[ CAS No. 912773-21-8 ] {[proInfo.proName]}

Name: 912773-21-8|2-Bromo-5-chloropyrazine|97%
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SKU: A225706
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Quality Control of [ 912773-21-8 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 912773-21-8 ]

SDS Specification

Alternatived Products of [ 912773-21-8 ]

Product Details of [ 912773-21-8 ]

CAS No. :	912773-21-8	MDL No. :	MFCD08460074
Formula :	C₄H₂BrClN₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UXCPLGLOAZWCKO-UHFFFAOYSA-N
M.W :	193.43	Pubchem ID :	37818725
Synonyms :

Calculated chemistry of [ 912773-21-8 ]

Physicochemical Properties

Num. heavy atoms :	8
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	34.74
TPSA :	25.78 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) :	-6.32 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.6
Log Po/w (XLOGP3) :	1.64
Log Po/w (WLOGP) :	1.89
Log Po/w (MLOGP) :	0.58
Log Po/w (SILICOS-IT) :	2.38
Consensus Log Po/w :	1.62

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.63
Solubility :	0.456 mg/ml ; 0.00236 mol/l
Class :	Soluble
Log S (Ali) :	-1.79
Solubility :	3.11 mg/ml ; 0.0161 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.12
Solubility :	0.145 mg/ml ; 0.000752 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.31

Safety of [ 912773-21-8 ]

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 [ 912773-21-8 ]

* 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 [ 912773-21-8 ]

[ 912773-21-8 ] Synthesis Path-Downstream 1~25

1
[ 667-27-6 ]
[ 912773-21-8 ]
[ 1416806-20-6 ]

Yield	Reaction Conditions	Operation in experiment
70%		Preparation of ethyl 2-(5-chloropyrazin-2-yl)-2,2-difluoroacetate (39A) To a suspension of copper powder (244 g, 3877 mmol) in DMSO (5000 mL) was added ethyl 2-bromo-2,2-difluoroacetate (394 g, 1939 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 1 hour. 2-Bromo-5-chloropyrazine (250 g, 1292 mmol) was added to the reaction mixture portion-wise. The reaction mixture was stirred at ambient temperature for 3 hours. After the completion of reaction (monitored by TLC), the reaction mixture was quenched with aq. NH4C1 (2.0 L), filtrate through celite pad and filtrate was extracted with ethyl acetate (2 x 2 L). The combined organic extracts were dried over sodium sulfate and concentration under reduced pressure to get crude residue, which was purified by column chromatography (60-120 silica mesh, mobile phase 0- 2% ethyl acetate in hexane) affording ethyl 2-(5-chloropyrazin-2-yl)-2,2-difluoroacetate (39A) (215 g, 70% yield) as viscous clear liquid. lH NMR (400 MHz, DMSO-t/6) delta 9.05 (d, J = 1.4 Hz, 1H), 8.98 (dd, J= 1.4, 0.7 Hz, 1H), 4.39 - 4.34 (m, 2H), 1.24 (t, J= 7.1 Hz, 3H).
70%		To a suspension of copper(O) powder (244 g, 3877 mmol) in DMSO (5 L) was added ethyl 2-bromo-2,2-difluoroacetate (394 g, 1939 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour and <strong>[912773-21-8]2-bromo-5-chloropyrazine</strong> (Shanghai Fchemicals Technology Co., Ltd., Shanghai, China) (250 g, 1292 mmol) was added in portion-wise. The reaction mixture was stirred at room temperature for 3 hours, and quenched with sat'd solution of ammonia chloride (2.0 L). The mixture was filtered through a celite pad and the filtrate was extracted with EtOAc (2 x 2 L). The combined solution was dried over Na2S04 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 - 2% EtOAc in hexanes) to afford 9a (215 g, 70% yield) as a viscous colorless liquid. NMR (400 MHz, DMSO- 6) delta 9.05 (d, J= 1.4 Hz, 1H), 8.98 (dd, J= 1.4, 0.7 Hz, 1H), 4.39 - 4.34 (m, 2H), 1.24 (t, J= 7.1 Hz, 3H).
70%		To a suspension of copper(O) powder (244 g, 3877 mmol) in DMSO (5 L) was added ethyl 2-bromo-2,2-difluoroacetate (394 g, 1939 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour and <strong>[912773-21-8]2-bromo-5-chloropyrazine</strong> (Shanghai Fchemicals Technology Co., Ltd., Shanghai, China) (250 g, 1292 mmol) was added in a portion-wise manner. The reaction mixture was stirred at room temperature for 3 hours then quenched with sat'd aqueous ammonia chloride (2.0 L). The mixture was filtered through a celite pad and the filtrate was extracted with ethyl acetate (2 x 2 L). The combined organic layers were dried over Na2SC>4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 2% ethyl acetate in hexanes) to afford 3a (215 g, 70% yield) as a viscous colorless liquid. NMR (400 MHz, DMSO-t/6) delta 9.05 (d, J= 1.4 Hz, 1H), 8.98 (dd, J= 1.4, 0.7 Hz, 1H), 4.39 - 4.34 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H).

70%		To a suspension of copper (0) powder (244 g, 3880 mmol) in DMSO (5 L) was added ethyl 2-bromo-2,2-difluoroacetate (394 g, 1940 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour and <strong>[912773-21-8]2-bromo-5-chloropyrazine</strong> (Shanghai Fchemicals Technology Co., Ltd., Shanghai, China) (250 g, 1290 mmol) was added in portion-wise manner. The reaction mixture was stirred at room temperature for 3 hours, then quenched with sat'd solution of ammonium chloride (2.0 L). The mixture was filtered through a celite pad and the filtrate was extracted with ethyl acetate (2 x 2 L). The combined organic layers were dried over Na2S04 and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0 to 2% ethyl acetate in hexanes) to afford 4a (215 g, 70% yield) as a viscous colorless liquid. NMR (400 MHz, DMSO-t/6) delta 9.05 (d, J = 1.4 Hz, 1H), 8.98 (dd, J= 1.4, 0.7 Hz, 1H), 4.39 - 4.34 (m, 2H), 1.24 (t, J= 7.1 Hz, 3H).
70%		To a suspension of copper (0) powder (244 g, 3877 mmol) in DMSO (5 L) was added ethyl 2-bromo-2,2-difluoroacetate (394 g, 1939 mmol) at RT. The reaction mixture was stirred at RT for 1 h and <strong>[912773-21-8]2-bromo-5-chloropyrazine</strong> (Shanghai Fchemicals Technology Co., Ltd., Shanghai, China) (250 g, 1292 mmol) was added in portion-wise manner. The reaction mixture was stirred at RT for 3 h, and quenched with sat'd solution of ammonium chloride (2.0 L). The mixture was filtered through a celite pad and the filtrate was extracted with ethyl acetate (2 x 2 L). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 - 2% ethyl acetate in hexanes) to afford 11a (215 g, 70% yield) as a viscous colorless liquid. 1H NMR (400 MHz, DMSO-d6) _ 9.05 (d, J = 1.4 Hz, 1H), 8.98 (dd, J = 1.4, 0.7 Hz, 1H), 4.39- 4.34 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H).
54.5%		To a stirred suspension of copper powder (1.48 g, 23.30 mmol) in DMSO (20 mL) was added ethyl bromodifluoroacetate (1.6 mL, 11.65 mmol) at RT and stirred at RT for 1 h under inert atmosphere. A solution of <strong>[912773-21-8]2-bromo-5-chloropyrazine</strong> AS (1.5 g, 7.77 mmol) in DMSO (5 mL) was added to the reaction mixture and stirring was continued for another 16 h at RT. After complete consumption of the starting material (by TLC), the reaction was diluted with saturated aqueous NH4C1 solution (100 mL), filtered through a pad of celite and washed celite cake with DCM (3 x 75 mL). The collected filtrate was washed with water (100 mL), brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude. The crude material was purified by silica gel column chromatography (eluent: 5% EtOAc/Hexane) to afford ester AT (1.0 g, 4.23 mmol, 54.5%) as a pale yellow syrup. 1H NMR (500 MHz, CDC13): delta 8.78 (s, 1H), 8.62 (s, 1H), 4.38 (q, / = 7.0 Hz, 2H), 1.34 (t, / = 7.0 Hz, 3H).
31%		Example 19 1-(5-Chloropyrazin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (49) To a stirred suspension of copper powder (3.0 g, 46.51 mmol) in DMSO (10 mL) was added ethyl 2-bromo-2,2-difluoroacetate (4.7 g, 23.15 mmol) at RT, and the mixture was stirred at RT for 1 h under inert atmosphere. A solution of <strong>[912773-21-8]2-bromo-5-chloropyrazine</strong> (3.0 g, 15.54 mmol) in DMSO (20 mL) was added to the reaction mixture, and stirring was continued for another 16 h at RT. After the consumption of starting material (by TLC), the reaction mixture was diluted with aq NH4Cl solution (40 mL), filtered through a Celite pad and washed with CH2Cl2 (3*25 mL). The collected filtrate was washed with H2O (30 mL) and brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude material. Purification by column chromatography (eluting with 20% EtOAc/hexane) afforded ester AS (1.12 g, 4.73 mmol, 31%) as a liquid. 1H NMR (500 MHz, CDCl3): delta 8.78 (s, 1H), 8.62 (s, 1H), 4.38 (q, J=7.0 Hz, 2H), 1.37 (t, J=7.0 Hz, 3H).
	With copper; In dimethyl sulfoxide;	20. Reaction of <strong>[912773-21-8]2-bromo-5-chloropyrazine</strong> with copper powder and ethyl bromo(difluoro)acetate in dimethyl sulfoxide provided ethyl (5-chloropyrazin-2- yl)(difluoro)acetate. Reduction to the alcohol with sodium borohydride in ethanol was followed by methyl ether formation with iodomethane and silver(l) oxide. The resulting 2-chloro-5-(1 , 1 -difluoro-2-methoxyethyl)pyrazine was reacted with carbon monoxide, 1 - propanol, [(R)-(+)-1 , 1 '-binaphthalene-2,2'-diylbis(diphenylphosphane)]palladium(ll) chloride, and triethylamine, followed by ester hydrolysis with sodium hydroxide in aqueous tetrahydrofuran, to provide the requisite 5-(1 , 1 -difluoro-2- methoxyethyl)pyrazine-2-carboxylic acid.

Reference： [1]Patent: WO2017/24180,2017,A1 .Location in patent: Page/Page column 256-257
[2]Patent: WO2018/112084,2018,A1 .Location in patent: Page/Page column 64
[3]Patent: WO2018/112083,2018,A1 .Location in patent: Page/Page column 37
[4]Patent: WO2018/112081,2018,A1 .Location in patent: Page/Page column 45-46
[5]Patent: WO2018/112094,2018,A1 .Location in patent: Page/Page column 84-85
[6]Patent: WO2013/90210,2013,A1 .Location in patent: Page/Page column 86
[7]Patent: US2012/329802,2012,A1 .Location in patent: Page/Page column 34
[8]Patent: WO2015/155626,2015,A1 .Location in patent: Page/Page column 123

2
[ 912773-21-8 ]
[ 67-64-1 ]
[ 1240596-83-1 ]

Yield	Reaction Conditions	Operation in experiment
28.1%		To a suspension of <strong>[912773-21-8]2-bromo-5-chloropyrazine</strong> (2.02 g, 10.44 mmol) in diethylether (30 mL)at -78 oC was added n-butyllithium (4.26 mL, 10.65 mmol) over 10 mm.The resulting mixture was stirred at -78 oC for 15 mm before propan-2-one (1.9 17 mL, 26.1 mmol) was indroduced over 2 mm. The mixture was stirred at -78 oC for 15 mm and then at rt for 30 mm. The reaction was quenched with saturated NH4C1 solution (30 mL), and the solution was extracted with ethyl acetate (4 x 40 mL). The combined extract wasdried over anhydrous Na2SO4. The desired product, 2-(5-chloropyrazin-2-yl)propan-2-ol (0.507 g, 2.94 mmol, 28.1 % yield), was isolated by ISCO (120 g silica gel, solid loading, 10-40% ethyl acetate/hexane).

Reference： [1]Patent: WO2015/89143,2015,A1 .Location in patent: Page/Page column 185; 186

3
[ 912773-21-8 ]
N-[(1S,2S)-2-aminocyclopentyl]-2-(2H-1,2_,3-triazol-2-yl)benzamide hydrochloride [ No CAS ]
[ 411235-57-9 ]
N-[(1S,2S)-2-[(5-cyclopropylpyrazin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benz amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 30a and 30b: N-[(1S,2S)-2-[(5-Bromopyrazin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 30a) and N-[(1S,2S)-2-[(5-Chloropyrazin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 30b) A solution of N-[(1S,2S)-2-aminocyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 4; 1.00 g, 3.25 mmol), <strong>[912773-21-8]2-bromo-5-chloropyrazine</strong> (CAS number 912773-21-8; 0.691 g, 3.57 mmol) and DIPEA (1.7 ml, 9.75 mmol) in DMSO (11 ml) was subjected to microwave irradiation at 140 C. for 3 hours. The reaction was partitioned between ethyl acetate and water, washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. This was then purified by column chromatography (silica, 0-100% ethyl acetate/petrol then 0-20% methanol ethyl acetate) to afford title compound as a mixture of both products Example 112 N-[(1S,2S)-2-[(5-Cyclopropylpyrazin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide A mixture of N-[(1S,2S)-2-[(5-bromopyrazin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide and N-[(1S,2S)-2-[(5-chloropyrazin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 30a and 30b; 100 mg, 0.23 mmol), cyclopropylboronic acid (CAS number 411235-57-9; 60 mg, 0.70 mmol), sodium carbonate (aq. 2 M, 350 mul, 0.70 mmol) and tetrakis(triphenylphosphine)palladium (27 mg, 0.023 mmol) in 1,4-dioxane (778 mul) was sealed, purged and evacuated with nitrogen and then subjected to microwave irradiation at 100 C. for 1 hour. To this was then added further cyclopropylboronic acid (CAS number 411235-57-9; 60 mg, 0.70 mmol) and tetrakis(triphenylphosphine)palladium (27 mg, 0.023 mmol). The reaction was sealed, purged and evacuated with nitrogen and again subjected to microwave irradiation at 140 C. for 20 minutes. The reaction was partitioned between ethyl acetate and water, washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) and then purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% formic acid) and further purified by column chromatography (basic silica, 0-100% ethyl acetate/petrol) to afford the title compound. 1H NMR (400 MHz, DCM-d2) delta ppm 0.77-0.92 (m, 4H), 1.40-1.60 (m, 2H), 1.68-1.94 (m, 3H), 2.14-2.29 (m, 2H), 3.80-3.91 (m, 1H), 3.99-4.10 (m, 1H), 6.65-6.73 (m, 1H), 7.43-7.59 (m, 4H), 7.64 (s, 2H), 7.68-7.72 (m, 1H), 7.74-7.78 (m, 1H) and 7.84 (br. s., 1H). MS ES+: 390

Reference： [1]Patent: US2015/232460,2015,A1 .Location in patent: Paragraph 0630-0631; 1256-1259

4
[ 912773-21-8 ]
N-[(1S,2S)-2-aminocyclopentyl]-2-(2H-1,2_,3-triazol-2-yl)benzamide hydrochloride [ No CAS ]
[ 126726-62-3 ]
N-[(1S,2S)-2-[5-(propan-2-yl)pyrazin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 30a and 30b: N-[(1S,2S)-2-[(5-Bromopyrazin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 30a) and N-[(1S,2S)-2-[(5-Chloropyrazin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 30b) A solution of N-[(1S,2S)-2-aminocyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 4; 1.00 g, 3.25 mmol), <strong>[912773-21-8]2-bromo-5-chloropyrazine</strong> (CAS number 912773-21-8; 0.691 g, 3.57 mmol) and DIPEA (1.7 ml, 9.75 mmol) in DMSO (11 ml) was subjected to microwave irradiation at 140 C. for 3 hours. The reaction was partitioned between ethyl acetate and water, washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. This was then purified by column chromatography (silica, 0-100% ethyl acetate/petrol then 0-20% methanol ethyl acetate) to afford title compound as a mixture of both products Example 112 N-[(1S,2S)-2-[(5-Cyclopropylpyrazin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide A mixture of N-[(1S,2S)-2-[(5-bromopyrazin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide and N-[(1S,2S)-2-[(5-chloropyrazin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 30a and 30b; 100 mg, 0.23 mmol), cyclopropylboronic acid (CAS number 411235-57-9; 60 mg, 0.70 mmol), sodium carbonate (aq. 2 M, 350 mul, 0.70 mmol) and tetrakis(triphenylphosphine)palladium (27 mg, 0.023 mmol) in 1,4-dioxane (778 mul) was sealed, purged and evacuated with nitrogen and then subjected to microwave irradiation at 100 C. for 1 hour. To this was then added further cyclopropylboronic acid (CAS number 411235-57-9; 60 mg, 0.70 mmol) and tetrakis(triphenylphosphine)palladium (27 mg, 0.023 mmol). The reaction was sealed, purged and evacuated with nitrogen and again subjected to microwave irradiation at 140 C. for 20 minutes. The reaction was partitioned between ethyl acetate and water, washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) and then purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% formic acid) and further purified by column chromatography (basic silica, 0-100% ethyl acetate/petrol) to afford the title compound. 1H NMR (400 MHz, DCM-d2) delta ppm 0.77-0.92 (m, 4H), 1.40-1.60 (m, 2H), 1.68-1.94 (m, 3H), 2.14-2.29 (m, 2H), 3.80-3.91 (m, 1H), 3.99-4.10 (m, 1H), 6.65-6.73 (m, 1H), 7.43-7.59 (m, 4H), 7.64 (s, 2H), 7.68-7.72 (m, 1H), 7.74-7.78 (m, 1H) and 7.84 (br. s., 1H). MS ES+: 390 Example 113 N-[(1S,2S)-2-[5-(Propan-2-yl)pyrazin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide Prepared according to the procedure for N-[(1S,2S)-2-[(5-cyclopropylpyrazin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 112) from N-[(1S,2S)-2-[(5-bromopyrazin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide and N-[(1S,2S)-2-[(5-chloropyrazin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 30a and 30b; 100 mg, 0.23 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (CAS number 126726-62-3; 165 mg, 0.98 mmol) except this was purified only by column chromatography (silica, 0-100% ethyl acetate petrol) and then was dissolved in ethanol (2.5 ml). To this was then added palladium on carbon (10% wt, 50% wet) (26 mg, 0.025 mmol) and the resulting mixture was stirred under a balloon of hydrogen gas for 2 hours. The reaction was filtered through diatomaceous earth (commercially sold under the trade mark ?Celite?) and concentrated in vacuo. This was purified by column chromatography (basic silica, 0-100% ethyl acetate petrol) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.13-1.20 (m, 6H), 1.37-1.57 (m, 2H), 1.58-1.72 (m, 2H), 1.93-2.07 (m, 2H), 2.81-2.91 (m, 1H), 3.95-4.09 (m, 2H), 6.72-6.78 (m, 1H), 7.40-7.44 (m, 1H), 7.46-7.51 (m, 1H), 7.57-7.62 (m, 1H), 7.75-7.78 (m, 1H), 7.80-7.82 (m, 1H), 7.92-7.93 (m, 1H), 7.94 (s, 2H), 8.35-8.39 (m, 1H). MS ES+: 392

Reference： [1]Patent: US2015/232460,2015,A1 .Location in patent: Paragraph 0630-0631; 1256-1263

5
[ 912773-21-8 ]
(N-heterocyclic carbene)Ag(SCF₂H) [ No CAS ]
C₅H₃ClF₂N₂S [ No CAS ]

Reference： [1]Chemical Science,2016,vol. 7,p. 3757 - 3762

6
[ 912773-21-8 ]
[ 149104-88-1 ]
2-chloro-5-(4-(methylsulfonyl)phenyl)pyrazine [ No CAS ]

Reference： [1]Organic Process Research and Development,2016,vol. 20,p. 1469 - 1475

7
[ 912773-21-8 ]
2-(trifluoromethyl)pyridine-3-thiol [ No CAS ]
2-chloro-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
252 mg	With N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; at 120℃; for 2.5h;	Intermediate C-3 2-chloro-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrazine A mixture of 2-(trifluoromethyl)pyridine-3-thiol (100 mg, 0.558 mmol), 2- bromo-5-chloro-pyrazine (195 mu, 0.670 mmol), Pd2(dba)3 (12.8 mg, 0.014 mmol), XantPhos (17.8 mg, 0.031 mmol), and DIPEA (144 mg, 1.12 mmol) in dioxane (degassed, 2.79 n L) was stirred for 2.5 h at 120 C. After cooling to RT, the reaction mixture was filtered through a pad of Celite followed by EtOAc (10 mL) wash. The combined filtrates were concentrated under reduced pressure and the resulting residue was purified by silica chromatography (0 to 25% gradient of EtO Ac/heptane) to give 2-chloro-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrazine (252 mg, 0.864 mmol) as a brown oil. NMR (400 MHz, Chloroform- ) delta ppm 8.68 (dd, 7=4.7, 1.5 Hz, 1 H), 8.25 (d, 7=1.5 Hz, 1 H), 8.18 (d, 7=1.5 Hz, 1 H), 7.98 (dd, 7=8.1, 1.5 Hz, 1 H), 7.49 (dd, 7=8.0, 4.7 Hz, 1 H). MS m/z 292.0 (M+H)+.

Reference： [1]Patent: WO2016/203406,2016,A1 .Location in patent: Paragraph 00275

8
[ 912773-21-8 ]
(1S,8R)-5-(2,6-difluoro-phenyl)-11,11-dimethyl-1-(6-trimethylstannanyl-pyridin-2-yl)-3,4-diaza-tricyclo[6.2.1.0^2,7]undeca-2⁽⁷⁾,3,5-triene [ No CAS ]
(1S,8R)-1-[6-(5-chloro-pyrazin-2-yl)-pyridin-2-yl]-5-(2,6-difluoro-phenyl)-11,11-dimethyl-3,4-diaza-tricyclo[6.2.1.0^2,7]undeca-2⁽⁷⁾,3,5-triene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97 mg	With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); In toluene; at 100℃; for 3.25h;Inert atmosphere; Sealed tube;	N2 was bubbled through a solution of the product from step 1 (0.37 mmol) in toluene for 30 min. Separately, a flask was charged with <strong>[912773-21-8]2-bromo-5-chloropyrazine</strong> (108 mg, 0.56 mmol), (Ph3P)4Pd (21.5 mg, 0.19 mmol) and copper(I) iodide (7.1 mg, 0.037 mmol), then sealed evacuated and purged with N2 thrice. The toluene solution was inhjected in to the flask and the solution stirred at 100 C for 3 h 15 min. The cooled solution was concentrated in vacuo to ~1/2 volume. FCC (5-40% EtOAc in cyclohexane) gave the title compound as a solid (97 mg). LCMS (Method A) 4.66 min, ES+ 476 [M+1]+.

Reference： [1]Patent: WO2018/83105,2018,A1 .Location in patent: Page/Page column 139

9
[ 912773-21-8 ]
[5-fluoro-6-(2,2,2-trifluoro-1-methylethoxy)-3-pyridyl]boronic acid [ No CAS ]
2-chloro-5-[5-fluoro-6-[2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]pyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
210 mg	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 60℃; for 5h;Inert atmosphere;	A mixture of 2-bromo-5-chloro-pyrazine (229.4 mg, 1.19 mmol), [5-fluoro-6-(2,2,2- trifluoro-1-methyl-ethoxy)-3-pyridyl]boronic acid (300 mg, 1.19 mmol), Pd(dppf)Cl2 (130.16 mg, 0.18 mmol) and CS2CO3 (772.77 mg, 2.37 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was stirred at 60 C for 5 hours under N2. After cooling to r.t., the mixture was diluted with _0 (30 mL), and the mixture was extracted with EtOAc (50 mL x 2). The combined organic phase was washed with water (20 mL x 2) and brine (20 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 1% to 3% ) to give the product (210 mg, 0.64 mmol) as a solid. The product was analyzed by SFC to show two peaks (Peak 1: Rt = 2.02 min, Peak 2: Rt = 2.28 min). Method: Column: Chiralpak AD-3 150 x 4.6mm I.D, 3_ Mobile phase: A: C02 B:ethanol (0.05% DEA), Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5mL/min Column temp.: 35 C. 1H NMR (400MHz CDC13) _ = 8.77 (d, 1H), 8.65 (d, 1H), 8.53 (d, 1H), 8.08 (dd, 1H), 5.95 - 5.85 (m, 1H), 1.63 -1.48 (m, 3H). LCMS Rt = 0.92 min in 1.5 min chromatography, 5-95AB, purity 98.54%, MS ESI calcd. for Ci2H9ClF4N30 [M+H]+ 322.0, found 321.9

Reference： [1]Patent: WO2018/98499,2018,A1 .Location in patent: Page/Page column 228-229

10
[ 110-91-8 ]
[ 912773-21-8 ]
[ 955050-08-5 ]

Yield	Reaction Conditions	Operation in experiment
		<strong>[912773-21-8]2-chloro-5-bromopyrazine</strong> (4.0 mmol) in CHC13 (40 mL), stirring under nitrogen, BPO (0.08 mmol) and NBS (4.4 mmol) were added to the reaction mixture, heated to reflux for 5 h, cooled . The solvent was distilled off under reduced pressure to give a crude product. A solution of morpholine (0.50 mol) in ethanol was added to the crude product of the previous step under nitrogen and stirred at room temperature overnight.The solvent was removed under reduced pressure.The crude product was purified by column chromatography to give 4-(4-bromo-2-fluorophenyl)morpholine.

Reference： [1]Patent: CN108658937,2018,A .Location in patent: Paragraph 0169

11
[ 1221439-83-3 ]
[ 912773-21-8 ]
tert-butyl (3aR,5s,6aS)-5-((5-bromopyrazin-2-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 180℃; for 1h;Microwave irradiation;	To a solution of tert-butyl (3aR, 5s,6a5)-5-aminohexahydrocyclopenta[c]pyrrole-2( 1 H)-carboxylate (274 mg, 1.21 mmol) in NIVIP (4.5 mL) was added <strong>[912773-21-8]2-bromo-5-chloropyrazine</strong> (585 mg, 3.02 mmol) and J7N- diisopropylethylamine (0.63 mL, 3.63 mmol). The mixture was stirred at 180 C under microwave irradiation for 1 h. Solids were removed by syringe filtration, and crude residue was purified by RP-HPLC (20-70% MeCN in 0.05% NH4OH aqueous solution over 20 mm). Fractions containing product were combined and concentrated to give the title compound as a brown oil (148 mg, 32%). ES-MS [M+H]b = 383.2.

Reference： [1]Patent: WO2019/79783,2019,A1 .Location in patent: Paragraph 00330

12
[ 912773-21-8 ]
[ 405520-68-5 ]
4-(5-chloropyrazin-2-yl)-N,N-dimethylbenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; ethanol; water; at 70℃; for 0.5h;	Step 1: 4-(5-Chloropyrazin-2-yl)-N,N-dimethyl-benzamide [0471] The title compound was prepared as described in Intermediate 3, starting from 2-bromo-5-chloro-pyrazine and <strong>[405520-68-5][4-(dimethylcarbamoyl)phenyl]boronic acid</strong> and stirring the mixture at 70 C for 30 min, to give the product as a solid (250 mg, 92%). MS ES+ m/z 262 [M+H]+.

Reference： [1]Patent: WO2019/126731,2019,A1 .Location in patent: Paragraph 0471

13
[ 912773-21-8 ]
sodium 2-amino-3-chloropyridine-4-thiolate [ No CAS ]
3-chloro-4-((5-chloropyrazin-2-yl)thio)pyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10%	With tris-(dibenzylideneacetone)dipalladium(0); N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃; for 3h;	To a solution of <strong>[912773-21-8]2-bromo-5-chloropyrazine</strong> (20.0 g, 103 mmol) and sodium 2-amino- 3-chloropyridine-4-thiolate (18.9 g 103 mmol, Intermediate AC) in dioxane (80.0 mL) was added Pd2(dba)3 (3.79 g, 4.14 mmol), Xantphos (2.99 g, 5.17 mmol) and DIPEA (26.7 g, 207 mmol, 36.0 mL) at 25 C. Then the mixture was heated to 80 C and stirred at 80C for 3 h. The mixture was then cooled to 25 C and filtered. The filter cake was washed with ethyl acetate (50.0 mL x 3). The combined organic layer was concentrated to give a residue. The residue was purified by column chromatography twice (Si02, petroleum ether : ethyl acetate = 20 : 1 to 3 : 1, TLC: petroleum ether : ethyl acetate = 3 : 1, Rf = 0.25) to afford 3-chloro-4- ((5-chloropyrazin-2-yl)thio)pyridin-2-amine (3.00 g, 10.4 mmol, 10% yield) as a yellow solid. LC-MS (ESI+) m/z 273.0 (M+H)+; 1HNMR (400 MHz, CDCl3): d 8.50 (d, 7= 1.2 Hz, 1H), 8.34 (d, J= 1.2 Hz, 1H), 7.87 (d, J= 4.0 Hz, 1H), 8.55 (d, J= 4.0 Hz, 1H), 8.52 (s, 2H).

Reference： [1]Patent: WO2019/183367,2019,A1 .Location in patent: Paragraph 0300

14
[ 5466-06-8 ]
[ 912773-21-8 ]
ethyl 3-((5-chloropyrazin-2-yl)thio)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With tris-(dibenzylideneacetone)dipalladium(0); N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 80℃; for 2h;Inert atmosphere;	To a mixture of <strong>[912773-21-8]2-bromo-5-chloropyrazine</strong> (46.0 g, 237 mmol) and ethyl 3- mercaptopropanoate (31.9 g, 237 mmol) in dioxane (460 mL) was added DIPEA (61.4 g, 475 mmol, 82.8 mL), Xantphos (13.7 g, 23.8 mmol) and Pd2(dba)3 (10.8 g, 11.8 mmol) in one portion under N2. The mixture was stirred at 80 C for 2 hours under N2. The mixture was then filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Si02, petroleum ether/ethyl acetate = 1 :0 to 5: 1, petroleum ether: ethyl acetate = 10: 1) to afford ethyl 3-((5-chloropyrazin-2-yl)thio)propanoate (52.0 g, 192 mmol, 81% yield) as a light yellow oil. LC-MS (ESI+) m/z 247.1 (M+H)+; 1HNMR (400 MHz, CDCI3): d 8.37 (s, 1H), 8.20 (s, 1H), 4.18 - 4.13 (m, 2H), 3.40 (t, J= 7.0 Hz, 2H), 2.73 (t, J = 7.2 Hz, 2H), 1.25 (t, J= 7.2 Hz, 3H).

Reference： [1]Patent: WO2019/183367,2019,A1 .Location in patent: Paragraph 0296

15
[ 912773-21-8 ]
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[1-(trifluoromethyl)cyclobutoxy]pyridine [ No CAS ]
2-chloro-5-[6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]pyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.5 g	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 60℃; for 6h;Inert atmosphere;	A mixture of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-2-[l-(trifluoromethyl)cyclobutoxy]pyridine (2.1 g, 6.12 mmol), 2-bromo-5-chloro- pyrazine (1.18 g, 6.12 mmol), Pd(dppf)Cl2(671.68 mg, 0.92 mmol) and CS2CO3(3.99 g, 12.24 mmol) in l,4-Dioxane (20 mL) and Water (2 mL)was stirred at 60 C for 6 hours under N2. After cooling to room temperature, the mixture was concentrated to give the residue. The residue was diluted with H2O (20 mL), and the mixture was extracted with EtOAc (20 mL x 2). The combined organic phase was washed with water (20 mL) and brine (40 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 1% to 10%) to give the product (1.5 g, 4.263mmol, 70% yield) as an oil. 'H NMR (CDCI3, 400MHz) 5H = 8.80 - 8.72 (m, 2H), 8.63 (d, 1H), 8.25 (dd, 1H), 6.91 (d, 1H), 3.01 - 2.83 (m, 2H), 2.78 - 2.62 (m, 2H), 2.18 - 1.84 (m, 2H).

Reference： [1]Patent: WO2019/232209,2019,A1 .Location in patent: Paragraph 00337

16
[ 912773-21-8 ]
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methylethoxy]pyridine [ No CAS ]
2-chloro-5-[6-[(1S)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]pyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 60℃; for 5h;Inert atmosphere;	A mixture of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-2-[(lS)-2,2,2-trifluoro-l-methyl-ethoxy]pyridine (600 mg, 1.89 mmol), 2-bromo-5- chloro-pyrazine (329.39 mg, 1.7 mmol), Pd(dppf)Cl2 (207.67 mg, 0.28 mmol) and CS2CO3 (1232.88 mg, 3.78 mmol) in l,4-Dioxane (15 mL) and Water (1.5 mL) was stirred at 60 C for 5 hours under N2. After cooling to room temperature, the mixture was concentrated to give the residue. The residue was diluted with FLO (20 mL), and the mixture was extracted with EtOAc (30 mL x 2). The combined organic phase was washed with water (20 mL) and brine (20 mL), dried over Na2S04,filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 3%) to give the product (350 mg, 1.15 mmol, 61% yield) as an oil. LCMS Rt= 0.95 min in 1.5 min chromatography, 5-95 AB, MS ESI calcd. for C i HioCIFiN iO [M+H]+304.0, found 304.1.

Reference： [1]Patent: WO2019/232209,2019,A1 .Location in patent: Paragraph 00348

17
[ 912773-21-8 ]
2-benzyloxy-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine [ No CAS ]
2-(6-benzyloxy-5-fluoro-3-pyridyl)-5-chloropyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 50℃; for 16h;Inert atmosphere;	A mixture of 2-bromo-5-chloro-pyrazine (4 g, 20.68 mmol), 2-benzyloxy-3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (6.81 g, 20.68 mmol), CS2CO3 (13.47 g, 41.36 mmol) and Pd(dppf)Cl2 (2.27 g, 3.1 mmol) in 1,4- dioxane (30 mL) and water (3 mL) was stirred at 50 C under N2 for 16 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated. Water (50 mL) was added and the aqueous layer was extracted with EtOAc (50 mL x 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2S04, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 15% to 30%) to give the product (5.5 g, 17.42 mmol, 84% yield) as a solid. 'H NMR (400MHz, DMSO-r) dH= 9.15 (s, 1H), 8.85 (s, 1H), 8.77 (s, 1H), 8.37 (d, 1H), 7.52 - 7.46 (m, 2H), 7.44 - 7.32 (m, 3H), 5.51 (s, 2H).

Reference： [1]Patent: WO2019/232209,2019,A1 .Location in patent: Paragraph 00367

18
[ 832735-54-3 ]
[ 912773-21-8 ]
2-(6-benzyloxy-3-pyridyl)-5-chloropyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 50℃; for 3h;Inert atmosphere;	A mixture of 2-bromo-5-chloro-pyrazine (4 g, 20.68 mmol), 2-benzyloxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (7.08 g, 22.75 mmol), CS2CO3 (l3.47g, 4l.36mmol) and Pd(dppf)Cl2 (1.51 g, 2.07 mmol) in l,4-dioxane (50mL) and water (lOmL) was stirred at 50 C under N2 for 3 hours. After cooling to room temperature, the mixture was filtered and concentrated to give a residue. To the residue was added water (100 mL), extracted with EtOAc (150 mL x 2). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2S04, filtered and concentrated to give the crude product. The crude product was filtered through silica gel (~ 50 g) and eluted with DCM (150 mL x 3). The filtrate was concentrated to give the impure product. The impure product was triturated from /-Pi O (15 mL) to give the product of (4 g, 13.44 mmol, 65% yield) as a solid. LCMS Rt= 1.03 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for Ci6H13ClN30 [M+H]+298.1, found 297.9.

Reference： [1]Patent: WO2019/232209,2019,A1 .Location in patent: Paragraph 00413

19
[ 912773-21-8 ]
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-1-ethoxy]pyridine [ No CAS ]
2-chloro-5-[6-[(1R)-2,2,2-trifluoro-1-methylethoxy]-3-pyridyl]pyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 60℃; for 4h;Inert atmosphere;	A mixture of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-2-[(lR)-2,2,2-trifluoro-l-methy l-ethoxy]pyridine (200 g, 630.7 mmol), 2-bromo-5- chloro-pyrazine (122 g, 630.7 mmol) , Pd(dppf)Cl2(46.15 g, 63.07 mmol) and CS2CO3(513.7 g, 1.58 mol) in l,4-dioxane (2000 mL) and water (500 mL) was stirred at 50C for 2 hours under N2. After cooling to 25 C, the mixture was separated and the organic phase was concentrated to remove most of dioxane. The residue was poured into water (1 L) and the mixture was extracted with EtOAc (800 mL x 2). The combined organic phase was washed with water (500 mL) and brine (500 mL), dried over anhydrous Na2S04, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 1% to 3% to 20%) to give the product (122 g, 401.75 mmol, 64% yield) as a solid. 'H NMR (400MHz, CDCl3) dH= 8.77 - 8.73 (m, 2H), 8.63 (d, 1H), 8.26 (dd, 1H),6.96 (d, 1H), 5.93 - 5.82 (m, 1H), 1.54 (d, 3H).

Reference： [1]Patent: WO2019/232209,2019,A1 .Location in patent: Paragraph 00450

20
[ 912773-21-8 ]
3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethylethoxy)pyridine [ No CAS ]
2-chloro-5-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethylethoxy)-3-pyridyl]pyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.3 g	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 60℃; for 5h;Inert atmosphere;	A mixture of 2-bromo-5-chloro-pyrazine (2 g, 10.34 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-l,l- dimethyl-ethoxy)pyridine (3.61 g, 10.34 mmol), CS2CO3 (6.74 g, 20.68 mmol) andPd(dppf)Cl2 (1.13 g, 1.55 mmol) in l,4-Dioxane (80 mL) and Water (8 mL) was stirred at 55 C under N2 for 5 hours. The mixture was cooled to room temperature and concentrated to give a residue. To the residue was added water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic phase was washed with water (50 mL), brine (50 mL x 2), dried over anhydrous Na2S04, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography column on silica gel (EtOAc in PE = 0% to 5% to 10%) to give the product (2.3 g, 5.45 mmol) as a solid. 'H NMR (400 MHz, CDCI3) dH= 8.77 (d, 1H), 8.64 (d, 1H), 8.53 (d, 1H), 8.05 (dd, 1H), 1.88 (s, 6H). LCMS R, = 0.96 min in 1.5 min chromatography, MS ESI calcd. for Ci3HnClF4N30 [M+H]+336.0, found 335.9.

Reference： [1]Patent: WO2019/232209,2019,A1 .Location in patent: Paragraph 00445

21
[ 912773-21-8 ]
3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine [ No CAS ]
2-chloro-5-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]pyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 55℃; for 5h;Inert atmosphere;	A mixture of 2-bromo-5-chloro-pyrazine (1 g, 5.17 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-[(lS)-2,2,2-trifluoro-l- methyl -ethoxy ] pyridine (1.73 g, 5.17 mmol), CS2CO3 (3.37 g, 10.34 mmol) and Pd(dppf)Cl2 (567.41 mg, 0.78 mmol) in l,4-Dioxane (100 mL) and Water (10 mL) was stirred at 55 C under N2 for 5 hours. From LCMS, desired MS was observed and no starting material was remained. The solution was cooled to room temperature and concentrated to give a residue. To the residue was added water (50 mL), extracted with EtOAc (50 mL x 2). The combined organic phase was washed with water (50 mL), brine (50 mL x 2), dried over anhydrous Na2S04, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography column on silica gel (EtOAc in PE = 0% to 5%) to give the product (1.4 g,4.35 mmol, 84% yield) as a solid. 'H NMR (DMSO-c, 400MHz) 5H= 9.18 (s, 1H), 8.91 - 8.74 (m, 2H), 8.46 (dd, 1H), 6.05 - 5.99 (m, 1H), 1.53 (d, 3H).

Reference： [1]Patent: WO2019/232209,2019,A1 .Location in patent: Paragraph 00438

22
[ 912773-21-8 ]
3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine [ No CAS ]
2-chloro-5-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]pyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 50℃; for 5h;Inert atmosphere;	A mixture of 2-bromo-5-chloro-pyrazine (2 g, 10.34 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-[(lR)-2,2,2-trifluoro-l- methyl-ethoxy]pyridine (3.12 g, 9.31 mmol), Pd(dppf)Cl2 (1.13 g, 1.55 mmol) and CS2CO3 (6.74 g, 20.68 mmol) in l,4-dioxane (100 mL) and water (10 mL) was stirred under N2 at 50 C for 5 hours. After cooling to room temperature, the mixture was diluted with EtOAc (10 mL), filtered with silica gel, eluted with EtOAc (20 mL) and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 20%) to give the product (2500 mg, 7.21 mmol, 70% yield) as a solid. 'H NMR (400MHz, CDCI3) dH= 8.77 (d, 1H), 8.64 (d, 1H), 8.53 (d, 1H), 8.08 (dd, 1H), 6.00 - 5.83 (m, 1H), 1.59 (d, 3H).

Reference： [1]Patent: WO2019/232209,2019,A1 .Location in patent: Paragraph 00450

23
[ 912773-21-8 ]
3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[1-(trifluoromethyl)cyclobutoxy]pyridine [ No CAS ]
2-chloro-5-[5-fluoro-6-[1-(trifluoromethyl)cyclobutoxy]-3-pyridyl]pyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 50℃; for 8h;	A mixture of 2-bromo-5-chloro-pyrazine (800 mg, 4.14 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-[l- (trifluoromethyl)cyclobutoxy]pyridine (1642.99 mg, 4.55 mmol), CS2CO3(4042.64 mg,12.41 mmol), Pd(dppf)Cl2(60.52 mg, 0.08 mmol) in l,4-dioxane (12 mL) and H2O (4 mL) was stirred at 50 C for 8 hours. After cooling to room temperature, the reaction mixture was concentrated to remove solvent, diluted with water (20 mL), and extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (40 mL), dried over Na2S04and concentrated to give a crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 10%) to give the product as a solid, which was confirmed by LCMS Rt= 1.01 min in 1.5 min chromatography, MS ESI calcd. for C14H11CIF4N3O [M+H]+348.1, found 347.9.

Reference： [1]Patent: WO2019/232209,2019,A1 .Location in patent: Paragraph 00447

24
[ 912773-21-8 ]
3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine [ No CAS ]
2-chloro-5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]pyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 35℃; for 2h;Inert atmosphere;	A mixture of Pd(dppf)Cl2 (15.13 g, 20.68 mmol), CS2CO3 (269.49 g, 827.17 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-(2,2,2- trifluoroethoxy)pyridine (141.18 g, 439.69 mmol) and 2-bromo-5-chloro-pyrazine (80 g, 413.59 mmol) in l,4-Dioxane (1 L) and Water (150 mL) under N2 was stirred at 35 C for 2 hours. After cooling to room temperature, to the mixture was added water (300 mL) and the mixture was filtered through Celite. After separating, the organic phase was washed with brine (300 mL), dried over anhydrous Na2S04, filtered and concentrated to give the crude product. The crude product was re-dissolved in EA/PE = 1/3 (500 mL) and then filtered through silica gel mat. The cake was washed with EA/PE = 1/3 (500 mL). The combined organic phase was concentrated to give a residue as oil. To the oil was added PE (500 mL) slowly and some solid was obtained. The solid was collected and dried in oven to give the product (100 g, 242.4 mmol, 58% yield) as a solid. LCMS Rt= 1.28 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C11H7CIF4N3O [M+H]+308.0, found 307.9.

Reference： [1]Patent: WO2019/232209,2019,A1 .Location in patent: Paragraph 00261; 00330; 00463

25
[ 912773-21-8 ]
[ 64099-82-7 ]
2-chloro-5-(prop-1-yn-1-yl)pyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With copper(l) iodide; trans-bis(triphenylphosphine)palladium dichloride; triethylamine In tetrahydrofuran at 70℃; for 16h; Inert atmosphere;	2-chloro-5-(prop-l-yn-l-yl)pyrazine: To a solution of 2-bromo-5-chloropyrazine (1.00 g, 5.17 mmol) and tributyl(prop- l-yn- l-yl)stannane (1.70 g, 5.17 mmol, 1.58 mL) in THF (10 mL) were added Cul (0.197 g, 1.03 mmol), Pd(PPh3)2Cl2 (0.726 g, 1.03 mmol) and TEA (1.05 g, 10.34 mmol, 1.43 mL). The mixture was stirred at 70°C for 16 hours under N2. The mixture was evaporated to dryness in vacuo and the residue purified by columnchromatography over silica gel column (petroleum ether/EtOAc; 10: 1) to afford the title compound as a yellow oil (750 mg, 95%). LCMS (ESI): [M+H] 153.0

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2020/163193, 2020, A1 Location in patent: Paragraph 00164

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Prevention
Code	Phrase
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Code	Phrase
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P321
P322
P330	Rinse mouth.
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P342	If experiencing respiratory symptoms:
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P372	Explosion risk in case of fire.
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P378
P380	Evacuate area.
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P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
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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.
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Code	Phrase
P401
P402	Store in a dry place.
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P413
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P422
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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
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Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
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H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
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H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
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. 912773-21-8 ] {[proInfo.proName]}

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[ 912773-21-8 ] Synthesis Path-Downstream 1~25

Related Functional Groups of [ 912773-21-8 ]

Bromides

Chlorides

Related Parent Nucleus of [ 912773-21-8 ]

Pyrazines

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[ 912773-21-8 ]

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[ 912773-21-8 ]