2-Amino-6-chloropyrazine | 6-Chloro-pyrazin-2-ylamine | Pyrazines

Structure of 2-Amino-6-chloropyrazine
CAS No.: 33332-28-4

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Synonyms: 6-Chloro-pyrazin-2-ylamine

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Quality Control of [ 33332-28-4 ] Purity: 98% SDS Specification

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Product Details of [ 33332-28-4 ]

CAS No. :	33332-28-4
Formula :	C₄H₄ClN₃
M.W :	129.55
SMILES Code :	C1=C(N=C(C=N1)Cl)N
Synonyms :	6-Chloro-pyrazin-2-ylamine
MDL No. :	MFCD00055024
InChI Key :	JTPXVCKCLBROOJ-UHFFFAOYSA-N
Pubchem ID :	118458

Safety of [ 33332-28-4 ]

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

Computational Chemistry of [ 33332-28-4 ] Show Less

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	1.0
Molar Refractivity	31.45
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	51.8 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.11
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	0.95
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.72
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	-0.45
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	0.98
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.66

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.8
Solubility	2.07 mg/ml ; 0.016 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.62
Solubility	3.07 mg/ml ; 0.0237 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-1.87
Solubility	1.74 mg/ml ; 0.0135 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.42 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	2.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.02

Application In Synthesis of [ 33332-28-4 ]

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

Upstream synthesis route of [ 33332-28-4 ]
Downstream synthetic route of [ 33332-28-4 ]

[ 33332-28-4 ] Synthesis Path-Upstream 1~3

1
[ 544-97-8 ]
[ 33332-28-4 ]
[ 5521-56-2 ]

Yield	Reaction Conditions	Operation in experiment
28%	at 105℃; for 16.25 h;	A. 6-Methylpyrazine-2-ylamine. To a solution containing 6-chloro-2- pyrazineamine (5.0 g, 38.75 mmol) in 1,4-dioxane (70 mL) was added [1,3- bis(diphenylphosphino]Ni(II)Cl₂ (2.10 g, 38.76 mmol), followed by drop-wise addition of dimethylzinc in toluene (38.75 mL, 2.0 M, 77.50 mmol), over 15 min. The solution was allowed stir at 105 °C for 16 hours. The solution was then condensed under reduced pressure, diluted with ethyl acetate and filtered through celite to remove the nickel salts. The resultant slurry was purified via Biotage silica gel chromatography (0-8percent methanol in dichloromethane) to afford the title compound as an orange solid (1.18 g, 28percent yield). MS (ESI) m/z 1 10.3 [M+ 1]⁺.

References: [1] Tetrahedron Letters, 2006, vol. 47, # 3, p. 341 - 344.
[2] Patent: WO2008/51493, 2008, A2, . Location in patent: Page/Page column 101.
[3] Patent: WO2008/83070, 2008, A1, . Location in patent: Page/Page column 85.
[4] Patent: US2013/210818, 2013, A1, . Location in patent: Paragraph 0390.
[5] Patent: WO2009/115486, 2009, A1, . Location in patent: Page/Page column 25-26.
[6] Patent: WO2009/115572, 2009, A2, . Location in patent: Page/Page column 117-118.
[7] Patent: WO2004/108692, 2004, A1, . Location in patent: Page 37-38.

2
[ 75-16-1 ]
[ 33332-28-4 ]
[ 5521-56-2 ]

References: [1] Patent: US2015/175616, 2015, A1, . Location in patent: Paragraph 0242; 0243.
[2] Patent: WO2015/100217, 2015, A1, . Location in patent: Page/Page column 99.
[3] Patent: WO2016/10809, 2016, A1, . Location in patent: Paragraph 0279.
[4] Patent: WO2016/172117, 2016, A1, . Location in patent: Page/Page column 32-33.

3
[ 33332-28-4 ]
[ 5158-46-3 ]
[ 5521-56-2 ]

References: [1] Tetrahedron Letters, 2006, vol. 47, # 3, p. 341 - 344.

[ 33332-28-4 ] Synthesis Path-Downstream 1~54

1
[ 4774-14-5 ]
[ 33332-28-4 ]

Yield	Reaction Conditions	Operation in experiment
95%	With ammonia; at 100℃; for 5h;	In the hydrothermal reaction kettle are respectively added with 2, 6 - two chlorine pyrrole qin (10.0 g, 67.1 mmol) and ammonia (100 ml), 100 C lower reaction 5 h. The completion of the reaction, cooling to room temperature, filtered, the filter cake is hexane (16 ml) beating shall 2 - amino -6 - chloropyrazine white solid 8.2 g, yield is 95.0%.
91%	With ammonia; In water; at 100℃; for 18h;Sealed tube;	2,6-Dichloropyrazine (2.89 g, 19.4 mmol) was stirred in aqueous NH3 (28%, 10 ml.) and heated to 100C in a sealed tube for 18 hours. The reaction mixture was cooled and the resultant precipitate was filtered. Trituration with water and then ether gave 6- chloropyrazin-2-amine as a white solid (2.28 g, 17.6 mmol, 91 % yield). 1H NMR (d6-DMSO, 400 MHz) ? 6.9 (brs, 2H), 7.70 (d, J = 0.4, 1 H), 7.80 (d, J = 0.4, 1 H); LC-MS (ZQ, 6 minutes) Rt = 1.05 minutes; m/z (ESI+) 130 (M+H).6-Chloropyrazin-2-amine (2.50 g, 19.3 mmol) was stirred in CH2CI2 (60 ml.) at 0C.A/-Bromosuccinimide (2.92 g, 16.4 mmol) was added slowly and the reaction mixture was stirred at 0C for 60 minutes. The reaction mixture was filtered through celite and concentrated to give a brown oil. Purification by flash chromatography, eluting with 0-25% EtOAc-hexanes, gave 5-bromo-6-chloropyrazin-2-amine as a yellow solid (1 .69 g, 8.16 mmol, 42% yield). 1H NMR (de-DMSO, 400 MHz) ? 7.1 (brs, 2H), 7.65 (s, 1 H); LC-MS (ZQ, 4 minutes) Rt = 1.46 minutes; m/z (ESI-) 205 (M-H).A mixture of 5-bromo-6-chloropyrazin-2-amine (1 .00 g, 4.8 mmol), copper (I) iodide (914 mg, 4.8 mmol), 18-crown-6 (95 mg, 0.36 mmol) andtetrakis(triphenylphosphine)palladium (0) (83 mg, 0.072 mmol) was suspended in dry DMF (20 ml.) and a stream of nitrogen was passed through for 5 minutes. Potassium cyanide (312 mg, 4.8 mmol) was added and the mixture was stirred at room temperature for 30 minutes, then refluxed at 200C for 3 hours. The mixture was cooled, diluted with EtOAc and absorbed onto silica gel (10 g). DMF was removed by evaporation. The product was purified by flash chromatography, eluting with 1 :1 EtOAc-hexanes, to yield 5- amino-3-chloropyrazine-2-carbonitrile as a yellow solid (607 mg, 3.93 mmol, 82% yield). 1H NMR (d6 DMSO, 400 MHz) ? 7.87 (s, 1 H), 8.1 (brs, 2H); LC-MS (ZQ, 4 minutes) Rt = 1.20 minutes; m/z (ESI-) 153 (M-H).
80%	With ammonia; In water; at 135℃;Autoclave;	A solution of compound 8 4500 g, 302 mol) in conc. aq. NH3 (3.0 L) was stirred at135C overnight in a 10 L sealed pressure vessel. TLC and LC/MS showed completeconversion of the starting material. The reaction mixture was cooled to roomtemperature and filtered to afford a white solid. The solid was washed with water (200mL x 3), and then dried to afford compound 9 (312 g, 80% yield) as a solid.1HNMR (400 MHz, DMSO-d6): 7,82 (s, 1 H), 712 (s, 1 H), 6.93 (s, 2H). MS Calcd.:129 MS Found: 130 ([M+Hj).

80%	With ammonium hydroxide; at 135℃;Sealed tube;	A solution of compound 8 (450.0 g, 3.02 mol) in cone. aq. NH3 (3.0 L) was stirred at 135°C overnight in a 10 L sealed pressure vessel. TLC and LC/MS showed complete conversion of the starting material. The reaction mixture was cooled to room temperature and filtered to afford a white solid. The solid was washed with water (200 mL x 3), and then dried to afford compound 9 (312 g, 80percent yield) as a solid. 1HNMR (400 MHz, DMSO- 6): delta 7.82 (s, 1 H), 7.12 (s, 1 H), 6.93 (s, 2H). MS Calcd.: 129 MS Found: 130 ([M+H]+).
63%	With ammonia; In water; at 20 - 140℃; for 63h;In sealed autoclave;	EXAMPLE 5 2-amino-6-chloropyrazine 120 ml of water, 20.8 ml (0.31 mol, 4.6 eq) of an aqueous 28% ammonia solution and 10 g (0.067 mol, 1 eq) of 2,6-dichloropyrazine were successively added to an autoclave reactor. The autoclave was sealed and the mixture heated at 140 C. for 3 h, then left at room temperature for 60 h. The mixture was filtered, the precipitate washed with water, then vacuum dried. The reaction produced 5.4 g of a fine powder (yield: 63%). 1H NMR (CDCl3) delta (ppm): 7.88 (s, 1H, CH); 7.84 (s, 1H, CH); 4.68 (m, 2H, NH2). HPLC: t=1.07 min MS: 130 (MH+) HPLC purity: 100%
60%	With ammonium hydroxide; In water; at 120℃; for 6h;Large scale;	A solution of 2,6-dichloropyrazine (15kg, 1O1.4mol, 1.00 equiv) in water(20 L), ammonia water (25 L, 25 %) was placed in a 100 L pressure tank reactor. The resulting solution was stirred for 6 h at 120C. The reaction progress was monitored by TLC (EA:PE = 1 : 1) until the starting material was consumed, and cooled to room temperature. Thesolids were collected by filtration. The solid was washed with water and dried. The solidwas washed with petroleum ether to remove the unreacted starting materials. The product (7.8kg, purity = 95 %, 60% yield) was obtained as a white solid.
59.7%	With ammonia; In water; at 140℃; for 14h;	Example B-10: Preparation of (2S)-1-(4-(1-isopropyl-3-(5-methyl-5H-pyrrolo[3,2-b]pyrazin-2-yl)-1H- pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-10) <n="80"/>cr Et3NB-10-1 B-10-2 B-10-3Preparation of 6-chloropyrazin-2-amine (B-10-2). B-10-1 B-10-2A mixture of 2,6-dichloropyrazine (300 g, 2 mol) and 28% aq. NH3 (8 L) was stirred at 14O0C in a sealed system for 14 hours. TLC (petroleum ether/EtOAc 3:1 ) indicated complete consumption of starting material. The reaction mixture was extracted with EtOAc (3 L x 3). The combined organic layers were washed with saturated aqueous NaCI (3 L), dried over Na2SO4 and concentrated in vacuo to give crude compound B-10-2, which was purified by column chromatography (silica gel, petroleum ether/EtOAc 2:1) to yield pure compound B-10-2 (410 g, yield: 59.7%) as a white solid.
41.98 g (48%)	In ammonia;	3. 2-Chloro-6-amino-pyrazine A suspension of 2,6-dichloropyrazine (100 g, 0.67 mole, Lancaster) in 0.880 ammonia (500 ml) was stirred and heated at 150 C. in a glass lined autoclave at 20 atm for 16 hrs. The cooled mixture was filtered, washed well with water (200 ml) and dried. The product was recrystallized from chloroform. Yield 41.98 g (48%), M.p. 150-152 C.
	With ammonia; In water; at 100℃;Autoclave;	Svnthesis 2-1-A 6-Chloropyrazin-2-amine 2,6-Dichloropyrazine (2.89 g, 19.4 mmol) was stirred in aqueous ammonia (28%, 10 mL) and heated to 100C overnight in a sealed tube. The reaction mixture was cooled and the resultant precipitate was filtered. Trituration with water and then ether gave the title compound as a white solid (2.28 g, 17.6 mmol, 91%). 1H NMR (d6-DMSO, 400 MHz) delta 7.80 (d, 1 H1 J = 0.4 Hz), 7.70 (d, 1 H, J = 0.4 Hz), 6.9 (br s, 2H). LC-MS (2) rt 1.05 min; m/z (ESI+) 130/132.

References: [1]Patent: CN107857737,2018,A .Location in patent: Paragraph 0011-0013; 0021-0023; 0030-0032; 0040-0042; 0049.
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 8328 - 8342.
[3]Patent: WO2013/68755,2013,A1 .Location in patent: Page/Page column 67, 68.
[4]Patent: WO2017/5786,2017,A1 .Location in patent: Page/Page column 23; 24.
[5]Patent: WO2018/9424,2018,A1 .Location in patent: Paragraph 00195; 00198-00199.
[6]Tetrahedron,1984,vol. 40,p. 5081 - 5088.
[7]Patent: US2005/267126,2005,A1 .Location in patent: Page/Page column 10-11.
[8]Patent: WO2017/29602,2017,A2 .Location in patent: Paragraph 75; 133; 134.
[9]Patent: WO2009/16460,2009,A2 .Location in patent: Page/Page column 78-79.
[10]Patent: US6255307,2001,B1 .
[11]Patent: WO2009/103966,2009,A1 .Location in patent: Page/Page column 88.

2
[ 108-24-7 ]
[ 33332-28-4 ]
[ 132453-63-5 ]

References: [1]Tetrahedron,1984,vol. 40,p. 5081 - 5088.

3
[ 100-39-0 ]
[ 33332-28-4 ]
6-benzyl-pyrazin-2-ylamine [ No CAS ]

References: [1]Tetrahedron Letters,2006,vol. 47,p. 341 - 344.

4
[ 103-63-9 ]
[ 33332-28-4 ]
2-amino-6-(2-phenylethyl)pyrazine [ No CAS ]

References: [1]Tetrahedron Letters,2006,vol. 47,p. 341 - 344.

5
[ 17376-04-4 ]
[ 33332-28-4 ]
2-amino-6-(2-phenylethyl)pyrazine [ No CAS ]

References: [1]Tetrahedron Letters,2006,vol. 47,p. 341 - 344.

6
[ 544-97-8 ]
[ 33332-28-4 ]
[ 5521-56-2 ]

Yield	Reaction Conditions	Operation in experiment
28%	[1,3- bisdiphenylphosphino]Ni(II)Cl2; In 1,4-dioxane; toluene; at 105℃; for 16.25h;	A. 6-Methylpyrazine-2-ylamine. To a solution containing 6-chloro-2- pyrazineamine (5.0 g, 38.75 mmol) in 1,4-dioxane (70 mL) was added [1,3- bis(diphenylphosphino]Ni(II)Cl2 (2.10 g, 38.76 mmol), followed by drop-wise addition of dimethylzinc in toluene (38.75 mL, 2.0 M, 77.50 mmol), over 15 min. The solution was allowed stir at 105 °C for 16 hours. The solution was then condensed under reduced pressure, diluted with ethyl acetate and filtered through celite to remove the nickel salts. The resultant slurry was purified via Biotage silica gel chromatography (0-8percent methanol in dichloromethane) to afford the title compound as an orange solid (1.18 g, 28percent yield). MS (ESI) m/z 1 10.3 [M+ 1]+.
	1,3-bis[(diphenylphosphino)propane]dichloronickel(II); In tetrahydrofuran; diethyl ether; for 3h;	Example 29: Preparation of:2-(4-Ch]oro-2-mophiholin-4-yl-1.24hiazol-5-yl)-5-(dicvcloprorhoyImethylV3,7-dimethyl-5H-pyitauolof2.3- ipyrazine; Part A: 2-Amino-6-methy] pyrazine; A solution of zinc chloride (2.0M in THF, 96.5 mL, 48.2 mmol, 5.0 equiv.) is treated dropwise with methylmagnesium bromide (3.0 M in Et2O, 32.2 mL, 96.5 mmoi, 10.0 equiv.) at 0 °C. The mixture is wanned to room temp and stirred for 45 min. A solution of 2-amino-6-chloro pyrazine (1.25 g. 9.65 mmol, 1.0 equiv) and NiC12(dppp) (157 mg, 0.29 mmol, 0.03 equiv) in THF (15 mL) is added to the freshly prepared dimethylzinc reagent. The reaction mixture is stirred under for 3h and cooied to room temp. The reaction is quenched carefully with sat'd NH4CI solution and allowed to stir overnight. The layers are separated and the aqueous layer is extracted with EtOAc (2 X 30 mL). The combined organic extracts are washed with brine, dried over Na2Spsi4 and concentrated under reduced pressure to give a cream-colored solid that is used without further purification. MS = 110.08 (M +1). 1H NMR (400 MHz, CDCI3) delta 7.78 (IH, s), 7.72 (IH, s), 4.59 (2H, bs), 2.35 (3H, s).
	With 1,3-bis[(diphenylphosphino)propane]dichloronickel(II); In 1,4-dioxane; toluene; at 20 - 95℃;Inert atmosphere;	Following a literature procedure (Walters, I. A. S. Tetrahedron Lett. 2006, 47, 341), a solution of dimethylzinc (2.0 M in toluene, 75.0 mL, 150.0 mmol) was carefully added in 25 mL portions to a solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (10.0 g, 77.0 mmol) and 1,3-bis(diphenylphosphino)propane-nickel (II) chloride (4.2 g, 7.8 mmol) were dry in dioxane (400 mL) under a nitrogen atmosphere. The reaction was stirred at rt for 2 h and then heated to 50° C. for 1 h and 95° C. overnight. The reaction was allowed to cool to rt and an additional charge of dimethylzinc was added (22 mL, 44 mmol) and the reaction was then maintained at 95° C. overnight. The reaction was cooled to rt, quenched over 15 min with MeOH and then concentrated to a brown solid. Water and EtOAc were added to the solid, and the mixture was sonicated. The solid was removed by filtration and brine was added to the EtOAc-water mixture. The layers were separated, and the organic layer was dried (Na2SO4), and concentrated to give 9.72 g (?70 purity) of 6-methylpyrazin-2-amine, which was carried forward without further purification: LCMS (m/z): 110.0 (MH+), tR=0.21 min.

		Intermediate 1 : 6-Methyl-2-pyrazinamine <n="27"/>; Dimethyl zinc (15.44 ml, 30.9 mmol) was added to a solution of 6-chloro-2- pyrazinamine (2 g, 15.44 mmol) and NiCI2(dppp) (0.837 g, 1.544 mmol) in dry 1 ,4- dioxane (75 ml) and the mixture was refluxed for 24 hours. The mixture was then cooled to room temperature, quenched with methanol and concentrated in vacuum. The residue was partitioned between EtOAc and brine. The organic phase was dried over Na2SO4, filtered and the solvent evaporated. The residue was purified by silica chromatography (MeOH-NH3-DCM) to afford the title compound as a pale yellow solid.
	1,3-bis[(diphenylphosphino)propane]dichloronickel(II); In 1,4-dioxane; toluene; at 20 - 95℃;Inert atmosphere;	Following a literature procedure (Walters, I.A.S. Tetrahedron Lett. 2006, 47, 341), a solution of dimethylzinc (2.0 M in toluene, 75.0 mL, 150.0 mmol) was carefully added in 25 mL portions to a solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (10.0 g, 77.0 mmol) and l ,3-bis(diphenylphosphino)propane-nickel (II) chloride (4.2 g, 7.8 mmol) were <n="119"/>dry in dioxane (400 mL) under a nitrogen atmosphere. The reaction was stirred at rt for 2 h and then heated to 50 0C for 1 h and 95 0C overnight. The reaction was allowed to cool to rt and an additional charge of dimethylzinc was added (22 mL, 44 mmol) and the reaction was then maintained at 95 0C overnight. The reaction was cooled to rt, quenched over 15 min with MeOH and then concentrated to a brown solid. Water and EtOAc were added to the solid, and the mixture was sonicated. The solid was removed by filtration and brine was added to the EtO Ac-water mixture. The layers were separated, and the organic layer was dried (Na2SO^, and concentrated to give 9.72 g (~70 purity) of 6-methylpyrazin-2-amine, which was carried forward without further purification: LCMS (m/z): 110.0 (MH+), R = 0.21 min.
	1,3-bis[(diphenylphosphino)propane]dichloronickel(II); In 1,4-dioxane; for 18.5h;Heating / reflux;	Dimethylzinc (lOOmL of a 2M solution in toluene) was added dropwise over 0.5h to astirred solution of 6-chloro-2-pyrazinamine (12.9g) and [1,3-fe(diphenylphosphmo)propane]nickel(n) chloride (5.4g) in dioxane (200mL) under anitrogen atmosphere. The reaction mixture was heated at reflux for 18h, then cooled toroom temperature and quenched cautiously with zso-propanol (30mL) and methanol(50mL). After removal of solvent in vacua, the residue was partitioned betweendichloromethane and aqueous ammonium chloride. The organic phase was filtered throughcelite, dried (MgSO4), filtered and evaporated to give the crude product as an orange solid.Chromatography on silica gel eluting with ethyl acetate/methanol mixtures gave the sub- title compound (5.1g). Used directly.

References: [1]Tetrahedron Letters,2006,vol. 47,p. 341 - 344.
[2]Patent: WO2008/51493,2008,A2 .Location in patent: Page/Page column 101.
[3]Patent: WO2008/83070,2008,A1 .Location in patent: Page/Page column 85.
[4]Patent: US2013/210818,2013,A1 .Location in patent: Paragraph 0390.
[5]Patent: WO2009/115486,2009,A1 .Location in patent: Page/Page column 25-26.
[6]Patent: WO2009/115572,2009,A2 .Location in patent: Page/Page column 117-118.
[7]Patent: WO2004/108692,2004,A1 .Location in patent: Page 37-38.

7
[ 557-20-0 ]
[ 33332-28-4 ]
6-ethyl-2-aminopyrazine [ No CAS ]

References: [1]Tetrahedron Letters,2006,vol. 47,p. 341 - 344.

8
[ 98398-49-3 ]
[ 33332-28-4 ]
2-amino-6-propylpyrazine [ No CAS ]

References: [1]Tetrahedron Letters,2006,vol. 47,p. 341 - 344.

9
[ 33332-28-4 ]
cyclopentylzinc bromide [ No CAS ]
2-amino-6-cyclopentylpyrazine [ No CAS ]

References: [1]Tetrahedron Letters,2006,vol. 47,p. 341 - 344.

10
[ 33332-28-4 ]
[ 5158-46-3 ]
[ 5521-56-2 ]

References: [1]Tetrahedron Letters,2006,vol. 47,p. 341 - 344.

11
[ 33332-28-4 ]
[ 960510-36-5 ]

Yield	Reaction Conditions	Operation in experiment
97%		A solution of 2-amino-6- chloropyrazine (25g, 193.1 mmol) in MeOH (500 mL) was treated with NBS (34.3 g, 193.1 mmol), portion-wise, over 1 hour. The resulting mixture was stirred for 16 hours thereafter. TLC analysis at this time shows a small amount of starting material remaining. Another 1.4 g NBS added and reaction heated to 50 0C for 2 hours. The mixture was then cooled to 38 "C and treated with NCS (25.8 g, 193.1 mmol). The reaction mixture was heated to 50 0C for 16 hours thereafter. The mixture was then cooled to room temperature and treated with water (500 mL). The precipitate was collected by filtration and dried in a vacuum dessicator to afford 45.4 g (97% yield) of 2-amino-5-bromo-3,6-dichloropyrazine as a white solid: 13C NMR (75 MHz, CDCI3) delta 149.9 (s), 145.6 (s), 129.6 (s), 121.5 (s). LCMS (15-95% gradient acetonitrile in 0.1% TFA over 10 min), single peak retention time = 4.51 min on 30 mm column, (M+H)+ = 244, (M+H+ACN)* = 285
97%		A solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (25g, 193.1 mmol) in MeOH (500 ml_) was treated with NBS (34.3 g, 193.1 mmol), portion-wise, over 1 hour. The resulting mixture was stirred for 16 hours thereafter. TLC analysis at this time shows a small amount of starting material remaining. Another 1.4 g NBS added and reaction heated to 50 0C for 2 hours. The mixture15 was then cooled to 38 0C and treated with NCS (25.8 g, 193.1 mmol). The reaction mixture was heated to 500C for 16 hours thereafter. The mixture was then cooled to room temperature and treated with water (500 ml_). The precipitate was collected by filtration and dried in a vacuum dessicator to afford 45.4 g (97% yield) of 2-amino-5-bromo-3,6- dichloropyrazine as a white solid: 13C NMR (75 MHz, CDCI3) delta 149.9 (s), 145.6 (s), 129.6 (s),20 121.5 (S). LCMS (15-95% gradient acetonitrile in 0.1 % TFA over 10 min), single peak retention time = 4.51 min on 30 mm column, (M+H)+ = 244, (M+H+ACN)* = 285.
97%		A solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (25 g, 193.1 mmol) in MeOH (500 mL) was treated with NBS (34.3 g, 193.1 mmol), portion-wise, over 1 hour. The resulting mixture was stirred for 16 hours thereafter. TLC analysis at this time shows a small amount of starting material remaining. Another 1.4 g NBS added and reaction heated to 50 C. for 2 hours. The mixture was then cooled to 38 C. and treated with NCS (25.8 g, 193.1 mmol). The reaction mixture was heated to 50 C. for 16 hours thereafter. The mixture was then cooled to room temperature and treated with water (500 mL). The precipitate was collected by filtration and dried in a vacuum dessicator to afford 45.4 g (97% yield) of 2-amino-5-bromo-3,6- dichloropyrazine as a white solid: 13C NMR (75 MHz, CDC13) delta 149.9 (s), 145.6 (s), 129.6 (s), 121.5 (s). LCMS (15-95% gradient acetonitrile in 0.1% TFA over 10 min), single peak retention time=4.51 min on 30 mm column, (M+H)+=244, (M+H+ACN)+=285.

97%		A solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (25 g, 193.1 mmol) in MeOH (500 mL) was treated with NBS (34.3 g, 193.1 mmol), portion-wise, over 1 hour. The resulting mixture was stirred for 16 hours thereafter. TLC analysis at this time shows a small amount of starting material remaining. Another 1.4 g NBS added and reaction heated to 50° C. for 2 hours. The mixture was then cooled to 38° C. and treated with NCS (25.8 g, 193.1 mmol). The reaction mixture was heated to 50° C. for 16 hours thereafter. The mixture was then cooled to room temperature and treated with water (500 mL). The precipitate was collected by filtration and dried in a vacuum desiccator to afford 45.4 g (97percent yield) of 2-amino-5-bromo-3,6-dichloropyrazine as a white solid: 13C NMR (75 MHz, CDCl3) delta 149.9 (s), 145.6 (s), 129.6 (s), 121.5 (s). LCMS (15-95percent gradient acetonitrile in 0.1percent TFA over 10 min), single peak retention time=4.51 min on 30 mm column, (M+H)+=244, (M+H+ACN)+=285.
97%		A solution of 82 <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (25 g, 193.1 mmol) in 83 MeOH (500 mL) was treated with 84 NBS (34.3 g, 193.1 mmol), portion-wise, over 1 hour. The resulting mixture was stirred for 16 hours thereafter. TLC analysis at this time shows a small amount of starting material remaining. Another 1.4 g NBS added and reaction heated to 50° C. for 2 hours. The mixture was then cooled to 38° C. and treated with 85 NCS (25.8 g, 193.1 mmol). The reaction mixture was heated to 50° C. for 16 hours thereafter. The mixture was then cooled to room temperature and treated with 39 water (500 mL). The precipitate was collected by filtration and dried in a vacuum desiccator to afford 45.4 g (97percent yield) of 86 2-amino-5-bromo-3,6-dichloropyrazine as a white solid: 13C NMR (75 MHz, CDCl3) ? 149.9 (s), 145.6 (s), 129.6 (s), 121.5 (s). LCMS (15-95percent gradient acetonitrile in 0.1percent TFA over 10 min), single peak retention time=4.51 min on 30 mm column, (M+H)+=244, (M+H+ACN)+=285.

References: [1]Patent: WO2007/149478,2007,A2 .Location in patent: Page/Page column 25.
[2]Patent: WO2007/149479,2007,A1 .Location in patent: Page/Page column 24.
[3]Patent: WO2016/183351,2016,A1 .Location in patent: Paragraph 0196.
[4]Patent: US2019/125902,2019,A1 .Location in patent: Paragraph 0152; 0153.
[5]Patent: US2019/125901,2019,A1 .Location in patent: Paragraph 0156; 0157.

12
[ 33332-28-4 ]
[ 352359-23-0 ]
[ 1000068-14-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; acetonitrile; at 80℃; for 1h;	To <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (3.1 mmol), l-Boc-5-fluoroindole-2-boronic acid (3.1 mmol), Pd(PPh3)4, (100 mg, 0.0865 mmol) and K2CO3 (7.2 mmol) were added 7 mL MeCN and 3 mL H2O and the mixture was heated in a sealed tube at 80 0C for 1 h. The water layer was separated and the organic phase was dried over MgSO4. Filtration and removal of the solvent gave 1.05 g of the title compound.

References: [1]Patent: WO2007/147874,2007,A1 .Location in patent: Page/Page column 131-132.

13
[ 33332-28-4 ]
[ 213318-44-6 ]
[ 1000068-28-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; acetonitrile; at 85℃; for 20h;	[l-(tert-butoxycarbonyl)-lH-indol-2-yl]boronic acid (2.22 g, 8.49 mmol), 6- chloropyrazin-2-amine (1.00 g, 7.72 mmol), K2CO3 (2.67 g, 19.3 mmol) and Pd(PPh3)4 (180 mg, 0.15 mmol) were mixed in MeCN/water (3.5: 1) and stirred at 85 0C for 20 hours. The reaction mixture was concentrated and the residue was extracted with EtOAc (2x 40 mL) and water (50 mL). The organic layers were combined, dried (Na2SO^, filtered and concentrated to give 2.5 g of a brown solid of tert-butyl 2-(6-aminopyrazin-2-yl)- lH-indole-l-carboxylate. The material was used in the next step without further purification. To tert-butyl 2-(6-aminopyrazin-2-yl)-lH-indole- l-carboxylate (1.1 g, 3.5 mmol) in dry toluene (10 mL) were added methyl 6-chloronicotinate (0.67 g, 3.90 mmol), K2CO3 (7.35 g, 53.2 mmol), (+/-)-BINAP (0.1 1 g, 0.18 mmol) and Pd(OAc)2 (40 mg, 0.18 mmol). The mixture was re fluxed for 50 minutes. The solvent was evaporated and the residue was extracted with EtOAc (2x100 mL) and washed with water/brine (1 : 1 ; 100 mL). The organic layers were combined, dried (Na2Spsi4), filtered and concentrated to give 2 g of crude product. Purification was performed by flash chromatography (1percent NEt3 in DCM-> 1percent NEt3, 1percent MeOH in DCM). This gave tert-butyl 2-(6-[5-(methoxycarbonyl)pyridin-2- yl]amino}pyrazin-2-yl)-lH-indole- l-carboxylate (620 mg). The material was divided into four microwave tubes (155 mg, 0.35 mmol in each) and dissolved in MeOH. 2M aq NaOH (0.35 mL, 0.70 mmol) was added and the reaction mixture was irradiated in a microwave oven at 1 10 0C for 15 minutes. 6M aq HCl (0.12 mL, 0.70 mmol) was added. The reactions were combined and concen- trated in vacuo to give the crude title compound as a brown solid (720 mg). MS (ESI+) for C18H 13N5O2 m/z 332 (M+H)+.

References: [1]Patent: WO2007/147874,2007,A1 .Location in patent: Page/Page column 160.

14
[ 925638-41-1 ]
[ 33332-28-4 ]
[ 1000068-31-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In toluene; at 120℃; for 5h;	6-Chloronicotinoyl chloride (1.00 g, 5.68 mmol) in dry DCM (4 mL) was added dropwise to an ice cold solution of 1 -methyl- 1,4-diazepane (648 mg, 5.68 mmol) and NEt3 (1.18 mL, 8.52 mmol) in dry DCM (16 mL). The mixture was allowed to attain rt and stirred for 2 hours. Saturated aq Na2CO3/water (1 : 1, 40 mL) was added and the mixture was extracted with DCM (2x 30 mL). The organic layers were combined, dried (Na2SO4), filtered and concentrated to1.33 g of a light brown oil. MS (ESI+) for C12H 16C1N3O m/z 254 (M+H)+. Part of the material (294 mg, 1.16 mmol) was added to 6-chloropyrazin-2-amine (150 mg, 1.16 mmol), palladiumacetate (13 mg, 0.06 mmol), (+/-)-BINAP (36 mg, 0.06) and K2CO3 (2.4O g, 17.4 mmol) in dry toluene (12 mL) and stirred at 120 0C for 1.5 hours. The solvent was evaporated and the crude material was extracted with water/brine (1 : 1; 50 mL) and EtOAc (2x 50 mL). The organic layers were combined and concentrated. The title compound was obtained after purification by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10, MeCN), as a light brown solid (55 mg). MS (ESI+) for C16H19C1N6O m/z 347 (M+H)+.HPLC 92percent(System A), 85percent(System B).

References: [1]Patent: WO2007/147874,2007,A1 .Location in patent: Page/Page column 166.

15
[ 627-27-0 ]
[ 33332-28-4 ]
[ 851025-63-3 ]

Yield	Reaction Conditions	Operation in experiment
31%	With sodium hydride; In 1,4-dioxane; at 0 - 100℃; for 62h;	EXAMPLE 1C 6-(3-butenyloxy)-2-pyrazinamine A suspension of NaH (60percent, 618 mg, 15.45 mmol) in dioxane (30 mL) at 0° C. was treated with 3-buten-1-ol (1.33 mL, 15.45 mmol), stirred for 2 hours, treated with <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (1 g, 7.72 mmol), stirred at 100° C. for 2.5 days, cooled to room temperature, and diluted with ethyl acetate. The mixture was washed with water, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography eluding with hexanes/ethyl acetate (2:1) to provide the desired product (390 mg, 31 percent). MS (DCI/NH3) m/z 166.12 (M+H)+; 1H NMR (500 MHz, benzene-d6) delta 2.66 (m, 2H), 4.42 (t, J=6.87 Hz, 2H), 5.24 (dd, J=10.22, 1.98 Hz, 1H), 5.30 (m, 1H), 6.04 (m, 1H), 7.64 (s, 1H), 7.65 (s, 1H).
31%		Example 1C 6-(3-butenyloxy)-2-pyrazinamine A suspension of NaH (60percent, 618 mg, 15.45 mmol) in dioxane (30 mL) at 0° C. was treated with 3-buten-1-ol (1.33 mL, 15.45 mmol), stirred for 2 hours, treated with <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (1 g, 7.72 mmol), stirred at 100° C. for 2.5 days, cooled to room temperature, and diluted with ethyl acetate. The mixture was washed with water, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography eluding with hexanes/ethyl acetate (2:1) to provide the desired product (390 mg, 31percent). MS (DCI/NH3) m/z 166.12 (M+H)+; 1H NMR (500 MHz, benzene-d6) delta 2.66 (m, 2H), 4.42 (t, J=6.87 Hz, 2H), 5.24 (dd, J=10.22, 1.98 Hz, 1H), 5.30 (m, 1H), 6.04 (m, 1H), 7.64 (s, 1H), 7.65 (s, 1H).

References: [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 1514 - 1527.
[2]Patent: US2005/96324,2005,A1 .Location in patent: Page/Page column 8.
[3]Patent: US2005/215556,2005,A1 .Location in patent: Page/Page column 58.

16
[ 108-16-7 ]
[ 33332-28-4 ]
[ 936004-96-5 ]

References: [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 1514 - 1527.

17
[ 813-19-4 ]
[ 33332-28-4 ]
[ 446285-53-6 ]

Yield	Reaction Conditions	Operation in experiment
	tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 110 - 120℃; for 10h;	Preparation of 2-amino-6-(tri-n-butylstannyl)pyrazine (Example of the general procedure Tin-04, below): To a sealed tube, 2-amino-6-chloro-pyrazine (1 g), bis(tri-butyltin) (3.92 mL) and tetrakis-triphenylphosphine palladium, Pd(Ph3P)4 (100 mg) were combined in dioxane (10 mL). The reaction was heated at 110-120° C. for 10 h. After the mixture cooled down to room temperature, it was poured into 20 mL of water. The solution was extracted with EtOAc (4.x.20 mL). The combined extract was concentrated in vacuo to give a residue which was purified by silica gel chromatography to afford 2-amino-6-(tri-n-butylstannyl)pyrazine (0.5 g)

References: [1]Patent: US2004/110785,2004,A1 .Location in patent: Page 101; 104.

18
[ 33332-28-4 ]
C₂₃H₁₉Cl₂N₅O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		[0504] Compound 481A was prepared by an analogous method as that of 473B, except using compound 2-chloro-6-aminopyrazine in place of compound 2-bromo-6-aminopyridine.

References: [1]Patent: US2004/54186,2004,A1 .Location in patent: Page 123.

19
[ 33332-28-4 ]
[ 566205-01-4 ]

Yield	Reaction Conditions	Operation in experiment
94.7%	With N-Bromosuccinimide; In water; acetonitrile; at 0 - 20℃; for 18h;	Synthesis Example 12-Amino-3,5-dibromo-6-chloropyrazine (4)To a solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (3) (8.00 g, 61.8 mmol) in acetonitrile (80 mL) was gradually added N-bromosuccinimide (NBS) (27.5 g, 155 mmol) at 0° C.After elevating to room temperature, the mixture was stirred overnight (18 hours).To the mixture was added water and the product was extracted with diethyl ether (3).The combined organic extract was washed successively with water (1) and brine (*1), followed by drying over anhydrous sodium sulfate.After filtration and concentration under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=3/1) to give 2-amino-3,5-dibromo-6-chloropyrazine (4) (16.8 g, 58.5 mmol, 94.7percent) as a yellow solid. TLC Rf=0.31 (n-hexane/ethyl acetate=4/1); 1H NMR (500 MHz, CDCl3) delta 5.14 (s, 2H); 13C NMR (126 MHz, CDCl3) delta 120.7, 122.0, 146.1, 151.0.
94.7%	With N-Bromosuccinimide; In acetonitrile; at 0 - 20℃; for 18h;	N-bromosuccinimide(NBS) (27.5 g, 155 mmol) was slowly added, was warmed up to room temperatureovernight (18 hours) and the mixture was stirred. Water was added thereto andthe product was extracted with ethyl acetate (× 3). The organic layer waswashed with water (× 1) and saturated brine (× 1), and dried over anhydroussodium sulfate. After filtration, the filtrate was concentrated under reducedpressure, and the residue was purified by silica gel flash columnchromatography (n- hexane / ethyl acetate = 3/1),2-amino-3,5-dibromo-6-chloropyrazine (4) (16.8 g , 58.5 mmol, 94.7percent) as ayellow solid
82%	With N-Bromosuccinimide; In methanol; at 20℃; for 0.5h;Inert atmosphere;	<strong>[33332-28-4]2-Amino-6-chloropyrazin</strong>e (0.6 g, 4.63 mmol) was dissolved in MeOH (50 mL), and N-bromosuccinimide (1.81 g, 10.19 mmol) was added to the solution with stirring. The mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated, ethyl acetate was added and washed with water. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give 2-amino-3,5-dibromo-6-chloropyrazine 1c (1.09 g, 82percent) as a slightly yellow solid. 1H NMR (400 MHz, CDCl3) delta5.26 (br, 2H).

70%	With N-Bromosuccinimide; In acetonitrile; at 0 - 20℃;	To a solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (1 g, 7.72 mmol) in anhydrous acetonitrile (10 mL) was gradually added NBS (4.12 g, 23.16 mmol, 3 equiv.) at 0°C. The reaction mixture was slowly warmed up to r.t. and stirred overnight then diluted with water and extracted with Et20. Combined organic layers were washed with water and brine, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified byflash chromatography on silica eluting with Hexane/EtOAc (1:1)to give the title compound (1.55 g, 5.39 mmol, 70percent) as a pale yellow solid. ESI-MS: 287.90 [M+H]+.
38%	With N-Bromosuccinimide; In chloroform; at 20℃; for 5h;Inert atmosphere;	To a solution of 6-chloro-pyrazin-2-ylamine (5.0 g, 38.8 mmol) in chloroform (194 mL) was added N-bromosuccinimide (20.7 g, 116 mmol) under a nitrogen atmosphere and the reaction mixture was stirred at room temperature for 5 h. The resulting mixture was poured into an aqueous solution of K2CO3 (300 mL) and extracted with dichloromethane (200 mL x 4). The combined organic extracts were dried and purified by chromatography (silica, 10-20 percent ethyl acetate in hexanes) to give 3,5-dibromo-6-chloro-pyrazin-2-ylamine (4.2 g, 38percent) as a yellow solid. LC-MS: 286.0 (M-H).
	With N-Bromosuccinimide; In chloroform; for 20h;Reflux;	A solution of 6-chloropyrazin-2-amine (2 g, 15.44 mmol) and N BS (13.7 g, 77 mmol) in CHCI3 (100 ml) was heated at reflux for 20 hours. The resulting mixture was purified bychromatography on silica eluting with DCM. The relevant fractions were concentrated in vacuo and the crude product was dissolved in EtOAc (~100 ml), washed with 10 percent sodium thiosulfate (2 x 100 ml), brine, dried (MgS04) and were concentrated in vacuo to afford the title compound; 1 H NMR (400 MHz, CDCI3) delta 5.4-5.0 (2H, br s).
	With N-Bromosuccinimide; In methanol; at 15 - 20℃; for 2h;Cooling with ice;	6-Chloropyrazin-2-amine (100 g, 772 mmol) in MeOH (2000 ml) cooled using a water bath was treated with N-bromosuccinimide (151.2 g, 170 mmol) portionwise over 30 mins, maintaining the reaction temperature between 15-20° C. After stirring for 1.5 hours, the mixture was poured carefully into a stirred vessel of ice-cooled water (4 litres). The resultant suspension was stirred for 2 hours in the ice bath, collected by filtration, rinsing the filter cake with water (800 ml) and dried in a vacuum oven to afford the titled compound; LC-MS Rt 0.99 mins; Method 2 minLowpH
	With N-Bromosuccinimide; In chloroform; for 20h;Heating / reflux;	A stirred solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (2.0g) and JV-bromosuccinimide (13.71g) inchloroform (100 mL) was heated to reflux for 20 hours. The reaction mixture was cooledand concentrated onto silica gel (20g) and the residue loaded onto a column of silica gel(5cm x 2cm) and the column was eluted with dichloromethane. Concentration afforded3,5-dibromo-<strong>[33332-28-4]6-chloro-2-aminopyrazine</strong> that was dissolved into methanol (200 mL) andsodium methoxide (32g of a 25percent solution in methanol) added. The reaction was heated to70°C for 1.5h, cooled and concentrated to approx. 50 mL capacity. The reaction mixturewas poured into water (200mL) and the sub-titled adduct (2.0g) collected as an off-whitesolid.m/e 235, 237 (M+l+, 100percent)

References: [1]Patent: US2012/232272,2012,A1 .Location in patent: Page/Page column 18.
[2]Organic Letters,2015,vol. 17,p. 3888 - 3891.
[3]Patent: JP5837973,2015,B2 .Location in patent: Paragraph 0180; 0181.
[4]Bulletin of the Korean Chemical Society,2012,vol. 33,p. 4271 - 4274.
[5]Patent: WO2019/2606,2019,A1 .Location in patent: Page/Page column 93.
[6]Patent: WO2014/29732,2014,A1 .Location in patent: Page/Page column 88.
[7]Patent: WO2012/7539,2012,A1 .Location in patent: Page/Page column 144; 145.
[8]Patent: US2013/184282,2013,A1 .Location in patent: Paragraph 0359; 0360.
[9]Patent: WO2004/108692,2004,A1 .Location in patent: Page 34.

20
[ 107-18-6 ]
[ 33332-28-4 ]
6-(allyloxy)-2-pyrazinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With sodium hydride; In 1,4-dioxane; at 140℃; for 1.11117h;Smith synthesizer;	EXAMPLE 4A 6-(allyloxy)-2-pyrazinamine A mixture of allyl alcohol (0.21 mL, 3.08 mmol) in dioxane (4 mL) was treated with NaH (60percent, 3.08 mmol), stirred for 30 minutes, treated with <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (200 mg, 1.54 mmol), heated to 140° C. in a Smith Synthesizer for 2200 seconds, and filtered. The filtrate was concentrated and purified by flash column chromatography eluding with hexanes/ethyl acetate (2:1) to provide the desired product (133 mg, 57percent). MS (DCI/NH3) m/z 152.0 (M+H)+; 1H NMR (500 MHz, CD2Cl2) delta 4.75 (m, 2H), 5.24 (m, 1H), 5.37 (m, 1H), 6.05 (m, 1H), 7.50 (s, 1H), 7.53 (s, 1H).
57%		Example 4A 6-(allyloxy)-2-pyrazinamine A mixture of allyl alcohol (0.21 mL, 3.08 mmol) in dioxane (4 mL) was treated with NaH (60percent, 3.08 mmol), stirred for 30 minutes, treated with <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (200 mg, 1.54 mmol), heated to 140° C. in a Smith Synthesizer for 2200 seconds, and filtered. The filtrate was concentrated and purified by flash column chromatography eluding with hexanes/ethyl acetate (2:1) to provide the desired product (133 mg, 57percent). MS (DCI/NH3) m/z 152.0 (M+H)+; 1H NMR (500 MHz, CD2Cl2) delta 4.75 (m, 2H), 5.24 (m, 1H), 5.37 (m, 1H), 6.05 (m, 1H), 7.50 (s, 1H), 7.53 (s, 1H).

References: [1]Patent: US2005/96324,2005,A1 .Location in patent: Page/Page column 9.
[2]Patent: US2005/215556,2005,A1 .Location in patent: Page/Page column 59.

21
[ 33332-28-4 ]
[ 6905-47-1 ]

Yield	Reaction Conditions	Operation in experiment
80%	With sodium methylate; In methanol;	Pre Step A 6-(Methyloxy)-2-pyrazinamine A mixture of 6-chloro-2-pyrazinamine (200 mg, 1.544 mmol) and sodium methoxide (250 mg, 4.63 mmol) in methanol (3.9 ml) was heated to 130° C. via a microwave reactor for 60 min. The crude product mixture was purified by RP-HPLC to give 6-(methyloxy)-2-pyrazinamine (154 mg, 1.231 mmol, 80percent yield). MS (ES+) m/z 125.8 (MH+).
11%	In 1,4-dioxane; methanol; ethyl acetate;	Step 1: 2-amino-6-methoxypyrazine. To a stirred solution of methanol (89 muL; 2.2 mmol) in dioxane (1 mL) was added sodium hydride (53 mg; 2.2 mmol). After stirring for 30 minutes, <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (258 mg; 2.0 mmol) was added and the reaction was heated to 90° C. After stirring for 12 hours, the reaction was cooled to room temperature, diluted with 30 mL of ethyl acetate and washed with aqueous 10percent sodium carbonate (1*30 mL), and brine (30 mL), then dried (MgSO4), and filtered. The crude product was purified using the Biotage 12i cartridge eluding with hexane and ethyl acetate (3:1) to yield a white solid (11percent yield).

References: [1]Patent: US2013/345120,2013,A1 .Location in patent: Page/Page column.
[2]Patent: US2003/69284,2003,A1 .

22
[ 33332-28-4 ]
[ 173253-42-4 ]

Yield	Reaction Conditions	Operation in experiment
79%	With N-Bromosuccinimide; In methanol; chloroform; acetonitrile; at 0 - 20℃; for 1h;	To a solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (5 g, 38.60 mmol) in a mixture of anhydrous chloroform (120 mL), anhydrous acetonitrile (12 mL) and anhydrous methanol (12 mL) was addedslowly, at 0CC, NBS (7.56 g, 42.45 mmol, 1.1 eq.) and the mixture was warmed to room temper-ature and continuously stirred for 1 h. The excess solvent was removed in vacuo and the obtained crude material (light brown solid) was purified by column chromatography (Hexane/DCM/MeOH = 50/50/0 then 0/1 00/0 then 0/95/5) to afford 5-bromo-6-chloropyrazin-2-amine(6.34 g, 30.42 mmol, 79percent) as white crystals. ESI-MS: 209.90 [M+H]+. 1 H NMR (300 MHz,CDCI3) 6 7.69 (s, 1 H), 4.78 (br s, 2H).
72%	With N-Bromosuccinimide; In methanol; at 20℃; for 1h;	6-chloropyrazine-2-amine (10.4 g, 80 mmol) was dissolved in methanol (300 ml), and N-bromosuccinimide (15.6 g, 88 mmol) was added thereto while stirring at room temperature. After stirring for additional 60 minutes, the reaction product was concentrated under reduced pressure, followed by adding water so that the reaction product was extracted 3 times with ethyl acetate. The organic later was collected, dried over magnesium sulfate, and then concentrated under reduced pressure. Thereafter, the residue was purified on a silica gel column using chromatography. The title compound (12.0 g, 72percent) was obtained by eluting as a mixed solvent (3:1 v/v) of hexane and ethyl acetate. 1H NMR (500 MHz, CDCl3) delta 7.69 (s, 1H), 4.73 (s, 2H).
42%	With N-Bromosuccinimide; In dichloromethane; at 0℃; for 1h;	2,6-Dichloropyrazine (2.89 g, 19.4 mmol) was stirred in aqueous NH3 (28percent, 10 ml.) and heated to 100°C in a sealed tube for 18 hours. The reaction mixture was cooled and the resultant precipitate was filtered. Trituration with water and then ether gave 6- chloropyrazin-2-amine as a white solid (2.28 g, 17.6 mmol, 91 percent yield). 1H NMR (d6-DMSO, 400 MHz) ? 6.9 (brs, 2H), 7.70 (d, J = 0.4, 1 H), 7.80 (d, J = 0.4, 1 H); LC-MS (ZQ, 6 minutes) Rt = 1.05 minutes; m/z (ESI+) 130 (M+H).6-Chloropyrazin-2-amine (2.50 g, 19.3 mmol) was stirred in CH2CI2 (60 ml.) at 0°C.A/-Bromosuccinimide (2.92 g, 16.4 mmol) was added slowly and the reaction mixture was stirred at 0°C for 60 minutes. The reaction mixture was filtered through celite and concentrated to give a brown oil. Purification by flash chromatography, eluting with 0-25percent EtOAc-hexanes, gave 5-bromo-6-chloropyrazin-2-amine as a yellow solid (1 .69 g, 8.16 mmol, 42percent yield). 1H NMR (de-DMSO, 400 MHz) ? 7.1 (brs, 2H), 7.65 (s, 1 H); LC-MS (ZQ, 4 minutes) Rt = 1.46 minutes; m/z (ESI-) 205 (M-H).A mixture of 5-bromo-6-chloropyrazin-2-amine (1 .00 g, 4.8 mmol), copper (I) iodide (914 mg, 4.8 mmol), 18-crown-6 (95 mg, 0.36 mmol) andtetrakis(triphenylphosphine)palladium (0) (83 mg, 0.072 mmol) was suspended in dry DMF (20 ml.) and a stream of nitrogen was passed through for 5 minutes. Potassium cyanide (312 mg, 4.8 mmol) was added and the mixture was stirred at room temperature for 30 minutes, then refluxed at 200°C for 3 hours. The mixture was cooled, diluted with EtOAc and absorbed onto silica gel (10 g). DMF was removed by evaporation. The product was purified by flash chromatography, eluting with 1 :1 EtOAc-hexanes, to yield 5- amino-3-chloropyrazine-2-carbonitrile as a yellow solid (607 mg, 3.93 mmol, 82percent yield). 1H NMR (d6 DMSO, 400 MHz) ? 7.87 (s, 1 H), 8.1 (brs, 2H); LC-MS (ZQ, 4 minutes) Rt = 1.20 minutes; m/z (ESI-) 153 (M-H).

42%	With N-Bromosuccinimide; In dichloromethane; at 0℃;	Synthesis 2-1 -B 5-bromo-6-chloropyrazin-2-amine 6-Chloropyrazin-2-amine (2.50 g, 19.3 mmol) was stirred in dichloromethane (60 mL) and cooled to O°C. N-Bromosuccinimide (2.92 g, 16.4 mmol) was added slowly and the reaction mixture was stirred at 0°C for 60 minutes. The reaction mixture was filtered through celite and concentrated to give a brown oil. Purification by flash chromatography, eluting with 0-25percent ethyl acetate-hexane, gave the title compound as a yellow solid (1.69 g, 8.16 mmol, 42percent). 1HMR (d6-DMSO, 400 MHz) delta 7.65 (s, 1H), 7.1 (br s, 2H). LC-MS (1) rt 1.46 min; m/z (ESI-) 205 (M-H).
	With N-Bromosuccinimide; In chloroform;	The starting 2-amino-5-bromo-6-chloropyrazine was obtained as follows: A solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (5.0 g) and N-bromosuccinimide (13.9 g) in chloroform (200 ml) was heated under reflux for 2 hours. Insoluble material was removed by filtration and the filtrate was concentrated by evaporation. The residue was purified by flash chromatography on silica gel, eluding with dichloromethane, to give 2-amino-5-bromo-6-chloropyrazine (1.5 g); m.p. 120°-122° C.; mass spectrum (+ve CI): 208 (M+H)+.

References: [1]Patent: WO2019/2606,2019,A1 .Location in patent: Page/Page column 78; 79.
[2]Patent: EP3231800,2017,A2 .Location in patent: Paragraph 0050.
[3]Journal of Medicinal Chemistry,2011,vol. 54,p. 8328 - 8342.
[4]Patent: WO2013/68755,2013,A1 .Location in patent: Page/Page column 67, 68.
[5]Patent: WO2009/103966,2009,A1 .Location in patent: Page/Page column 88.
[6]Patent: US5861401,1999,A .

23
[ 292638-84-7 ]
[ 33332-28-4 ]
[ 59489-29-1 ]

Yield	Reaction Conditions	Operation in experiment
	With N-chloro-succinimide; In chloroform;	Preparation 5 2-Amino-5,6-dichloropyrazine A mixture of 5 g. of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (commercially available), 10.3 g. of N-chlorosuccinimide, and 100 ml. of chloroform was refluxed for about 1.5 hours. The reaction mixture was cooled and filtered, the solid collected on the funnel being discarded. The filtrate was evaporated and the residue washed with water and hot aqueous sodium bisulfite solution, and the solid which formed under this treatment was collected on a funnel. The solid was chromatographed on a column of 5*8 mm. styrene and divinylbenzene copolymer beads using chloroform as solvent and eluant. There were obtained by this chromatography three compounds: Compound 1, having a melting point of about 132°-135° C., was identified as 2-amino-3,6-dichloropyrazine. Compound 2, having a melting point of about 132°-134° C., was identified as 2-amino-3,5,6-trichloropyrazine. Compound 3, having a melting point of about 143°-144° C., was identified as 2-amino-5,6-dichloropyrazine, the desired compound.

References: [1]Patent: US4293552,1981,A .

24
[ 4461-34-1 ]
[ 33332-28-4 ]
[ 69816-63-3 ]

Yield	Reaction Conditions	Operation in experiment
		1F. 1-(2-Chlorobenzoyl)-3-(6-chloro-2-pyrazinyl)urea, having a melting point of about 202°-203° C., from 1.5 g. of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> and 2.0 g. of 2-chlorobenzoylisocyanate. 1G.

References: [1]Patent: US4293552,1981,A .

25
2-[2-(2,2,2-trifluoroethyl)guanidino]-2-(2-aminoethylthio)pyrazine [ No CAS ]
trifluoroethylisothiocyanate [ No CAS ]
[ 33332-28-4 ]
[ 79668-20-5 ]

Yield	Reaction Conditions	Operation in experiment
	In acetonitrile;	The 2-[2-(2,2,2-trifluoroethyl)guanidino]-2-(2-aminoethylthio)pyrazine used as starting material may be obtained as follows: A solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (1 g.) in warm acetonitrile (15 ml.) was cooled to room temperature. Trifluoroethylisothiocyanate (1.6 g.) was added and the mixture stirred overnight. Further trifluoroethylisothiocyanate (1.6 g.) was added, and the mixture warmed gently on a steam bath for 2 hours, then heated under reflux for 2 hours. The mixture was allowed to cool and evaporated to dryness to yield a brown solid. This was washed with water, 2 N HCl solution, water again, and sucked dry. Recrystallisation from boiling toluene diluted with petroleum ether (b.p. 60°-80°) yielded colourless needles (0.77 g.) of 2-[3-(2,2,2-trifluoroethyl)thioureido]-6-chloropyrazine m.p. 170°-172°.

References: [1]Patent: US4362728,1982,A .

26
1,1,1 -trifluoro-2-isothiocyanatoethane [ No CAS ]
[ 33332-28-4 ]
[ 79668-20-5 ]

Yield	Reaction Conditions	Operation in experiment
	In acetonitrile;	To a solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (6 g.) in acetonitrile (50 ml.) was added 2,2,2-trifluoroethylisothiocyanate (6 ml.) and the mixture heated under reflux on a steam bath for 6 hours. The mixture was allowed to cool, the resulting solid filtered and recrystallized from toluene to give 2-chloro-6-(3-[2,2,2-trifluoroethyl]thioureido)pyrazine.
	In acetonitrile;	2,2,2-Trifluoroethylisothiocyanate (6 ml.) was added to <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (6 g.) in acetonitrile (50 ml.) and the mixture heated under reflux on the steam bath for 6 hours. On cooling the precipitated solid was recrystallized from toluene to give 2-chloro-6-(3-[2,2,2-trifluoroethyl]thioureido)pyrazine, m.p. 170°-172°.

References: [1]Patent: US4447441,1984,A .
[2]Patent: US4451463,1984,A .

27
[ 35511-15-0 ]
[ 33332-28-4 ]
N-(6-chloro-pyrazin-2-yl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide [ No CAS ]