI2(PPh3J2 (66 mg; 0.09 mmol), cesium fluoride (357 mg; 2.35 mmol) in dioxane (4 ml_) and water (2 mL) was stirred at 85C for 2 days. After concentration in vacuo, the residue was triturated in water, filtered and dried to afford the title compound (235 mg, quantitative yield) as a brown solid. LC/MS, M+(ESI): 242.1.

Reference： [1]Patent: WO2010/100144,2010,A1 .Location in patent: Page/Page column 165

4
[ 269410-25-5 ]
[ 947248-68-2 ]
[ 1309682-18-5 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenol With hydrogenchloride In dichloromethane; water for 1.5h; Stage #2: 6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine With potassium carbonate In propan-1-ol for 2h; Reflux;	Int2.1 Intermediate [Example Int2.14-(2-amino[1 , 2, 4]triazolo[1 ,5-a] pyridin-6-yl)-2,6-dimethyl phenol4-Hydroxy-3,5-dimethylphenylboronic acid pinacol ester (700 mg) was dissolved in dichloromethane (2.5 ml) and 2N hydrochloric acid (2.5 ml) was added. It was stirred vigorously for 1 ,5 h and the mixture was extracted with a mixture of dichloromethane an methanol (100: 1 ; 50 ml). The solution was dried (sodium sulfate) and the solvent was removed in vacuum. The residue was dissolved in 1 -propanol (35 ml) and Int1.2 (500 mg), 2M potassium carbonate-solution (3,5 ml), triphenylphosphine (12.6 mg) and PdCl2(PPh3)2 (161 mg) were added. The mixture was heated to reflux for 2h, water (50 ml) was added and the mixture was extracted with ethyl acetate. The solution was dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 266 mg of the title compound.1 H-NMR (300MHz, DMSO-d6): δ [ppm]= 2.18 (s, 6H), 5.94 (s, 2H), 7.24 (s, 2H), 7.32 (dd, 1 H), 7.64 (dd, 1 H), 8.56 - 8.78 (m, 1 H).

Reference： [1]Current Patent Assignee: BAYER AG - WO2011/64328, 2011, A1 Location in patent: Page/Page column 64

5
[ 947248-68-2 ]
[ 380430-49-9 ]
[ 1309593-62-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; triphenylphosphine; In propan-1-ol; for 4h;Reflux;	Intermediate [Example Int4.1 tert-butyl [4-(2-amino[1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl)phenyl]carbamateTo a stirred solution of Int1.2 (5.82 g) in 1 -propanol (400 ml) was added 2M potassium carbonate solution (41 ml), {4-[(tert-butoxycarbonyl) amino] phenyl} boronic acid (8.6 g), triphenylphosphine (150 mg) and PdCl2(PPh3)2 (1 .9 g). The mixture was heated to reflux for 4h, the solvent was removed in vacuum, water (150 mL) was added and the mixture was extracted with ethyl acetate (500 mL). The organic phase was dried (sodium sulfate), filtered through Celite and the solvent was removed in vacuum. The residue was triturated with DCM to give the title compound as a white solid. Yield: 7.2 g.1 H-NMR (400MHz, DMSO-d6): delta [ppm]= 1 .37 - 1 .55 (m, 9H), 5.99 (s, 2H), 7.36 (dd, 1 H), 7.48 - 7.55 (m, 2H), 7.55 - 7.62 (m, 2H), 7.69 (dd, 1 H), 8.78 (dd, 1 H), 9.44 (s, 1 H).
	With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; triphenylphosphine; In propan-1-ol; for 4h;Reflux;	Intermediate Example Int4.1tert-butyl [4-(2-amino[1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl)phenyl]carbamateTo a stirred solution of Int1.2 (5.82 g) in 1 -propanol (400 ml) was added 2M potassium carbonate solution (41 ml), (4-[(tert-butoxycarbonyl) amino] phenyl} boronic acid (8.6 g), triphenylphosphine (150 mg) and PdCl2(PPh3)2 (1.9 g). The mixture was heated to reflux for 4h, the solvent was removed in vacuum, water (150 mL) was added and the mixture was extracted with ethyl acetate (500 mL). The organic phase was dried (sodium sulfate), filtered through Celite and the solvent was removed in vacuum. The residue was titurated with DCM to give the title compound as a white solid. Yield: 7.2 g. 1H-NMR (400MHz, DMSO-d6): delta [ppm]= 1.37 - 1.55 (m, 9H), 5.99 (s, 2H), 7.36 (dd, 1H), 7.48 - 7.55 (m, 2H), 7.55 - 7.62 (m, 2H), 7.69 (dd, 1H), 8.78 (dd, 1H), 9.44 (s, 1H).
	With potassium carbonate; triphenylphosphine;bis-triphenylphosphine-palladium(II) chloride; In propan-1-ol; for 4h;Reflux;	To a stirred solution of Int1.2 (5.82 g) in 1-propanol (400 ml) was added 2M potassium carbonate solution (41 ml), {4-[(tert-butoxycarbonyl) amino] phenyl} boronic acid (8.6 g), triphenylphosphine (150 mg) and PdCl2(PPh3)2 (1.9 g). The mixture was heated to reflux for 4h, the solvent was removed in vacuum, water (150 mL) was added and the mixture was extracted with ethyl acetate (500 mL). The organic phase was dried (sodium sulfate), filtered through Celite and the solvent was removed in vacuum. The residue was triturated with DCM to give the title compound as a white solid. Yield: 7.2 g. 1H-NMR (400MHz, DMSO-d6): delta [ppm]= 1.37 - 1.55 (m, 9H), 5.99 (s, 2H), 7.36 (dd, 1 H), 7.48 - 7.55 (m, 2H), 7.55 - 7.62 (m, 2H), 7.69 (dd, 1 H), 8.78 (dd, 1 H), 9.44 (s, 1 H).

	With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; triphenylphosphine; In propan-1-ol; water; for 4h;Reflux;	To a stirred solution of Int1.2 (5.82 g) in 1-propanol (400 ml) was added 2M potassium carbonate solution (41 ml), {4-[(tert-butoxycarbonyl) amino] phenyl} boronic acid (8.6 g), triphenylphosphine (150 mg) and PdCl2(PPh3)2 (1.9 g). The mixture was heated to reflux for 4h, the solvent was removed in vacuum, water (150 mL) was added and the mixture was extracted with ethyl acetate (500 mL). The organic phase was dried (sodium sulfate), filtered through Celite and the solvent was removed in vacuum. The residue was titurated with DCM to give the title compound as a white solid. Yield: 7.2 g. 1H-NMR (400MHz, DMSO-d6): delta [ppm]= 1.37 - 1.55 (m, 9H), 5.99 (s, 2H), 7.36 (dd, 1 H), 7.48 - 7.55 (m, 2H), 7.55 - 7.62 (m, 2H), 7.69 (dd, 1 H), 8.78 (dd, 1H), 9.44 (s, 1 H).
	With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; triphenylphosphine; In propan-1-ol; for 1h;Reflux;	Intermediate Example Int02.01tert-butyl [4-(2-amino[1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl)phenyl]carbamateTo a stirred solution of Int01.02 (12.0 g) in 1 -propanol (350 ml) was added 2M potassium carbonate solution (85 ml), {4-[(tert-butoxycarbonyl) amino] phenyl} boronic acid (14.7 g), triphenylphosphine (739 mg) and PdCl2(PPh3)2 (1.98 g). The mixture was heated to reflux for 1 h, the solvent was removed in vacuum, water (250 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate), filtered through Celite and the solvent was removed in vacuum. The residue was titurated with DCM to give the title compound as a white solid. Yield: 15.7 g.1H-NMR (400MHz, DMSO-d6): delta [ppm]= 1.37 - 1.55 (m, 9H), 5.99 (s, 2H), 7.36 (dd, 1 H), 7.48 - 7.55 (m, 2H), 7.55 - 7.62 (m, 2H), 7.69 (dd, 1 H), 8.78 (dd, 1 H), 9.44 (s, 1 H).
	With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; triphenylphosphine; In propan-1-ol; for 4h;Reflux;	Intermediate Example Int3.1tert-butyl [4-(2-amino[1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl)phenyl]carbamateTo a stirred solution of Int 1.2 (5.82 g) in 1 -propanol (400 mL) was added 2M potassium carbonate solution (41 mL), {4-[(£ert-butoxycarbonyl) amino] phenyl} boronic acid (8.6 g), triphenylphosphine (150 mg) and PdCl2(PPh3)2 (1.9 g). The mixture was heated to reflux for 4h, the solvent was removed in vacuum, water (150 mL) was added and the mixture was extracted with ethyl acetate (500 mL). The organic phase was dried (sodium sulfate), filtered through Celite and the solvent was removed in vacuum. The residue was titurated with DCM to give the title compound as a white solid. Yield: 7.2 g. 1H-NMR (400MHz, DMSO-d6): delta [ppm]= 1.37 - 1.55 (m, 9H), 5.99 (s, 2H), 7.36 (dd, 1 H), 7.48 - 7.55 (m, 2H), 7.55 - 7.62 (m, 2H), 7.69 (dd, 1 H), 8.78 (dd, 1 H), 9.44 (s, 1 H).
	With potassium carbonate;[1,4-bis(diphenylphosphino)butane] palladium(ll) dichloride; triphenylphosphine; In propan-1-ol; for 1h;Reflux;	Intermediate Example Int02.01ieri-butyl [4-(2-amino[1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl)phenyl]carbamateTo a stirred solution of Int01.02 (12.0 g) in 1 -propanol (350 mL) was added 2M potassium carbonate solution (85 mL), {4-[(tert-butoxycarbonyl) amino] phenyl} boronic acid (14.7 g), triphenylphosphine (739 mg) and PdCl2(PPh3)2 (1.98 g). The mixture was heated to reflux for 1 h, the solvent was removed in vacuum, water (250 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate), filtered through Celite and the solvent was removed in vacuum. The residue was titurated with DCM to give the title compound as a white solid. Yield: 15.7 g.1H-NMR (400MHz, DMSO-d6): delta [ppm]= 1.37 - 1.55 (m, 9H), 5.99 (s, 2H), 7.36 (dd, 1 H), 7.48 - 7.55 (m, 2H), 7.55 - 7.62 (m, 2H), 7.69 (dd, 1 H), 8.78 (dd, 1 H), 9.44 (s, 1 H).
7.2 g	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; triphenylphosphine; In propan-1-ol; for 4h;Reflux;	To a stirred solution of Int01.02 (5.82 g) in 1-propanol (400 mL) was added 2M potassium carbonate solution (41 mL), (4-[(£er£-butoxycarbonyl) amino] phenyl} boronic acid (8.6 g), triphenylphosphine (150 mg) and PdC (PPh3)2 (1.9 g). The mixture was heated to reflux for 4 h, the solvent was removed in vacuum, water (150 mL) was added and the mixture was extracted with ethyl acetate (500 mL). The organic phase was dried (sodium sulfate), filtered through Celite and the solvent was removed in vacuum. The residue was triturated with DCM to give the title compound as a white solid. Yield: 7.2 g. 1H-NMR (400MHz, DMSO-d6): delta [ppm]= 1.37 - 1.55 (m, 9H), 5.99 (s, 2H), 7.36 (dd, 1H), 7.48 - 7.55 (m, 2H), 7.55 - 7.62 (m, 2H), 7.69 (dd, 1H), 8.78 (dd, 1H), 9.44 (s, 1H).
7.2 g	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; triphenylphosphine; In propan-1-ol; for 4h;Reflux;	To a stirred solution of Int01.02 (5.82 g) in 1 -propanol (400 mL) was added 2M potassium carbonate solution (41 mL), {4-[(tert-butoxycarbonyl) amino] phenyl} boronic acid (8.6 g), triphenylphosphine (150 mg) and PdCl2(PPh3)2 (1.9 g). The mixture was heated to reflux for 4 h, the solvent was removed in vacuum, water (150 mL) was added and the mixture was extracted with ethyl acetate (500 mL). The organic phase was dried (sodium sulfate), filtered through Celite and the solvent was removed in vacuum. The residue was triturated with DCM to give the title compound as a white solid. Yield: 7.2 g. 1H-NMR (400MHz, DMSO-d6): delta [ppm] = 1.37 - 1.55 (m, 9H), 5.99 (s, 2H), 7.36 (dd, 1 H), 7.48 - 7.55 (m, 2H), 7.55 - 7.62 (m, 2H), 7.69 (dd, 1 H), 8.78 (dd, 1 H), 9.44 (s, 1 H).
7.2 g	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; triphenylphosphine; In propan-1-ol; for 4h;Inert atmosphere; Reflux;	To a stirred solution of Int01 .02 (5.82 g) in 1 -propanol (400 mL) was added 2M potassium carbonate solution (41 mL), {4-[(tert-butoxycarbonyl) amino] phenyl} boronic acid (8.6 g), triphenylphosphine (1 50 mg) and PdCl2(PPh3)2 (1 .9 g). The mixture was heated to reflux for 4 h, the solvent was removed in vacuum, water (150 mL) was added and the mixture was extracted with ethyl acetate (500 mL). The organic phase was dried (sodium sulfate), filtered through Celite and the solvent was removed in vacuum. The residue was triturated with DCM to give the title compound as a white solid. Yield: 7.2 g. 1H-NMR (400MHz, DMSO-de): delta [ppm]= 1 .37 - 1 .55 (m, 9H), 5.99 (s, 2H), 7.36 (dd, 1 H), 7.48 - 7.55 (m, 2H), 7.55 - 7.62 (m, 2H), 7.69 (dd, 1 H), 8.78 (dd, 1 H), 9.44 (s, 1 H).
7.2 g	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; triphenylphosphine; In propan-1-ol; for 4h;Reflux;	To a stirred solution of Int01.02 (5.82 g) in 1 -propanol (400 mL) was added 2M potassium carbonate solution (41 mL), {4-[(tert-butoxycarbonyl) amino] phenyl} boronic acid (8.6 g), triphenylphosphine (150 mg) and PdCl2(PPh3)2 (1.9 g). The mixture was heated to reflux for 4 h, the solvent was removed in vacuum, water (150 mL) was added and the mixture was extracted with ethyl acetate (500 mL). The organic phase was dried (sodium sulfate), filtered through Celite and the solvent was removed in vacuum. The residue was triturated with DCM to give the title compound as a white solid. Yield: 7.2 g. 1H-NMR (400MHz, DMSO-d6): delta [ppm] = 1.37 - 1.55 (m, 9H), 5.99 (s, 2H), 7.36 (dd, 1 H), 7.48 - 7.55 (m, 2H), 7.55 - 7.62 (m, 2H), 7.69 (dd, 1 H), 8.78 (dd, 1 H), 9.44 (s, 1 H).
7.2 g	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; triphenylphosphine; In propan-1-ol; for 4h;Reflux;	To a stirred solution of IntOl.02 (5.82 g) in 1-propanol (400 mL) was added 2M potassium carbonate solution (41 mL), f4-[(tert-butoxycarbonyl) amino]phenyl boronic acid (8.6 g), triphenylphosphine (1 50 mg) and PdCI2(PPh3)2 (1 .9g). The mixture was heated to reflux for 4 h, the solvent was removed in vacuum, water (150 mL) was added and the mixture was extracted with ethyl acetate (500 mL). The organic phase was dried (sodium sulfate), filtered through Celite and the solvent was removed in vacuum. The residue was triturated with DCM to give the title compound as a white solid. Yield: 7.2 g.1H-NMR (400MHz, DMSO-d6): 6 [ppm] = 1.37 - 1.55 (m, 9H), 5.99 (5, 2H), 7.36(dd, 1H), 7.48 - 7.55 (m, 2H), 7.55 - 7.62 (m, 2H), 7.69 (dd, 1H), 8.78 (dd, 1H),9.44 (5, 1H).
7.2 g	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; triphenylphosphine; In propan-1-ol; for 4h;Reflux;	To a stirred solution of Int01.02 (5.82 g) in 1-propanol (400 mL) was added 2M potassium carbonate solution (41 mL), {4-[(tert-butoxycarbonyl)amino]phenyl} boronic acid (8.6 g), triphenylphosphine (150 mg) and PdCl2(PPh3)2 (1.9 g). The mixture was heated to reflux for 4 h, the solvent was removed in vacuum, water (150 mL) was added and the mixture was extracted with ethyl acetate (500 mL). The organic phase was dried (sodium sulfate), filtered through Celite and the solvent was removed in vacuum. The residue was triturated with DCM to give the title compound as a white solid. Yield: 7.2 g. 1H-NMR (400 MHz, DMSO-d6): delta [ppm]=1.37-1.55 (m, 9H), 5.99 (s, 2H), 7.36 (dd, 1H), 7.48-7.55 (m, 2H), 7.55-7.62 (m, 2H), 7.69 (dd, 1H), 8.78 (dd, 1H), 9.44 (s, 1H).

Reference： [1]Patent: WO2011/64328,2011,A1 .Location in patent: Page/Page column 65-66
[2]Patent: WO2011/63908,2011,A1 .Location in patent: Page/Page column 55
[3]Patent: EP2343295,2011,A1 .Location in patent: Page/Page column 25
[4]Patent: EP2343297,2011,A1 .Location in patent: Page/Page column 26
[5]Patent: WO2011/157688,2011,A1 .Location in patent: Page/Page column 93
[6]Patent: WO2012/143329,2012,A1 .Location in patent: Page/Page column 74
[7]Patent: WO2012/160029,2012,A1 .Location in patent: Page/Page column 70
[8]Patent: WO2013/87579,2013,A1 .Location in patent: Page/Page column 94
[9]Patent: WO2014/9219,2014,A1 .Location in patent: Page/Page column 68; 69
[10]Patent: WO2014/20041,2014,A1 .Location in patent: Page/Page column 124-125
[11]Patent: WO2014/195276,2014,A1 .Location in patent: Page/Page column 97
[12]Patent: WO2014/198647,2014,A2 .Location in patent: Page/Page column 70; 71
[13]Patent: US2015/148542,2015,A1 .Location in patent: Paragraph 0329-0331

6
[ 120153-08-4 ]
[ 947248-68-2 ]
[ 1309682-26-5 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate [Example Int10.14- 2-amino[1 ,2,4]triazolo[1 ,5-a] pyridin-6-yl)-2-fluorobenzoic acidTo a stirred solution of Int1.2 (4.45 g) in 1 -propanol (150 ml) was added 2M potassium carbonate solution (31 ml), <strong>[120153-08-4]4-carboxy-3-fluorophenylboronic acid</strong> (3.92 g), triphenylphosphine (0.55 g) and PdCl2(PPh3)2 (1 .50 g). The mixture was heated to reflux for 2 h. Water (800 mL) was added and the mixture was extracted with ethyl acetate (2 x 500 mL). 1 N hydrochloric acid was added to the aqueous phase until pH 3 was reached. The precipitated solid was collected by filtration, was washed with water, ethanol and ether and was dried in vacuum to give 3.10 g of the title compound.1 H-NMR (300MHz, DMSO-d6): delta [ppm]= 6.13 (s, 2H), 7.41 (d, 1 H), 7.59 - 7.96 (m, 4H), 9.06 (s, 1 H), 13.24 (br. s. , 1 H).
	With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; triphenylphosphine; In propan-1-ol; for 2h;Reflux;	Intermediate Example Int04.01; 4-(2-amino[1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl)-2-fluorobenzoic acid To a stirred solution of Int01.02 (4.45 g) in 1 -propanol (150 ml) was added 2M potassium carbonate solution (31 ml), <strong>[120153-08-4]4-carboxy-3-fluorophenylboronic acid</strong> (3.92 g), triphenylphosphine (0.55 g) and PdCl2(PPh3)2 (1 .50 g). The mixture was heated to reflux for 2 h. Water (800 mL) was added and the mixture was extracted with ethyl acetate (2 x 500 mL). 1 N hydrochloric acid was added to the aqueous phase until pH 3 was reached. The precipitated solid was collected by filtration, was washed with water, ethanol and ether and was dried in vacuum to give 3.10 g of the title compound.1H-NMR (300MHz, DMSO-d6): delta [ppm]= 6.13 (s, 2H), 7.41 (d, 1 H), 7.59 - 7.96 (m, 4H), 9.06 (s, 1 H), 13.24 (br. s., 1 H).
		Intermediate Example Int6.14- 2-amino[1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl)-2-fluorobenzoic acidTo a stirred solution of Int 1.2 (4.45 g) in 1 -propanol (150 mL) was added 2M potassium carbonate solution (31 mL), <strong>[120153-08-4]4-carboxy-3-fluorophenylboronic acid</strong> (3.92 g), triphenylphosphine (0.55 g) and PdCl2(PPh3)2 (1 .50 g). The mixture was heated to reflux for 2 h. Water (800 mL) was added and the mixture was extracted with ethyl acetate (2 x 500 mL). 1 N hydrochloric acid was added to the aqueous phase until pH 3 was reached. The precipitated solid was collected by filtration, was washed with water, ethanol and ether and was dried in vacuum to give 3.10 g of the title compound.1H-NMR (300MHz, DMSO-d6): delta [ppm]= 6.13 (s, 2H), 7.41 (d, 1 H), 7.59 - 7.96 (m, 4H), 9.06 (s, 1 H), 13.24 (br. s., 1 H).

With potassium carbonate;[1,4-bis(diphenylphosphino)butane] palladium(ll) dichloride; triphenylphosphine; In propan-1-ol; for 2h;Reflux;

Intermediate Example Int04.014- 2-amino[1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl)-2-fluorobenzoic acidTo a stirred solution of Int01.02 (4.45 g) in 1 -propanol (150 mL) was added 2M potassium carbonate solution (31 mL), <strong>[120153-08-4]4-carboxy-3-fluorophenylboronic acid</strong> (3.92 g), triphenylphosphine (0.55 g) and PdCl2(PPh3)2 (1 .50 g). The mixture was heated to reflux for 2 h. Water (800 mL) was added and the mixture was extracted with ethyl acetate (2 x 500 mL). 1 N hydrochloric acid was added to the aqueous phase until pH 3 was reached. The precipitated solid was collected by filtration, was washed with water, ethanol and ether and was dried in vacuum to give 3.10 g of the title compound.1H-NMR (300MHz, DMSO-d6): delta [ppm]= 6.13 (s, 2H), 7.41 (d, 1 H), 7.59 - 7.96 (m, 4H), 9.06 (s, 1 H), 13.24 (br. s., 1 H).

Reference： [1]Patent: WO2011/64328,2011,A1 .Location in patent: Page/Page column 73
[2]Patent: WO2011/157688,2011,A1 .Location in patent: Page/Page column 102-103
[3]Patent: WO2012/143329,2012,A1 .Location in patent: Page/Page column 83
[4]Patent: WO2012/160029,2012,A1 .Location in patent: Page/Page column 79

7
[ 220210-56-0 ]
[ 947248-68-2 ]
[ 1309593-82-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; triphenylphosphine; In propan-1-ol; for 15h;Reflux;	Intermediate [Example Int8.1tert-butyl 3-(2-amino[1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl)benzoateTo a stirred solution of Int1.2 (1 .2 g) in 1 -propanol (83 ml) was added 2M potassium carbonate solution (8.3 ml), <strong>[220210-56-0][3-(tert-butoxycarbonyl)phenyl]boronic acid</strong> (2.45 g), triphenylphosphine (30 mg) and PdCl2(PPh3 )2 (387 g). The mixture was heated to reflux for 15h. Water (50 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 1 .04 g of the title compound.1 H-NMR (300MHz, DMSO-d6): delta [ppm]= 1 .57 (s, 9H), 6.10 (s, 2H), 7.45 (dd, 1 H), 7.56 - 7.64 (m, 1 H), 7.78 (dd, 1 H), 7.90 (dt, 1 H), 7.94 - 8.01 (m, 1 H), 8.15 (t, 1 H), 8.95 (dd, 1 H).
	With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; triphenylphosphine; In propan-1-ol; for 15h;Reflux;	Intermediate Example Int11.1tert-butyl 3-(2-amino[1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl)benzoateTo a stirred solution of Int1.2 (1.2 g) in 1 -propanol (83 ml) was added 2M potassium carbonate solution (8.3 ml), <strong>[220210-56-0][3-(tert-butoxycarbonyl)phenyl]boronic acid</strong> (2.45 g), triphenylphosphine (30 mg) and PdCl2(PPh3)2 (387 g). The mixture was heated to reflux for 15h. Water (50 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 1.04 g of the title compound. 1H-NMR (300MHz, DMSO-d6): delta [ppm]= 1.57 (s, 9H), 6.10 (s, 2H), 7.45 (dd, 1H), 7.56 - 7.64 (m, 1 H), 7.78 (dd, 1 H), 7.90 (dt, 1H), 7.94 - 8.01 (m, 1 H), 8.15 (t, 1 H), 8.95 (dd, 1H)
	With potassium carbonate; triphenylphosphine;bis-triphenylphosphine-palladium(II) chloride; In propan-1-ol; for 15h;Reflux;	To a stirred solution of lnt1.2 (1.2 g) in 1-propanol (83 ml) was added 2M potassium carbonate solution (8.3 ml), <strong>[220210-56-0][3-(tert-butoxycarbonyl)phenyl]boronic acid</strong> (2.45 g), triphenylphosphine (30 mg) and PdCl2(PPh3)2 (387 g). The mixture was heated to reflux for 15h. Water (50 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 1.04 g of the title compound. 1H-NMR (300MHz, DMSO-d6): delta [ppm]= 1.57 (s, 9H), 6.10 (s, 2H), 7.45 (dd, 1H), 7.56 - 7.64 (m, 1 H), 7.78 (dd, 1 H), 7.90 (dt, 1 H), 7.94 - 8.01 (m, 1 H), 8.15 (t, 1 H), 8.95 (dd, 1 H).

With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; triphenylphosphine; In propan-1-ol; water; for 15h;Reflux;

To a stirred solution of Int1.2 (1.2 g) in 1-propanol (83 ml) was added 2M potassium carbonate solution (8.3 ml), <strong>[220210-56-0][3-(tert-butoxycarbonyl)phenyl]boronic acid</strong> (2.45 g), triphenylphosphine (30 mg) and PdC[2(PPh3)2 (387 g). The mixture was heated to reflux for 15h. Water (50 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 1.04 g of the title compound. 1H-NMR (300MHz, DMSO-d6): delta [ppm]= 1.57 (s, 9H), 6.10 (s, 2H), 7.45 (dd, 1H), 7.56 - 7.64 (m, 1 H), 7.78 (dd, 1 H), 7.90 (dt, 1 H), 7.94 - 8.01 (m, 1 H), 8.15 (t, 1 H), 8.95 (dd, 1 H).

Reference： [1]Patent: WO2011/64328,2011,A1 .Location in patent: Page/Page column 70
[2]Patent: WO2011/63908,2011,A1 .Location in patent: Page/Page column 68-69
[3]Patent: EP2343295,2011,A1 .Location in patent: Page/Page column 26
[4]Patent: EP2343297,2011,A1 .Location in patent: Page/Page column 35

8
[ 947248-68-2 ]
[ 380430-68-2 ]
[ 1309593-75-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; triphenylphosphine; In propan-1-ol; for 1h;Reflux;	Intermediate [Example Int6.1tert-butyl [3-(2-amino[1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl)phenyl]carbamateTo a stirred solution of Int1.2 (5.0 g) in 1 -propanol (350 ml) was added 2M potassium carbonate solution (34.5 ml), {3-[(tert-butoxycarbonyl) amino] phenyl} boronic acid (10.9 g), triphenylphosphine (126 mg) and PdCl2(PPh3)2 (1 .61 g). The mixture was heated to reflux for 1 h, the solvent was removed in vacuum, water was added and the mixture was extracted with ethyl acetate and methanol (9: 1 ). The organic phase was dried (sodium sulfate), filtered through Celite and the solvent was removed in vacuum. The residue was triturated with DCM to give the title compound as a white solid. Yield: 6.65 g. 1 H-NMR (300MHz, DMSO-d6): delta [ppm]= 1 .49 (s, 9H), 6.08 (s, 2H), 7.26 - 7.39 (m, 2H), 7.44 (dd, 2H), 7.65 (dd, 1 H), 7.78 (s, 1 H), 8.74 (d, 1 H), 9.45 (s, 1 H).
	With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; triphenylphosphine; In propan-1-ol; for 1h;Reflux;	Intermediate Example Int9.1tert-butyl [3-(2-amino[1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl)phenyl]carbamateTo a stirred solution of Int1.2 (5.0 g) in 1 -propanol (350 ml) was added 2M potassium carbonate solution (34.5 ml), (3-[(tert-butoxycarbonyl) amino] phenyl} boronic acid (10.9 g), triphenylphosphine (126 mg) and PdCl2(PPh3)2 (1.61 g). The mixture was heated to reflux for 1h, the solvent was removed in vacuum, water was added and the mixture was extracted with ethyl acetate and methanol (9:1 ). The organic phase was dried (sodium sulfate), filtered through Celite and the solvent was removed in vacuum. The residue was titurated with DCM to give the title compound as a white solid. Yield: 6.65 g. 1H-NMR (300MHz, DMSO-d6): delta [ppm]= 1.49 (s, 9H), 6.08 (s, 2H), 7.26 - 7.39 (m, 2H), 7.44 (dd, 2H), 7.65 (dd, 1H), 7.78 (s, 1H), 8.74 (d, 1 H), 9.45 (s, 1 H).
	With potassium carbonate; triphenylphosphine;bis-triphenylphosphine-palladium(II) chloride; In propan-1-ol; for 1h;Reflux;	To a stirred solution of Int1.2 (5.0 g) in 1-propanol (350 ml) was added 2M potassium carbonate solution (34.5 ml), {3-[(tert-butoxycarbonyl) amino] phenyl} boronic acid (10.9 g), triphenylphosphine (126 mg) and PdCl2(PPh3)2 (1.61 g). The mixture was heated to reflux for 1h, the solvent was removed in vacuum, water was added and the mixture was extracted with ethyl acetate and methanol (9:1). The organic phase was dried (sodium sulfate), filtered through Celite and the solvent was removed in vacuum. The residue was triturated with DCM to give the title compound as a white solid. Yield: 6.65 g. 1H-NMR (300MHz, DMSO-d6): delta [ppm]= 1.49 (s, 9H), 6.08 (s, 2H), 7.26 - 7.39 (m, 2H), 7.44 (dd, 2H), 7.65 (dd, 1 H), 7.78 (s, 1 H), 8.74 (d, 1 H), 9.45 (s, 1 H).

With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; triphenylphosphine; In propan-1-ol; water; for 1h;Reflux;

To a stirred solution of Int1.2 (5.0 g) in 1-propanol (350 ml) was added 2M potassium carbonate solution (34.5 ml), {3-[(tert-butoxycarbonyl) amino] phenyl} boronic acid (10.9 g), triphenylphosphine (126 mg) and PdCl2(PPh3)2 (1.61 g). The mixture was heated to reflux for 1 h, the solvent was removed in vacuum, water was added and the mixture was extracted with ethyl acetate and methanol (9:1). The organic phase was dried (sodium sulfate), filtered through Celite and the solvent was removed in vacuum. The residue was titurated with DCM to give the title compound as a white solid. Yield: 6.65 g. 1H-NMR (300MHz, DMSO-d6): delta [ppm]= 1.49 (s, 9H), 6.08 (s, 2H), 7.26 - 7.39 (m, 2H), 7.44 (dd, 2H), 7.65 (dd, 1 H), 7.78 (s, 1 H), 8.74 (d, 1 H), 9.45 (s, 1 H).

Reference： [1]Patent: WO2011/64328,2011,A1 .Location in patent: Page/Page column 67-68
[2]Patent: WO2011/63908,2011,A1 .Location in patent: Page/Page column 63
[3]Patent: EP2343295,2011,A1 .Location in patent: Page/Page column 25-26
[4]Patent: EP2343297,2011,A1 .Location in patent: Page/Page column 31-32

9
[ 191089-06-2 ]
[ 947248-68-2 ]
[ 1309682-28-7 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3-methyl-4-p-carboxybenzeneboronic acid,; 6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine With potassium carbonate In propan-1-ol for 1h; Reflux; Stage #2: With hydrogenchloride In water	Int11.1 Intermediate [Example Intl 1.14- 2-amino[1 , 2, 4]triazolo[1 ,5-a] pyridin-6-yl)-2-methyl benzoic acidTo a stirred solution of Int1.2 (1 .45 g) in 1 -propanol (65 mL) was added 2M potassium carbonate solution (10 mL), 4-carboxy-3-methylphenylboronic aci (1 .22 g), triphenylphosphine (0.17 g) and PdCl2(PPh3)2 (0.35 g). The mixture was heated to reflux for 1 h. Water (200 mL) was added and the mixture was extracted with ethyl acetate (2 x 100 mL). 1 N hydrochloric acid was added to the aqueous phase until pH 5 was reached. The precipitated solid was collected by filtration, was washed with water, ethanol and ether and was dried in vacuum to give 0.8 g of the title compound.1 H-NMR (400MHz, DMSO-d6): δ [ppm]= 2.57 (s, 3H), 6.37 (br. s., 2H), 7.52 (d, 1 H), 7.65 (dd, 1 H), 7.70 (s, 1 H), 7.89 (d, 1 H), 7.95 (dd, 1 H), 9.06 (d, 1 H), 12.87 (br. s., 1 H).
	With potassium carbonate In propan-1-ol for 1h; Reflux;	Int05.01 Intermediate Example Int05.01; 4- 2-amino[1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl)-2-methylbenzoic acid To a stirred solution of Int01.02 (1.45 g) in 1 -propanol (65 ml) was added 2M potassium carbonate solution (10 ml), 4-carboxy-3-methylphenylboronic acid (1.22 g), triphenylphosphine (0.17 g) and PdCl2(PPh3)2 (0.35 g). The mixture was heated to reflux for 1 h. Water (200 mL) was added and the mixture was extracted with ethyl acetate (2 x 100 mL). 1 N hydrochloric acid was added to the aqueous phase until pH 5 was reached. The precipitated solid was collected by filtration, was washed with water, ethanol and ether and was dried in vacuum to give 0.8 g of the title compound.1H-NMR (400MHz, DMSO-d6): δ [ppm]= 2.57 (s, 3H), 6.37 (br. s., 2H), 7.52 (d, 1 H), 7.65 (dd, 1 H), 7.70 (s, 1 H), 7.89 (d, 1 H), 7.95 (dd, 1 H), 9.06 (d, 1 H), 12.87 (br. s., 1 H).
	Stage #1: 3-methyl-4-p-carboxybenzeneboronic acid,; 6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine With potassium carbonate In propan-1-ol for 1h; Reflux; Stage #2: With hydrogenchloride In water	Intermediate Example Int7.14- 2-amino[1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl)-2-methylbenzoic acid To a stirred solution of Int 1.2 (1.45 g) in 1 -propanol (65 mL) was added 2M potassium carbonate solution (10 mL), 4-carboxy-3-methylphenylboronic acid (1.22 g), triphenylphosphine (0.17 g) and PdCl2(PPh3)2 (0.35 g). The mixture was heated to reflux for 1 h. Water (200 mL) was added and the mixture was extracted with ethyl acetate (2 x 100 mL). 1 N hydrochloric acid was added to the aqueous phase until pH 5 was reached. The precipitated solid was collected by filtration, was washed with water, ethanol and ether and was dried in vacuum to give 0.8 g of the title compound.1H-NMR (400MHz, DMSO-d6): δ [ppm]= 2.57 (s, 3H), 6.37 (br. s., 2H), 7.52 (d, 1 H), 7.65 (dd, 1 H), 7.70 (s, 1 H), 7.89 (d, 1 H), 7.95 (dd, 1 H), 9.06 (d, 1 H), 12.87 (br. s., 1 H).

With potassium carbonate In propan-1-ol

05.01 Intermediate Example Int05.014- 2-amino[1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl)-2-methylbenzoic acidTo a stirred solution of Int01.02 (1.45 g) in 1 -propanol (65 mL) was added 2M potassium carbonate solution (10 mL), 4-carboxy-3-methylphenylboronic acid (1 .22 g), triphenylphosphine (0.17 g) and PdCl2(PPh3)2 (0.35 g). The mixture was heated to reflux for 1 h. Water (200 mL) was added and the mixture was extracted with ethyl acetate (2 x 100 mL). 1 N hydrochloric acid was added to the aqueous phase until pH 5 was reached. The precipitated solid was collected by filtration, was washed with water, ethanol and ether and was dried in vacuum to give 0.8 g of the title compound.1H-NMR (400MHz, DMSO-d6): δ [ppm]= 2.57 (s, 3H), 6.37 (br. s., 2H), 7.52 (d, 1 H), 7.65 (dd, 1 H), 7.70 (s, 1 H), 7.89 (d, 1 H), 7.95 (dd, 1 H), 9.06 (d, 1 H), 12.87 (br. s., 1 H).

Reference： [1]Current Patent Assignee: BAYER AG - WO2011/64328, 2011, A1 Location in patent: Page/Page column 74-75
[2]Current Patent Assignee: BAYER AG - WO2011/157688, 2011, A1 Location in patent: Page/Page column 104
[3]Current Patent Assignee: BAYER AG - WO2012/143329, 2012, A1 Location in patent: Page/Page column 84-85
[4]Current Patent Assignee: BAYER AG - WO2012/160029, 2012, A1 Location in patent: Page/Page column 80-81

10
[ 947248-68-2 ]
[ 871329-75-8 ]
[ 1309682-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In propan-1-ol for 2h; Reflux;	Int13.1 Intermediate [Example Int13.13-(2-amino[1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl)-N-methylbenzenesulfonamideTo a stirred solution of Int1.2 (300 mg) in 1 -propanol (15 ml) was added 2M potassium carbonate solution (2.1 ml), [4-(methylsulfamoyl)phenyl]boronic acid (394 mg), triphenylphosphine (18 mg) and PdCl2(PPh3)2 (99 mg). The mixture was heated to reflux for 2 h. The mixture was concentrated in vacuum. Water was added and the mixture was extracted with a mixture of ethyl acetate and methanol (9: 1 ). Silica gel chromatography gave a solid that was triturated with ethanol to give 306 mg of the title compound.1 H-NMR (300MHz, DMSO-d6): δ [ppm]= 2.41 (s, 3H), 6.1 1 (s, 2H), 7.44 (d, 2H), 7.62 - 7.81 (m, 3H), 7.94 - 8.06 (m, 2H), 8.95 (d, 1 H).

Reference： [1]Current Patent Assignee: BAYER AG - WO2011/64328, 2011, A1 Location in patent: Page/Page column 77

11
[ 851335-12-1 ]
[ 947248-68-2 ]
[ 1352620-88-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; triphenylphosphine; In propan-1-ol; for 1.0h;Reflux;	Intermediate Example Int07.014-(2-amino[1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl)-2-methoxybenzoic acidTo a stirred solution of Int01.02 (0.52 g) in 1 -propanol (24 mL) was added 2M potassium carbonate solution (3.6 mL), 4-carboxy-3-methoxyphenylboronic acid (0.48 g), triphenylphosphine (63 mg) and PdCl2(PPh3)2 (170 mg). The mixture was heated to reflux for 1 h. Water (200 mL) was added and the mixture was extracted with ethyl acetate (2 x 100 mL). 2 N hydrochloric acid was added to the aqueous phase until pH 4 was reached. The precipitated solid was collected by filtration, was washed with water, ethanol and ether and was dried in vacuum to give 466 mg of the title compound.1H-NMR (300MHz, DMSO-d6, detected signals): delta [ppm]= 3.98 (s, 3H), 4.46 (d, 2H), 6.08 (s, 2H), 7.07 - 7.18 (m, 2H), 7.29 - 7.47 (m, 5H), 7.75 - 7.88 (m, 2H), 8.72 (t, 1 H), 9.03 (dd, 1 H).
		Intermediate Example Int9.14-(2-amino[1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl)-2-methoxybenzoic acid To a stirred solution of Int 1.2 (0.52 g) in 1 -propanol (24 m) was added 2M potassium carbonate solution (3.6 ml_), 4-carboxy-3-methoxyphenylboronic acid (0.48 g), triphenylphosphine (63 mg) and PdCl2(PPh3)2 (170 mg). The mixture was heated to reflux for 1 h. Water (200 mL) was added and the mixture was extracted with ethyl acetate (2 x 100 mL). 2N hydrochloric acid was added to the aqueous phase until pH 4 was reached. The precipitated solid was collected by filtration, was washed with water, ethanol and ether and was dried in vacuum to give 466 mg of the title compound.1H-NMR (300MHz, DMSO-d6, detected signals): delta [ppm]= 3.98 (s, 3H), 4.46 (d, 2H), 6.08 (s, 2H), 7.07 - 7.18 (m, 2H), 7.29 - 7.47 (m, 5H), 7.75 - 7.88 (m, 2H), 8.72 (t, 1 H), 9.03 (dd, 1 H).
	With potassium carbonate;[1,4-bis(diphenylphosphino)butane] palladium(ll) dichloride; triphenylphosphine; for 1.0h;Reflux;	Intermediate Example Int07.014-(2-amino[1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl)-2-methoxybenzoic acid To a stirred solution of Int01.02 (0.52 g) in 1 -propanol (24 mL) was added 2M potassium carbonate solution (3.6 mL), 4-carboxy-3-methoxyphenylboronic acid (0.48 g), triphenylphosphine (63 mg) and PdCl2(PPh3)2 (170 mg). The mixture was heated to reflux for 1 h. Water (200 mL) was added and the mixture was extracted with ethyl acetate (2 x 100 mL). 2N hydrochloric acid was added to the aqueous phase until pH 4 was reached. The precipitated solid was collected by filtration, was washed with water, ethanol and ether and was dried in vacuum to give 466 mg of the title compound.1H-NMR (300MHz, DMSO-d6, detected signals): delta [ppm]= 3.98 (s, 3H), 4.46 (d, 2H), 6.08 (s, 2H), 7.07 - 7.18 (m, 2H), 7.29 - 7.47 (m, 5H), 7.75 - 7.88 (m, 2H), 8.72 (t, 1 H), 9.03 (dd, 1 H).

Reference： [1]Patent: WO2011/157688,2011,A1 .Location in patent: Page/Page column 107
[2]Patent: WO2012/143329,2012,A1 .Location in patent: Page/Page column 87-88
[3]Patent: WO2012/160029,2012,A1 .Location in patent: Page/Page column 83-84

12
[ 947248-68-2 ]
[ 1401624-81-4 ]

Yield	Reaction Conditions	Operation in experiment
70%		6-Bromo-2-(4-methylplperazin-1 -yl)-[1 ,2,4]triazolot1 ,5-a]pyridine (PZ972-3): At 15-20 C, sodium nitrite (1.17 g, 16.98 mmol) and cone. H2S04 (6 mL) were added to a mixture ofPZ972-2 (3 g, 14.2 mmol) In glacial acetic acid (30 mL). The mixture was stirred at rt for 1 h, and added to a mixture of CuBr (2 g, 14.15 mmol) in HBr (10 mL, 40%) at 0 C. The reaction was stirred at rt for 2 h. pH was adjusted to 8 by 20% sodium carbonate and extracted with ethyl acetate (50 mLx2) and dichloromethane (50 mLx2). The organic phasese were collected, dried over anhydrous sodium sulfate and concentrated. The residue was purified by HPFC (PE: EA = 5 : l) to afford 2,6-dlbromo-[1 ,2,4]triazolo[1 ,5-a]pyridine (2.7 g, 70%). LC- MS: 276.1, 278.2, 280.1 (M+l).
26%		c) 2,6-Dibromo-[ 1 ,2,4] triazolo[ 1 ,5-a]pyridineA mixture of 6-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-amine (20.86 g, 97.9 mmol), sodi- um nitrite (67.6 g, 979 mmol) and benzyltriethylammonium bromide (53.3 g, 196 mmol) in bromoform (1.47 kg, 508 ml, 5.81 mol) was stirred for 30 minutes at 25 C. Then dichloroacetic acid (25.3 g, 16.2 ml, 196 mmol) was added and the mixture was stirred for 20 hours at 25 C under exclusion of light. 600 ml of water were added to the mixture and stirred for 30 minutes. The mixture was diluted with water and dichloromethane, filtrated over dicalite and the filtrate extracted 3 times with dichloromethane. The organic layers were combined, washed with water, dried over magnesium sulfate, filtrated and evaporated to dryness under reduced pressure. The crude material was purified by flash chromatography in 2 portions over 2 x 70 g silica columns using dichloromethane/methanol 5 % as eluent, affording 2,6-dibromo-[l,2,4]triazolo[l,5- a]pyridine (7 g, 26%) as light brown solid. Mp.: 201C. MS: m/z=277.7/279.9 (M+H+).

Reference： [1]Patent: WO2012/130299,2012,A1 .Location in patent: Page/Page column 130
[2]Patent: WO2013/41472,2013,A1 .Location in patent: Page/Page column 36

13
[ 947248-68-2 ]
[ 1443763-60-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: potassium carbonate; bis-triphenylphosphine-palladium(II) chloride; triphenylphosphine / propan-1-ol / 4 h / Reflux 2: chloro(2-dicyclohexylphosphino-2’,4’,6’-tri-i-propyl-1,1‘-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-t-butyl ether adduct; XPhos; potassium phosphate / toluene; 1-methyl-pyrrolidin-2-one / 16 h / Inert atmosphere; Reflux 3: trifluoroacetic acid / dichloromethane / 21 h / 20 °C 4: sodium hydrogencarbonate; HATU / dichloromethane; N,N-dimethyl-formamide / 4 h / 20 °C
	Multi-step reaction with 4 steps 1: potassium carbonate; triphenylphosphine; bis-triphenylphosphine-palladium(II) chloride / propan-1-ol / 4 h / Reflux 2: chloro(2-dicyclohexylphosphino-2’,4’,6’-tri-i-propyl-1,1‘-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-t-butyl ether adduct; XPhos; potassium phosphate / toluene; 1-methyl-pyrrolidin-2-one / 16 h / Inert atmosphere; Reflux 3: trifluoroacetic acid / dichloromethane / 21 h / 20 °C 4: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; sodium hydrogencarbonate / N,N-dimethyl-formamide; dichloromethane / 4 h / 20 °C
	Multi-step reaction with 4 steps 1: potassium carbonate; triphenylphosphine; bis-triphenylphosphine-palladium(II) chloride / propan-1-ol / 4 h / Reflux 2: chloro(2-dicyclohexylphosphino-2’,4’,6’-tri-isopropyl-1,1’-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)methyl-tertbutyl ether; potassium phosphate; XPhos / toluene; 1-methyl-pyrrolidin-2-one / 16 h / Inert atmosphere; Reflux 3: trifluoroacetic acid / dichloromethane / 21 h / 20 °C 4: sodium hydrogencarbonate; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide; dichloromethane / 4 h / 20 °C

Multi-step reaction with 4 steps 1: potassium carbonate; triphenylphosphine; bis-triphenylphosphine-palladium(II) chloride / propan-1-ol / 4 h / Reflux 2: chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether; XPhos; potassium phosphate / toluene; 1-methyl-pyrrolidin-2-one / 16 h / Inert atmosphere; Reflux 3: trifluoroacetic acid / dichloromethane / 21 h / 20 °C 4: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; sodium hydrogencarbonate / dichloromethane; N,N-dimethyl-formamide / 4 h / 20 °C

Reference： [1]Current Patent Assignee: BAYER AG - WO2013/87579, 2013, A1
[2]Current Patent Assignee: BAYER AG - WO2014/9219, 2014, A1
[3]Current Patent Assignee: BAYER AG - WO2014/198647, 2014, A2
[4]Current Patent Assignee: BAYER AG - US2015/148542, 2015, A1

14
[ 934-98-5 ]
[ 947248-68-2 ]
[ 530-62-1 ]
1-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-3-(2-(4-methylpiperazin-1-yl)ethyl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81.0%		General procedure: To the suspension of sodium hydride (60percent, 0.23 g, 5.66 mmol) in dried dimethyl formamide (15 mL) was added 6-bromo (or 7-bromo)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (0.60 g, 2.82 mmol),stirred for 10 min at room temperature, added N,N'-carbonyldimidazole(CDI, 1.37 g, 8.46 mmol), stirred at 60 °C until the starting material consumed, then added amine (9.87 mmol) and stirred at 60 °C for 6 h. The volatile was removed under reduced pressure to give a white pale yellow residue. Water (30 mL) was added tothe residue. The mixture was stirred. The precipitate was collected by filtration, dried to afford the expected product as a white solid. 5.1.1.7 1-(6-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-3-(2-(4-methylpiperazin-1-yl)ethyl)urea (2g) White solid; yield: 81.0percent; mp: 182-184 °C; 1H NMR (CDCl3): delta 9.60 (s, 1H, NH), 8.80 (s, 1H, Ar-H), 8.46 (s, 1H, NH), 7.63 (m, 2H, Ar-H), 2.60 (m, 10H, CH2 * 5), 2.36 (s, 3H, CH3). MS m/z (ESI): 382.1 [M+H]+.

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 5662 - 5671

15
[ 947248-68-2 ]
[ 2265-93-2 ]
6-bromo-N-(2,4-difluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 95℃; for 16h;	The mixture of 6-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-amine (550 mg, 2.58 mmol), 2,4-difluoro-l-iodobenzene (745 mg, 3.10 mmol), CS2C03 (2.53 g, 7.77 mmol), Xant-phos (300 mg, 0.518 mmol), and Pd2(dba)3 (237 mg, 0.259 mmol) in dioxane (10 mL) was stirred at 95 C for 16 h. The resulting mixture was diluted with water, and then extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine (50 mL x 2), dried over Na2S04, and concentrated. The residue was purified by flash column (hexane/ethyl acetate = 1/5) to get 6-bromo-N-(2,4-difluorophenyl)-[l,2,4] triazolo[l,5- a]pyridin-2- amine (brown solid, 600 mg, yield 72%). LCMS (m/z): 325 [M + H]+.

Reference： [1]Patent: WO2020/97396,2020,A1 .Location in patent: Paragraph 00225; 00234

16
[ 947248-68-2 ]
[ 1609394-78-6 ]
4-((6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-6-chloro-N-methylpyridazine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45.6%	With lithium hexamethyldisilazane In tetrahydrofuran at 20℃; for 1h;

Reference： [1]Current Patent Assignee: BEIGENE LTD. - WO2021/170046, 2021, A1 Location in patent: Paragraph 0189-0191

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[ 7169-95-1 ]

6-Bromo-2-methyl-[1,2,4]triazolo[1,5-a]pyridine

Similarity: 0.84

[ 1053655-66-5 ]

7-Bromo-[1,2,4]triazolo[1,5-a]pyridine

Similarity: 0.83

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Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
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
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
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
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

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
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
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
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
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. 947248-68-2 ]

Quality Control of [ 947248-68-2 ]

Related Doc. of [ 947248-68-2 ]

Product Details of [ 947248-68-2 ]

Calculated chemistry of [ 947248-68-2 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 947248-68-2 ]

Application In Synthesis of [ 947248-68-2 ]

[ 947248-68-2 ] Synthesis Path-Upstream 1~3

[ 947248-68-2 ] Synthesis Path-Downstream 1~16

Related Functional Groups of [ 947248-68-2 ]

Bromides

Amines

Related Parent Nucleus of [ 947248-68-2 ]

Other Aromatic Heterocycles

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 947248-68-2 ]

Related Parent Nucleus of
[ 947248-68-2 ]