[ CAS No. 74290-65-6 ]

Name: 74290-65-6|3-Bromo-5-methylpyrazin-2-amine|95%
Brand: Ambeed
SKU: A215877
Price: 18.0 USD
Availability: InStock
Rating: 95 (27 reviews)

{[proInfo.proName]} ,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

DV 2D 3D

3d Animation Molecule Structure of 74290-65-6

Structure of 74290-65-6 * Storage: {[proInfo.prStorage]}

Cart0 Add to My Favorites Bulk Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

For Research Only 100K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 74290-65-6 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 74290-65-6 ]

SDS Specification

Alternatived Products of [ 74290-65-6 ]

Product Details of [ 74290-65-6 ]

CAS No. :	74290-65-6	MDL No. :	MFCD09750037
Formula :	C₅H₆BrN₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	VQNGEHYFPRPIGF-UHFFFAOYSA-N
M.W :	188.03 g/mol	Pubchem ID :	9899043
Synonyms :

Calculated chemistry of [ 74290-65-6 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.2
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	39.1
TPSA :	51.8 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.84 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.44
Log Po/w (XLOGP3) :	0.86
Log Po/w (WLOGP) :	1.14
Log Po/w (MLOGP) :	0.11
Log Po/w (SILICOS-IT) :	1.34
Consensus Log Po/w :	0.98

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.04
Solubility :	1.71 mg/ml ; 0.0091 mol/l
Class :	Soluble
Log S (Ali) :	-1.53
Solubility :	5.53 mg/ml ; 0.0294 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.54
Solubility :	0.549 mg/ml ; 0.00292 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.25

Safety of [ 74290-65-6 ]

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 [ 74290-65-6 ]

* 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 [ 74290-65-6 ]
Downstream synthetic route of [ 74290-65-6 ]

[ 74290-65-6 ] Synthesis Path-Upstream 1~7

1
[ 74290-65-6 ]
[ 5521-58-4 ]

Reference： [1] Journal of Heterocyclic Chemistry, 1980, vol. 17, p. 143 - 147

2
[ 74290-65-6 ]
[ 89464-87-9 ]

Yield	Reaction Conditions	Operation in experiment
75%	With sodium methylate; sodium In methanol; water	(i) 2-Amino-3-bromo-5-methylpyrazine (0.374 g) was added to a freshly prepared solution of sodium methoxide in methanol (made by addition of sodium (0.115 g) to methanol (6 ml)). The reaction was heated under reflux for 18 hours, cooled to ambient temperature and the solvent removed by evaporation. Water (5 ml) was added to the residue and extracted with dichloromethane (3*20 ml). The combined organic extracts were dried (MgSO₄) and the solvent removed by evaporation. The residue was purified by chromatography on silica gel, eluding with dichloromethane to give 2-amino-3-methoxy-5-methylpyrazine as a white crystalline solid (0.208 g, 75percent), m.p. 67°-69° C.; mass spectrum (+ve CI): 140 (M+H)⁺.
75%	With sodium methylate; sodium In methanol; water	(b) 2-Amino-3-bromo-5-methylpyrazine (0.374 g) was added to a freshly prepared solution of sodium methoxide in methanol (made by addition of sodium (0.115 g) to methanol (6 ml)). The reaction was heated under reflux for 18 hours, cooled to ambient temperature and the solvent removed by evaporation. Water (5 ml) was added to the residue and extracted with dichloromethane (3*20 ml). The combined organic extracts were dried (MgSO₄) and the solvent removed by evaporation. The residue was purified by chromatography on silica gel, eluding with dichloromethane to give 2-amino-3-methoxy-5-methylpyrazine as a white crystalline solid (0.208 g, 75percent), m.p. 67°-69° C.; mass spectrum (+ve CI): 140 (M+H)⁺.
75%	With sodium methylate; sodium In methanol; water	(ii) 2-Amino-3-bromo-5-methylpyrazine (0.374 g) was added to a freshly prepared solution of sodium methoxide in methanol (made by addition of sodium (0.115 g) to methanol (6 ml). The reaction mixture was heated under reflux for 18 hours, cooled to ambient temperature and the solvent removed by evaporation. Water (5 ml) was added to the residue and extracted with dichloromethane (3*20 ml). The combined organic extracts were dried (MgSO₄) and the solvent removed by evaporation. The residue was purified by chromatography on silica gel, eluding with dichloromethane to give 2-amino-3-methoxy-5-methylpyrazine as a white crystalline solid (0.208 g, 75percent), m.p. 67°-69° C.; mass spectrum (+ve CI): 140 (M+H)⁺.

Reference： [1] Patent: US5861401, 1999, A,
[2] Patent: US5866568, 1999, A,
[3] Patent: US5668137, 1997, A,

3
[ 67-56-1 ]
[ 124-41-4 ]
[ 74290-65-6 ]
[ 89464-87-9 ]

Yield	Reaction Conditions	Operation in experiment
92%	at 30 - 100℃; for 6 h; Inert atmosphere	[00791] To a mixture of 3-bromo-5-methyl-pyrazin-2-amine (31 g, 164.87 mmol) in MeOH (150 mL) was added NaOMe (14 g, 263.79 mmol) in one portion at 30 °C under N2. The mixture was stirred at 100 °C for 6 hrs. The mixture was concentrated under reduced pressure and the resulting residue was dissolved in water (100 mL). The mixture was extracted with EtOAc and the combined organic layers were washed with brine (20 mL), dried with Na2S04, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (to afford 3-methoxy-5-methyl-pyrazin-2-amine (21 g, 92percent yield) as a white solid. 1H MR (400 MHz, CDCh-d) δ ppm 7.39 (s, 1H) 4.59 (br s, 2 H) 3.97 (s, 3 H) 2.29 (s, 3 H)

Reference： [1] Patent: WO2018/136265, 2018, A1, . Location in patent: Paragraph 00791

4
[ 124-41-4 ]
[ 74290-65-6 ]
[ 89464-87-9 ]

Reference： [1] Journal of Medicinal Chemistry, 1997, vol. 40, # 6, p. 996 - 1004

5
[ 5521-58-4 ]
[ 74290-65-6 ]

Yield	Reaction Conditions	Operation in experiment
88%	With pyridine; bromine In dichloromethane at 20℃;	To a solution of 5-methylpyrazin-2-amine (5.00g, 45.8 mmol) and pyridine (4.35g,55.0 mmol) in DCM (250 mL) was added bromine (8.80 g, 55.0 mmol). The mixture was stirredat rt overnight. To the reaction mixture was added water (150 mL), and the resulting mixture waspartitioned. The organic layer was washed with saturated brine (100 mL), dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound asa yellow solid (7.64 g, 88 percent).MS (ESI, pos. ion) m/z: 190.2 [M+Ht;1H NMR (400 MHz, CDCh) 8 (ppm): 7.83 (s, lH), 4.93 (s, 2H), 2.41 (s, 3H).
69%	With N-Bromosuccinimide In dichloromethane at 0 - 30℃; for 1 h; Inert atmosphere	[00790] To a mixture of 5-methylpyrazin-2-amine (10 g, 92 mmol) in DCM (300 mL) was added BS (16 g, 91.63 mmol) in one portion at 0 °C under N2. The mixture was stirred at 30 °C for 1 hr. The resulting mixture was poured into saturated aq. Na2S03 (100 mL) and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried with Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford 3-bromo-5-methyl-pyrazin-2-amine (12 g, 69percent yield,) as a light yellow solid. MR (400 MHz, CDCh-d) δ ppm 7.82 (s, 1H) 4.79 - 5.03 (m, 2 H) 2.39 (s, 3 H).
65%	With N-Bromosuccinimide In dichloromethane at 0 - 20℃; for 12 h;	Step 1. 3-Bromo-5-methylpyrazin-2-amine. To a cooled, 0° C., solution of 5-methylpyrazin-2-amine (5.00 g, 0.05 mol) in DCM (230 mL) was added 1-bromopyrrolidine-2,5-dione (8.97 g, 0.05 mol) all at once. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The reaction was quenched with 1 N sodium thiosulfate (50 mL), the layers were separated and the organic phase was extracted with water (2*50 mL). The combined organic layers were dried (Na₂SO₄), and the solvent was removed under reduced pressure. Purification (FCC, SiO₂, 0-50percent, EtOAc/hexanes) afforded the title compound as a yellow solid (8.61 g, 65percent). [M+H]=188.9/190.11

56.4%

With pyridine; bromine In chloroform for 0.5 h;

To a suspension of 5-methylpyrazin-2-amine (1.09g, 10 mmol) in chloroform (100 mL) was added pyridine(0.85 ml., 10.5 mmol). The mixture was stirred in a foilwrappedflask fitted with an addition funnel, and a solution ofbromine (0.54 ml., 10.5 mmol) in chloroform (10 mL) wasadded dropwise over 10 min. The mixture was allowed toreact an additional 20 minutes after addition was completeand then poured into a separatory funnel containing 10 mLwater. The phases were separated and the organics washedagain with water, dried over sodium sulfate, filtered and concentratedin vacuo. The resulting red oil was purified by silicagel chromatography with 12-100percent EtOAc/hexanes. Themajor UV active peak was collected to give 3-bromo-5-methylpyrazin-2-amine (1.06 g, 5.64 mmol, 56.4percent yield) as a cream-colored solid.

Reference： [1] Patent: WO2018/108125, 2018, A1, . Location in patent: Paragraph 00511
[2] Patent: WO2018/136265, 2018, A1, . Location in patent: Paragraph 00790
[3] Patent: US2014/275531, 2014, A1, . Location in patent: Paragraph 0353
[4] Patent: JP5714745, 2015, B2, . Location in patent: Paragraph 0687; 0688
[5] Patent: US5866568, 1999, A,
[6] Patent: US5668137, 1997, A,

6
[ 5521-58-4 ]
[ 74290-65-6 ]
[ 74290-68-9 ]

Yield	Reaction Conditions	Operation in experiment
50%	Stage #1: With hydrogen bromide; acetic acid In chloroform at 50℃; for 0.5 h; Darkness Stage #2: With bromine In chloroform at 55℃; for 21 h; Stage #3: With sodium carbonate In chloroform; water	A solution of HBr/CH₃CO₂H (360 g (260 mL), 1.50 mol, 33percent HBr in CH₃CO₂H) in anhydrous CHCl₃ (300 mL) was added over 15 min to a solution of 5-methylpyrazin-2-amine 15 (42 g, 0.38 mmol) in CHCl₃ (1 L). The reaction flask was wrapped in aluminum foil and heated to 50 °C for 30 min in the dark whereupon a solution of Br₂ (68 g, 0.42 mmol) in CHCl₃ (500 mL) was added dropwise over 3 h during which time the internal temperature of the reaction never exceeded 55 °C. After 18 h at 55 °C the solvent was evaporated under reduced pressure. The crude mixture was diluted with water (200 mL) and the pH was adjusted to pH=9 by the addition of solid Na₂CO₃. The suspension was filtered under vacuum and the filtrate was extracted with EtOAc (1 L.x.5). The combined organic extracts were concentrated under reduced pressure and purified by flash silica gel chromatography eluting with petroleum ether/EtOAc (5:1-->1:1) to give compound 6-bromo-5-methylpyrazin-2-amine 17a (36 g, 50percent) as a light orange solid; mp 154-157 °C; IR (KBr): 3315, 3188, 1744, 1638, 1575, 1482, 1375, 1308, 1051 cm^-1; ¹H NMR (400 MHz, CDCl₃): δ=7.84 (s, 1H), 4.55 (br s, 2H), 2.52 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ=152.2, 141.8, 138.4, 129.2, 22.2; HRMS-ESI: calcd for C₅H₇BrN₃ (M+H)⁺: 187.9823 and 189.9803; found: 187.9816 and 189.9796. An analytical sample of 3-bromo-5-methylpyrazin-2-amine (17b) was also isolated for spectroscopic analysis; mp 56-57 °C. ¹H NMR (400 MHz, CDCl₃): δ=7.80 (s, 1H), 4.95 (br s, 2H), 2.38 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ=150.6, 142.8, 139.9, 125.2, 19.7; HRMS-ESI: calcd for C₅H₇BrN₃ (M+H)⁺: 187.9823 and 189.9803; found: 187.9817 and 189.9796.

Reference： [1] Journal of Heterocyclic Chemistry, 1980, vol. 17, p. 143 - 147
[2] Tetrahedron, 2011, vol. 67, # 47, p. 9063 - 9066

7
[ 5521-58-4 ]
[ 74290-65-6 ]
[ 74290-68-9 ]

Yield	Reaction Conditions	Operation in experiment
50%	Stage #1: With hydrogen bromide; acetic acid In chloroform at 50℃; for 0.5 h; Darkness Stage #2: With bromine In chloroform at 55℃; for 21 h; Stage #3: With sodium carbonate In chloroform; water	A solution of HBr/CH₃CO₂H (360 g (260 mL), 1.50 mol, 33percent HBr in CH₃CO₂H) in anhydrous CHCl₃ (300 mL) was added over 15 min to a solution of 5-methylpyrazin-2-amine 15 (42 g, 0.38 mmol) in CHCl₃ (1 L). The reaction flask was wrapped in aluminum foil and heated to 50 °C for 30 min in the dark whereupon a solution of Br₂ (68 g, 0.42 mmol) in CHCl₃ (500 mL) was added dropwise over 3 h during which time the internal temperature of the reaction never exceeded 55 °C. After 18 h at 55 °C the solvent was evaporated under reduced pressure. The crude mixture was diluted with water (200 mL) and the pH was adjusted to pH=9 by the addition of solid Na₂CO₃. The suspension was filtered under vacuum and the filtrate was extracted with EtOAc (1 L.x.5). The combined organic extracts were concentrated under reduced pressure and purified by flash silica gel chromatography eluting with petroleum ether/EtOAc (5:1-->1:1) to give compound 6-bromo-5-methylpyrazin-2-amine 17a (36 g, 50percent) as a light orange solid; mp 154-157 °C; IR (KBr): 3315, 3188, 1744, 1638, 1575, 1482, 1375, 1308, 1051 cm^-1; ¹H NMR (400 MHz, CDCl₃): δ=7.84 (s, 1H), 4.55 (br s, 2H), 2.52 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ=152.2, 141.8, 138.4, 129.2, 22.2; HRMS-ESI: calcd for C₅H₇BrN₃ (M+H)⁺: 187.9823 and 189.9803; found: 187.9816 and 189.9796. An analytical sample of 3-bromo-5-methylpyrazin-2-amine (17b) was also isolated for spectroscopic analysis; mp 56-57 °C. ¹H NMR (400 MHz, CDCl₃): δ=7.80 (s, 1H), 4.95 (br s, 2H), 2.38 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ=150.6, 142.8, 139.9, 125.2, 19.7; HRMS-ESI: calcd for C₅H₇BrN₃ (M+H)⁺: 187.9823 and 189.9803; found: 187.9817 and 189.9796.

Reference： [1] Journal of Heterocyclic Chemistry, 1980, vol. 17, p. 143 - 147
[2] Tetrahedron, 2011, vol. 67, # 47, p. 9063 - 9066

[ 74290-65-6 ] Synthesis Path-Downstream 1~46

1
[ 5521-58-4 ]
[ 74290-65-6 ]
[ 74290-68-9 ]

Yield	Reaction Conditions	Operation in experiment
50%		A solution of HBr/CH3CO2H (360 g (260 mL), 1.50 mol, 33% HBr in CH3CO2H) in anhydrous CHCl3 (300 mL) was added over 15 min to a solution of 5-methylpyrazin-2-amine 15 (42 g, 0.38 mmol) in CHCl3 (1 L). The reaction flask was wrapped in aluminum foil and heated to 50 C for 30 min in the dark whereupon a solution of Br2 (68 g, 0.42 mmol) in CHCl3 (500 mL) was added dropwise over 3 h during which time the internal temperature of the reaction never exceeded 55 C. After 18 h at 55 C the solvent was evaporated under reduced pressure. The crude mixture was diluted with water (200 mL) and the pH was adjusted to pH=9 by the addition of solid Na2CO3. The suspension was filtered under vacuum and the filtrate was extracted with EtOAc (1 L×5). The combined organic extracts were concentrated under reduced pressure and purified by flash silica gel chromatography eluting with petroleum ether/EtOAc (5:1?1:1) to give compound 6-bromo-5-methylpyrazin-2-amine 17a (36 g, 50%) as a light orange solid; mp 154-157 C; IR (KBr): 3315, 3188, 1744, 1638, 1575, 1482, 1375, 1308, 1051 cm-1; 1H NMR (400 MHz, CDCl3): delta=7.84 (s, 1H), 4.55 (br s, 2H), 2.52 (s, 3H); 13C NMR (100 MHz, CDCl3): delta=152.2, 141.8, 138.4, 129.2, 22.2; HRMS-ESI: calcd for C5H7BrN3 (M+H)+: 187.9823 and 189.9803; found: 187.9816 and 189.9796. An analytical sample of 3-bromo-5-methylpyrazin-2-amine (17b) was also isolated for spectroscopic analysis; mp 56-57 C. 1H NMR (400 MHz, CDCl3): delta=7.80 (s, 1H), 4.95 (br s, 2H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3): delta=150.6, 142.8, 139.9, 125.2, 19.7; HRMS-ESI: calcd for C5H7BrN3 (M+H)+: 187.9823 and 189.9803; found: 187.9817 and 189.9796.

Reference： [1]Journal of Heterocyclic Chemistry,1980,vol. 17,p. 143 - 147
[2]Tetrahedron,2011,vol. 67,p. 9063 - 9066

2
[ 74290-65-6 ]
[ 5521-58-4 ]

Reference： [1]Journal of Heterocyclic Chemistry,1980,vol. 17,p. 143 - 147

3
[ 74290-65-6 ]
[ 17890-82-3 ]

Reference： [1]Synthesis,1990,p. 659 - 660

4
[ 124-41-4 ]
[ 74290-65-6 ]
[ 89464-87-9 ]

Reference： [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 996 - 1004

5
[ 74290-65-6 ]
NaCu(CN)2 [ No CAS ]
[ 17890-82-3 ]

Reference： [1]Synthesis,1990,p. 659 - 660

6
[ 74290-65-6 ]
5-dimethylamino-N-(3-methoxy-5-methyl-2-pyrazinyl)-1-naphthalenesulphonamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 996 - 1004

7
[ 74290-65-6 ]
[ 114192-09-5 ]
[ 446273-47-8 ]

Yield	Reaction Conditions	Operation in experiment
	at 130℃; for 1h;	<strong>[74290-65-6]3-Bromo-5-methyl-2-pyrazineamine</strong> (3.5 g, 18.6 mmol) and methyl 2-chloro-3-oxopentanoate (6.7 mL, 48.6 mmol) were mixed, and the mixture was heated under stirring at 130C for 1 hour. After being allowed to cool, the unnecessary materials were filtered off and washed with ethyl acetate, and then the filtrates were combined and evaporated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give the title compound (0.32 g) as pale yellow crystals. 1H NMR (400MHz, CDCl3) delta 1.35 (t, J = 7.5 Hz, 3H), 2.56 (s, 3H), 3.15 (q, J = 7.5 Hz, 2H), 4.01 (s, 3H), 8.98 (s, 1H).

Reference： [1]Patent: EP1364952,2003,A1 .Location in patent: Page/Page column 34

8
[ 5521-58-4 ]
[ 74290-65-6 ]

Yield	Reaction Conditions	Operation in experiment
88%	With pyridine; bromine; In dichloromethane; at 20℃;	To a solution of 5-methylpyrazin-2-amine (5.00g, 45.8 mmol) and pyridine (4.35g,55.0 mmol) in DCM (250 mL) was added bromine (8.80 g, 55.0 mmol). The mixture was stirredat rt overnight. To the reaction mixture was added water (150 mL), and the resulting mixture waspartitioned. The organic layer was washed with saturated brine (100 mL), dried over anhydroussodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound asa yellow solid (7.64 g, 88 %).MS (ESI, pos. ion) m/z: 190.2 [M+Ht;1H NMR (400 MHz, CDCh) 8 (ppm): 7.83 (s, lH), 4.93 (s, 2H), 2.41 (s, 3H).
69%	With N-Bromosuccinimide; In dichloromethane; at 0 - 30℃; for 1h;Inert atmosphere;	[00790] To a mixture of 5-methylpyrazin-2-amine (10 g, 92 mmol) in DCM (300 mL) was added BS (16 g, 91.63 mmol) in one portion at 0 C under N2. The mixture was stirred at 30 C for 1 hr. The resulting mixture was poured into saturated aq. Na2S03 (100 mL) and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried with Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford 3-bromo-5-methyl-pyrazin-2-amine (12 g, 69% yield,) as a light yellow solid. MR (400 MHz, CDCh-d) delta ppm 7.82 (s, 1H) 4.79 - 5.03 (m, 2 H) 2.39 (s, 3 H).
65%	With N-Bromosuccinimide; In dichloromethane; at 0 - 20℃; for 12h;	Step 1. 3-Bromo-5-methylpyrazin-2-amine. To a cooled, 0 C., solution of 5-methylpyrazin-2-amine (5.00 g, 0.05 mol) in DCM (230 mL) was added 1-bromopyrrolidine-2,5-dione (8.97 g, 0.05 mol) all at once. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The reaction was quenched with 1 N sodium thiosulfate (50 mL), the layers were separated and the organic phase was extracted with water (2*50 mL). The combined organic layers were dried (Na2SO4), and the solvent was removed under reduced pressure. Purification (FCC, SiO2, 0-50%, EtOAc/hexanes) afforded the title compound as a yellow solid (8.61 g, 65%). [M+H]=188.9/190.11

56.4%	With pyridine; bromine; In chloroform; for 0.5h;	To a suspension of 5-methylpyrazin-2-amine (1.09g, 10 mmol) in chloroform (100 mL) was added pyridine(0.85 ml., 10.5 mmol). The mixture was stirred in a foilwrappedflask fitted with an addition funnel, and a solution ofbromine (0.54 ml., 10.5 mmol) in chloroform (10 mL) wasadded dropwise over 10 min. The mixture was allowed toreact an additional 20 minutes after addition was completeand then poured into a separatory funnel containing 10 mLwater. The phases were separated and the organics washedagain with water, dried over sodium sulfate, filtered and concentratedin vacuo. The resulting red oil was purified by silicagel chromatography with 12-100% EtOAc/hexanes. Themajor UV active peak was collected to give 3-bromo-5-methylpyrazin-2-amine (1.06 g, 5.64 mmol, 56.4% yield) as a cream-colored solid.
	With bromine; In chloroform;	(a) A solution of bromine (0.11 ml) in chloroform (20 ml) was added dropwise over 20 minutes to a solution of 2-amino-5-methylpyrazine (0.218 g) in chloroform (30 ml) which was protected from light. The reaction mixture was stirred for 90 minutes after addition was complete and was then washed with water (50 ml). The organic phase was dried (MgSO4) and volatile material was removed by evaporation to give a yellow oil. The oil was purified by elution with dichloromethane through a silica gel Mega Bond Elut column to give 2-amino-3-bromo-5-methylpyrazine (0.286 g) as a white solid, m.p. 51-52 C.; mass spectrum (+ve CI): 188 (M+H)+.
	With bromine; In chloroform;	(i) A solution of bromine (0.11 ml) in chloroform (20 ml) was added dropwise over 20 minutes to a solution of 2-amino-5-methylpyrazine (0.218 g) in chloroform (30 ml) which was protected from light. The reaction mixture was stirred for 90 minutes after addition was complete and was then washed with water (50 ml). The organic phase was dried (MgSO4) and volatile material was removed by evaporation to give a yellow oil. The oil was purified by elution with dichloromethane through a silica gel Mega Bond Elut column to give 2-amino-3-bromo-5-methylpyrazine (0.286 g) as white solid, m.p. 51-52 C.; mass spectrum (positive chemical ionisation (+ve CI)): 188 (M+H)+.

Reference： [1]Patent: WO2018/108125,2018,A1 .Location in patent: Paragraph 00511
[2]Patent: WO2018/136265,2018,A1 .Location in patent: Paragraph 00790
[3]Patent: US2014/275531,2014,A1 .Location in patent: Paragraph 0353
[4]Patent: JP5714745,2015,B2 .Location in patent: Paragraph 0687; 0688
[5]Patent: US5866568,1999,A
[6]Patent: US5668137,1997,A

9
[ 74290-65-6 ]
[ 89464-87-9 ]

Yield	Reaction Conditions	Operation in experiment
75%	With sodium methylate; sodium; In methanol; water;	(i) 2-Amino-3-bromo-5-methylpyrazine (0.374 g) was added to a freshly prepared solution of sodium methoxide in methanol (made by addition of sodium (0.115 g) to methanol (6 ml)). The reaction was heated under reflux for 18 hours, cooled to ambient temperature and the solvent removed by evaporation. Water (5 ml) was added to the residue and extracted with dichloromethane (3*20 ml). The combined organic extracts were dried (MgSO4) and the solvent removed by evaporation. The residue was purified by chromatography on silica gel, eluding with dichloromethane to give 2-amino-3-methoxy-5-methylpyrazine as a white crystalline solid (0.208 g, 75%), m.p. 67-69 C.; mass spectrum (+ve CI): 140 (M+H)+.
75%	With sodium methylate; sodium; In methanol; water;	(b) 2-Amino-3-bromo-5-methylpyrazine (0.374 g) was added to a freshly prepared solution of sodium methoxide in methanol (made by addition of sodium (0.115 g) to methanol (6 ml)). The reaction was heated under reflux for 18 hours, cooled to ambient temperature and the solvent removed by evaporation. Water (5 ml) was added to the residue and extracted with dichloromethane (3*20 ml). The combined organic extracts were dried (MgSO4) and the solvent removed by evaporation. The residue was purified by chromatography on silica gel, eluding with dichloromethane to give 2-amino-3-methoxy-5-methylpyrazine as a white crystalline solid (0.208 g, 75%), m.p. 67-69 C.; mass spectrum (+ve CI): 140 (M+H)+.
75%	With sodium methylate; sodium; In methanol; water;	(ii) 2-Amino-3-bromo-5-methylpyrazine (0.374 g) was added to a freshly prepared solution of sodium methoxide in methanol (made by addition of sodium (0.115 g) to methanol (6 ml). The reaction mixture was heated under reflux for 18 hours, cooled to ambient temperature and the solvent removed by evaporation. Water (5 ml) was added to the residue and extracted with dichloromethane (3*20 ml). The combined organic extracts were dried (MgSO4) and the solvent removed by evaporation. The residue was purified by chromatography on silica gel, eluding with dichloromethane to give 2-amino-3-methoxy-5-methylpyrazine as a white crystalline solid (0.208 g, 75%), m.p. 67-69 C.; mass spectrum (+ve CI): 140 (M+H)+.

Reference： [1]Patent: US5861401,1999,A
[2]Patent: US5866568,1999,A
[3]Patent: US5668137,1997,A

10
[ 74290-65-6 ]
5-(bromomethyl)-3-(3-(difluoromethoxy)phenyl)-2-ethoxypyrazine [ No CAS ]

Reference： [1]Patent: US2014/275531,2014,A1

11
[ 74290-65-6 ]
3-(3-(difluoromethoxy)phenyl)-2-ethoxy-5-methylpyrazine [ No CAS ]

Reference： [1]Patent: US2014/275531,2014,A1

12
[ 74290-65-6 ]
5-({6-[3-(difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidine-2-carbonitrile [ No CAS ]

Reference： [1]Patent: US2014/275531,2014,A1

13
[ 74290-65-6 ]
5-({6-[3-(difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidine-2-carboxamide [ No CAS ]

Reference： [1]Patent: US2014/275531,2014,A1

14
[ 64-17-5 ]
[ 74290-65-6 ]
3-bromo-2-ethoxy-5-methylpyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With hydrogenchloride; tert.-butylnitrite; In 1,4-dioxane; at 0 - 20℃; for 8h;	Step 2. 3-Bromo-2-ethoxy-5-methylpyrazine. To a solution of <strong>[74290-65-6]3-bromo-5-methylpyrazin-2-amine</strong> (4.00 g, 21.27 mmol) in EtOH (42 mL), at 0 C., was added tert-butyl nitrite (7.65 mL, 63.82 mmol) followed by 4 N hydrochloric acid in 1,4-dioxane (1.91 mL, 7.66 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 8 h. The mixture was concentrated under reduced pressure. The residue was diluted with aq. NaHCO3 and extracted into DCM. The combined organic layers were dried, and the solvent was removed under reduced pressure. Purification (FCC, SiO2, 0-20%, EtOAc/hexanes) afforded the title compound as a white solid (2.5 g, 54%). [M+H]=217.06/219.05.

Reference： [1]Patent: US2014/275531,2014,A1 .Location in patent: Paragraph 0354

15
[ 107-20-0 ]
[ 74290-65-6 ]
8-bromo-6-methylimidazo[ 1,2-a]pyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	at 100℃; for 1h;	A mixture of <strong>[74290-65-6]3-bromo-5-methylpyrazin-2-amine</strong> (1 g, 5.3 mmol) in chloroacetaldehyde (5 mL) was heated to 100 C for 1 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulphate, filtered and concentrated to get residue. The residue was purified by flash chromatography using 20% ethyl acetate in hexanes to get pure titled compound (0.6 g, 53%). ?HNMR (300 MHz, DMSO- d6): oe 8.40 (d, J = 0.9 Hz, 1H), 8.02 (d, J = 0.6 Hz, 1H), 7.79 (d, J =0.9 Hz, 1H), 2.37 (s, 3H).

Reference： [1]Patent: WO2016/185342,2016,A1 .Location in patent: Page/Page column 39

16
[ 74290-65-6 ]
3-ethynyl-5-methylpyrazine-2-amine [ No CAS ]

Reference： [1]Patent: WO2018/108125,2018,A1

17
[ 74290-65-6 ]
2-methyl-5H-pyrrolo[2,3-b]pyrazine [ No CAS ]

Reference： [1]Patent: WO2018/108125,2018,A1

18
[ 74290-65-6 ]
7-iodo-2-methyl-5H-pyrrolo[2,3-b]pyrazine [ No CAS ]

Reference： [1]Patent: WO2018/108125,2018,A1

19
[ 74290-65-6 ]
7-iodo-2-methyl-5-trityl-5H-pyrrolo[2,3-b]pyrazine [ No CAS ]

Reference： [1]Patent: WO2018/108125,2018,A1

20
[ 74290-65-6 ]
2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-trityl-5H-pyrrolo[2,3-b]pyrazine [ No CAS ]

Reference： [1]Patent: WO2018/108125,2018,A1

21
[ 74290-65-6 ]
(2S,3S)-ethyl 3-((5-fluoro-2-(2-methyl-5-trityl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-6-(thiophen-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]

Reference： [1]Patent: WO2018/108125,2018,A1

22
[ 74290-65-6 ]
(2S,3S)-ethyl 3-((5-fluoro-2-(2-methyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-6-(thiophen-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate [ No CAS ]

Reference： [1]Patent: WO2018/108125,2018,A1

23
[ 74290-65-6 ]
(2S,3S)-3-((5-fluoro-2-(2-methyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-6-(thiophen-2-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2018/108125,2018,A1

24
[ 74290-65-6 ]
[ 1066-54-2 ]
5-methyl-3-((trimethylsilyl)ethynyl)pyrazin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%		3-Bromo-5-methylpyrazin-2-amine (7.64 g, 40.6 mmol), triethylamine (12.3 g, 122mmol), cuprous iodide (0.77 g, 4.06 mmol) and palladium(II)bis(triphenylphosphine) dichloride(2.85 g, 4.06 mmol) were dissolved in tetrahydrofuran (150 mL). The mixture was stirred at rt,then trimethylsilylacetylene (8.00 mL, 56.9 mmol) was added dropwise slowly to the mixture.The resulting mixture was continued to stir for 4 h.The reaction mixture was diluted with ethylacetate (50 mL). The mixture was filtered. The filtrate was concentrated in vacuo, and theresidue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 3011) to give thetitle compound as a light yellow solid (7 .0 g, 84 % ).MS (ESI, pos. ion) m/z: 206.1 [M+Ht.

Reference： [1]Patent: WO2018/108125,2018,A1 .Location in patent: Paragraph 00512

25
[ 74290-65-6 ]
[ 16182-04-0 ]
ethyl 6-methylthiazolo[5,4-b]pyrazin-2-ylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63.1%	In methanol; toluene; at 100℃; for 0.5h;	To <strong>[74290-65-6]3-bromo-5-methylpyrazin-2-amine</strong> (850 mg,4.52 mmol) was added ethoxycarbonyl isothiocyanate (0.51ml., 4.52 mmol) followed by toluene (1 mL). The mixturewas placed in a preheated 100 C. oil bath, and within aminute, all the solids had dissolved. After 15 min, all hadseized to a solid mass. After an additional 15 minutes, methanol(-5 mL) was added and the mixture refluxed to digest thesolids. The mixture was cooled to rt after 5 minutes and thesolids collected by filtration, washing with methanol to giveethyl 6-methylthiazolo[5,4-b]pyrazin-2-ylcarbamate (680mg, 2.85 mmol, 63.1% yield).

Reference： [1]Patent: JP5714745,2015,B2 .Location in patent: Paragraph 0687; 0689

26
[ 74290-65-6 ]
6-methylthiazolo[5,4-b]pyrazin-2-amine [ No CAS ]

Reference： [1]Patent: JP5714745,2015,B2

27
[ 74290-65-6 ]
2-iodo-3-methoxy-5-methyl-pyrazine [ No CAS ]