Name: 98006-90-7|2-Bromo-5-methylpyrazine|98%
Brand: Ambeed
SKU: A227758
Rating: 90 (28 reviews)

1
[ 98006-90-7 ]
[ 683-60-3 ]
[ 67-63-0 ]
[ 1206124-38-0 ]

Yield	Reaction Conditions	Operation in experiment
	at 115℃; for 1.1h; Microwave irradiation;	1.5.A Step A: Preparation of 2-Isopropoxy-5-methylpyrazine.To a solution of 2-bromo-5-methylpyrazine (3 g, 17.34 mmol) in 2-propanol (14 mL) was added sodium propan-2-olate (3.56 g, 43.3 mmol) and heated under microwave irradiation at 115 0C for 1.1 h. The organic solvent was evaporated before water was added to the residue.The mixture was extracted with dichloromethane (2 x 75 mL). The organic phase was dϖed over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a brown oil (1.0 g). LCMS mlz - 153.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.27 (d, J= 6.19 Hz, 6H), 2.39 (s, 3H), 5.10-5 20 (m, IH), 7.84 (s, IH), 7.99(s, IH).

Reference： [1]Current Patent Assignee: PFIZER INC - WO2010/11316, 2010, A1 Location in patent: Page/Page column 57-58

2
[ 98006-90-7 ]
[ 7486-35-3 ]
[ 13925-08-1 ]

Yield	Reaction Conditions	Operation in experiment
71%	In N,N-dimethyl-formamide at 20 - 100℃; Inert atmosphere;	11 Example 11 Preparation of 2-methyl-5-vmyl-pyrazme[0376] The title compound was prepared by following general procedure 2 5-Bromo-2- methyl pyrazme (2 0 g, 11 mmol) was dissolved in DMF THF (3 1 , 24 mL) Tϖbutylvmyltm (3 0 g, 12 6 mmol) and Pd(PPh3)4 (0 172 g, 0 143 mmol) was added to this solution at RT under nitrogen and was heated at 100 0C for 3 h The reaction mixture was cooled to RT and diluted with water (240 mL) and extracted with ethyl acetate (3x150 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure below 40° C The crude was purified through column chromatography (2% ethylacetate hexane in silica 100- 200 mesh, Diameter of column - 5 0 cm, Height of silica - approx 5 inch) to provide 2-methyl- 5-vmylpyrazme as a light yellow oil (1 0 g, 71% yield)

Reference： [1]Current Patent Assignee: PFIZER INC - WO2010/51503, 2010, A1 Location in patent: Page/Page column 250-251

3
[ 98006-90-7 ]
[ 135884-31-0 ]
[ 1177420-26-6 ]

Yield	Reaction Conditions	Operation in experiment
96%	With potassium carbonate In 1,2-dimethoxyethane; water at 100℃; for 19h; Inert atmosphere;	10.a (10a) t-Butyl 2-(5-methylpyrazin-2-yl]-1H-pyrrole-1-carboxylate Commercially available 2-bromo-5-methylpyrazine (260 mg, 1.50 mmol) and commercially available 1-(t-butoxycarbonyl)pyrrole-2-boronic acid (380 mg, 1.80 mmol) were dissolved in 1,2-dimethoxyethane (20 mL), and palladium (II) acetate (17.0 mg, 0.076 mmol), triphenylphosphine (79.0 mg, 0.301 mmol) and an aqueous potassium carbonate solution (1.5M, 2.0 mL, 3.00 mmol) were added, followed by stirring at 100°C for 19 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (20 mL) and ethyl acetate (20 mL) were added, and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=5%-30%) to afford the desired compound (373 mg, yield 96%) as a yellow oil. 1H-NMR (CDCl3, 400 MHz): δ 1.41 (9H, s), 2.59 (3H, s), 6.28 (1H, m), 6.48 (1H, m), 7.41 (1H, m), 8.45 (1H, brs), 8.56 (1H, brs).

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP2239253, 2010, A1 Location in patent: Page/Page column 54

4
[ 5382-16-1 ]
[ 98006-90-7 ]
[ 1261146-61-5 ]

Yield	Reaction Conditions	Operation in experiment
86%	In isopropyl alcohol at 150℃; for 17h;	6.1 A mixture of 2-bromo-5-methylpyrazine (73 g, 422 mmol) and piperidin-4-ol (107 g, 1055 mmol) in 470 mL isopropanol was loaded into two high-pressure vessels respectively. Reaction was stirred at 150 0C for 17 h. Solvent was removed under reduced pressure to half volume and the residue was diluted with DCM and water. The organic layer was separated and the aqueous layer was extracted with DCM. The organic layers were dried over anhydrous MgSθ4 and concentrated in vacuo. The residue was filtered through a plug of silica gel eluting with 100% EtOAc to afford l-(5-methylpyrazin-2-yl)piperidin-4-ol as solid (69.75 g, 361 mmol, 86 % yield). Exact mass calculated for Ci0H15N3O 193.12, found 194.3 [M+H]+.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2011/5929, 2011, A1 Location in patent: Page/Page column 76

5
[ 98006-90-7 ]
[ 1261146-60-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: isopropyl alcohol / 17 h / 150 °C 2: potassium <i>tert</i>-butylate / tetrahydrofuran / 19 h / 0 - 20 °C 3: sodium t-butanolate / palladium diacetate; 1,1'-bis(di-tertbutylphosphino)ferrocene / 1,4-dioxane / 1 h / 100 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: PFIZER INC - WO2011/5929, 2011, A1

6
[ 98006-90-7 ]
[ 1261146-62-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: isopropyl alcohol / 17 h / 150 °C 2: potassium <i>tert</i>-butylate / tetrahydrofuran / 19 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: PFIZER INC - WO2011/5929, 2011, A1

7
[ 98006-90-7 ]
[ 1323075-51-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: n-butyllithium / tetrahydrofuran; hexanes / 0.33 h / -78 °C / Inert atmosphere 1.2: 2 h / -78 °C 2.1: dichloromethane / 0 - 20 °C 3.1: N-Bromosuccinimide / tetrahydrofuran / -15 - 20 °C 4.1: sodium hydroxide / water / 1 h / 0 - 20 °C 5.1: 1,4-dioxane / 48 h / Reflux 6.1: sodium carbonate / bis-triphenylphosphine-palladium(II) chloride / 1,2-dimethoxyethane; ethanol; water / 100 °C / Inert atmosphere; Sealed tube 7.1: pyridine / 1.08 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: VAXART INC - WO2011/94823, 2011, A1

8
[ 98006-90-7 ]
[ 1323077-53-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexanes / 0.33 h / -78 °C / Inert atmosphere 1.2: 2 h / -78 °C 2.1: dichloromethane / 0 - 20 °C

Reference： [1]Current Patent Assignee: VAXART INC - WO2011/94823, 2011, A1

9
[ 98006-90-7 ]
[ 1323077-54-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran; hexanes / 0.33 h / -78 °C / Inert atmosphere 1.2: 2 h / -78 °C 2.1: dichloromethane / 0 - 20 °C 3.1: N-Bromosuccinimide / tetrahydrofuran / -15 - 20 °C

Reference： [1]Current Patent Assignee: VAXART INC - WO2011/94823, 2011, A1

10
[ 98006-90-7 ]
[ 1323077-56-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran; hexanes / 0.33 h / -78 °C / Inert atmosphere 1.2: 2 h / -78 °C 2.1: dichloromethane / 0 - 20 °C 3.1: N-Bromosuccinimide / tetrahydrofuran / -15 - 20 °C 4.1: sodium hydroxide / water / 1 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: VAXART INC - WO2011/94823, 2011, A1

11
[ 98006-90-7 ]
[ 1323077-57-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: n-butyllithium / tetrahydrofuran; hexanes / 0.33 h / -78 °C / Inert atmosphere 1.2: 2 h / -78 °C 2.1: dichloromethane / 0 - 20 °C 3.1: N-Bromosuccinimide / tetrahydrofuran / -15 - 20 °C 4.1: sodium hydroxide / water / 1 h / 0 - 20 °C 5.1: 1,4-dioxane / 48 h / Reflux

Reference： [1]Current Patent Assignee: VAXART INC - WO2011/94823, 2011, A1

12
[ 98006-90-7 ]
[ 1323077-60-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: n-butyllithium / tetrahydrofuran; hexanes / 0.33 h / -78 °C / Inert atmosphere 1.2: 2 h / -78 °C 2.1: dichloromethane / 0 - 20 °C 3.1: N-Bromosuccinimide / tetrahydrofuran / -15 - 20 °C 4.1: sodium hydroxide / water / 1 h / 0 - 20 °C 5.1: 1,4-dioxane / 48 h / Reflux 6.1: sodium carbonate / bis-triphenylphosphine-palladium(II) chloride / 1,2-dimethoxyethane; ethanol; water / 100 °C / Inert atmosphere; Sealed tube

Reference： [1]Current Patent Assignee: VAXART INC - WO2011/94823, 2011, A1

13
[ 98006-90-7 ]
[ 1323077-43-5 ]
[ 1323077-52-6 ]

Yield	Reaction Conditions	Operation in experiment
32%	Stage #1: 2-bromo-5-methyl-pyrazine With n-butyllithium In tetrahydrofuran; hexanes at -78℃; for 0.333333h; Inert atmosphere; Stage #2: N-methoxy-N-methyl-2-(1H-pyrrol-1-yl)acetamide In tetrahydrofuran; hexanes at -78℃; for 2h;	P.b.4 Step 4: To a solution of 2-bromo-5-methyl-pyrazine (865 mg, 5.0 mmol) in dry THF (35 mL) was added n-BuLi (1.6 M solution in hexanes, 3.2 mL, 5.1 mmol) dropwise, at -78 °C and under nitrogen. The dark red-brown solution was stirred at -78 °C for 20 minutes before a solution of the Weinreb amide /V-methoxy-/V-methyl-2-(1 H-pyrrol-1 -yl)acetamide (900 mg, 5.35 mmol) in THF (26 mL) was added. The solution was stirred at -78 °C for 2 hours before being quenched with a saturated aqueous solution of NH4CI (40 mL) at -78°C and extracted with CH2CI2 (3 x 30 mL). The organic extracts were combined, dried (Na2S04), filtered and concentrated in vacuo to give a residue that was purified by flash chromatography (Biotage SP4, 40 g cartridge, gradient hexanes 1 CV, 0- 60% EtOAc in hexanes 15 CV) to give 1 -(5- methylpyrazin-2-yl)-2-(1 H-pyrrol-1 -yl)ethanone (318 mg, yield 32%).1H-NMR (400 MHz, CDCIs): δ 2.69 (s, 3H), 5.51 (s, 2H), 6.25 (t, 2H, J 2.1 Hz), 6.69 (t, 2H, J 2.1 Hz), 8.52-8.53 (m, 1 H), 9.13 (d, 1 H, J 1.3 Hz).

Reference： [1]Current Patent Assignee: VAXART INC - WO2011/94823, 2011, A1 Location in patent: Page/Page column 123-124

14
[ 98006-90-7 ]
[ 1346627-17-5 ]
[ 1346627-27-7 ]

Yield	Reaction Conditions	Operation in experiment
59%	With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 80 - 90℃; seal vial;	50 To a degassed solution of tert-butyl 4-(2-(piperidin-4- yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridine-l(2H)-carboxylate (119.4 mg, 0.287 mmol), 2-bromo-5-methylpyrazine (99 mg, 0.575 mmol), ?-BuONa (83 mg, 0.862 mmol), and ΒΓΝΑΡ (3.58 mg, 5.75 μιηο) in toluene (2.5 mL) was added Pd2(dba)3 (15.79 mg, 0.017 mmol). The reaction mixture was stirred in a seal vial at 80 °C overnight, then at 90 °C for additional 2.5 h. The mixture was cooled to rt, diluted with water (10 mL), and extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (8 mL), dried (Na2S04), and concentrated. The residue was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 70% EtOAc) to afford Compound 50B (86.6 mg, 0.171 mmol, 59% yield) as a light orange solid. XH NMR (500 MHz, CDC13) δ 8.1 1 (s, IH), 7.97 (s, IH), 7.62 (dd, J =9.9, 5.0 Hz, 2H), 7.40 (dd, J =8.5, 1.6 Hz, IH), 6.04 (s, IH), 5.44 (dt, J =7.6, 3.8 Hz, IH), 4.09 (s, 2H), 3.97 - 3.84 (m, 2H), 3.65 (d, J=5.2 Hz, 2H), 3.57 - 3.43 (m, 2H), 2.55 (s, 2H), 2.41 (s, 3H), 2.28 - 2.13 (m, 2H), 2.08 - 1.94 (m, 2H), 1.50 (s, 9H). LCMS (m/z) =508 (M+H)+.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2011/140160, 2011, A1 Location in patent: Page/Page column 146-147

15
[ 98006-90-7 ]
[ 1382137-31-6 ]
[ 1391082-00-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 125℃;	53 Example 53(S)-5-(1 -Methanesulfonyl-1 ,2,3,6-tetrahvdro-pyridin-4-yl)-2-methyl-2-ri -(5-methyl-Pyrazin-2-yl)-piperidin-4-yl1-2,3-dihvdro-furo[2,3-clpyridineThe title compound is prepared from (S)-5-(1 -methanesulfonyl-1 ,2,3,6-tetrahydro- pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 41 ; the configuration of the stereocenter is arbitrarily assigned) and 2-bromo-5- methyl-pyrazine in dimethylsulfoxide at 125°C in the presence of potassium carbonate. LC (method 4): tR = 0.84 min; Mass spectrum (EST): m/z = 470 [M+H]+.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2012/98217, 2012, A1 Location in patent: Page/Page column 118

16
[ 1072854-74-0 ]
[ 98006-90-7 ]
[ 1395896-87-3 ]

Yield	Reaction Conditions	Operation in experiment
66%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium carbonate In isopropyl alcohol at 140℃; for 0.333333h; Microwave irradiation;	(S)-N,N-Dibenzyl-5-(5-methylpyrazin-2-yl)chroman-3-amine A mixture of 2-bromo-5-methylpyrazine (0.190 g, 1.10 mmol), (S)-N,N-dibenzyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-3-amine (0.5 g, 1.10 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.045 g, 0.05 mmol) and 2 M potassium carbonate (1.65 mL, 3.29 mmol) in isopropanol (7 mL) was heated in a microwave synthesizer at 140 °C for 20 min. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic phase was washed with brine, dried (Na2SO) and evaporated. The crude product was purified by column chromatography (eluent: hept/EtOAc gradient) affording theb desired product (0.305 g, 66 % yield) as a yellow sticky oil.

Reference： [1]Kers, Inger; Csjernyik, Gabor; MacSari, Istvan; Nyloef, Martin; Sandberg, Lars; Skogholm, Karin; Bueters, Tjerk; Eriksson, Anders B.; Oerther, Sandra; Lund, Per-Eric; Venyike, Elisabet; Nystroem, Jan-Erik; Besidski, Yevgeni [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 17, p. 5618 - 5624]

17
[ 98006-90-7 ]
[ 1395896-79-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium carbonate / isopropyl alcohol / 0.33 h / 140 °C / Microwave irradiation 2: palladium 10% on activated carbon; ammonium formate / ethanol / 3 h / 60 °C / Inert atmosphere 3: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine / acetonitrile / 20 °C

Reference： [1]Kers, Inger; Csjernyik, Gabor; MacSari, Istvan; Nyloef, Martin; Sandberg, Lars; Skogholm, Karin; Bueters, Tjerk; Eriksson, Anders B.; Oerther, Sandra; Lund, Per-Eric; Venyike, Elisabet; Nystroem, Jan-Erik; Besidski, Yevgeni [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 17, p. 5618 - 5624]

18
[ 98006-90-7 ]
[ 1395896-80-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium carbonate / isopropyl alcohol / 0.33 h / 140 °C / Microwave irradiation 2: palladium 10% on activated carbon; ammonium formate / ethanol / 3 h / 60 °C / Inert atmosphere 3: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine / acetonitrile / 20 °C

Reference： [1]Kers, Inger; Csjernyik, Gabor; MacSari, Istvan; Nyloef, Martin; Sandberg, Lars; Skogholm, Karin; Bueters, Tjerk; Eriksson, Anders B.; Oerther, Sandra; Lund, Per-Eric; Venyike, Elisabet; Nystroem, Jan-Erik; Besidski, Yevgeni [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 17, p. 5618 - 5624]

19
[ 98006-90-7 ]
[ 1395896-88-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium carbonate / isopropyl alcohol / 0.33 h / 140 °C / Microwave irradiation 2: palladium 10% on activated carbon; ammonium formate / ethanol / 3 h / 60 °C / Inert atmosphere

Reference： [1]Kers, Inger; Csjernyik, Gabor; MacSari, Istvan; Nyloef, Martin; Sandberg, Lars; Skogholm, Karin; Bueters, Tjerk; Eriksson, Anders B.; Oerther, Sandra; Lund, Per-Eric; Venyike, Elisabet; Nystroem, Jan-Erik; Besidski, Yevgeni [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 17, p. 5618 - 5624]

20
[ 98006-90-7 ]
[ 1404115-24-7 ]
[ 1404115-25-8 ]

Yield	Reaction Conditions	Operation in experiment
52.5%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ In N,N-dimethyl-formamide at 100℃; for 2.5h; Inert atmosphere;	N,N-dibenzyl-2-(3,6-difluoro-2-(5-methylpyrazin-2-yl)phenyl)ethanamine Step 1: Bis(pinacolato)diboron (683 mg, 2.69 mmol), potassium acetate (396 mg, 4.03 mmol) and trans-dichlorobis(tricyclohexylphosphine)palladium (II) (99 mg, 0.13 mmol) were mixed under nitrogen and N,N-dibenzyl-2-(2-chloro-3,6-difluorophenyl)ethanamine (500 mg, 1.34 mmol) dissolved in dioxane (15 mL) and water (0.15 mL) was added. The reaction mixture was heated in a microwave oven at 120 °C for 45 min. The reaction mixture was filtered through a pad of celite which was rinsed with EtOAc and the organic layer was washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. MS (ESI) m/z 464 (M+H)+. Step 2: A mixture of N,N-dibenzyl-2-(3,6-difluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)ethanamine from step 1, 2-bromo-5-methylpyrazine (196 mg, 1.13 mmol) and PdCl2(dppf)-CH2Cl2 adduct (56.8 mg, 0.07 mmol) were suspended in DMF (8 mL) and the atmosphere was changed to nitrogen. The reaction mixture was heated to 100 °C for 2.5 hours. The reaction mixture was filtered through a pad of celite which was rinsed with EtOAc. The solution was washed with brine, dried over Na2SO4 and concentrated in vacuo, then coevaporated with heptane (3x) to remove the residual DMF. The crude was purified on silica using a gradient of EtOAc in heptane (0-30%) yielding the desired product in 196 mg (52.5 %) yield.

Reference： [1]Kers, Inger; MacSari, Istvan; Csjernyik, Gabor; Nyloef, Martin; Skogholm, Karin; Sandberg, Lars; Minidis, Alexander; Bueters, Tjerk; Malmborg, Jonas; Eriksson, Anders B.; Lund, Per-Eric; Venyike, Elisabet; Luo, Lei; Nystroem, Jan-Erik; Besidski, Yevgeni [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 19, p. 6108 - 6115]

21
[ 98006-90-7 ]
[ 1403779-33-8 ]
[ 1403778-83-5 ]

Yield	Reaction Conditions	Operation in experiment
26%	With sodium t-butanolate; DavePhos In 1,4-dioxane at 120℃; for 0.416667h; Inert atmosphere; Microwave irradiation;	54 1-((2S,4/?)-4-amino-2-methyl-6-(6-(morpholine-4-carbonyl)pyridin-3-yl)-3,4- dihydroquinolin-1 (2/-/)-yl)ethanone (for a preparation, see Intermediate 56) (80 mg, 0.203 mmol), 2-bromo-5-methylpyrazine (70.2 mg, 0.406 mmol), 2'-(dicyclohexylphosphino)- /V,/V-dimethyl-[1 ,1 '-biphenyl]-2-amine (16.0 mg, 0.041 mmol), tris(dibenzylideneacetone)dipalladium(0) (18.6 mg, 0.020 mmol) and sodium ie f-butoxide (27.3 mg, 0.284 mmol) were combined in 1 ,4-dioxane (2 mL). The mixture was degassed over a period of 15 mins before being heated under microwave irradiation to 120°C for 25 mins. The mixture was partitioned between saturated aq. sodium bicarbonate (50 mL) and DCM (3x50 mL). The organic layers were combined, dried by passing through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by MDAP (HpH) followed by further purification by MDAP (Formate) to give 1-((2S,4R)-2-methyl-4- ((5-methylpyrazin-2-yl)amino)-6-(6-(morpholine-4-carbonyl)pyridin-3-yl)-3,4- dihydroquinolin-1 (2H)-yl)ethanone (26 mg, 0.053 mmol, 26 % yield).LCMS: (Formate, 2 min), Rt = 0.71 mins, MH+ = 487.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2012/143415, 2012, A1 Location in patent: Page/Page column 97

22
[ 98006-90-7 ]
[ 1403779-44-1 ]
[ 1403778-91-5 ]

Yield	Reaction Conditions	Operation in experiment
34%	With sodium t-butanolate; DavePhos In 1,4-dioxane at 130℃; for 0.666667h; Inert atmosphere; Microwave irradiation;	60 1-((2S,4/?)-4-amino-2-methyl-6-(5-(morpholine-4-carbonyl)pyridin-2-yl)-3,4- dihydroquinolin-1 (2H)-yl) ethanone hydrochloride (for a preparation see Intermediate 65) (100 mg, 0.232 mmol), 2-bromo-5-methylpyrazine (80 mg, 0.464 mmol), 2'- (dicyclohexylphosphino)-/V,/V-dimethyl-[1 ,1 '-biphenyl]-2-amine (27.4 mg, 0.070 mmol), tris(dibenzylideneacetone)dipalladium(0) (42.5 mg, 0.046 mmol) and sodium ie f-butoxide (66.9 mg, 0.696 mmol) were combined in 1 ,4-dioxane (2 mL) and the mixture degassed over a period of 15 mins, before being heated under microwave irradiation to 130°C for 40 mins. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate (50 mL) and DCM (3x50 mL). The organics were combined, dried by passing through a hydrophobic frit and concentrated in vacuo to give a residue which was purified by MDAP (HpH) to give 1 -((2S,4R)-2-methyl-4-((5-methylpyrazin-2-yl)amino)-6-(5- (morpholine-4-carbonyl)pyridin-2-yl)-3,4-dihydroquinolin-1 (2/-/)-yl)ethanone (38 mg, 0.078 mmol, 34 % yield). LCMS: (Formate, 2 min), Rt = 0.71 mins, MH+ 487

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2012/143415, 2012, A1 Location in patent: Page/Page column 101-102

23
[ 98006-90-7 ]
5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine [ No CAS ]
5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-[1-(5-methyl-pyrazin-2-yl)-piperidin-4-yl]-2,3-dihydro-furo[2,3-c]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 125℃;	53 (S)-5-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-[1-(5-methyl-pyrazin-2-yl)-piperidin-4-yl]-2,3-dihydro-furo[2,3-c]pyridine The title compound is prepared from (S)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 41; the configuration of the stereocenter is arbitrarily assigned) and 2-bromo-5-methyl-pyrazine in dimethylsulfoxide at 125° C. in the presence of potassium carbonate. LC (method 4): tR=0.84 min; Mass spectrum (ESI+): m/z=470 [M+H]+.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2013/18030, 2013, A1 Location in patent: Paragraph 0531; 0532

24
[ 98006-90-7 ]
[ 1403396-62-2 ]
[ 1403396-95-1 ]

Yield	Reaction Conditions	Operation in experiment
49%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In 1,2-dimethoxyethane; water for 3h; Reflux;	87.1 (8R)-8-([Tert-butyl(dimethyl)silyl]oxy}methyl)-8-methyl-3-{1-[4-(5-methylpyrazin-2-yl)phenyl]cyclopropyl}-5,6,8,9-tetrahydro[1,2,4]triazolo[4,3-d][1,4]thiazepine A solution of the compound (300 mg, 0.54 mmol) synthesized in Example 52-2), 2-bromo-5-methylpyrazine (234 mg, 1.35 mmol), tetrakis(triphenylphosphine)palladium(0) (125 mg, 0.11 mmol), and potassium carbonate (149 mg, 1.08 mmol) in 1,2-dimethoxyethane (8R)-8-([tert-butyl(dimethyl)silyl]oxy}methyl)-8-methyl-3-{1-[4-(5-methylpyrazi 1,2-dimethoxyethane (4 mL) and water (2 mL) was heated to reflux for 3 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (70 ml). The organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane = 60:40 to 100:0) to obtain the title compound (139 mg, 49%) as a white solid. 1H-NMR (CDCl3) δ: 0.05 (3H, s), 0.07 (3H, s), 0.91 (9H, s), 1.19 (3H, s), 1.45-1.54 (2H, m), 1.61-1.71 (2H, m), 2.54 (1H, ddd, J = 15.7, 8.2, 2.0 Hz), 2.60 (3H, s), 2.68 (1H, ddd, J = 15.7, 7.8, 2.0 Hz), 3.40 (2H, s), 3.53 (2H, dd, J = 16.2, 10.0 Hz), 4.07 (3H, ddd, J = 14.5, 7.4, 2.3 Hz), 4.31 (1H, ddd, J = 14.5, 7.8, 2.3 Hz), 7.19 (2H, d, J = 7.8 Hz), 7.91 (2H, d, J = 7.8 Hz), 8.49 (1H, s), 8.86 (1H, d, J = 1.6 Hz)

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP2700643, 2014, A1 Location in patent: Paragraph 0414

25
[ 865245-32-5 ]
[ 98006-90-7 ]
C₁₅H₂₁N₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium hydroxide monohydrate; palladium diacetate; P(p-C₆H₄F)3 In toluene at 80℃; Sealed tube; Inert atmosphere;

Reference： [1]Hesp, Kevin D.; Fernando, Dilinie P.; Jiao, Wenhua; Londregan, Allyn T. [Organic Letters, 2014, vol. 16, # 2, p. 413 - 415]

26
[ 98006-90-7 ]
methyl 3-(((trans)-4-(dimethylamino)cyclohexyl)(ethyl)amino)-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate [ No CAS ]
methyl 3-(((trans)-4-(dimethylamino)cyclohexyl)(ethyl)amino)-2-methyl-5-(5-methylpyrazin-2-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73.2%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate In 1,4-dioxane; water at 80℃; for 8h; Inert atmosphere;	14.2 Step 2: Synthesis of methyl 3-(((trans)-4- (dimethylamino)cyclohexyl)(ethyl)amino)-2-methyl-5- (5-methylpyrazin-2-yl)benzoate: To a stirred solution of methyl 3-(((trans)-4- (dimethylamino)cyclohexyl)(ethyl)amino)-2-methyl-5- (4,4,5 „5-tetramethyl- 1,3,2- dioxaborolan-2-yl)benzoate (0.4 g, 0.9 mmol) in 1,4-dioxane/water (6/2 mL), were added 2- bromo-5-methylpyrazine (0.3 11 g, 1.80 mmol) and K3P04 (0.572 g, 2.70 mmol) and the reaction fiask was purged with argon for 10 min. PdC12(dppf) (0.073 g, 0.09 mmol) was added and the reaction fiask was agam purged with argon for 10 min. The resulting reaction mass was heated at 80 °C for 8 h. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was diluted with water and extracted with 10% MeOH in DCM. The combined organie layers were dried oyer Na2504 and concentrated under reduced pressure to afford erude material which then purified by silica gel column chromatography to afford the title compound (0.27 g, 73.2%).

Reference： [1]Current Patent Assignee: EPIZYME, INC. - WO2014/100646, 2014, A1 Location in patent: Paragraph 012; 013

27
[ 98006-90-7 ]
rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone [ No CAS ]
rac-1-((2S,3R,4R)-2-cyclopropyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3-methyl-4-((5-methylpyrazin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36 mg	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium t-butanolate; DavePhos In 1,4-dioxane at 100℃; for 18h;	137 rac-1 -((2S.3R.4R)-2-cyclopropyl-6-(1 -(2-methoxyethyl)-1 H-pyrazol-4-yl)-3- methyl-4-((5-methylpyrazin-2-yl)amino)-3.4-dihydroguinolin-1 (2H)-yl)ethanone The rac- I -((2S,3R,4R)-4-amino-2-cyclopropyl-6-( I -(2-methoxyethyl)- I H-pyrazol-4-yl)-3-methyl-3,4- dihydroquinolin-I(2H)-yl)ethanone (for a preparation see Intermediate 140, 70 mg, 0.190 mmol) was dispensed into a round bottomed flask and treated with DavePhos (7.48 mg, 0.019 mmol), Pd2(dba)3(26.1 mg, 0.028 mmol), sodium tert-butoxide (54.8 mg, 0.570 mmol), I ,4-dioxane (12 mL) and the 2- bromo-5-methylpyrazine (65.7 mg, 0.380 mmol) the reaction was allowed to stir at 100 °C for 16 h. Further 2-bromo-5-methylpyrazine (65.7 mg, 0.380 mmol) was added and the reaction was allowed to stir at 100 °C for 2 h. The reaction was allowed to cool to rt and partitioned between water andDCM, the aqueous layer was extracted with more DCM and the combined organics were washedwith brine, dried using a hydrophobic frit and concentrate to a gum. This was purified using a 10 gsilica column elute: 0-50% EtOAc:cyclohexane. Nothing eluted so the column was run again 0-5%MeOH:DCM one major peak was eluted and the appropriate fractions were summed andconcentrated to give the product but this was still impure. Therefore this was further purified using a10 g silica column, elute:0-5% 2M NH3/MeOH:DCM, the appropriate fractions were summed andconcentrated to give the product (36 mg) as a yellow solid. LCMS (2 mm Formic): Rt = 0.86 mi [MH] = 461.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2014/140076, 2014, A1 Location in patent: Page/Page column 306; 307

28
[ 98006-90-7 ]
rac-1-((2S,3R,4R)-4-amino-6-fluoro-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone [ No CAS ]
rac-1-((2S,3R,4R)-6-fluoro-2,3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium t-butanolate; DavePhos In 1,4-dioxane at 90℃; for 5h; Inert atmosphere;	140 rac-1 -((2S.3R.4R)-6-fluoro-2.3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-3.4-dihydrociuinolin-1(2H)-yl)ethanone A solution of rac- I -((2S,3R,4R)-4-am ino-6-fluoro-2,3-dimethyl-3,4-dihyd roquinolin- I (2H)-yl)ethanone (for a preparation see Intermediate 143,97mg, 0.411 mmol), DavePhos (16.16 mg, 0.041 mmol), 2- bromo-5-methylpyrazine (71.0 mg, 0.411 mmol), Pd2(dba)3 (18.80 mg, 0.021 mmol) and sodium ted-butoxide (79 mg, 0.821 mmol) in I ,4-dioxane (3 mL) was stirred under nitrogen at 90 °C for 5 h. The reaction mixture was allowed to cool to rt, filtered through celite and rinsed with ethyl acetate. The solvent was evaporated in vacuo, dissolved in 1:1 MeOH:DMSO and purified by MDAP (HpH). The appropriate fractions were combined and concentrated in vacuo to give the title compound (20 mg,0.061 mmol, 15%). LCMS (2 mm Formic): Rt = 0.83 mi [MH] = 329.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2014/140076, 2014, A1 Location in patent: Page/Page column 308

29
[ 98006-90-7 ]
rac-1-((2S,3R,4R)-4-amino-2-cyclopropyl-6-fluoro-3-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone [ No CAS ]
rac-1-((2S,3R,4R)-2-cyclopropyl-6-fluoro-3-methyl-4-((5-methylpyrazin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
19.24%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium t-butanolate; DavePhos In 1,4-dioxane at 100℃; for 4h;	159 rac-1 -((2S.3R.4R)-2-cyclopropyl-6-fluoro-3-methyl-4-((5-methylpyrazin-2-yl)amino)-3.4-dihydrociuinolin-1(2H)-yl)ethanone The rac-I -((2S,3R,4R)-4-am ino-2-cyclopropyl-6-fluoro-3-methyl-3,4-dihyd roquinolin- I (2H )- yl)ethanone (for a preparation see Intermediate 146, 100 mg, 0.381 mmol), 2-bromo-5- methylpyrazine (99mg, 0.572mmo1), Pd2(dba)3 (52.4 mg, 0.057 mmol), sodium tert-butoxide (110mg, 1.144 mmol) and DavePhos (15.00 mg, 0.038 mmol), were suspended in 1,4-dioxane (10 mL) and allowed to stir at 100 °C for 4 h. The reaction was filtered through celite and concentrated to anoil. This oil was purified using a MDAP (Formic) to give a solid which was eluted through a NH2 SPE (5 g) with MeOH, the eluent was concentrated and dried to give the product (26 mg, 0.073 mmol, 19.24%) as a yellow solid. LCMS (2 mm Formic): Rt = 0.92 mi [MH] = 355.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2014/140076, 2014, A1 Location in patent: Page/Page column 315; 316

30
[ 98006-90-7 ]
rac-1-((2S,3R,4R)-4-amino-6-(3,6-dihydro-2H-pyran-4-yl)-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone [ No CAS ]
rac-1-((2S,3R,4R)-6-(3,6-dihydro-2H-pyran-4-yl)-2,3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10.98%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium t-butanolate; DavePhos In 1,4-dioxane at 100℃; for 1h; Inert atmosphere; Microwave irradiation;	167 rac-1 -((2S.3R.4)-6-(3.6-dihydro-2H-pyran-4-yl)-2.3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-3.4-dihydroguinolin-1(2H)-yl)ethanone A 0.5-2 mL microwave vial was evacuated and back filled with N2. 1-((2S,3R,4R)-4-Amino-6-(3,6- dihydro-2H-pyran-4-yl)-2,3-dimethyl-3,4-dihyd roquinolin- I (2H)-yl)ethanone (for a preparation seeIntermediate 150,23mg, 0.077 mmol) in 1,4-dioxane (0.75 mL)was then added. To this was added2-bromo-5-methylpyrazine (0.017 mL, 0.153 mmol), sodium tert-butoxide (14.72 mg, 0.153 mmol) and DavePhos (6.03 mg, 0.015 mmol) and the resultant suspension then had N2 bubbled through it for -5 mi Pd2(dba)3 (14.02 mg, 0.015 mmol) was added and N2 was bubbled through the reaction mixture for a further -5 mm. The reaction was then heated to 100 °C for 30 mm in a microwave. Thereaction was then re-heated to 100 °C for a further 30 mm. The reaction mixture was then diluted with EtOAc and filtered though celite (2.5g). The celite was washed with further EtOAc (2x10 mL) and the resultant solution concentrated in vacuo. This was taken up in MeOH/DMSO (1:1, 0.9 mL) and purified by MDAP (Formic). The appropriate fraction was collected and concentrated in vacuo to afford a colourless gum (3.3 mg, 8.41 pmol, 10.98%).LCMS (2 mm Formic): Rt = 0.85 mi [MH] = 393.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2014/140076, 2014, A1 Location in patent: Page/Page column 320

31
[ 98006-90-7 ]
rac-tert-butyl 4-((2S,3R,4R)-1-acetyl-4-amino-2,3-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate [ No CAS ]
rac-tert-butyl 4-((2S,3R,4R)-1-acetyl-2,3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium t-butanolate; DavePhos In 1,4-dioxane at 90℃; for 5h; Inert atmosphere;	rac-tert-butvl 4-((2S.3R.4R)-1 -acetyl-2.3-dimethyl-4-((5-methylpyrazin-2-234-tetrahydroguinoIin-6-yI)piperidine-1 -carboxylate A solution of rac-tert-butyl 4-((2S,3R,4R)- I -acetyl-4-amino-2,3-dimethyl- I ,2,3,4-tetrahydroq uinolin-6- yl)piperidine-1-carboxylate (for a preparation see Intermediate 157, 60 mg, 0.149 mmol), DavePhos (5.88 mg, 0.015 mmol), 2-bromo-5-methylpyrazine (25.9 mg, 0.149 mmol), Pd2(dba)3 (6.84 mg, 7.47 iJmol) and sodium tert-butoxide (28.7 mg, 0.299 mmol) in I ,4-Dioxane (3 mL) was stirred undernitrogen at 90 °C for 5 h. The reaction mixture was allowed to cool to room temp, filtered through celite and rinsed with ethyl acetate. The solvent was evaporated in vacuo and dissolved in 1:1MeOH:DMSO (2x1 mL) and purified by MDAP (Formic). The appropriate fractions were combined and concentrated in vacuo to give the title compound (23 mg, 0.047 mmol, 31%).LCMS (2 mm Formic): Rt = 1.10 mi [MH] = 494.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2014/140076, 2014, A1 Location in patent: Page/Page column 130

32
[ 98006-90-7 ]
rac-1-((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone [ No CAS ]
rac-1-((2S,3R,4R)-2,3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54.1 mg	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium t-butanolate; DavePhos In 1,4-dioxane at 100℃; for 1.5h;	24 rac-1 -((2S.3R.4R)-2.3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-3.4- dihydrociuinolin-1(2H)-yl)ethanone To a test tube were added rac-1 -((2S,3R,4R)-4-amino-2,3-dimethyl-3,4-dihydroquinolin-1 (2H)- yl)ethanone (for a preparation see Intermediate 6, 55 mg, 0.252 mmol), 2-bromo-5-methylpyrazine (52.3 mg, 0.302 mmol), Pd2(dba)3 (11.54 mg, 0.013 mmol), DavePhos (9.92 mg, 0.025 mmol) and 1,4-dioxane (2.5 mL). The reaction mixture was then heated and stirred at 100°C in a greenhouse reactor for I h 30 mm. After cooling to rt, the reaction mixture was filtered through a pad of celite(rinsed with EtOAc). The filtrate was then evaporated in vacuo. The residue was purified by MDAP (Formic). Desired fractions were combined and evaporated in vacuo to afford the product as a yellow solid (54.1 mg). LCMS (2 mm Formic): Rt = 0.79 mi [MH] = 311.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2014/140076, 2014, A1 Location in patent: Page/Page column 251

33
[ 98006-90-7 ]
rac-(2S,3R,4R)-1-acetyl-4-amino-2-ethyl-N,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxamide [ No CAS ]
rac-(2S,3R,4R)-1-acetyl-2-ethyl-N,3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-1,2,3,4-tetrahydroquinoline-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5.4 mg	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium t-butanolate; DavePhos In 1,4-dioxane at 90℃; for 16h; Inert atmosphere;	233 rac-(2S.3R.4R)-1 -acetyl-2-ethyl-N.3-dimethyl-4-((5-methylpyrazin-2-yl)amino)-234-tetrahydroguinoline-6-carboxamide A solution of 2-bromo-5-methylpyrazine (27.3 mg, 0.158 mmol), DavePhos (5.2 mg, 0.013 mmol),Pd2(dba)3 (7 mg, 7.64 iJmol), sodium tert-butoxide (25.2 mg, 0.263 mmol) and rac-(2S,3R,4R)-1-acetyl-4-am ino-2-ethyl-N,3-dimethyl- 1,2 ,3,4-tetrahyd roqu inoline-6-carboxamide (for a preparation see Intermediate 192, 38 mg, 0.131 mmol) in 1,4-dioxane (3 mL) was stirred under a nitrogen atmosphere at 90 °C for 16 h. The reaction mixture was diluted with 5 mL MeOH and filtered through a plug of cotton wool. The solvent was removed by evaporation to give a residue which was purifiedby MDAP (Formic) to afford the desired product as a pale brown solid (5.4 mg).LCMS (2 mm Formic): Rt = 0.68 mi [MH] = 382.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2014/140076, 2014, A1 Location in patent: Page/Page column 349

34
2-(5-chloro-thien-2-yl)piperazine [ No CAS ]
[ 98006-90-7 ]
C₁₃H₁₅ClN₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34%	With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 165℃; for 1h; Microwave irradiation;	33a example 3o (100 mg, 0.55 mmol), 2-Chloropyrimidine (76.3 mg, 0.67 mmol) and N,N- diisopropylethylamine (192 μ, 1.11 mmol) are dissolved in 1 ml of DMSO and the reaction mixture is heated in a microwave reactor 30 minutes at 120°C. The crude product is partitioned between Et20 and water; the organic layer is then separated and concentrated under reduced pressure to obtain the title compound (158 mg). UPLC-MS (Method 2): Rt = 0.76 MS (ES+): m/z = 259 [M+H]+ . Example 33a is synthesized as described for example 28a using example 3r (150 mg, 0.67 mmol) instead of example 3o, 2-Bromo-5-Methylpyrazine (127 mg, 0.73 mmol) instead of 2-Chloropyrimidine, N,N-diisopropylethylamine (289 μ, 1.66 mmol) and 1 ml of DMSO. The mixture is heated in a microwave reactor 1 hour at 165 °C. The crude product is partitioned between DCM and water then the organic layer is separated and concentrated under reduced pressure; the residue is purified by Silica gel flash chromatography using as eluent DCM/MeOH 100:0 to 90: 10 to obtain the title compound (75 mg, 34 % yield). UPLC-MS (Method 1): Rt = 0.71 MS (ES+): m/z = 295 [M+H]+

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2015/55698, 2015, A1 Location in patent: Page/Page column 58; 59; 62

35
[ 98006-90-7 ]
3-bromo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfonamide [ No CAS ]
N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-3-(5-methylpyrazin-2-yl)benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 3-bromo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfonamide With chloro[(tricyclohexylphosphine)-2-(2'-aminobiphenyl)]palladium(II) second generation; potassium acetate; 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane In acetonitrile at 85℃; for 24h; Sealed tube; Stage #2: 2-bromo-5-methyl-pyrazine With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In water; acetonitrile at 95℃;	248.A Step A: N,N-bis(4-Methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-3 -(5- methylpyrazin-2-yl)benzenesulfonamide To a reaction vessel, was added 3-bromo-N,N-bis(4-methoxybenzyl)-2-(2-(4- methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfonamide (200 mg, 0.301 mmol), 5,5,5',5'- tetramethyl-2,2'-bi(l,3,2-dioxaborinane) (204 mg, 0.903 mmol), PCy3 Pd G2 (17.8 mg, 0.030 mmol), and potassium acetate (89 mg, 0.90 mmol). Then amhydrous CH3CN (1.5 mL) was added to this flask. The mixture was sealed and degassed for 10 min. This mixture was then heated at 85°C for 24 hr. LC-MS analysis indicated the formation of the desired boronic ester. After cooling to rt, to this reaction mixture, was added 2-bromo-5-methylpyrazine (78 mg, 0.451 mmol), PdCl2(dppf) (22.02 mg, 0.030 mmol), and Na2C03 (63.8 mg, 0.602 mmol) dissolved in water (0.4 mL). The reaction mixture was degassed for 10 min and heated at 95°C overnight. The mixture was cooled, water was added and the mixture was extracted with EtOAc. The combined organic fractions were washed with brine, dried (Na2S04), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/Hexanes (0-100%) to give the title compound. LC-MS 678 (M+l)+.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2015/112441, 2015, A1 Location in patent: Page/Page column 188

36
[ 98006-90-7 ]
3-bromo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfonamide [ No CAS ]
3-(5-methylpyrazin-2-yl)-2-(2H-tetrazol-5-yl)benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: chloro[(tricyclohexylphosphine)-2-(2'-aminobiphenyl)]palladium(II) second generation; potassium acetate; 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinane / acetonitrile / 24 h / 85 °C / Sealed tube 1.2: 95 °C 2.1: trifluoroacetic acid; methoxybenzene / 3 h / 60 °C

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2015/112441, 2015, A1

37
[ 98006-90-7 ]
methyl 4-((2-oxopyrrolidin-1-yl)methyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzoate [ No CAS ]
methyl 3-(4-(5-methylpyrazin-2-yl)phenoxy)-4-((2-oxopyrrolidin-1-yl)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In water; N,N-dimethyl-formamide at 100℃; for 16h; Inert atmosphere;	C8.F Methyl 3-(4-(5-methylpyrazin-2-yl)phenoxy)-4-((2-oxopyrrolidin-l -yl)methyl)benzoate A mixture of methyl 4-((2-oxopyrrolidin-l-yl)methyl)-3-(4-(4,4,5>5-tetramethyl- l ,3,2-dioxaborolan-2-yl)phenoxy)benzoate (500 mg, 1.10 mmol), 2-bromo-5-methylpyrazihe (192 mg, 1.20 mmol), Pd(PPh3)4 (190 mg, 0.165 mmol) and Na2C03 (233 mg in 0.8 mL of H20, 2.2 mmol) in DMF (8 mL) was heated at 100 °C under N2 atmosphere for 16 h. The reaction mixture was cooled to 23 °C, diluted with H20 (15 mL), and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with H20 (20 mL) and brine (20 mL), dried over Na2S04, and concentrated. The residue was purified by column chromatography (Si02, petroleum ether: EtOAc = 1 : 1) to give methyl 3-(4-(5-methylpyrazin-2-yl)phenoxy)-4-((2- oxopyrrolidin-l-yl)methyl)benzoate. MS: m/z = 418.1 (M + 1). NMR (400 MHz, CDC13): 5 8.81 (s, 1H), 8.42 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 7.6 Hz, 1H), 7.57 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 8.8 Hz, 2H), 4.53 (s, 2H), 3.80 (s, 3H), 3.30 (t, J = 6.8 Hz, 2H), 2.54 (s, 3H), 2.33 (t, J = 8.0 Hz, 2H), 1.94-1.91 (m, 2H).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2015/161011, 2015, A1 Location in patent: Page/Page column 96; 97

38
[ 98006-90-7 ]
methyl 3,3-dicyano-2-cyclopropylacrylate [ No CAS ]
C₁₄H₁₄N₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-bromo-5-methyl-pyrazine With tert.-butyl lithium In tetrahydrofuran; toluene at -78℃; for 0.5h; Inert atmosphere; Stage #2: methyl 3,3-dicyano-2-cyclopropylacrylate In tetrahydrofuran; toluene at 0℃; for 2h;	INTERMEDIATE 83, 83A, & 83B Methyl 2-(5-chloropyridin-2-yl)-3,3-dicyano-2-cyclopropylpropanoate A solution of 2-bromo-5-chloropyridine (2.67 g, 13.9 mmol) in toluene (36.3 mL) and THF (9.08 mL) was placed into a flask under nitrogen atmosphere and cooled to -78°C. To this mixture was added t-butyl lithium (16.4 mL, 27.9 mmol, 1.7 M in THF) dropwise, and the resulting solution was stirred at -78°C for 30 min. To this mixture was added a THF solution (1 mL) of ethyl 3,3- dicyano-2-cyclopropylacrylate (2.05 g, 11.6 mmol) (from Step B of 1-76) dropwise and the resulting solution was slowly warmed up to 0°C over 2 h. The reaction was quenched by the addition of ice-cold saturated aqueous ammonium chloride. The resulting solution was extracted with EtOAc (3X) and the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by silica gel chromatography with (EtOAc:EtOH 3: 1)/Hexane (0-70%) to afford the title compound in its racemic form. The racemic material was resolved using chiral SFC (AD column) to afford isomers I-83A (faster eluting) and I83B (slower eluting) of the title compound. 1H NMR (500 MHz, CDC13): δ 8.53 (1H, d, J=2.3 Hz), 7.78 (2H, m) 5.02 (s, 1H), 3.76 (3H, s), 0.96 (2H, m), 0.85 (2H, m), 0.55 (2H, m).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2015/187470, 2015, A1 Location in patent: Page/Page column 66; 67

39
[ 98006-90-7 ]
(2E)-3-(5-methylpyrazin-2-yl)prop-2-en-1-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: triphenylphosphine; palladium diacetate; caesium carbonate / acetonitrile; water / 1.5 h / 100 °C 2: tetrabutyl ammonium fluoride / tetrahydrofuran / 1 h / 0 °C

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2016/185423, 2016, A1

40
[ 98006-90-7 ]
(2E)-3-(5-methylpyrazin-2-yl)prop-2-enal [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: triphenylphosphine; palladium diacetate; caesium carbonate / acetonitrile; water / 1.5 h / 100 °C 2: tetrabutyl ammonium fluoride / tetrahydrofuran / 1 h / 0 °C 3: manganese(IV) oxide / dichloromethane / 4 h / 20 °C

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2016/185423, 2016, A1

41
[ 98006-90-7 ]
[ 114653-19-9 ]
2-[(1E)-3-[(tert-butyldimethylsilyl)oxy]prop-1-en-i-yl]-5-methylpyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With palladium diacetate; caesium carbonate; triphenylphosphine In water; acetonitrile at 100℃; for 1.5h;	3.1 Step 1: To 2-bromo-5-methylpyrazine (2 g, 11.6 mmol) in MeCN/H20 4/1 (40m1), tert-butyldimethyl { [(2E)-3 -(tetramethyl- 1,3 ,2-dioxaborolan-2-yl)prop-2-en- 1 -yl]oxy } silane(3.98 ml, 12.1 mmol), Cs2CO3 (7.53 g, 23.1 mmol), PPh3 (0.76 g, 2.9 mmol and Pd(OAc)2 (0.13 g, 0.58 mmol) were added and the reaction heated at reflux (1OO°C external temperature) for 1.5 h. The organic solvent was removed in vacuo and the organic mixture partitioned between water and EtOAc. The aqueous phase was back-extracted with EtOAc and the combined organic phases were washed with brine, dried over anhydrous Na2SO4 andthe solvent removed in vacuo. The obtained crude brown oil was purified by flash chromatography (Silica, 340 Snap cartridge, from 100% Cy to Cy/EtOAc 60/40) affording the title compound (2.57g, 84%). MS (m/z) 265 (M+H).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2016/185423, 2016, A1 Location in patent: Page/Page column 75

42
[ 98006-90-7 ]
tert-butyl 2-(3-acetyl-5-hydroxy-1H-indazol-1-yl)acetate [ No CAS ]
tert-butyl 2-(3-acetyl-5-((5-methylpyrazin-2-yl)oxy)-1H-indazol-1-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 18-crown-6 ether; potassium carbonate In N,N-dimethyl-formamide at 100℃; for 24h; Inert atmosphere;	6.1 Step 1 : tert- utyl 2-(3-cetyl-5-((5-methylpyrazin-2-yl)oxy)-lH-indazoI-l-yl)acetate (233) Step 1 : tert- utyl 2-(3-cetyl-5-((5-methylpyrazin-2-yl)oxy)-lH-indazoI-l-yl)acetate (233) [0729] A mixture of fert-butyl 2-(3-acetyl-5-hydroxy-lH-indazol-l-yl)acetate (1 equiv), 2-bromo-5-methylpyrazine (1.1 equiv), K2CO3 (3 equiv) and 18-Crown-6 (1 equiv) in DMF (10 vol) under argon, the pressure vessel was sealed and heated at 100 °C for 24 h. The reaction mixture was cooled to rt and diluted with water, then extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2S04, filtered, and then concentrated. The residue was purified by column chromatography on silica gel (EtOAc/DCM) to give compound 233.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35355, 2017, A1 Location in patent: Paragraph 0729

43
[ 98006-90-7 ]
(5-methylpyrazin-2-yl)acetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: copper (I) iodide; Cs₂CO₃; 2-Picolinic acid / 1,4-dioxane / 16 h / 95 °C 2: lithium hydroxide monohydrate; sodium hydroxide / tetrahydrofuran / 16 h / 10 °C
	Multi-step reaction with 2 steps 1: copper (I) iodide; 2-Picolinic acid; Cs₂CO₃ / 1,4-dioxane / 16 h / 95 °C 2: lithium hydroxide monohydrate; sodium hydroxide / tetrahydrofuran / 16 h / 20 °C

Reference： [1]Current Patent Assignee: PFIZER INC - US2017/73343, 2017, A1
[2]Current Patent Assignee: NALO THERAPEUTICS - WO2022/46861, 2022, A1

44
[ 98006-90-7 ]
8-chloro-2-[(5-methylpyrazin-2-yl)methyl]-1-[(2R,4R)-2-methyltetrahydro-2H-pyran-4-yl]-1H-imidazo[4,5-c]quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: copper(l) iodide; caesium carbonate; 2-Picolinic acid / 1,4-dioxane / 16 h / 95 °C 2: water; sodium hydroxide / tetrahydrofuran / 16 h / 10 °C 3: N-ethyl-N,N-diisopropylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 44 h / 80 °C

Reference： [1]Current Patent Assignee: PFIZER INC - US2017/73343, 2017, A1

45
[ 98006-90-7 ]
8-chloro-2-[(5-methylpyrazin-2-yl)methyl]-1-[(2R,4R)-2-methyltetrahydro-2H-pyran-4-yl]-1H-im idazo[4,5-c]quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: copper(l) iodide; caesium carbonate; 2-Picolinic acid / 1,4-dioxane / 16 h / 95 °C 2: water; sodium hydroxide / tetrahydrofuran / 16 h / 10 °C 3: N-ethyl-N,N-diisopropylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 1.5 h / 20 °C 4: toluene / 1.67 h / 105 °C

Reference： [1]Current Patent Assignee: PFIZER INC - US2017/73343, 2017, A1

46
[ 98006-90-7 ]
C₂₂H₂₄ClN₅O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: copper(l) iodide; caesium carbonate; 2-Picolinic acid / 1,4-dioxane / 16 h / 95 °C 2: water; sodium hydroxide / tetrahydrofuran / 16 h / 10 °C 3: N-ethyl-N,N-diisopropylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 1.5 h / 20 °C

Reference： [1]Current Patent Assignee: PFIZER INC - US2017/73343, 2017, A1

47
[ 98006-90-7 ]
2-[(5-methylpyrazin-2-yl)methyl]-1-[(2R,4R)-2-methyltetrahydro-2H-pyran-4-yl]-1H-imidazo[4,5-c]quinoline-8-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: copper(l) iodide; caesium carbonate; 2-Picolinic acid / 1,4-dioxane / 16 h / 95 °C 2: water; sodium hydroxide / tetrahydrofuran / 16 h / 10 °C 3: N-ethyl-N,N-diisopropylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate; N,N-dimethyl-formamide / 15 h / 110 °C

Reference： [1]Current Patent Assignee: PFIZER INC - US2017/73343, 2017, A1

48
[ 98006-90-7 ]
1-(cis-3-fluorocyclopentyl)-2-[(5-methylpyrazin-2-yl)methyl]-1H-imidazo[4,5-c]quinoline-8-carbonitrile [ No CAS ]
1-(cis-3-fluorocyclopentyl)-2-[(5-methylpyrazin-2-yl)methyl]-1H-imidazo[4,5-c]quinoline-8-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: copper(l) iodide; caesium carbonate; 2-Picolinic acid / 1,4-dioxane / 16 h / 95 °C 2: water; sodium hydroxide / tetrahydrofuran / 16 h / 10 °C 3: N-ethyl-N,N-diisopropylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate; N,N-dimethyl-formamide / 110 °C

Reference： [1]Current Patent Assignee: PFIZER INC - US2017/73343, 2017, A1

49
[ 98006-90-7 ]
[ 108-59-8 ]
dimethyl (5-methylpyrazin-2-yl)propanedioate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With 2-Picolinic acid; copper (I) iodide; Cs₂CO₃ In 1,4-dioxane at 95℃; for 16h;	104.1 Step 1. Synthesis of dimethyl (5-methylpyrazin-2-yl)propanedioate (C80) To a solution of 2-bromo-5-methylpyrazine (5.0 g, 28.9 mmol) in 1,4-dioxane (150 mL) were added dimethyl propanedioate (11.5 g, 87.0 mmol), pyridine-2-carboxylic acid (712 mg, 5.78 mmol), copper(I) iodide (2.20 g, 11.6 mmol), and cesium carbonate (28.2 g, 86.6 mmol). The reaction mixture was stirred at 95° C. for 16 hours, whereupon it was cooled to ambient temperature and combined with a similar reaction carried out using 2-bromo-5-methylpyrazine (100 mg, 0.578 mmol). The combined material was diluted with ethyl acetate (150 mL), washed with saturated aqueous sodium chloride solution (150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (Gradient: 1% to 67% ethyl acetate in petroleum ether) provided the product as a yellow solid. Yield: 5.1 g, 23 mmol, 78%. LCMS m/z 224.9 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J=1.5 Hz, 1H), 8.42-8.44 (m, 1H), 4.94 (s, 1H), 3.80 (s, 6H), 2.58 (s, 3H)
	With 2-Picolinic acid; copper (I) iodide; Cs₂CO₃ In 1,4-dioxane at 95℃; for 16h;	108.1 Step-1: Synthesis of dimethyl 2-(5-methylpyrazin-2-yl)malonate To a solution of 2-bromo-5-methylpyrazine(1.1 g, 6.358 mmol) in 1,4-dioxane (35 mL) were added dimethyl propanedioate (2.18 mL, 19.07 mmol), pyridine-2-carboxylic acid (156 mg, 1.271 mmol), copper(I) iodide (483 mg, 2.543 mmol), and cesium carbonate (6.19 g, 19.075 mmol). The reaction mixture was stirred at 95°C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to RT diluted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get the crude product. The obtained crude product was purified by biotage Isolera using 230- 400 silica mesh eluted with 0-80% ethyl acetate in pet ether as a eluent to yield dimethyl 2- (5-methylpyrazin-2-yl)malonate as a solid (1.1 g, 77.46%). LC purity: 93.28%; m/z: 225.1 [M+H]+ (Mol. formula C10H12N2O4, calcd. mol. wt. 224.2).
	With 2-Picolinic acid; copper (I) iodide; Cs₂CO₃ In 1,4-dioxane at 95℃; for 16h;	108.1 Step-1: Synthesis of dimethyl 2-(5-methylpyrazin-2-yl)malonate To a solution of 2-bromo-5-methylpyrazine(1.1 g, 6.358 mmol) in 1,4-dioxane (35 mL) were added dimethyl propanedioate (2.18 mL, 19.07 mmol), pyridine-2-carboxylic acid (156 mg, 1.271 mmol), copper(I) iodide (483 mg, 2.543 mmol), and cesium carbonate (6.19 g, 19.075 mmol). The reaction mixture was stirred at 95°C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to RT diluted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get the crude product. The obtained crude product was purified by biotage Isolera using 230- 400 silica mesh eluted with 0-80% ethyl acetate in pet ether as a eluent to yield dimethyl 2- (5-methylpyrazin-2-yl)malonate as a solid (1.1 g, 77.46%). LC purity: 93.28%; m/z: 225.1 [M+H]+ (Mol. formula C10H12N2O4, calcd. mol. wt. 224.2).

With 2-Picolinic acid; copper (I) iodide; Cs₂CO₃ In 1,4-dioxane at 95℃; for 16h;

108.1 Step-1: Synthesis of dimethyl 2-(5-methylpyrazin-2-yl)malonate To a solution of 2-bromo-5-methylpyrazine(1.1 g, 6.358 mmol) in 1,4-dioxane (35 mL) were added dimethyl propanedioate (2.18 mL, 19.07 mmol), pyridine-2-carboxylic acid (156 mg, 1.271 mmol), copper(I) iodide (483 mg, 2.543 mmol), and cesium carbonate (6.19 g, 19.075 mmol). The reaction mixture was stirred at 95°C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to RT diluted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get the crude product. The obtained crude product was purified by biotage Isolera using 230- 400 silica mesh eluted with 0-80% ethyl acetate in pet ether as a eluent to yield dimethyl 2- (5-methylpyrazin-2-yl)malonate as a solid (1.1 g, 77.46%). LC purity: 93.28%; m/z: 225.1 [M+H]+ (Mol. formula C10H12N2O4, calcd. mol. wt. 224.2).

Reference： [1]Current Patent Assignee: PFIZER INC - US2017/73343, 2017, A1 Location in patent: Paragraph 0320
[2]Current Patent Assignee: NALO THERAPEUTICS - WO2022/46861, 2022, A1 Location in patent: Paragraph 00253
[3]Current Patent Assignee: NALO THERAPEUTICS - WO2022/46861, 2022, A1 Location in patent: Paragraph 00253
[4]Current Patent Assignee: NALO THERAPEUTICS - WO2022/46861, 2022, A1 Location in patent: Paragraph 00253

50
[ 98006-90-7 ]
tert-butyl 2-(3-acetyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)acetate [ No CAS ]
tert-butyl 2-(3-acetyl-5-(5-methylpyrazin-2-yl)-1H-indazol-1-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In water; N,N-dimethyl-formamide at 90℃; for 5h;	6.1 Step 1: tert-Butyl 2-(3-acetyl-5-(5-methylpyrazin-2-yl)-1H-indazol-1-yl)acetate (S3) To a solution of 2-bromo-5-methylpyrazine (S2, 1 equiv) in DMF/H2O (9:1, 10 vol) was added compound S1 (1 equiv), K2CO3(2 equiv), and tetrakis(triphenylphosphine)palladium (0.1 equiv). The reaction mixture was stirred at 90° C. for 5 h and then concentrated under reduced pressure. The remaining residue was purified by column chromatography on silica gel to give compound S3.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2017/35353, 2017, A1 Location in patent: Paragraph 1319

51
[ 98006-90-7 ]
potassium (tert-butyl 3-azabicyclo[3.1.0]hexane-3-carboxylate-1-yl)trifluoroborate [ No CAS ]
C₁₅H₂₁N₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With [(di(1-adamantyl)-butylphosphine)-2-(2-amino-1,1-biphenyl)]palladium(II) methanesulfonate; caesium carbonate In water; toluene at 90℃; for 18h; Sealed tube; Inert atmosphere;

Reference： [1]Harris, Michael R.; Li, Qifang; Lian, Yajing; Xiao, Jun; Londregan, Allyn T. [Organic Letters, 2017, vol. 19, # 9, p. 2450 - 2453]

52
[ 1110642-47-1 ]
[ 98006-90-7 ]
(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(5-methylpyrazin-2-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate In 1,4-dioxane at 120℃; for 0.5h; Microwave irradiation;	General procedure: To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (19, 200 mg, 0.42 mmol) in 1,4-dioxane (1.5mL) was added 6-bromonicotinonitrile (123 mg, 0.67 mmol), Pd(PPh3)2Cl2 (30 mg, 0.042 mmol), andCs2CO3 (1 mL, 2 M ) were added. The vessel was sealed with a septum and placed into the microwavecavity. Microwave irradiation of 100 W was used, and the temperature being ramped from rt to 120 C.Once this temperature was reached, the reaction mixture was held at this temperature for 30 min. Afterthe mixture was cooled to rt, the mixture was filtered. The filtrate was extracted with EtOAc (4 x 20mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated to give the crudeproduct, which was purified by preparative TLC to give 6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinonitrile (11d, 120 mg, 62%).

Reference： [1]Zhuang, Linghang; Tice, Colin M.; Xu, Zhenrong; Zhao, Wei; Cacatian, Salvacion; Ye, Yuan-Jie; Singh, Suresh B.; Lindblom, Peter; McKeever, Brian M.; Krosky, Paula M.; Zhao, Yi; Lala, Deepak; Kruk, Barbara A.; Meng, Shi; Howard, Lamont; Johnson, Judith A.; Bukhtiyarov, Yuri; Panemangalore, Reshma; Guo, Joan; Guo, Rong; Himmelsbach, Frank; Hamilton, Bradford; Schuler-Metz, Annette; Schauerte, Heike; Gregg, Richard; McGeehan, Gerard M.; Leftheris, Katerina; Claremon, David A. [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3649 - 3657]

53
[ 98006-90-7 ]
2-bromo-5-(bromomethyl)pyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32.1%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane Reflux;	186 Intermediate 186a: 2-bromo-5-(bromomethyl)pyrazine 2-bromo-5-methylpyrazine (300 mg, 1.734 mmol) was dissolved in carbon tetrachloride (8 mL), NBS (370 mg, 2.081 mmol) and benzoyl peroxide (21.00 mg, 0.087 mmol) were added , and the resulting mixture was heated and refluxed for overnight. The reaction solution was returned to RT, concentrated under reduced pressure and purified by ISCO (Hexanes/AcOEt, 0-100%) to afford the title compound (Intermediate 186a, 140 mg, 0.556 mmol, 32.1 % yield) as a white solid. LC-MS (Method A5): 1.77 min, [M + H]+= 250.9 and 251.9; lH NMR (500 MHz, CDC13) δ 8.80 (s, 2H), 4.58 (s, 2H).

Reference： [1]Current Patent Assignee: UNIVERSITY OF MONTREAL; BRISTOL-MYERS SQUIBB CO - WO2018/5591, 2018, A1 Location in patent: Page/Page column 286-287

54
[ 98006-90-7 ]
3-((5-bromopyrazin-2-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: N-Bromosuccinimide; dibenzoyl peroxide / tetrachloromethane / Reflux 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 20 °C 2.2: 2 h

Reference： [1]Current Patent Assignee: UNIVERSITY OF MONTREAL; BRISTOL-MYERS SQUIBB CO - WO2018/5591, 2018, A1

55
[ 98006-90-7 ]
4-chloro-2-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyrazin-2-yl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: N-Bromosuccinimide; dibenzoyl peroxide / tetrachloromethane / Reflux 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 20 °C 2.2: 2 h 3.1: sodium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / tetrahydrofuran / 1 h / 125 °C / Inert atmosphere; Sealed tube; Microwave irradiation

Reference： [1]Current Patent Assignee: UNIVERSITY OF MONTREAL; BRISTOL-MYERS SQUIBB CO - WO2018/5591, 2018, A1

56
[ 98006-90-7 ]
3-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyrazin-2-yl)-3'-methylbiphenyl-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: N-Bromosuccinimide; dibenzoyl peroxide / tetrachloromethane / Reflux 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 20 °C 2.2: 2 h 3.1: sodium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / tetrahydrofuran / 1 h / 125 °C / Inert atmosphere; Sealed tube; Microwave irradiation 4.1: potassium phosphate; methanesulfonic acid(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) / tetrahydrofuran / 1 h / 140 °C / Inert atmosphere; Sealed tube; Microwave irradiation

Reference： [1]Current Patent Assignee: UNIVERSITY OF MONTREAL; BRISTOL-MYERS SQUIBB CO - WO2018/5591, 2018, A1

57
[ 98006-90-7 ]
2-ethyl-5,7-dimethyl-3-((5-(3'-methyl-4-(1H-tetrazol-5-yl)biphenyl-3-yl)pyrazin-2-yl)methyl)-3H-imidazo[4,5-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: N-Bromosuccinimide; dibenzoyl peroxide / tetrachloromethane / Reflux 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 20 °C 2.2: 2 h 3.1: sodium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / tetrahydrofuran / 1 h / 125 °C / Inert atmosphere; Sealed tube; Microwave irradiation 4.1: potassium phosphate; methanesulfonic acid(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) / tetrahydrofuran / 1 h / 140 °C / Inert atmosphere; Sealed tube; Microwave irradiation 5.1: trimethylsilylazide; di(n-butyl)tin oxide / toluene / 100 °C / Sealed tube

Reference： [1]Current Patent Assignee: UNIVERSITY OF MONTREAL; BRISTOL-MYERS SQUIBB CO - WO2018/5591, 2018, A1

58
[ 98006-90-7 ]
ethyl 4-chloro-2-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyrazin-2-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: N-Bromosuccinimide; dibenzoyl peroxide / tetrachloromethane / Reflux 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 20 °C 2.2: 2 h 3.1: sodium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / tetrahydrofuran / 0.75 h / 125 °C / Inert atmosphere; Sealed tube; Microwave irradiation

Reference： [1]Current Patent Assignee: UNIVERSITY OF MONTREAL; BRISTOL-MYERS SQUIBB CO - WO2018/5591, 2018, A1

59
[ 98006-90-7 ]
3-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyrazin-2-yl)-3'-methylbiphenyl-4-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: N-Bromosuccinimide; dibenzoyl peroxide / tetrachloromethane / Reflux 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 20 °C 2.2: 2 h 3.1: sodium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / tetrahydrofuran / 0.75 h / 125 °C / Inert atmosphere; Sealed tube; Microwave irradiation 4.1: potassium phosphate; methanesulfonic acid(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) / tetrahydrofuran / 0.75 h / 140 °C / Inert atmosphere; Sealed tube; Microwave irradiation 4.2: 0.5 h / 100 °C / Microwave irradiation

Reference： [1]Current Patent Assignee: UNIVERSITY OF MONTREAL; BRISTOL-MYERS SQUIBB CO - WO2018/5591, 2018, A1

60
[ 41110-33-2 ]
[ 98006-90-7 ]

Reference： [1]Journal of Heterocyclic Chemistry,2019,vol. 56,p. 972 - 979

61
[ 5521-57-3 ]
[ 98006-90-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: potassium hydroxide; bromine / water / 0 - 90 °C 2.1: hydrogen bromide / water / 25 - 30 °C 2.2: 1 h / -50 °C 2.3: 1.5 h / -50 °C

Reference： [1]KomReddy, Venugopal; Rillema, D. Paul; Nguyen, Huy; Kadel, Lava [Journal of Heterocyclic Chemistry, 2019, vol. 56, # 3, p. 972 - 979]

62
[ 5521-58-4 ]
[ 98006-90-7 ]

Reference： [1]Journal of Heterocyclic Chemistry,2019,vol. 56,p. 972 - 979

63
[ 98006-90-7 ]
5-methyl-2,2'-bipyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: n-butyllithium / diethyl ether; hexane / 2 h / -78 °C / Inert atmosphere; Schlenk technique 1.2: 16 h / -78 - 20 °C / Inert atmosphere; Schlenk technique 2.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 5,5-dimethyl-1,3-cyclohexadiene / 12 h / 120 °C / Inert atmosphere

Reference： [1]KomReddy, Venugopal; Rillema, D. Paul; Nguyen, Huy; Kadel, Lava [Journal of Heterocyclic Chemistry, 2019, vol. 56, # 3, p. 972 - 979]

64
[ 98006-90-7 ]
2-methyl-5-(2-pyridinyl)pyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: n-butyllithium / diethyl ether; hexane / 2 h / -78 °C / Inert atmosphere; Schlenk technique 1.2: 16 h / -78 - 20 °C / Inert atmosphere; Schlenk technique 2.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 5,5-dimethyl-1,3-cyclohexadiene / 12 h / 120 °C / Inert atmosphere

Reference： [1]KomReddy, Venugopal; Rillema, D. Paul; Nguyen, Huy; Kadel, Lava [Journal of Heterocyclic Chemistry, 2019, vol. 56, # 3, p. 972 - 979]

65
[ 98006-90-7 ]
[ 37830-10-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: n-butyllithium / diethyl ether; hexane / 2 h / -78 °C / Inert atmosphere; Schlenk technique 1.2: 16 h / -78 - 20 °C / Inert atmosphere; Schlenk technique 2.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 5,5-dimethyl-1,3-cyclohexadiene / 12 h / 120 °C / Inert atmosphere

Reference： [1]KomReddy, Venugopal; Rillema, D. Paul; Nguyen, Huy; Kadel, Lava [Journal of Heterocyclic Chemistry, 2019, vol. 56, # 3, p. 972 - 979]

66
[ 98006-90-7 ]
[2,2'-bipyrazine]-5,5'-dicarboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: n-butyllithium / diethyl ether; hexane / 2 h / -78 °C / Inert atmosphere; Schlenk technique 1.2: 16 h / -78 - 20 °C / Inert atmosphere; Schlenk technique 2.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 5,5-dimethyl-1,3-cyclohexadiene / 12 h / 120 °C / Inert atmosphere 3.1: sulfuric acid; potassium dichromate / 40 - 80 °C

Reference： [1]KomReddy, Venugopal; Rillema, D. Paul; Nguyen, Huy; Kadel, Lava [Journal of Heterocyclic Chemistry, 2019, vol. 56, # 3, p. 972 - 979]

67
[ 98006-90-7 ]
2-(tributylstannyl)-5-methylpyrazine [ No CAS ]
[ 37830-10-7 ]

Yield	Reaction Conditions	Operation in experiment
68%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾ In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 12h; Inert atmosphere;

Reference： [1]KomReddy, Venugopal; Rillema, D. Paul; Nguyen, Huy; Kadel, Lava [Journal of Heterocyclic Chemistry, 2019, vol. 56, # 3, p. 972 - 979]

68
[ 98006-90-7 ]
2-(tributylstannyl)-5-methylpyrazine [ No CAS ]
[2,2'-bipyrazine]-5,5'-dicarboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 5,5-dimethyl-1,3-cyclohexadiene / 12 h / 120 °C / Inert atmosphere 2: sulfuric acid; potassium dichromate / 40 - 80 °C

Reference： [1]KomReddy, Venugopal; Rillema, D. Paul; Nguyen, Huy; Kadel, Lava [Journal of Heterocyclic Chemistry, 2019, vol. 56, # 3, p. 972 - 979]

69
[ 98006-90-7 ]
[ 1461-22-9 ]
2-(tributylstannyl)-5-methylpyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	Stage #1: 2-bromo-5-methyl-pyrazine With n-butyllithium In diethyl ether; hexane at -78℃; for 2h; Inert atmosphere; Schlenk technique; Stage #2: tributyltin chloride In diethyl ether; hexane at -78 - 20℃; for 16h; Inert atmosphere; Schlenk technique;
27%	With n-butyllithium In tetrahydrofuran at -78℃;	26.1 [00463] To a solution of 2-bromo-5-methyl-pyrazine (1 g, 5.78 mmol) and tributylchlorostannane (3.16 g, 9.71 mmol) in THE (15 mL) was added -BuLi (2,8 mL, 7.0 mmol) dropwise at -78 °C and stirred for a further 2 hours at this temperature. The reaction was quenched with water (50 mL) and extracted with hexanes (50 mL x 2). The combined organics were dried over NaiSOy filtered and concentrated. The crude was purified by column chromatography (0 - 10 % ethyl acetate in petroleum ether) to afford the title compound (600 mg, 27%) as a colorless oil NMR (400 MHz, CDCb): d 8.62 (s, 1H), 8.42 (s, 1H), 2,51 (s, 3H), 1.59 - 1.49 (rn. 6H), 1.36 - 1.30 (m, 6H), 1.15 (t,./ 8.0 Hz, 6H), 0.88 (t, J ------ 7.2 Hz, 9H).

Reference： [1]KomReddy, Venugopal; Rillema, D. Paul; Nguyen, Huy; Kadel, Lava [Journal of Heterocyclic Chemistry, 2019, vol. 56, # 3, p. 972 - 979]
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2021/108483, 2021, A1 Location in patent: Paragraph 00462-00463

70
[ 5521-55-1 ]
[ 98006-90-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sulfuric acid / 8 h / 0 - 65 °C 2.1: ammonia / methanol / 4 h / 0 - 5 °C 3.1: potassium hydroxide; bromine / water / 0 - 90 °C 4.1: hydrogen bromide / water / 25 - 30 °C 4.2: 1 h / -50 °C 4.3: 1.5 h / -50 °C

Reference： [1]KomReddy, Venugopal; Rillema, D. Paul; Nguyen, Huy; Kadel, Lava [Journal of Heterocyclic Chemistry, 2019, vol. 56, # 3, p. 972 - 979]

71
[ 5049-61-6 ]
[ 98006-90-7 ]
C₉H₉N₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 90℃; Inert atmosphere;	BH 5-Methyl-/V-(pyrazin-2-yl)-/V-({5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3- yl]thiophen-2-yl}methyl)pyrazin-2-amine A suspension of pyrazin-2-amine (1) (343mg, 3.6mmol), 2-bromo-5- methylpyrazine (2) (567mg, 3.3mmol), Cs2C03 (2.1 g, 6.6mmol), Pd2(dba)3 (150mg, 0.16mmol) and Xantphos (209mg, 0.36mmol) in dioxane (15mL) was degassed with Ar(g) for 20min. The reaction mixture was then heated up to 90°C overnight. Once cooled down to rt, it was partitioned between H20 (10ml_), brine (5mL) and EtOAc (2 x 10ml_). The combined organics were dried over MgS04, filtered and concentrated in vacuo. The residue was dissolved in CH2CI2/MeOH (1 :1 , 20ml_) and Pd-scavenged with MP-TMT resin (~150mg) overnight. The suspension was then filtered and solvent removed in vacuo. Purification by silica gel column chromatography with hexane/EtOAc (1 :0-0:1 ) followed by SCX-2 with CH2CI2/MeOH (1 :0-0: 1 +0.3M NH3) yielded (3) as a yellow solid (242mg, 40%). LCMS (ES): Found 188.1 [M+Hf. (0427) 1H NMR (300 MHz, DMSO-cfe), d: 10.22 (s, 1 H), 8.96 (d, J=1.5 Hz, 1 H), 8.92 (d, J=1.5 Hz, 1 H), 8.27 (dd, J= 2.6, 1.5 Hz, 1 H), 8.20 (d, J= 0.8 Hz, 1 H), 8.12 (d, J= 2.6 Hz, 1 H), 2.41 (s, 3H).

Reference： [1]Current Patent Assignee: KARUS THERAPEUTICS LIMITED - WO2019/166824, 2019, A1 Location in patent: Page/Page column 58

72
[ 98006-90-7 ]
5-methyl-N-(pyrazin-2-yl)-N-({5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]thiophen-2-yl}methyl)pyrazin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: caesium carbonate; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane / 90 °C / Inert atmosphere 2.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.33 h / 0 °C / Inert atmosphere 2.2: 0 - 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: KARUS THERAPEUTICS LIMITED - WO2019/166824, 2019, A1

73
[ 98006-90-7 ]
C₅H₄F₃N₃*2C₂HF₃O₂ [ No CAS ]
C₁₀H₈F₃N₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 90℃; for 4h; Inert atmosphere;	EO /V-(5-Methylpyrazin-2-yl)-5-(trifluoromethyl)-/V-({5-[5-(trifluoromethyl)-1,2,4- oxadiazol-3-yl]thiophen-2-yl}methyl)pyridazin-3-amine A suspension of (1) (171 mg, 0.44mmol), 2-bromo-5-methylpyrazine (2) (76mg, 0.44mmol), Cs2C03 (570mg, 1.75mmol) and Xantphos (25mg, 0.04mmol) in 1 ,4-dioxane (4mL) was purged with Ar(g) for 1 h. Pd2(dba)3 (20mg, 0.02mmol) was added and the reaction mixture was heated up to 90°C overnight. Once cooled down to rt, it was poured into a mixture of H20 (20ml_) and brine (10ml_), then extracted with EtOAc (4 x 10ml_). The combined organics were washed with brine (20ml_), dried over MgS04, filtered and concentrated in vacuo. Purification by silica gel column chromatography with hexane/EtOAc (1 :0- 1 :1 ) yielded (3) as a solid (75mg, 67%).

Reference： [1]Current Patent Assignee: KARUS THERAPEUTICS LIMITED - WO2019/166824, 2019, A1 Location in patent: Page/Page column 139

74
[ 98006-90-7 ]
[ 69610-40-8 ]
tert-butyl (S)-2-(((5-methylpyrazin-2-yl)oxy)methyl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With 5-(di-tert-butylphosphino)-1′, 3′, 5′-triphenyl-1′H-[1,4′]bipyrazole; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; caesium carbonate In toluene at 85℃; for 14h; Inert atmosphere;

Reference： [1]Mikus, Malte S.; Sanchez, Carina; Fridrich, Cary; Larrow, Jay F. [Advanced Synthesis and Catalysis, 2020, vol. 362, # 2, p. 430 - 436]

75
[ 98006-90-7 ]
6-(2-(1H-tetrazol-5-yl)phenyl)-N₂-benzyl-N₂-isobutylpyridine-2,4-diamine [ No CAS ]
6-(2-(1H-tetrazol-5-yl)phenyl)-N₂-benzyl-N₂-isobutyl-N₄-(5-methylpyrazin-2-yl)pyridine-2,4-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
16%	Stage #1: 2-bromo-5-methyl-pyrazine; 6-(2-(1H-tetrazol-5-yl)phenyl)-N₂-benzyl-N₂-isobutylpyridine-2,4-diamine With 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium t-butanolate In 1,4-dioxane for 0.166667h; Sealed tube; Inert atmosphere; Stage #2: With bis(dibenzylideneacetone)-palladium⁽⁰⁾ In 1,4-dioxane at 100℃; for 6h;	49 Example 49 To a 100 mL sealed tube 49D (54 mg, 0.135 mmol), 2-bromo-5-methylpyrazine (23.39 mg, 0.135 mmol), XantPhos (19.55 mg, 0.034 mmol), sodium t-butoxide (39.0 mg, 0.406 mmol) in dioxane (5 mL) were added and the resulting solution was purged with nitrogen gas for 10 mins. Bis(dibenzylideneacetone)palladium (7.77 mg, 0.014 mmol) was added to The reaction mixture and nitrogen gas was purged through the solution with for 10 mins. The reaction mixture was heated at 100 °C for 6 h. The reaction mixture was cooled to RT and reaction mixture was concentrated under reduced pressure. The residue was reconstituted in ethyl acetate (30 mL) and filtered through celite. The celite bed washed with ethyl acetate (50 mL) and filtrate was concentrated under reduced pressure to afford brown colored residue. The residue was purified by prep. Purification by preparative 1TPLC gave Example 49 (light yellow solid, 14 mg, 0.022 mmol, 16 % yield). LC-MS Anal.Calc’d for C28H29N9 491.255, found [M+H] 492.4, Tr =2.095 (Method U). 8.20 (m, 2H), 7.96-8.04 (m, 2H), 7.72-7.80 (m, 2H), 7.59-7.61 (m, 1H), 7.31-7.39 (m, 2H), 7.26-7.29 (m, 3H), 6.74 (s, 1H), 4.83 (s, 2H), 3.48 (d, J= 7.60 Hz, 2H), 2.49 (s, 3H), 1.99-2.06 (m, 1H), 0.96-0.98 (m, 6H).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO; BIOCON LIMITED - WO2020/23355, 2020, A1 Location in patent: Page/Page column 39; 86; 88-89

76
[ 98006-90-7 ]
[ 134-32-7 ]
C₁₅H₁₃N₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene for 12h; Reflux;	1; 3; 10 General procedure: 6-chloro-3-methylpyridazine (12.8 g, 0.1 mol), 1-naphthalenamine (14.3 g, 0.1 mol), palladium acetate (0.08 g, 0.32 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene(0.26 g, 0.42 mmol) and sodium tert-butoxide (15.2 g, 0.16 mol) were added to 150 mL of toluene and refluxed for 12 hours. After cooling to room temperature, washed with methanol, and recrystallized with dichloromethane and methanol to give [Intermediate 1-a] 18.1 g (77% yield).
75%	With palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene for 12h; Reflux;	10 [Scheme 1-1] Synthesis of [Intermediate 1-a] General procedure: 1-cyano-4-chlorobenzene (13.8 g, 0.1 mol), 2-methyl-5-aminopyridine (10.8 g, 0.1 mol), palladium acetate (0.08 g, 0.32 mmol), 2,2'-bis ( Diphenylphosphino)-1-1'-binaphthyl (0.26 g, 0.42 mmol), sodium tertiary butoxide (15.2 g, 0.16 mol) was added to 150 mL of toluene and refluxed for 12 hours. After cooling to room temperature, washed with methanol and recrystallized from dichloromethane and methanol to obtain [Intermediate 1-a] 15.3 g (yield 73%).

Reference： [1]Current Patent Assignee: HODOGAYA CHEMICAL CO LTD - KR102193832, 2020, B1 Location in patent: Paragraph 0198-0202; 0238-0242; 0392-0396
[2]Current Patent Assignee: HODOGAYA CHEMICAL CO LTD - KR102080738, 2020, B1 Location in patent: Paragraph 0239-0243; 0465; 0474-0477

77
[ 98006-90-7 ]
[ 134-32-7 ]
C₂₁H₁₈BN₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; palladium diacetate; sodium t-butanolate / toluene / 12 h / Reflux 2: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; palladium diacetate; sodium t-butanolate / toluene / 12 h / Reflux

Reference： [1]Current Patent Assignee: HODOGAYA CHEMICAL CO LTD - KR102080738, 2020, B1

78
[ 98006-90-7 ]
[ 91-59-8 ]
C₁₅H₁₃N₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene for 12h; Reflux;	1; 3 General procedure: 6-chloro-3-methylpyridazine (12.8 g, 0.1 mol), 1-naphthalenamine (14.3 g, 0.1 mol), palladium acetate (0.08 g, 0.32 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene(0.26 g, 0.42 mmol) and sodium tert-butoxide (15.2 g, 0.16 mol) were added to 150 mL of toluene and refluxed for 12 hours. After cooling to room temperature, washed with methanol, and recrystallized with dichloromethane and methanol to give [Intermediate 1-a] 18.1 g (77% yield).

Reference： [1]Current Patent Assignee: HODOGAYA CHEMICAL CO LTD - KR102193832, 2020, B1 Location in patent: Paragraph 0198-0202; 0238; 0255-0258

79
[ 98006-90-7 ]
C₂₁H₃₂N₂O₂ [ No CAS ]
(R)-6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-(5-methylpyrazin-2-yl)-2-azaspiro[3.4]octane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10.6 mg	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 110℃; for 2h; Inert atmosphere;	5.Y Example 5Y Example 5Y (R)-6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-(5-methylpyrazin-2-yl)-2-azaspiro[3.4]octane To a toluene (1 mL) solution of (R)-6-(4-(2-(2-methoxyethoxy)phenyl)piperidin-1-yl)-2-azaspiro[3.4]octane (Intermediate 4E, 33 mg, 0.096 mmol) was added Pd2(dba)3 (17.54 mg, 0.019 mmol), rac-BINAP (11.93 mg, 0.019 mmol), 2-bromo-5-methylpyrazine (24.86 mg, 0.144 mmol) and sodium tert-butoxide (13.81 mg, 0.144 mmol). The reaction mixture was stirred under N2 at 110° C. for 2 hours and the reaction was then filtered through a celite plug, concentrated and purified by preparative HPLC (XBridge C18 30*50 mm 45-70% MeCN/H2O (5 mM NH4OH), 75 mL/min) to afford the title compound (10.6 mg, 0.023 mmol) as a pale yellow oil. LCMS: Rt: 2.51 min (LCMS Method 2) MS m/z 437.6 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 7.93 (s, 1H), 7.74 (d, J=1.4 Hz, 1H), 7.24-7.11 (m, 2H), 6.99-6.89 (m, 2H), 4.20-4.10 (m, 2H), 4.05-3.96 (m, 2H), 3.93 (q, J=7.8 Hz, 2H), 3.82-3.76 (m, 2H), 3.46 (s, 3H), 3.30-3.20 (m, 2H), 3.18-3.05 (m, 1H), 2.89 (s, 1H), 2.50-2.21 (m, 6H), 2.08 (m, 2H), 2.00 (m, 1H), 1.95-1.59 (m, 6H).

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US2021/107889, 2021, A1 Location in patent: Paragraph 1353-1355

80
[ 98006-90-7 ]
[ 216854-23-8 ]
tert-butyl N-[(3S)-1-(5-methylpyrazin-2-yl)piperidin-3-yl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 100℃; Inert atmosphere; Sealed tube;	81 Preparation of tert- butyl N-[(3S)^~1-(5-methylpyrazin-2-yl)pipendin-3-yl]carbamate A suspension of fevf-butyl A/-[(35 -piperidin-3-yl]carbamate (0.60 g, 1.3 eq.), 2-bromo-5- methylpyrazine (0.4 g, 1.0 eq.), Cs2C03(1.0 g, 1.4 eq.) in anh. 1, 4-dioxane (10.0 mL) was purged with nitrogen for 10 min. Then, Xantphos (0.08 g, 0.06 eq.) and Pd2(dba)3(0.11 g, 0.05 eq.) were added and the resulting mixture was purged again with nitrogen for 10 min. The vessel was closed and the reaction mixture was heated overnight at 100 °C. Subsequently, the mixture was filtered through a pad of celite and the pad was washed with EtOAc. The filtrate was concen trated in vacuo and the residue was purified by FCC (Si HP; Hex: EtOAc) to give the product (0.71 g, 87% yield) as a brown solid. ESI-MS: 293.3 [M+H]+.
87%	Stage #1: 2-bromo-5-methyl-pyrazine; tert-butyl (S)-piperidin-3-yl-carbamate With caesium carbonate In 1,4-dioxane for 0.166667h; Inert atmosphere; Stage #2: With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene at 100℃; Inert atmosphere; Sealed tube;	81 Preparation of tert-butyl N-[(3S)-1-(5-methylpyrazin-2-yl)piperidin-3-yl]carbamate A suspension of tert-butyl N-[(3S)-piperidin-3-yl]carbamate (0.60 g, 1.3 eq.), 2-bromo-5- methylpyrazine (0.4 g, 1.0 eq.), Cs2CO3 (1.0 g, 1.4 eq.) in anh.1,4-dioxane (10.0 mL) was purged with nitrogen for 10 min. Then, Xantphos (0.08 g, 0.06 eq.) and Pd2(dba)3 (0.11 g, 0.05 eq.) were added and the resulting mixture was purged again with nitrogen for 10 min. The ves- sel was closed and the reaction mixture was heated overnight at 100 °C. Subsequently, the mix- ture was filtered through a pad of celite and the pad was washed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by FCC (SiHP; Hex:EtOAc) to give the prod- uct (0.71 g, 87% yield) as a brown solid. ESI-MS: 293.3 [M+H]+.

Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA - WO2021/116451, 2021, A1 Location in patent: Page/Page column 176
[2]Current Patent Assignee: RYVU THERAPEUTICS SA - WO2021/116446, 2021, A1 Location in patent: Page/Page column 212

81
[ 98006-90-7 ]
(3S)-1-(5-methylpyrazin-2-yl)piperidin-3-amine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: caesium carbonate; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane / 100 °C / Inert atmosphere; Sealed tube 2: hydrogenchloride / 1,4-dioxane / 40 °C

Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA - WO2021/116451, 2021, A1

82
[ 98006-90-7 ]
(3S)-1-(5-methylpyrazin-2-yl)-N-[(2-methylpyridin-4-yl)methyl]piperidin-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: caesium carbonate; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane / 100 °C / Inert atmosphere; Sealed tube 2.1: hydrogenchloride / 1,4-dioxane / 40 °C 3.1: sodium acetate / methanol / 20 °C 3.2: 1 h / 20 °C

Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA - WO2021/116451, 2021, A1

83
[ 98006-90-7 ]
7-chloro-1-cyclopropyl-6-fluoro-3-([(3S)-1-(5-methylpyrazin-2-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: caesium carbonate; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane / 100 °C / Inert atmosphere; Sealed tube 2.1: hydrogenchloride / 1,4-dioxane / 40 °C 3.1: sodium acetate / methanol / 20 °C 3.2: 1 h / 20 °C 4.1: 1,2-dichloro-ethane / 50 °C 4.2: 2 h / 20 °C

Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA - WO2021/116451, 2021, A1

84
[ 98006-90-7 ]
1-cyclopropyl-6-fluoro-7-[(3S)-3-hydroxypiperidin-1-yl]-3-([(3S)-1-(5-methylpyrazin-2-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: caesium carbonate; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane / 100 °C / Inert atmosphere; Sealed tube 2.1: hydrogenchloride / 1,4-dioxane / 40 °C 3.1: sodium acetate / methanol / 20 °C 3.2: 1 h / 20 °C 4.1: 1,2-dichloro-ethane / 50 °C 4.2: 2 h / 20 °C 5.1: sodium t-butanolate; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 100 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA - WO2021/116451, 2021, A1

85
[ 98006-90-7 ]
(3S,5S)-5-fluoro-1-(5-methylpyrazin-2-yl)piperidin-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: caesium carbonate; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane / 100 °C / Inert atmosphere 2: hydrogenchloride / 1,4-dioxane / 40 °C
	Multi-step reaction with 2 steps 1.1: caesium carbonate / 1,4-dioxane / 0.17 h / Inert atmosphere 1.2: 100 °C / Inert atmosphere; Sealed tube 2.1: hydrogenchloride / 1,4-dioxane / 40 °C

Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA - WO2021/116451, 2021, A1
[2]Current Patent Assignee: RYVU THERAPEUTICS SA - WO2021/116446, 2021, A1

86
[ 98006-90-7 ]
(3S,5S)-5-fluoro-1-(5-methylpyrazin-2-yl)-N-[(2-methylpyridin-4-yl)methyl]piperidin-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: caesium carbonate; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane / 100 °C / Inert atmosphere 2.1: hydrogenchloride / 1,4-dioxane / 40 °C 3.1: sodium acetate / methanol / 20 °C 3.2: 1 h / 20 °C
	Multi-step reaction with 3 steps 1.1: caesium carbonate / 1,4-dioxane / 0.17 h / Inert atmosphere 1.2: 100 °C / Inert atmosphere; Sealed tube 2.1: hydrogenchloride / 1,4-dioxane / 40 °C 3.1: sodium acetate / methanol / 20 °C 3.2: 1 h / 20 °C

Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA - WO2021/116451, 2021, A1
[2]Current Patent Assignee: RYVU THERAPEUTICS SA - WO2021/116446, 2021, A1

87
[ 98006-90-7 ]
7-chloro-1-cyclopropyl-6-fluoro-3-([(3S,5S)-5-fluoro-1-(5-methylpyrazin-2-yl)piperidin-3-yl][(2-methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: caesium carbonate; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane / 100 °C / Inert atmosphere 2.1: hydrogenchloride / 1,4-dioxane / 40 °C 3.1: sodium acetate / methanol / 20 °C 3.2: 1 h / 20 °C 4.1: 1,2-dichloro-ethane / 50 °C 4.2: 2 h / 20 °C
	Multi-step reaction with 4 steps 1.1: caesium carbonate / 1,4-dioxane / 0.17 h / Inert atmosphere 1.2: 100 °C / Inert atmosphere; Sealed tube 2.1: hydrogenchloride / 1,4-dioxane / 40 °C 3.1: sodium acetate / methanol / 20 °C 3.2: 1 h / 20 °C 4.1: 1,2-dichloro-ethane / 50 °C 4.2: 2 h / 20 °C

Reference： [1]Current Patent Assignee: RYVU THERAPEUTICS SA - WO2021/116451, 2021, A1
[2]Current Patent Assignee: RYVU THERAPEUTICS SA - WO2021/116446, 2021, A1

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CAS No. :	98006-90-7	MDL No. :	MFCD08705754
Formula :	C₅H₅BrN₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	OBZRGWKVWAXNKZ-UHFFFAOYSA-N
M.W :	173.01	Pubchem ID :	22419346
Synonyms :

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P301+P312-P302+P352-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H320-H335	Packing Group:	N/A
GHS Pictogram:

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 98006-90-7 ] {[proInfo.proName]}

Quality Control of [ 98006-90-7 ]

Related Doc. of [ 98006-90-7 ]

Product Details of [ 98006-90-7 ]

Safety of [ 98006-90-7 ]

Application In Synthesis of [ 98006-90-7 ]

[ 98006-90-7 ] Synthesis Path-Downstream 1~87

Related Functional Groups of
[ 98006-90-7 ]

Bromides

Related Parent Nucleus of
[ 98006-90-7 ]

Pyrazines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

[ CAS No. 98006-90-7 ] {[proInfo.proName]}

Quality Control of [ 98006-90-7 ]

Related Doc. of [ 98006-90-7 ]

Product Details of [ 98006-90-7 ]

Safety of [ 98006-90-7 ]

Application In Synthesis of [ 98006-90-7 ]

[ 98006-90-7 ] Synthesis Path-Downstream 1~87

Related Functional Groups of [ 98006-90-7 ]

Bromides

Related Parent Nucleus of [ 98006-90-7 ]

Pyrazines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 98006-90-7 ]

Related Parent Nucleus of
[ 98006-90-7 ]