1010120-55-4|5-Bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine| Ambeed

Structure of 1010120-55-4

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Quality Control of [ 1010120-55-4 ] Purity: 98% SDS Specification

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Product Details of [ 1010120-55-4 ]

CAS No. :	1010120-55-4
Formula :	C₆H₅BrN₄
M.W :	213.04
SMILES Code :	NC1=NN2C(Br)=CC=CC2=N1
MDL No. :	MFCD11655928
InChI Key :	TVGFHUIJNZRKFW-UHFFFAOYSA-N
Pubchem ID :	25215939

Safety of [ 1010120-55-4 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P301+P312-P302+P352-P304+P340-P305+P351+P338

Computational Chemistry of [ 1010120-55-4 ] Show Less

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 ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	56.21 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.53
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.42
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.08
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.58
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	0.45
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.21

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.66
Solubility	0.465 mg/ml ; 0.00218 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.21
Solubility	1.33 mg/ml ; 0.00624 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-2.21
Solubility	1.3 mg/ml ; 0.00612 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.59 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	1.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.14

Application In Synthesis of [ 1010120-55-4 ]

* 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.

Downstream synthetic route of [ 1010120-55-4 ]

[ 1010120-55-4 ] Synthesis Path-Downstream 1~35

2
[ 288-13-1 ]
[ 1010120-55-4 ]
[ 1124382-69-9 ]

Yield	Reaction Conditions	Operation in experiment
65%	With potassium hydroxide; at 110℃;	Intermediate A12 : 5-flH-pyrazol-l-yl)[l,2,41triazolo[l,5-alpyridin-2-amine; Intermediate A125-bromo[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A3); 1,06 g; 5.0 mmol; 1.0 eq.), pyrazole (3.40 g; 50.0 mmol; 10 eq.) and potassium hydroxide (842 mg; 15.0 mmol; 3.0 eq.) were melted and stirred overnight at 110 0C. After this time, reaction mixture was cooled to rt poured into water and extracted with Et2O. The combined organic layers were washed with water, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give the title compound as a white solid (650 mg, 65%). HPLC, Rt: 1.22 min. (purity 96.6%). LC/MS, M+(ESI): 201.0.

References: [1]Patent: WO2009/27283,2009,A1 .Location in patent: Page/Page column 61.

3
[ 1010120-55-4 ]
[ 98-88-4 ]
[ 1124382-75-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With pyridine; In dichloromethane; for 4h;Heating / reflux;	Intermediate Bl : N-f5-bromo[l,2,41triazolo[l,5-alpyridin-2-yl)benzamide; Intermediate BlBenzoyl chloride (4.40 g; 31.4 mmol; 2.0 eq.) was added to a suspension of 5- bromo[l,2,4]triazolo[l,5-a]pyridin-2-amine ((A3), 3.34 g; 15.7 mmol; 1.0 eq.) in pyridine (2.53 mL; 31.4 mmol; 2.0 eq.) and DCM (60 mL). The reaction mixture was then heated at <n="69"/>reflux for 4 hours, after which it was cooled down to rt. Diethyl ether was added to the reaction mixture and the solid which precipitated was filtered off. The precipitate was resuspended in an aqueous mixture (pH 4/5), filtered and dried under vacuum to give the title compound as a white powder (4.97 g, quant, yield). HPLC, Rt: 2.40 min. (purity 93.4%), LC/MS, M+(ESI): 317.1, M (ESI): 315.1.

References: [1]Patent: WO2009/27283,2009,A1 .Location in patent: Page/Page column 67-68.

4
[ 1010120-55-4 ]
[ 63503-60-6 ]
[ 1111106-76-3 ]

Yield	Reaction Conditions	Operation in experiment
61%	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); at 150℃; for 1h;Microwave irradiation;	A suspension of 5-bromo[l,2,4]triazolo[l,5-alpha]pyridin-2-amine (5.1 g, 24 mmol, 1 equiv), 3-chlorophenylboronic acid (3.8 g, 24 mmol, 1.0 equiv), cesium carbonate (9.4 g, 29 mmol, 1.2 equiv), tetrakistriphenylphosphine palladium (2.7 g, 2.4 mmol, 0.1 equiv) was heated to 150 C for 1 h under <n="96"/>microwave irradiation. The reaction mixture was diluted with ethyl acetate and filtered through Celite. The filtrate was washed with saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered, and concentrated. Purification by flash column chromatography (30% ethyl acetate in petroleum ether) provided product as a solid (3.5 g, 61%). LCMS (ESI) m/z: 244.9.
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; for 5h;Reflux;	Compound 14Compound 13 (750 mg, 3.5 mmol) was dissolved in toluene/ethanol (1 :1, 20 ml), to which was added 2M aqueous Na2CO3 (3.5 ml) and 3- chlorophenylboronicacid (1.1 g, 7.0 mmol). Pd (PPh3) 4 (202 mg) was added last, the mixture was flushed with nitrogen and refluxed for 5 hours in a sealed tube. The reaction mixture was allowed to cool.The reaction solvent was removed and the residue was purified on silica gel (ethylacetate : hexanes 50%) to give 514mg of compound 14 as white solid. LC-MS (ESI, positive): 247 [M+H]+.

References: [1]Patent: WO2009/155565,2009,A1 .Location in patent: Page/Page column 94-95.
[2]Patent: WO2009/17954,2009,A1 .Location in patent: Page/Page column 27; 28.

5
[ 1010120-59-8 ]
[ 1010120-55-4 ]

Yield	Reaction Conditions	Operation in experiment
79.5%	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine; In methanol; ethanol; at 70℃; for 3.5h;	A solution was ethyl [(6-methylpyridin-2-yl)carbamothioyl]carbamate (43.7 g, 0.144 mmol, 1 equiv), hydroxylamine hydrochloride (51.3 g, 0.738 mmol, 5.13 equiv), and diisopropylethylamine (75.2 mL, 0.432 mmol, 3.00 equiv) in 1:1 methanol / ethanol (500 mL) was heated to 70 0C for 3.5 h. The reaction mixture was cooled to 24 C, and the resulting solids were filtered.The solids were rinsed with cold water (2 x 100 mL) and dried in vacuo (~1 mm Hg) to afford product as a white solid (24.4 g, 79.5%). 1H NMR (400 MHz, OMSO-d6), delta: 7.32-7.38 (m, 2 H), 7.21 (m, 1 H), 6.23 (br s, 2 H).
78%	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine; In methanol; ethanol; at 20℃; for 4h;Reflux;	Step (ii)To a suspension of hydroxylamine hydrochloride (85.5g, 1230mmol) in EtOH/MeOH (1 : 1, 400mL) was added DIPEA (129mL, 738mmol) and the mixture was stirred at rt (20C) for lh. l-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (74.7g, 246mmol) was then added and the mixture slowly heated to reflux (Note: bleach trap required to quench H2S evolved). After 3h at reflux the mixture was allowed to cool overnight. The resulting precipitate was removed by filtration and washed thoroughly with water followed by diethylether and air-dried to afford the desired compound as a white solid (41g, 78%). LCMS (method A), (M+H+) 213/215, RT = 0.70min.
74%	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine; In methanol; ethanol; at 20 - 60℃; for 20h;Product distribution / selectivity;	To a stirred suspension of hydroxylamine hydrochloride (20.0 g, 288 mmol) and N,N-diisopropylethylamine (30.0 mL, 172 mmol) in a mixture of methanol (80 mL) and ethanol (80 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. The recovered off-white solid was consistent for 5-bromo-[l,2,4]triazolo[l,5- a]pyridin-2-ylamine (9.04 g, 74%). 1H NMR (400 MHz, (D3C)2SO, delta, ppm): 7.36 (m, 2H), 7.22 (d, J= 7.5 Hz, IH), 6.27 (br s, 2H) MS = 213, 215 (MH)+.

	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine; In methanol; ethanol; at 20 - 60℃; for 5h;	Compound 13To a stirred suspension of hydroxylamine hydrochloride (959.1 g, 13.8 mmol) and DIPEA (1.2 g, 9.2 mmol) in methanol/ethanol (1 : 1 , 50 ml) was added compound 12 (1.4 g, 4.6 mmol) as solid. The mixture was stirred at room temperature for 2 hours, followed by 3hours at 600C. The reaction mixture wasallowed to cool, diluted with CH2Cl2, which was then washed with water (2chi80 ml), the organic phase was evaporated and the residue was chromatographed in MeOH/ CH2Cl2 (8% -10%) to afford 750 mg of compound 13 as a white solid. LC-MS (ESI, positive): 215 [M+H]+.
	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine; In methanol; ethanol; at 20℃;Reflux;	To a suspension of hydroxylamine hydrochloride (101.8 g, 1.465 mol) in EtOH/MeOH (1:1,900 mL) is added N,N-diisopropylethylamine (145.3 mL, 0.879 mol) and the mixture is stirred at room temp. (2O0C) for 1 h. l-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2) (89.0 g, 0.293 mol) may then be added and the mixture slowly heated to reflux (Note: bleach scrubber is required to quench H2S evolved). After 3 h at reflux, the mixture is allowed to cool and filtered to collect the precipitated solid. Further product may be collected by evaporation in vacuo of the filtrate, addition of H2O (250 mL) and filtration. The combined solids are 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 is required. 1H (400 MHz, DMSO-d6) delta: 7.43-7.34 (2H, m, 2 Hz aromatic-H), 7.24 (IH, dd, J 6.8 and 1.8 Hz, aromatic-H), 6.30 (2H, b, NH2); m/z 213/215 (1 :1, M+H+, 100%).
	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine; In methanol; ethanol; at 20℃;Reflux;	To a suspension of hydroxylamine hydrochloride (101.8 g, 1.465 mol) in EtOH/MeOH (1:1, 900 mL) is added N,N-diisopropylethylamine (145.3 mL, 0.879 mol) and the mixture is stirred at room temp. (20 C.) for 1 h. 1-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2) (89.0 g, 0.293 mol) may then be added and the mixture slowly heated to reflux (Note: bleach scrubber is required to quench H2S evolved). After 3 h at reflux, the mixture is allowed to cool and filtered to collect the precipitated solid. Further product may be collected by evaporation in vacuo of the filtrate, addition of H2O (250 mL) and filtration. The combined solids are washed successively with H2O (250 mL), EtOH/MeOH (1:1, 250 mL) and Et2O (250 mL) then dried in vacuo to afford the triazolopyridine derivative (3) as a solid. The compound may be used as such for the next step without any purification. 1H (400 MHz, DMSO-d6) delta 7.43-7.34 (2H, m, 2* aromatic-H), 7.24 (1H, dd, J 6.8 and 1.8 Hz, aromatic-H), 6.30 (2H, br, NH2); m/z 213/215 (1:1, M+H+, 100%).
	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine; In methanol; ethanol; water; for 3h;Reflux;	1.1.2 5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (3) To a suspension of hydroxylamine hydrochloride (101.8 g, 1.465 mol) in EtOH/MeOH (1:1, 900 mL) is added N,N-diisopropylethylamine (145.3 mL, 0.879 mol) and the mixture is stirred at room temp. (20 C.) for 1 h. 1-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2) (89.0 g, 0.293 mol) is 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 is allowed to cool and filtered to collect the precipitated solid. Further product is collected by evaporation in vacuo of the filtrate, addition of H2O (250 mL) and filtration. The combined solids are washed successively with H2O (250 mL), EtOH/MeOH (1:1, 250 mL) and Et2O (250 mL) then dried in vacuo to afford the triazolopyridine derivative (3) as a solid. The compound may be used as such for the next step without any purification. 1H (400 MHz, DMSO-d6) delta 7.43-7.34 (2H, m, 2*aromatic-H), 7.24 (1H, dd, J 6.8 and 1.8 Hz, aromatic-H), 6.30 (2H, br, NH2); m/z 213/215 (1:1, M+H+, 100%).
	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine; In methanol; ethanol; at 20℃; for 3h;Reflux;	To a suspension of hydroxylamine hydrochloride (101.8 g, 1.465 mol) in EtOH/MeOH(1:1, 900 mL) was added N,N-diisopropylethylamine (145.3 mL, 0.879 mol) and the mixture wasstirred at room temp. (20 oq for 1 h. 1-(6-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 wasrequired to quench H2S evolved). After 3 h at reflux, the mixture was allowed to cool and filtered tocollect the precipitated solid. Further product was collected by evaporation in vacuo of the filtrate,addition of H20 (250 mL) and filtration. The combined solids were washed successively with H20 (250 mL), EtOH/MeOH (1:1, 250 mL) and Et20 (250 mL) then dried in vacuo to afford thetriazolopyridine derivative (3) as a solid. The compound was used as such in the next step without anypurification.[00159] 1H ( 400 MHz, DMSO-d6) 8 7.43-7.34 (2H, m, 2 x aromatic-H), 7.24 (lH, dd, J 6.8 and 1.8Hz, aromatic-H), 6.30 (2H, br, NH2); m/z 213/215 (1:1, M+H+, 100%).
	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine; In methanol; ethanol; for 3h;Reflux;	1.1.2.2. Step ii): 5-Bromo-[1,2,4]triazolo[1,5-a]kyridin-2-ylamine To a suspension of hydroxylamine hydrochloride (101.8 g, 1.465 mol) in EtOH/MeOH (1:1, 900 mL) is added N,N-diisopropylethylamine (145.3 mL, 0.879 mol) and the mixture is stirred at room temp. (20 C.) for 1 h. 1-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2) (89.0 g, 0.293 mol) is then added and the mixture slowly heated to reflux (Note: bleach scrubber is required to quench H2S evolved). After 3h at reflux, the mixture is allowed to cool and filtered to collect the precipitated solid. Further product is collected by evaporation in vacuo of the filtrate, addition of H2O (250 mL) and filtration. The combined solids are washed successively with H2O (250 mL), EtOH/MeOH (1:1, 250 mL) and Et2O (250 mL) then dried in vacuo to afford the triazolopyridine derivative (3) as a solid. The compound may be used as such for the next step without any purification. 1H (400 MHz, DMSO-d6) delta 7.43-7.34 (2H, m, 2×aromatic-H), 7.24 (1H, dd, J6.8 and 1.8 Hz, aromatic-H), 6.30 (2H, br, NH2); m/z 213/215 (1:1, M+H+, 100%).
	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine; In methanol; ethanol; at 20℃;Reflux;	Step ii : 5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine To a suspension of hydroxylamine hydrochloride (101.8 g, 1.465 mol) in EtOH/MeOH (1:1, 900 mL) is added N,N-diisopropylethylamine (145.3 mL, 0.879 mol) and the mixture is stirred at room temp. (20 C.) for 1 h. 1-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2) (89.0 g, 0.293 mol) is 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 is allowed to cool and filtered to collect the precipitated solid. Further product is collected by evaporation in vacuo of the filtrate, addition of H2O (250 mL) and filtration. The combined solids are washed successively with H2O (250 mL), EtOH/MeOH (1:1, 250 mL) and Et2O (250 mL) then dried in vacuo to afford the triazolopyridine derivative (3) as a solid. The compound may be used as such for the next step without any purification. 1H (400 MHz, DMSO-d6) delta 7.43-7.34 (2H, m, 2* aromatic-H), 7.24 (1H, dd, J 6.8 and 1.8 Hz, aromatic-H), 6.30 (2H, br, NH2); m/z 213/215 (1:1, M+H+, 100%).
	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine; In methanol; ethanol; for 3h;Reflux;	[0165] To a suspension of hydroxylamine hydrochloride (101.8 g, 1.465 mol) in EtOH/MeOH (1 : 1, 900 mL) is added N,N-diisopropylethylamine (145.3 mL, 0.879 mol) and the mixture is stirred at room temp. (20 C) for 1 h. l-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2) (89.0 g, 0.293 mol) is 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 is allowed to cool and filtered to collect the precipitated solid. Further product is collected by evaporation in vacuo of the filtrate, addition of H20 (250 mL) and filtration. The combined solids are washed successively with H20 (250 mL), EtOH/MeOH (1 : 1, 250 mL) and Et20 (250 mL) then dried in vacuo to afford the triazolopyridine derivative (3) as a solid. The compound may be used as such for the next step without any purification. [0166] lH (400 MHz, DMSO-dg) delta 7.43-7.34 (2H, m, 2 x aromatic-H), 7.24 (1H, dd, J 6.8 and 1.8 Hz, aromatic-H), 6.30 (2H, br, NH2); m/z 213/215 (1 : 1, M+H+, 100%).
6 g	With hydroxylamine hydrochloride; N-ethyl-N,N-diisopropylamine; In ethanol; at 20℃; for 4h;Reflux;	Step 2, 5-bromo-[1,2,4]triazolo[1,5a]pyridin-2-ylamine 10.0g of hydroxylamine hydrochloride was dissolved in 100 ml of ethanol, 14.5 ml of N,N-diisopropylethylamine was added, and the reaction was stirred at room temperature for 1 hour. 9 g of the product of step 1 was then added, and the mixture was heated under reflux. After 3 hours, the mixture was cooled and solid was precipitated. The solid was filtered, washed, and air-dried to afford 6 g of the desired product.

References: [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 5014 - 5021.
[2]Patent: WO2009/155565,2009,A1 .Location in patent: Page/Page column 92-93.
[3]Patent: WO2012/970,2012,A1 .Location in patent: Page/Page column 30-31.
[4]Journal of Medicinal Chemistry,2017,vol. 60,p. 5663 - 5672.
[5]Patent: WO2010/141796,2010,A2 .Location in patent: Page/Page column 182.
[6]Patent: WO2009/17954,2009,A1 .Location in patent: Page/Page column 27; 28.
[7]Patent: WO2010/10187,2010,A1 .Location in patent: Page/Page column 47; 48.
[8]Patent: US2010/29709,2010,A1 .Location in patent: Page/Page column 22.
[9]Patent: US2010/331319,2010,A1 .Location in patent: Page/Page column 11.
[10]Patent: WO2013/189771,2013,A1 .Location in patent: Paragraph 00158; 00159.
[11]Drugs of the Future,2014,vol. 39,p. 547 - 551.
[12]Journal of Medicinal Chemistry,2014,vol. 57,p. 9323 - 9342.
[13]Patent: US2015/224199,2015,A1 .Location in patent: Paragraph 0276-0278.
[14]Patent: US2015/225398,2015,A1 .Location in patent: Paragraph 0268.
[15]Patent: WO2016/165952,2016,A1 .Location in patent: Paragraph 0165-0166.
[16]Patent: EP3492469,2019,A1 .Location in patent: Paragraph 0041; 0042.

6
[ 1010120-55-4 ]
[ 75-36-5 ]
[ 1206101-26-9 ]

Yield	Reaction Conditions	Operation in experiment
		N-(5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-acetamide To a solution of the 5-bromo-2-amino-triazolopyridine (1 eq.) in dry CH3CN at 5 C. is added Et3N (2.5 eq.) followed by acetyl chloride (2.5 eq.). The reaction mixture is then allowed to warm to ambient temperature and stirred until all starting material is consumed. If required, further Et3N (1 eq.) and acid chloride (1 eq.) are added to ensure complete reaction. Following solvent evaporation in vacuo the resultant residue is treated with 7 N methanolic ammonia solution and stirred at ambient temp. (for 16 h) to hydrolyse any bis-acylated product. Product isolation is made by removal of volatiles in vacuo followed by addition of water and extraction with ethyl acetate. The organic phase is then dried over MgSO4, evaporated in vacuo. The compound is used without further purification.

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 9323 - 9342.
[2]Patent: US2010/29709,2010,A1 .Location in patent: Page/Page column 23.

7
[ 1010120-55-4 ]
[ 4023-34-1 ]
[ 1142943-96-1 ]

Yield	Reaction Conditions	Operation in experiment
76%	With triethylamine; In 1,2-dichloro-ethane; at 20℃;	<strong>[1010120-55-4]5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine</strong> (10 g, 50 mmol) and triethylamine (10 g, 100 mmol) in dichloroethane (200 mL) Cyclopropionyl chloride (5.7 g, 55 mmol) was added and stirred at room temperature overnight. After the reaction mixture was diluted, it was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. Purification by silica gel column chromatography gave white solid (10 g, 76%)
58%		Step (Hi)5-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-amine (10.7g, 50mmol) was suspended in acetonitrile (200mL) and DIPEA (9.6mL, 55mmol). Cyclopropanecarbonyl chloride (5.0mL, 55mmol) and 4-(Dimethylamino)pyridine (287mg, 2.35mmol) were added in one portion and the suspension heated at 80C for 18h. After this time the solvents were removed in vacuo and the resulting solid was stirred in ammonia/methanol (2M) for 2h at rt. The solvents were removed in vacuo and the resulting solid was triturated, filtered and washed with diethyl ether (3 x lOOmL) to afford the desired compound as a white solid (8.12g, 58% ). LCMS (method A), (M+H+) 281/283, RT = 0.78min.
56.64%		To <strong>[1010120-55-4]5-bromo-[1,2,4] triazolo[1,5-a]pyridin-2-amine</strong>(15.00 g, 70.41 mmol) and triethylamine(21.4 g, 211.2 mmol), dissolved in acetonitrile(150 mL) was added dropwise cyclopropanecarboxylic acid chloride(8.8 g, 84.5 mmol) at 0C. After adding, the mixture was warmed to room temperature for the reaction for 16 hours. After TLC showed that the reaction was completed through monitoring, the reaction mixture was distilled under reduced pressure. The resulting residue was dissolved in an alcoholic solution of methylamine(150 mL), heated to 80C for the reaction for 1 hour, cooled, distilled under reduced pressure. The resulting residue was dissolved in mixed solution of water(100 mL) and ethyl acetate(200 mL), and the layers were separated and extracted. The combined organic phase was dried with anhydrous sodium sulfate and filtered, and the filtrate was distilled under reduced pressure. The resulting crude product was purified through silica gel column chromatography (eluting with ethyl acetate/petroleum ether =0?70%) to give N-(5-bromo-[1,2,4]triazolo[1,5-a] pyridin-2-yl)cyclopropyl carboxamide (7.2 g, 56.64% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) delta = 11.20 (br. s., 1 H), 7.68 - 7.73 (m, 1 H), 7.52 - 7.58 (m, 1 H), 7.46 - 7.51 (m, 1 H), 1.96 - 2.09 (m, 1 H), 0.82 (d, J=6.28 Hz, 4 H). MS (ESI) Calcd. for C10H9 BrN4O [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 50C 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 rnL), acetone (50 rnL) and Et2O (50 rnL), then dried in vacuo to give the required intermediate (4). In some cases column chromatography (petrol/EtOAc) may be required to obtain pure compounds.
		To a solution of the 2-amino-triazolopyridine (3) (7.10 g, 33.3 mmol) in dry CH3CN (150 mL) at 5 C. 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 the 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 (2×50 mL), acetone (50 mL) and Et2O (50 mL), then dried in vacuo to give the required acyl intermediate (4). In some cases column chromatography (petrol/EtOAc) may be required to obtain pure compounds.
		1.1.3 General Procedure for Mono-Acylation to Afford Intermediate (4) To a solution of the 2-amino-triazolopyridine (3) (7.10 g, 33.3 mmol) in dry CH3CN (150 mL) at 5 C. is added Et3N (11.6 mL, 83.3 mmol) followed by cyclopropanecarbonyl 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 cyclopropanecarbonyl chloride (33.3 mmol) is 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 are collected by filtration, washed with H2O (2*50 mL), acetone (50 mL) and Et2O (50 mL), then dried in vacuo to give the required bromo intermediate (4).
	With triethylamine; In acetonitrile; at 5 - 20℃;	Step iii : Cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide To a solution of the 2-amino-triazolopyridine obtained in the previous step (7.10 g, 33.3 mmol) in dry MeCN (150 mL) at 5 C. is added Et3N (11.6 mL, 83.3 mmol) followed by cyclopropanecarbonyl chloride (83.3 mmol). The reaction mixture is then allowed to warm to ambient temperature and stirred until all starting material is consumed. If required, further Et3N (4.64 mL, 33.3 mmol) and cyclopropanecarbonyl chloride (33.3 mmol) is 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 are collected by filtration, washed with H2O (2*50 mL), acetone (50 mL) and Et2O (50 mL), then dried in vacuo to give the desired compound.
		Step iii : Cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide To a solution of the 2-amino-triazolopyridine obtained in the previous step (7.10 g, 33.3 mmol) in dry MeCN (150 mL) at 5 C. is added Et3N (11.6 mL, 83.3 mmol) followed by cyclopropanecarbonyl chloride (83.3 mmol). The reaction mixture is then allowed to warm to ambient temperature and stirred until all starting material is consumed. If required, further Et3N (4.64 mL, 33.3 mmol) and cyclopropanecarbonyl chloride (33.3 mmol) is 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 are collected by filtration, washed with H2O (2*50 mL), acetone (50 mL) and Et2O (50 mL), then dried in vacuo to give the desired compound.
	With triethylamine; In acetonitrile; at 5 - 20℃;	[0167] To a solution of the 2-amino-triazolopyridine obtained in the previous step (7.10 g, 33.3 mmol) in dry MeCN (150 mL) at 5C is added Et3N (11.6 mL, 83.3 mmol) followed by cyclopropanecarbonyl chloride (83.3 mmol). The reaction mixture is then allowed to warm to ambient temperature and stirred until all starting material is consumed. If required, further Et3N (4.64 mL, 33.3 mmol) and cyclopropanecarbonyl chloride (33.3 mmol) is 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 h-16 h) to hydro lyse any bis-acylated product. Product isolation is made by removal of volatiles in vacuo followed by trituration with Et20 (50 mL). The solids are collected by filtration, washed with H20 (2x50 mL), acetone (50 mL) and Et20 (50 mL), then dried in vacuo to give the desired compound
4.5 g	With pyridine; at -50℃; for 0.166667h;	Add 50mL pyridine to the reaction flask,Cyclopropane chloride (2.9 g, 28 mmol) was added dropwise to the reaction flask at -50C.Stir for 10 minutes,5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (5 g, 23 mmol) was then added to the reaction flaskin,The reaction was stirred overnight at room temperature.After the reaction is completed,Add 100 mL of petroleum ether to the reaction solution.FilteringFilter cake washed twice with petroleum ether, Each time 100mL,Then wash once with 100mL of waterTo get the title product,Earth gray solid 4.5g
4 g	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 5h;	100 ml of 6 dichloromethane and 9 g of 12 diisopropylethylamine were added to 5 g of the product of Step 2. The mixture was cooled to 0 C in an ice bath. 6.1 g of 15 cyclopropanecarbonyl chloride was added dropwise. The mixture became clear after 1 hour of reaction. After the reaction was continued for 4 hours, the reaction system was concentrated to dryness to give an oily 16 solid. Then, a mixed solution of 7 ml of ammonia water and 43 ml of methanol was added to the oily solid under cooling in an ice salt bath, and stirred for about 3 hours. The system became a brown turbid liquid. After filtration by suction, the solid was washed with water and dried to obtain 4 g of the target.

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 9323 - 9342.
[2]Patent: CN108341814,2018,A .Location in patent: Paragraph 0035-0040; 0116.
[3]Patent: WO2012/970,2012,A1 .Location in patent: Page/Page column 31.
[4]Patent: EP3290418,2018,A1 .Location in patent: Paragraph 0077.
[5]Patent: WO2010/10187,2010,A1 .Location in patent: Page/Page column 48-49.
[6]Patent: US2010/29709,2010,A1 .Location in patent: Page/Page column 22.
[7]Patent: US2010/331319,2010,A1 .Location in patent: Page/Page column 11.
[8]Drugs of the Future,2014,vol. 39,p. 547 - 551.
[9]Patent: US2015/224199,2015,A1 .Location in patent: Paragraph 0279.
[10]Patent: US2015/225398,2015,A1 .Location in patent: Paragraph 0269.
[11]Patent: WO2016/165952,2016,A1 .Location in patent: Paragraph 0167.
[12]Patent: CN107759587,2018,A .Location in patent: Paragraph 0255-0256.
[13]Patent: EP3492469,2019,A1 .Location in patent: Paragraph 0043; 0044.

8
[ 1010120-55-4 ]
[ 5720-07-0 ]
[ 1142943-95-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 90 - 140℃;Microwave irradiation;	An appropriate Ar substituted boronic acid derivative (2eq.) is added to a solution of 2-amino-8- bromo-triazolopyridine (Commercially available, BiofocusDPI) in dioxan/water (5: 1). K2CO3 (2 eq.) and PdCl2dppf (5%) are added to the mixture. The resulting mixture is heated in a microwave oven at 1400C for 15-45 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 anhyd. 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-5-Ar-triazolopyridine derivative (2).

References: [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 5014 - 5021.
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 9323 - 9342.
[3]Patent: WO2010/10188,2010,A1 .Location in patent: Page/Page column 47.

9
[ 636-98-6 ]
[ 1010120-55-4 ]
[ 1206195-33-6 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In toluene;Sonographic reaction; Inert atmosphere;	A mixture of 5-Bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine (1 eq), Cs2CO3 (5eq), Pd(OAc)2 (0.1 eq), BINAP (0.1 eq), l-Iodo-4-nitro-benzene (1.5 eq) and 1,4-dioxan was sonicated for 5 minutes under nitrogen. Afterwards, the reaction was left in a sealed tube at 1200C or in a flasked equipped with a cooling system for 16 hrs. The crude mixture was extracted with ethyl acetate and the extracts were combined, washed with water and dried over anhydrous magnesium sulfate. The organic solvent was removed under high vacuum to yield the crude product. The crude product was then purified by preparative HPLC to give the corresponding (5-Bromo-[l,2,4]triazolo[l,5-a]pyridin-2-yl)-(4-nitro-phenyl)-amine.
	With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In 1,4-dioxane;Sonographic reaction; Inert atmosphere;	A mixture of 5-Bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine (1 eq), Cs2CO3 (5eq), Pd(OAc)2 (0.1 eq), BINAP (0.1 eq), 1 -Iodo-4-nitro-benzene (1.5 eq) and 1,4-dioxan was sonicated for 5 minutes under nitrogen. Afterwards, the reaction was left in a sealed tube at 1200C or in a flasked equipped with a cooling system for 16 hrs. The crude mixture was extracted with ethyl acetate and the extracts were combined, washed with water and dried over anhydrous magnesium sulfate. The organic solvent was removed under high vacuum to yield the crude product. The crude product was then purified by preparative HPLC to give the corresponding (5-Bromo-[l,2,4]triazolo[l,5-a]pyridin-2-yl)-(4-nitro-phenyl)-amine

References: [1]Patent: WO2010/10188,2010,A1 .Location in patent: Page/Page column 60.
[2]Patent: WO2010/10189,2010,A1 .Location in patent: Page/Page column 65.

10
[ 591-50-4 ]
[ 1010120-55-4 ]
[ 1206195-26-7 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;palladium diacetate; In 1,4-dioxane;Sonographic reaction; Inert atmosphere;	A mixture of 5-Bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine (1 eq), Cs2CO3 (5eq), Pd(OAc)2 (0.1 eq), Xantphos (0.1 eq.), Iodobenzene (1.5 eq) and 1,4-dioxane were sonicated for 5 minutes under nitrogen. Afterwards, the reaction was left in a sealed tube at 1000C or in a flasked equipped with a cooling system for 5 hrs. The crude mixture was extracted with ethyl acetate and the extracts were combined, washed with water and dried over anhydrous magnesium sulfate. The organic solvent was removed under high vacuum to yield the crude product. The crude product was purified by flash chromatography.
	With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;palladium diacetate; In 1,4-dioxane;Sonographic reaction;	A mixture of 5-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine (1 eq), Cs2CO3 (5eq), Pd(OAc)2 (0.1 eq), Xantphos (0.1 eq.), iodobenzene (1.5 eq) and 1,4-dioxane is sonicated for 5 minutes under nitrogen. Afterwards, the reaction is left in a sealed tube at 1000C or in a flask equipped with a cooling system for 5 hrs. The crude 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 may be purified by flash chromatography.

References: [1]Patent: WO2010/10188,2010,A1 .Location in patent: Page/Page column 49; 50.
[2]Patent: WO2010/10189,2010,A1 .Location in patent: Page/Page column 55.

11
[ 1010120-55-4 ]
[ 51934-41-9 ]
[ 1206195-39-2 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In 1,4-dioxane;Sonographic reaction; Inert atmosphere;	A mixture of 5-Bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine (1 eq), Cs2CO3 (5eq), Pd(OAc)2 (0.1 eq), BINAP (0.1 eq), 4-Iodo-benzoic acid ethyl ester (1.5 eq) and 1,4-dioxane was sonicated for 5 minutes under nitrogen. Afterwards, the reaction was left in a sealed tube at 1200C or in a flasked equipped with a cooling system for 16 hrs. The crude mixture was extracted with ethyl acetate and the extracts were combined, washed with water and dried over anhydrous magnesium sulfate. The organic solvent was removed under high vacuum to yield the crude product. The product was used in the next step without futher purification.

References: [1]Patent: WO2010/10188,2010,A1 .Location in patent: Page/Page column 66.

12
[ 1010120-55-4 ]
[ 619-44-3 ]
[ 1206195-27-8 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;palladium diacetate; In 1,4-dioxane;Sonographic reaction; Inert atmosphere;	A mixture of 5-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine (1 eq), Cs2CO3 (5eq), Pd(OAc)2 (0.1 eq), Xantphos (0.1 eq.), 4-Iodo-benzoic acid methyl ester (1.5 eq) and 1,4-dioxane was sonicated for 5 minutes under nitrogen. Afterwards, the reaction was left in a sealed tube at 1000C or in a flasked equipped with a cooling system for 5 hrs. The crude mixture was extracted with ethyl acetate and the extracts were combined, washed with water and dried over anhydrous magnesium sulfate. The organic solvent was removed under high vacuum to yield the crude product. The crude product was purified by flash chromatography.
	With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;palladium diacetate; In 1,4-dioxane;Sonographic reaction;	A mixture of 5-Bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine (1 eq), Cs2CO3 (5eq), Pd(OAc)2 (0.1 eq), Xantphos (0.1 eq.), 4-Iodo-benzoic acid methyl ester (1.5 eq) and 1,4-dioxane was sonicated for 5 minutes under nitrogen. Afterwards, the reaction was left in a sealed tube at 1000C or in a flasked equipped with a cooling system for 5 hrs. The crude mixture was extracted with ethyl acetate and the extracts were combined, washed with water and dried over anhydrous magnesium sulfate. The organic solvent was removed under high vacuum to yield the crude product. The crude product was purified by flash chromatography.

References: [1]Patent: WO2010/10188,2010,A1 .Location in patent: Page/Page column 51.
[2]Patent: WO2010/10189,2010,A1 .Location in patent: Page/Page column 61.

13
[ 389621-83-4 ]
[ 1010120-55-4 ]
C₁₈H₁₉N₅O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water;	An appropriate Ar substituted boronic acid derivative (2eq.) is added to a solution of 2-amino-8-bromo-triazolopyridine (Commercially available, BiofocusDPI) in dioxan/water (5:1). K2CO3 (2 eq.) and PdC^dppf (5%) are added to the mixture. The resulting mixture is heated in a microwave oven at 1400C for 15-45 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 anhyd. 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-5-Ar-triazolopyridine derivative (2).

References: [1]Patent: WO2010/10189,2010,A1 .Location in patent: Page/Page column 53-54.

14
[ 1010120-55-4 ]
[ 4334-88-7 ]
[ 1206594-04-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 140℃; under 7757.43 Torr; for 1h;Microwave irradiation;	4-Ethoxycarbonyl-phenylboronic acid (2eq.) was added to a solution of 5-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine in dioxane/water (5:1) K2CO3 (2 eq.) and PdCl2dppf (cat.) were added to the mixture. The resultion mixture was subjected to macrowave: T: 1400C, 60 min, Wmax: 150, Pmax: 150 PSI. The crude of the reaction was diluted with water. The product was extracted with ethyl acetate (3 times). The organic layers were dried with MgSO4. The solvent was removed under high vacuum to afford a brown solid used in the next step without further purification.

References: [1]Patent: WO2010/10189,2010,A1 .Location in patent: Page/Page column 63.

15
[ 1010120-55-4 ]
[ 149104-88-1 ]
[ 1257704-24-7 ]

Yield	Reaction Conditions	Operation in experiment
33%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; N,N-dimethyl-formamide; at 80℃; for 18h;Inert atmosphere; Sealed tube;	A dry tube was charged with tetrakis(triphenylphopshine)palladium(0) (1.29 g, 1.1 mmol), 5-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine (2.98 g, 14.0 mmol), (4- methylsulfonylphenyl) boronic acid (3.08 g, 15.4 mmol), sodium carbonate (3.26 g, 31.04 mmol), dioxane (30 mL), N,N-dimethylformamide (60 mL) and water (30 mL). The tube was evacuated with a high vacuum and backflushed under a stream of nitrogen three times. 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 evaporated under reduced pressure. Water (100 mL) was added and solution extracted with dichloromethane (3 portions of 50 mL). The combined organic was dried over magnesium sulfate, filtered and evaporated. The solid was triturated with ether/dichloromethane (4:1; 10 mL), filtered and rinsed with ether. The recovered material was consistent for 5-(4-methanesulfonyl-phenyl)-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine (1.3 g, 33%). 1H NMR (400 MHz, CDCl3, delta, ppm): 8.21 (d, J = 8.0 Hz, 2H) 8.08 (d, J = 8.0 Hz, 2H), 7.55 (m, IH), 7.44 (d, J = 9.1 Hz, IH), 7.13 (d, J = 7.5 Hz, IH), 6.10 (br s, 2H) 3.31 (s, 3H). MS = 289 (MH)+.

References: [1]Patent: WO2010/141796,2010,A2 .Location in patent: Page/Page column 182; 183.

16
[ 747413-23-6 ]
[ 1010120-55-4 ]
[ 1257705-09-1 ]

Yield	Reaction Conditions	Operation in experiment
79%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; N,N-dimethyl-formamide; at 80℃; for 18h;Inert atmosphere; Sealed tube;Product distribution / selectivity;	5- {4-[(l , 1 -dioxidothiomorpholin-4-yl)methyl]phenyl} [ 1 ,2,4]triazolo[ 1 ,5-a]pyridin- 2-amine was prepared from 5-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine (368 mg, 1.73 mmol) and 4-[(4-boronophenyl)methyl]-thiomorpholine 1,1-dioxide (0.512 mg, 1.90 mmol), in a manner analogous to Step 73c. The residue was purified on a 12 g Isco silica gel column using a gradient of 0-15% methanol in dichloromethane as an eluent. 5- {4- [(1,1 -dioxidothiomorpholin-4-yl)methyl]phenyl} [ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-amine (490 mg, 79 %) was isolated as a beige foam. 1H NMR (400 MHz, (D3C)2SO, delta, ppm): 7.93 (d, J = 8.5 Hz, 2H), 7.50 (m, 3H), 7.37 (d, J = 7.8 Hz, IH), 7.07 (d, J= 7.8 Hz, IH), 6.02 (s, 2H), 3.78 (s, 2H), 3.15 (s, 4H), 2.91 (s, 4H). MS = 358 (MH)+.

References: [1]Patent: WO2010/141796,2010,A2 .Location in patent: Page/Page column 197; 198.

17
[ 1010120-55-4 ]
[ 364794-79-6 ]
[ 1202490-76-3 ]

Yield	Reaction Conditions	Operation in experiment
69%	With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 140℃; for 1h;Microwave irradiation;	A solution of 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzyl)morpholine (1.9 g, 6.3 mmol), 5-bromo-[l,2,4]triazolo[l,5- a]pyridine-2-amine (1 g, 5 mmol), 1,1'- bis(diphenylphosphino)ferrocenepalladium(II) chloride (250 mg, 0.63 mmol), and cesium carbonate (4.1 g, 12.6 mmol) in 10:1 dimethoxyethane / water (11 mL) was heated at 140 0C under microwave radiation for 1 h. The reaction mixture was diluted with ethyl acetate (200 mL), and the resulting suspension was filtered through celite. The filtrate was concentrated, and the resulting residue was purified by flash column chromatography (petroleum ether -> ethyl acetate) to provide product (1 g, 69% yield). LCMS (ESI) 310.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 90℃;Reflux;	In a 25 ml round-bottom flask, 2 ml of water and 10 ml of 1,4-dioxane were added and the mixture was stirred well.Further, 2.85 g (9.40 mmol) of 4- (4-morpholinomethyl) phenylboronic acid pinacol ester was added,(0.63 mmol) of K2CO3, 0.34 g (0.46 mmol) of PdCl2dppf,(9.29 mmol) of 5-bromo - [1,2,4] triazolo [1,5-a] pyridin-2-amine was added thereto, followed by stirring at room temperature for 10 minutes.The reaction solution was yellow; the reaction bottle transferred to the oil bath 90 reflux, 1 hour after the reaction liquid from yellow to black,The reaction was continued for 3-5 hours and the reaction was terminated by TLC until the end of the reaction (developing solvent: 5% CH3OH / CH2Cl2). The reaction mixture was then quenched by the addition of 10 ml of water, transferred to a 50 ml beaker, extracted with CH2Cl2 (3 x 50 ml)1 g of anhydrous magnesium sulfate was added thereto, followed by filtration, concentration, drying, and separation by silica gel column chromatography (silica gel 10 g, elution:0% - & gt; 2.0% CH3OH / CH2Cl2). The product was a pale yellow solid, yield and yield: 2.65 g (92%). The product 500 mg was weighed into a 20 ml ampoule,Slowly add 50 C hot ethanol,Constantly shake to the product completely dissolved,Transferred to the dark closed at room temperature overnight,After 12 hours,To give colorless product Form A.

References: [1]Patent: WO2009/155565,2009,A1 .Location in patent: Page/Page column 144.
[2]Patent: CN106117202,2016,A .Location in patent: Paragraph 0033 - 0044.

18
[ 1010120-55-4 ]
[ 216019-28-2 ]
[ 1202486-18-7 ]

Yield	Reaction Conditions	Operation in experiment
63%	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In water; acetonitrile; at 160℃; for 0.0333333h;Microwave irradiation;	A biphasic solution of 5-bromo[l,2,4]triazolo[l,5-a]pyridin-2-amine (0.800 g, 3.76 mmol, 1.00 equiv), 3-(2-propyl)phenyl boronic acid (0.739 g, 4.51 mmol, 1.20 equiv), bis(triphenylphosphine)palladium(II) chloride (0.264 g, 0.376 mmol, 0.100 equiv) in acetonitrile (6 mL) and l.OM sodium carbonate aqueous solution (6 mL) was heated in the microwave to 160 0C for2 min. The reaction mixture was partitioned between saturated aqueous sodium chloride solution (10 mL) and ethyl acetate (20 mL). The collected organic was dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification by flash column chromatography (2.5% methanol in dichoromethane) afforded product as a sticky solid (567 mg, 63%). 1HNMR (500 MHz, CDCl3), delta: 7.74 (m, 1 H), 7.68 (m, 1 H), 7.36-7.48 (m, 4 H), 6.79 (dd, J= 7.2, 1.3 Hz, 1 H), 4.46 (br s, 2 H), 3.01 (m, 1 H), 1.31 (d, J= 6.9 Hz, 6 H).

References: [1]Patent: WO2009/155565,2009,A1 .Location in patent: Page/Page column 93.

19
[ 4045-24-3 ]
[ 1010120-55-4 ]
[ 1202490-73-0 ]

Yield	Reaction Conditions	Operation in experiment
67%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); XPhos; In N,N-dimethyl-formamide; at 180℃; for 0.25h;Microwave irradiation;	A suspension of 5-bromo[l,2,4]triazolo[l,5-alpha]pyridin-2-amine (69.2 mg, 0.325 mmol, 1 equiv), 4-methoxypiperidine (150 mg, 1.3 mmol, 4.0 equiv), cesium carbonate (212 mg, 0.652 mmol, 2.00 equiv), XPhos (16.9 mg,0.0354 mmol, 0.109 equiv), and tris(dibenzylideneacetone)dipalladium (0) (9.3 mg, 0.010 mmol, 0.031 equiv) in N,7V-dimethylformamide (2 mL) was heated to 180 C in the microwave for 15 min. The reaction mixture was concentrated in vacuo. The resulting residue was partitioned between ethyl acetate (5 mL) and saturated aqueous sodium chloride solution (5 mL). The aqueous was extracted with ethyl acetate (2 x 5 mL). The combine organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromotagraphy (95:5 dichloromethane / methanol) afforded a white solid (557 mg, 67%). LCMS (ESI) w/z:248.3. 1H NMR (500 MHz, CDCl3), delta: 7.32 (m, 1 H), 7.05 (m, 1 H), 6.23 (m, 1 H), 4.39(br s, 2 H), 3.66 (m, 2 H), 3.48 (m, 1 H), 3.41 (s, 3 H), 3.18 (m, 2 H), 2.08 (m, 2 H), 1.89 (m, 2 H).

References: [1]Patent: WO2009/155565,2009,A1 .Location in patent: Page/Page column 101.

20
[ 19798-81-3 ]
[ 1010120-55-4 ]

References: [1]CrystEngComm,2018,vol. 20,p. 3006 - 3010.
[2]Patent: WO2012/970,2012,A1 .
[3]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 5014 - 5021.
[4]Patent: WO2013/189771,2013,A1 .
[5]Drugs of the Future,2014,vol. 39,p. 547 - 551.
[6]Journal of Medicinal Chemistry,2014,vol. 57,p. 9323 - 9342.
[7]Patent: US2015/224199,2015,A1 .
[8]Patent: US2015/225398,2015,A1 .
[9]Patent: WO2016/165952,2016,A1 .
[10]Journal of Medicinal Chemistry,2017,vol. 60,p. 5663 - 5672.
[11]Patent: WO2009/155565,2009,A1 .
[12]Patent: EP3492469,2019,A1 .

21
[ 1010120-55-4 ]
[ 1202490-65-0 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 5014 - 5021.
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 9323 - 9342.

22
[ 1010120-55-4 ]
[ 1202483-45-1 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 5014 - 5021.

23
[ 1092563-25-1 ]
[ 1010120-55-4 ]
[ 1257705-09-1 ]

Yield	Reaction Conditions	Operation in experiment
54%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 16h;Inert atmosphere;	5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (30.00 g, 0.14 mol) was added to a 1L three-necked bottle,To which 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolane-2-yl)-benzyl]-1,1-diyl is added successively oxygen-1-Thiomorpholine (58.50 g, 0.15 mol),Dioxane (400 mL),Potassium carbonate (58.60g, 0.42mol),Water (100mL),Pd(dppf)Cl2 (5.78 g, 0.007 mol).Under argon protection,The mixture was warmed to 90 C and the reaction was stirred for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, 400 mL of dichloromethane was added, and then washed twice with 800 mL of water each time. The organic layer was concentrated to dryness and the residue was purified by column chromatography (eluent: dichloromethane:methanol= 100:1), the title product was obtained as a pale yellow solid 27.2 g, yield 54%.
54%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 16h;Inert atmosphere;	3-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (purchased from Mesh Mall) 30.00 g (0.14 mol) was added to a 1L three-necked bottle,4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzyl) is added thereto in this orderThiomorpholine 1,1-dioxide 58.50 g (0.15 mol), dioxane 400 ml, potassium carbonate 58.60 g (0.42 mol), water 100 ml, Pd(dppf)Cl2 5.78 g (0.007 mol).Under argon protection, the mixture was warmed to 90 C and the reaction was stirred for 16 h.After the reaction is completed, cool to room temperature, add 400 ml of dichloromethane, then wash twice with water, 800 ml each time, and concentrate the organic layer to dryness.The residue was purified by column chromatography (eluent: dichloromethane:methanol = 100:1) to give the title product as a pale yellow solid, 27.2 g, 54% yield, purity 96%.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; at 90℃; for 16h;Inert atmosphere; Heating;	4-[ 4-( 4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-benzyl]-thiomorpholine-1, 1-dioxide(1.1eq.) was added to a solution of 5-bromo-[1,2,4]triazolo[1,5-a]pyrid in-2-ylamine (4:1). K2C03 (2eq.) and PdCbdppf (0.03 eq.) were added to the solution. The resulting mixture was then heated in anoil bath at 90C for 16h under N 2. Water was added and the solution was extracted with ethyl acetate.The organic layers were dried over anhydrous MgS04 and evaporated in vacuo. The final compoundwas obtained after purification by flash chromatography.[00162] 1H (400 MHz, CDCh) 8 7.94-7.92 (d, 2H), 7.52-7.48 (m, 3H), 7.37-7.34 (m, 1H), 7.02-7.00(m, 1H), 6.00 (d, 2H), 3.76 (d, 2H), 3.15-3.13 (m, 4H), 2.93-2.91 (m, 4H).[00163] m/z 358.2 (M+H+, 100%).

With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 85 - 90℃;

4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)benzyl)thiomorpholine 1,1-dioxide (2 eq) of Formula (III) was added to a solution of <strong>[1010120-55-4]5-Bromo-[1,2,4]Triazolo[1,5-a]pyridine-2-ylamine</strong> of Formula (II) in 1,4-dioxane/ water (5:1). Cesium carbonate Cs2CO3 (2 eq.) and PdCl2dppf (0.05%) was added to above solution. The resulting mixture was then heated in at 85-90 C. Water was added and to obtain 4-(4-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)benzyl)thiomorpholine1,1-dioxide compound of Formula (IV).

References: [1]Patent: CN107759587,2018,A .Location in patent: Paragraph 0222-0223.
[2]Patent: CN107880038,2018,A .Location in patent: Paragraph 0164; 0165; 0168; 0169.
[3]Patent: WO2013/189771,2013,A1 .Location in patent: Paragraph 00161; 00162; 00163.
[4]Patent: US2020/62744,2020,A1 .Location in patent: Paragraph 0078-0079.

24
[ 1010120-55-4 ]
[ 1142936-49-9 ]

References: [1]Drugs of the Future,2014,vol. 39,p. 547 - 551.
[2]Patent: US2015/224199,2015,A1 .
[3]Patent: US2015/225398,2015,A1 .
[4]Patent: WO2016/165952,2016,A1 .
[5]Patent: CN107759587,2018,A .

25
[ 1010120-55-4 ]
[ 1206163-59-8 ]

26
[ 1010120-55-4 ]
[ 1206161-97-8 ]

References: [1]Drugs of the Future,2014,vol. 39,p. 547 - 551.
[2]Drugs of the Future,2014,vol. 39,p. 547 - 551.
[3]Journal of Medicinal Chemistry,2014,vol. 57,p. 9323 - 9342.
[4]Patent: US2015/224199,2015,A1 .
[5]Patent: US2015/224199,2015,A1 .
[6]Patent: US2015/225398,2015,A1 .
[7]Patent: US2015/225398,2015,A1 .
[8]Patent: WO2016/165952,2016,A1 .
[9]Patent: WO2016/165952,2016,A1 .
[10]Patent: CN107759587,2018,A .

27
[ 1010120-55-4 ]
C₁₅H₁₆N₄O [ No CAS ]