[ CAS No. 38557-71-0 ] {[proInfo.proName]}

Name: 38557-71-0|2-Chloro-6-methylpyrazine|98%
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Quality Control of [ 38557-71-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 38557-71-0 ]

Product Details of [ 38557-71-0 ]

CAS No. :	38557-71-0	MDL No. :	MFCD00055032
Formula :	C₅H₅ClN₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	CKUVSPQGYLELRG-UHFFFAOYSA-N
M.W :	128.56	Pubchem ID :	7170095
Synonyms :

Calculated chemistry of [ 38557-71-0 ]

Physicochemical Properties

Num. heavy atoms :	8
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.2
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	32.01
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) :	-6.35 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.52
Log Po/w (XLOGP3) :	1.04
Log Po/w (WLOGP) :	1.44
Log Po/w (MLOGP) :	0.13
Log Po/w (SILICOS-IT) :	2.04
Consensus Log Po/w :	1.23

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.85
Solubility :	1.83 mg/ml ; 0.0142 mol/l
Class :	Very soluble
Log S (Ali) :	-1.17
Solubility :	8.66 mg/ml ; 0.0673 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.62
Solubility :	0.311 mg/ml ; 0.00242 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.93

Safety of [ 38557-71-0 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 38557-71-0 ]

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

Upstream synthesis route of [ 38557-71-0 ]
Downstream synthetic route of [ 38557-71-0 ]

[ 38557-71-0 ] Synthesis Path-Upstream 1~14

1
[ 38557-71-0 ]
[ 5521-56-2 ]

Reference： [1] Journal of the American Chemical Society, 1952, vol. 74, p. 1580,1582

2
[ 930798-25-7 ]
[ 38557-71-0 ]

Yield	Reaction Conditions	Operation in experiment
73%	at 130℃; Sealed tube	step 3: Into a 5-L sealed tube was placed 2-(6-chloropyrazin-2-yl)acetic acid (220 g, 1.27 mol, 1.00 equiv) and water (3 L). The resulting solution was stirred overnight at 130° C., cooled and extracted with Et₂O 2×3 L of ether. The organic layers were combined, dried (Na₂SO₄), filtered and concentrated in vacuo to afford 238 g (73percent) of 2-chloro-6-methylpyrazine as a yellow solid.

Reference： [1] Patent: US2015/31674, 2015, A1, . Location in patent: Paragraph 0325; 0322

3
[ 4774-14-5 ]
[ 676-58-4 ]
[ 38557-71-0 ]

Reference： [1] European Journal of Organic Chemistry, 2005, # 19, p. 4141 - 4153

4
[ 20721-18-0 ]
[ 38557-71-0 ]

Reference： [1] Journal of the American Chemical Society, 1952, vol. 74, p. 1580,1582

5
[ 930798-26-8 ]
[ 38557-71-0 ]

Reference： [1] Patent: US2015/31674, 2015, A1,

6
[ 4774-14-5 ]
[ 75-16-1 ]
[ 38557-71-0 ]

Reference： [1] Organic Letters, 2016, vol. 18, # 13, p. 3082 - 3085

7
[ 822-36-6 ]
[ 67-66-3 ]
[ 38557-71-0 ]
[ 3435-25-4 ]
[ 59303-10-5 ]
[ 54198-82-2 ]

Reference： [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1427 - 1430

8
[ 822-36-6 ]
[ 67-66-3 ]
[ 38557-71-0 ]
[ 3435-25-4 ]
[ 59303-10-5 ]
[ 54198-82-2 ]

Reference： [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1427 - 1430

9
[ 822-36-6 ]
[ 67-66-3 ]
[ 38557-71-0 ]
[ 3435-25-4 ]
[ 59303-10-5 ]
[ 54198-82-2 ]

Reference： [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 1427 - 1430

10
[ 38557-71-0 ]
[ 5315-24-2 ]

Yield	Reaction Conditions	Operation in experiment
72%	at 100℃; for 2 h;	General procedure: (0.1mole) of 2-halo nitrogen heterocycle and (0.5 mole) of hydrazine hydrate were mixed together in a 250mL round bottom flask equipped with reflux condenser and wereheated at 100^oC, progress of the reaction was monitored byTLC. After completion of the reaction the reaction mixture was cooled to (-5-0^oC) for 14hr and the precipitated solid was filtered and washed with two 5ml portions of ice coldwater and dried to give the compound 1 in good yield.

Reference： [1] Letters in Organic Chemistry, 2013, vol. 10, # 5, p. 348 - 352

11
[ 38557-71-0 ]
[ 2882-21-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sodium methylate In methanol at 60 - 70℃; for 16 h;	To a suspension of 2-chloro-6-methylpyrazine (24 g, 186.7 mmol) in anhydrous MeOH (240 mL) was added NaOMe (12.1 g, 224 mmol). The mixture was stirred at 60-70°C for 16hours. The mixture was cooled and filtered. The filtrate was concentrated in vacuo to give 2- methoxy-6-methylpyrazine (22 g, 95percent yield). 1H NMR (CDCI3400 MHz): 7.98 (s, 1H), 7.94(s, 1H), 3.91 (s, 3H), 3.40 (s, 3H). LC-MS: tR = 1.47 mm (method 14), mlz= 124.8 [M + H].

Reference： [1] Patent: WO2016/174188, 2016, A1, . Location in patent: Page/Page column 47; 48

12
[ 38557-71-0 ]
[ 124-41-4 ]
[ 2882-21-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	at 60 - 70℃; for 16 h;	To a suspension of 2-chloro-6-methylpyrazine (24 g, 186.7 mmol) in anhydrous MeOH (240 mL) was added NaOMe (12.1 g, 224 mmol). The mixture was stirred at 60-70°C for 16 hours. The mixture was cooled and filtered. The filtrate was concentrated in vacuo to give 2- methoxy-6-methylpyrazine (22 g, 95percent yield). ¹H NMR (CDCI₃400 MHz): δ 7.98 (s, 1 H), 7.94 (s, 1 H), 3.91 (s, 3H), 3.40 (s, 3H). LC-MS: t = 1.47 min (method 14), m/z = 124.8 [M + H]⁺.
95%	at 60 - 70℃; for 16 h;	To a suspension of 2-chloro-6-methylpyrazine (24 g, 186.7 mmol) in anhydrous MeOH (240 mL) was added NaOMe (12.1 g, 224 mmol). The mixture was stirred at 60-70°C for 16 hours. The mixture was cooled and filtered. The filtrate was concentrated in vacuo to give 2- methoxy-6-methylpyrazine (22 g, 95percent yield). H NMR (CDCI₃400 MHz): (5 7.98 (s, 1 H), 7.94 (s, 1 H), 3.91 (s, 3H), 3.40 (s, 3H). LC-MS: t_R = 1.47 min (method 14), m/z = 124.8 [M + H]⁺.

Reference： [1] Patent: WO2018/78038, 2018, A1, . Location in patent: Page/Page column 48-49
[2] Patent: WO2018/78042, 2018, A1, . Location in patent: Page/Page column 51-52

13
[ 38557-71-0 ]
[ 67-56-1 ]
[ 2882-21-5 ]

Reference： [1] European Journal of Organic Chemistry, 2005, # 19, p. 4141 - 4153

14
[ 38557-71-0 ]
[ 74290-66-7 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 13, p. 3030 - 3035

[ 38557-71-0 ] Synthesis Path-Downstream 1~88

1
[ 38557-71-0 ]
[ 76850-13-0 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1980,vol. 28,p. 2734 - 2747

2
[ 822-36-6 ]
[ 67-66-3 ]
[ 38557-71-0 ]
[ 3435-25-4 ]
[ 59303-10-5 ]
[ 54198-82-2 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1980,p. 1427 - 1430

3
[ 38557-71-0 ]
[ 67-56-1 ]
[ 2882-21-5 ]

Reference： [1]European Journal of Organic Chemistry,2005,p. 4141 - 4153

4
[ 4774-14-5 ]
[ 676-58-4 ]
[ 38557-71-0 ]

Reference： [1]European Journal of Organic Chemistry,2005,p. 4141 - 4153

5
[ 38557-71-0 ]
[ 139725-49-8 ]

Reference： [1]European Journal of Organic Chemistry,2005,p. 4141 - 4153
[2]Patent: WO2016/174188,2016,A1
[3]Patent: WO2018/78038,2018,A1
[4]Patent: WO2018/78042,2018,A1

6
[ 38557-71-0 ]
[ 870543-99-0 ]

Reference： [1]European Journal of Organic Chemistry,2005,p. 4141 - 4153

7
[ 38557-71-0 ]
[ 35250-89-6 ]

Reference： [1]European Journal of Organic Chemistry,2005,p. 4141 - 4153

8
[ 38557-71-0 ]
[ 36341-34-1 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1980,vol. 28,p. 2734 - 2747

9
[ 38557-71-0 ]
[ 19848-57-8 ]

Yield	Reaction Conditions	Operation in experiment
58%	With hydrazine hydrate; In toluene; at 0 - 100℃; for 0.5h;	Step 1: Compound 41-1 (2.9 g, 22.75 mmol) was added into hydrazine hydrate (15 mL), the reaction mixturewas subject to an preheated oil bath (50 C), then warmed to 100C above for 30 min. After cooled to room temperature,the reaction mixture was cooled to 0C for 1 h. The residue was collected by filtration and dried to deliver compound41-2 as white solid (1.6g, yield 58%). MS ESI calcd for C5H8N4 [M+H]+ 125, found 125.
	With hydrazine; at 20 - 100℃; for 0.5h;	To 15 mL of hydrazine hydrate at ambient temperature was added dropwise 2.9 g of <strong>[38557-71-0]2-chloro-6-methylpyrazine</strong>. The resultant mixture was placed in a pre-heated oil bath AT No. 50 C and then heated TO No. 100 C over 30 min. The mixture was allowed to cool to ambient temperature, and was then cooled in a refrigerator for 1 h. A portion of hydrazine hydrate was added to the solidified mixture, and the solid was collected by filtration. The filtrate was cooled in a refrigerator for 2 h, and a second crop was collected. The crops were combined and used without further purification. MS 124.9 (M+1).

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 589 - 602
[2]Patent: EP3124482,2017,A1 .Location in patent: Paragraph 0117; 0118
[3]Patent: EP2881395,2015,A1 .Location in patent: Paragraph 0076
[4]Patent: WO2004/58266,2004,A1 .Location in patent: Page/Page column 82

10
[ 38557-71-0 ]
[ 1035573-64-8 ]
[ 1035573-66-0 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium hexamethyldisilazane; In tetrahydrofuran; at 0 - 20℃;	General procedure for preparation of compounds with formula Ir. wherein Ar and HetAr is as defined above: <n="95"/>3,4-Dimethoxy-2-propylcarbamoylmethoxy-benzoic acid methyl ester (28mg,0.09 mmol) obtained from Preparation 6 and a Ar-Me or HetAr-Me compound (1.2 eq, see below) was dissolved in dry THF (1 mL) under argon. The mixture was cooled to 0 and treated dropwise with LiHMDS (0.273 mL of a IM solution).The reaction mixture was brought to room temperature and left overnight. The reaction was quenched with NH4CI (sat., 2 mL) and the organic products were extracted with EtOAc (2x2 mL). The combined organic phases was washed with NaCI (sat, 2 mL). The organic phase was dried over Na2SO4, evaporated in vacuo and redissolved in MeOH (0.350 mL) followed by standard HPLC purification.Using this procedure the following compounds were obtained:Example 286 (compound 286)2-{6-[2-(6-Chloro-pyrazin-2-yl)-acetyl]-2,3-dimethoxy-phenoxy}-N-propyl- acetamideLC/MS (METHOD B): (m/z) 408.4 (MH+); RT = 3.33 min; purity (UV) = 91%HetAr-Me: 2-Chloro-6-methyl-pyrazine

Reference： [1]Patent: WO2008/77404,2008,A1 .Location in patent: Page/Page column 93-94

11
[ 38557-71-0 ]
[ 675108-96-0 ]
[ 73183-34-3 ]
[ 675109-15-6 ]

Yield	Reaction Conditions	Operation in experiment
		Prepared in a similar manner to Example 7 using <strong>[38557-71-0]2-chloro-6-methylpyrazine</strong> (Tetrahedron, 1972, 28(15), 4155-70) to give the title compound. 1H NMR (400 MHz, CDCl3) ? 9.90 (1H, s), 8.70 (1H, s), 8.46 (1H, s), 8.11 (1H, dd, J=8.0, 1.4 Hz), 7.56-7.39 (6H, m), 4.08 (2H, s), 2.73 (3H, s), 2.66(3H, s), m/z (ES+) 407 (M+H)+.

Reference： [1]Patent: US2004/58970,2004,A1 .Location in patent: Page 10

12
[ 109-01-3 ]
[ 38557-71-0 ]
[ 1334136-03-6 ]

Yield	Reaction Conditions	Operation in experiment
45%	In ethanol;Reflux;	A 250 mL round bottom flask was charged with <strong>[38557-71-0]2-chloro-6-methylpyrazine</strong> (4.0 g, 0.031 mol), 1 -methylpiperazine (12.4 g, 0.125 mol) and EtOH (100 mL). The resulting mixture was heated at reflux overnight. Work-up: the solvent was evaporated. The residue was mixed with saturated aqueous NaHCC>3 (100 mL) and then extracted with CH2CI2 (100 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 4% MeOH in CH2CI2, to afford 2.7 g (45%) of the product as a white solid. MS m/z: 193 (M+H+).

Reference： [1]Patent: WO2011/112766,2011,A2 .Location in patent: Page/Page column 92; 93

13
[ 38557-71-0 ]
[ 1334133-79-7 ]

Reference： [1]Patent: WO2011/112766,2011,A2

14
[ 38557-71-0 ]
[ 1334136-06-9 ]

Reference： [1]Patent: WO2011/112766,2011,A2

15
[ 38557-71-0 ]
[ 1334136-09-2 ]

Reference： [1]Patent: WO2011/112766,2011,A2

16
[ 38557-71-0 ]
[ 1334136-12-7 ]

Reference： [1]Patent: WO2011/112766,2011,A2

17
[ 38557-71-0 ]
[ 108612-54-0 ]
[ 1365156-90-6 ]

Yield	Reaction Conditions	Operation in experiment
47%	With potassium tert-butylate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 20℃; for 16h;Inert atmosphere; Reflux;	Stage 1: tert-Butyl methyl(1-(6-methylpyrazin-2-yl)piperidin-4-yl)carbamate KOBut (483 mg, 4.32 mmol, 2.5 eq) was added at room temperature to a solution of tert-butyl methyl(piperidin-4-yl)carbamate (stage 3 AMN-60) (370 mg, 1.72 mmol, 1 eq) and <strong>[38557-71-0]2-chloro-6-methylpyrazine</strong> (244 mg, 1.9 mmol, 1.1 eq) in toluene (50 ml) and the mixture was degassed for 30 min with argon. BINAP (64.5 mg, 0.103 mmol, 0.06 eq) and Pd2(dba)3 (31.6 mg, 0.034 mmol, 0.02 eq) were added and the reaction mixture was refluxed for 16 h. After cooling, concentration under reduced pressure was carried out. The residue was taken up in dichloromethane (50 ml) and washed with water (30 ml) and saturated sodium chloride solution (30 ml) and dried over sodium sulfate. The solvent was removed by distillation under reduced pressure and the crude product so obtained was purified by column chromatography (Alox, 0.5% methanol/dichloromethane). The desired product was in the form of a brown solid. Yield: 47% (250 mg, 0.816 mmol)

Reference： [1]Patent: US2012/71461,2012,A1 .Location in patent: Page/Page column 146

18
[ 38557-71-0 ]
[ 6302-53-0 ]
[ 1375748-15-4 ]

Yield	Reaction Conditions	Operation in experiment
81%	With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃;Inert atmosphere;	General procedure (0.5-3.0 mmol scale) for the preparation of compounds 2a-t: A thick-glass, screw-capped pressure tube (50 mL) was charged with a suspension of the starting imidazoline (1.0 equiv), heteroaryl halide (1.1 equiv) and Cs2CO3 (1.0-3.0 equiv, an additional equivalent per salt component of the reactants) in toluene (3 mL/mmol). Pd(OAc)2 (0.02 equiv) and BINAP (0.4 equiv) were weighed out into a vial, suspended in toluene (2 mL/mmol) and shaken in a 100 C oil bath for 2 min. The resulting clear, purple catalyst solution was added in one portion to the vigorously stirred reaction mixture. The tube was filled with argon, capped, and stirred at 100 C for 16-20 h. The mixture was cooled, and partitioned between EtOAc and H2O. The organic layer was separated, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The resulting crude material was purified by column chromatography on silica gel using an appropriate gradient of acetone in hexane (or MeOH in CH2Cl2) as eluent to provide the target product 2.

Reference： [1]Tetrahedron Letters,2012,vol. 53,p. 2876 - 2880

19
[ 38557-71-0 ]
C₇H₁₄N₂*ClH [ No CAS ]
[ 1375748-13-2 ]

Yield	Reaction Conditions	Operation in experiment
78%	With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃;Inert atmosphere;	General procedure (0.5-3.0 mmol scale) for the preparation of compounds 2a-t: A thick-glass, screw-capped pressure tube (50 mL) was charged with a suspension of the starting imidazoline (1.0 equiv), heteroaryl halide (1.1 equiv) and Cs2CO3 (1.0-3.0 equiv, an additional equivalent per salt component of the reactants) in toluene (3 mL/mmol). Pd(OAc)2 (0.02 equiv) and BINAP (0.4 equiv) were weighed out into a vial, suspended in toluene (2 mL/mmol) and shaken in a 100 C oil bath for 2 min. The resulting clear, purple catalyst solution was added in one portion to the vigorously stirred reaction mixture. The tube was filled with argon, capped, and stirred at 100 C for 16-20 h. The mixture was cooled, and partitioned between EtOAc and H2O. The organic layer was separated, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The resulting crude material was purified by column chromatography on silica gel using an appropriate gradient of acetone in hexane (or MeOH in CH2Cl2) as eluent to provide the target product 2.

Reference： [1]Tetrahedron Letters,2012,vol. 53,p. 2876 - 2880

20
[ 38557-71-0 ]
[ 21381-61-3 ]
[ 1375748-09-6 ]

Yield	Reaction Conditions	Operation in experiment
65%	With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃;Inert atmosphere;	General procedure (0.5-3.0 mmol scale) for the preparation of compounds 2a-t: A thick-glass, screw-capped pressure tube (50 mL) was charged with a suspension of the starting imidazoline (1.0 equiv), heteroaryl halide (1.1 equiv) and Cs2CO3 (1.0-3.0 equiv, an additional equivalent per salt component of the reactants) in toluene (3 mL/mmol). Pd(OAc)2 (0.02 equiv) and BINAP (0.4 equiv) were weighed out into a vial, suspended in toluene (2 mL/mmol) and shaken in a 100 C oil bath for 2 min. The resulting clear, purple catalyst solution was added in one portion to the vigorously stirred reaction mixture. The tube was filled with argon, capped, and stirred at 100 C for 16-20 h. The mixture was cooled, and partitioned between EtOAc and H2O. The organic layer was separated, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The resulting crude material was purified by column chromatography on silica gel using an appropriate gradient of acetone in hexane (or MeOH in CH2Cl2) as eluent to provide the target product 2.

Reference： [1]Tetrahedron Letters,2012,vol. 53,p. 2876 - 2880

21
[ 38557-71-0 ]
[ 1432909-81-3 ]
[ 1432909-83-5 ]

Yield	Reaction Conditions	Operation in experiment
18%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In tetrahydrofuran; water; toluene; for 18h;Inert atmosphere; Reflux;	Step 8: Synthesis of methyl 2-(2-chloro-5-methyl-4-(6-methylpyrazin-2-yl)phenyl)acetate (15A) A mixture of methyl 2-(2-chloro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (0.8 g, 2.46 mmol, 1 eq), <strong>[38557-71-0]2-chloro-6-methylpyrazine</strong> (0.38 g, 2.95 mmol, 1.2 eq), KOAc (484 mg, 4.94 mmol, 2 eq) and Pd(dppf)Cl2 (300 mg) were refluxed in toluene/THF/H2O (3.2 ml/3.2 ml/1.6 ml) under N2 for 18 h. This mixture was filtered and the filtrate was diluted with water (20 mL), extracted with EtOAc (40 mL*3), the organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give 0.13 g (18%) of 15A. 1H NMR (400 MHz, DMSO-d6) d ppm 8.497 (s, 1H), 8.44 (s, 1H), 7.46 (s, 1H), 7.26-7.25 (s, 1H), 3.79 (s, 2H), 3.73-3.72 (s, 3H), 2.63 (s, 3H), 2.35 (s, 3H).

Reference： [1]Patent: US2013/116263,2013,A1 .Location in patent: Paragraph 0635

22
[ 38557-71-0 ]
[ 1427705-08-5 ]
[ 1427704-59-3 ]

Yield	Reaction Conditions	Operation in experiment
38%	With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine; In acetonitrile; at 70℃; for 3h;	Example 54: 3 ¾toro-iV-f3-(6-methyl-pyra^Example 54 was prepared from intermediate 8 via the process of Scheme 3, as follows:To a stirred mixture of intermediate 8, 3^hloiO-A^3-eth .-ad nwitaEt- 1 -y.)-ben2amide (60 mg, 0.1 .mmol) and 2-C:h.oro-6-oieih tpyTazine (60 mg, 0.47 mmol) in irieth.ylamine (0.5 mL) and acetonitri.e (2 mL) was added (3 nig, 0,02 mmol), followed by an addition of Cul (3 mg, 0.01.6 mmol). After heated at 70l,C for three hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (50 mL) and brine, dried over ¾804, and concentrated, under reduced pressure. The resulting residue was purified by Prep HPLC to give 30 mg (38%) of the title compound 3H:h ro-N>[3 6^metltyi>pyradit-2- y.e nyl adaraan(an-l-yl]-benzaraide. 5H NMR (500 MHz, CDCfc): S 8.57 i rs, IH), 7.69 (i, J ==== 2.0 Hz, 11-1). 7.59 (d, J - 8.0 Hz, IH), 7.45 (d, J 8.0 Hz, 1 H), 7.35 (L J 8.0 Hz, 1 E), 5.78 (s, H), 2.57 (s, 3H), 2.40 (s, 2H), 2.25 (s, 2H), 2,17-2.15 (m, 2H), 2.06-1.96 (ra, 6H)? 1.73-1,70 (ra, 2H); ESI-MS m/ : 406

Reference： [1]Patent: WO2013/40535,2013,A2 .Location in patent: Page/Page column 49

23
[ 38557-71-0 ]
[ 723286-86-0 ]

Reference： [1]Letters in Organic Chemistry,2013,vol. 10,p. 348 - 352
[2]Patent: EP3124482,2017,A1
[3]Patent: WO2004/58266,2004,A1

24
[ 38557-71-0 ]
[ 5315-24-2 ]

Yield	Reaction Conditions	Operation in experiment
72%	With hydrazine hydrate; at 100℃; for 2h;	General procedure: (0.1mole) of 2-halo nitrogen heterocycle and (0.5 mole) of hydrazine hydrate were mixed together in a 250mL round bottom flask equipped with reflux condenser and wereheated at 100oC, progress of the reaction was monitored byTLC. After completion of the reaction the reaction mixture was cooled to (-5-0oC) for 14hr and the precipitated solid was filtered and washed with two 5ml portions of ice coldwater and dried to give the compound 1 in good yield.

Reference： [1]Letters in Organic Chemistry,2013,vol. 10,p. 348 - 352

25
[ 38557-71-0 ]
[ 1447800-63-6 ]

Reference： [1]Letters in Organic Chemistry,2013,vol. 10,p. 348 - 352

26
[ 38557-71-0 ]
[ 1447800-66-9 ]

Reference： [1]Letters in Organic Chemistry,2013,vol. 10,p. 348 - 352

27
[ 38557-71-0 ]
[ 661-69-8 ]
[ 1527526-54-0 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 100℃;Inert atmosphere; Sealed tube;	A mixture of <strong>[38557-71-0]2-chloro-6-methylpyrazine</strong> (3.357 mmol; 431.6 mg), hexamethylditin (4.03 mmo 1; 1361 mg; 0.861 mL), and tetrakis(triphenylphosphine)palladium(0) (0.2756 mmol; 318.5 mg) in 1,4-Dioxane (10 mL) was purged with Argon. The resulting mixture was sealed in apressure tube and heated at 100 C overnight. The mixture was cooled to room temperature, and filtered through Celite. The filter cake was washed with DCM. The filtrate was concentrated toafford trimethyl-(6-methylpyrazin-2-yl)stannane, which was used without purification.

Reference： [1]Patent: WO2014/1377,2014,A1 .Location in patent: Page/Page column 96; 137

28
[ 38557-71-0 ]
[ 1527525-17-2 ]
[ 1527525-18-3 ]

Yield	Reaction Conditions	Operation in experiment
60%	With tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine; In N,N-dimethyl acetamide; at 130℃;Inert atmosphere;	A mixture of tributyl-(1-tetrahydropyran-2-ylpyrazolo[4,3-c]pyridin-6-yl)stannane (7.139 mmol; 3514.5 mg), <strong>[38557-71-0]2-chloro-6-methyl-pyrazine</strong> (10.71 mmol; 1377 mg), tricyclohexylphosphine; (0.5140 mmol; 144.1 mg) and tris(dibenzylideneacetone)dipalladium(0) (0.2142 mmol; 196.1 mg) in N,N-Dimethylacetamide (15 mL) was purged with Argon for 1 min. The reaction mixture was sealed in a pressure vial and heated at 130 C overnight. The mixture was partitioned between EtOAc and water. The organic layer was concentrated and the residue was purified on silica eluted with 0 to 100% EtOAc in DCM to afford 6-(6-methylpyrazin-2-yl)-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridine as a clear oil (1.3608 g,60%).

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 4458 - 4473
[2]Patent: WO2014/1377,2014,A1 .Location in patent: Page/Page column 122

29
[ 38557-71-0 ]
[ 1527523-63-2 ]

Reference： [1]Patent: WO2014/1377,2014,A1

30
[ 38557-71-0 ]
[ 1527523-93-8 ]

Reference： [1]Patent: WO2014/1377,2014,A1

31
[ 38557-71-0 ]
[ 1527524-08-8 ]

Reference： [1]Patent: WO2014/1377,2014,A1

32
[ 38557-71-0 ]
[ 1527521-97-6 ]

Reference： [1]Patent: WO2014/1377,2014,A1

33
[ 38557-71-0 ]
[ 1527524-97-5 ]

Reference： [1]Patent: WO2014/1377,2014,A1

34
[ 38557-71-0 ]
[ 1527525-06-9 ]

Reference： [1]Patent: WO2014/1377,2014,A1

35
[ 38557-71-0 ]
[ 1527525-13-8 ]

Reference： [1]Patent: WO2014/1377,2014,A1

36
[ 38557-71-0 ]
[ 1527525-34-3 ]

Reference： [1]Patent: WO2014/1377,2014,A1

37
[ 38557-71-0 ]
[ 1527525-51-4 ]

Reference： [1]Patent: WO2014/1377,2014,A1

38
[ 38557-71-0 ]
[ 1527522-87-7 ]

Reference： [1]Patent: WO2014/1377,2014,A1

39
[ 38557-71-0 ]
[ 1527523-08-5 ]

Reference： [1]Patent: WO2014/1377,2014,A1

40
[ 930798-26-8 ]
[ 38557-71-0 ]

Reference： [1]Patent: US2015/31674,2015,A1
[2]Patent: WO2019/99315,2019,A1

41
[ 930798-25-7 ]
[ 38557-71-0 ]

Yield	Reaction Conditions	Operation in experiment
73%	In water; at 130℃;Sealed tube;	step 3: Into a 5-L sealed tube was placed 2-(6-chloropyrazin-2-yl)acetic acid (220 g, 1.27 mol, 1.00 equiv) and water (3 L). The resulting solution was stirred overnight at 130 C., cooled and extracted with Et2O 2×3 L of ether. The organic layers were combined, dried (Na2SO4), filtered and concentrated in vacuo to afford 238 g (73%) of 2-chloro-6-methylpyrazine as a yellow solid.
	In water; at 130℃; for 24h;	Step 3: 2-chloro-6-methylpyrazine A 5-L pressure tank reactor was charged with water (3.5 L) and 2-(6-chloropyrazin-2-yl)acetic acid (850 g, 4.94 mol, 1.00 equiv). The reaction mixture was stirred for 24 h at 130 C, and then cooled to room temperature. The reaction mixture was extracted with ethyl acetate (3 x 3000 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound, which was used in the next step without further purification.

Reference： [1]Patent: US2015/31674,2015,A1 .Location in patent: Paragraph 0325; 0322
[2]Patent: WO2019/99315,2019,A1 .Location in patent: Page/Page column 59

42
[ 38557-71-0 ]
6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one [ No CAS ]