[ CAS No. 39919-65-8 ] {[proInfo.proName]}

Name: 39919-65-8|2,5-Dibromo-6-methylpyridine|97%
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Product Details of [ 39919-65-8 ]

CAS No. :	39919-65-8	MDL No. :	MFCD06254589
Formula :	C₆H₅Br₂N	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UCHKRHGVKYVGTC-UHFFFAOYSA-N
M.W :	250.92	Pubchem ID :	2762946
Synonyms :

Safety of [ 39919-65-8 ]

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

Application In Synthesis of [ 39919-65-8 ]

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

Upstream synthesis route of [ 39919-65-8 ]
Downstream synthetic route of [ 39919-65-8 ]

[ 39919-65-8 ] Synthesis Path-Upstream 1~11

1
[ 124-41-4 ]
[ 39919-65-8 ]
[ 126717-59-7 ]

Yield	Reaction Conditions	Operation in experiment
96%	at 65 - 75℃; for 6 h;	A solution of 2,5-dibromo-6-picoline (30.6 kg, 122 mol, 1.00 eq) intoluene (154.2 kg) was dried by vacuum distillation at 40 °C 775 mmHg to remove 105.7 kg of distillate to produce a solution containing 40 ppm water. This was mixed with 25 weight percent sodium methoxide in methanol (124.1 kg, 574 mol, 4.71 eq) and the mixture was heated at 65-75 °C for 6 hours until reaction completion, (HPLC analysis indicated 1.6 area percent starting material remained). The mixture was cooled to 5 °C and water (98 L) was charged to the mixture followed by t-butylmethylether (97 kg). The layers were separated and the organic phase washed twice with 5percent brine (139 kg) and once with 20percent brine (165 kg). The organic phase was clarified by filtration and 51 kg was removed by vacuum distillation at 40 °C to produce a 2-methoxy-5-bromo-6-picoline solution (58.4 kg) of 40.6 wt percent purity (96percent yield). Part of this was purified by distillation for the purposes of recording the ¹³C NMR spectrum: ¹³C NMR (400 MHz, CDC1₃) 8 162.4, 154.4, 142.0, 111.8, 109.5, 53.6, 24.6.

Reference： [1] Patent: WO2005/51954, 2005, A2, . Location in patent: Page/Page column 39; 40

2
[ 39919-65-8 ]
[ 68-12-2 ]
[ 137778-18-8 ]

Reference： [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 11, p. 4889 - 4905

3
[ 42753-71-9 ]
[ 39919-65-8 ]

Yield	Reaction Conditions	Operation in experiment
71%	Stage #1: With hydrogen bromide; bromine In water at 0℃; Stage #2: With sodium nitrite In water at 0 - 20℃; for 1.5 h; Stage #3: With sodium hydroxide In water	To a solution of 2-amino-5-bromo-6-methylpyridine (37.6 g, 200 mmol) in aqueous HBr (48percent, 200 mL), cooled at 0 ⁰C, was added bromine (64.0 g, 400 mmol), forming a yellow suspension. A solution OfNaNO₂ (34.5 g, 500 mmol) in water (40 mL) was then added drop- wise. After addition the mixture was brought to room temperature and stirred for 1.5 h, and was poured into ice (200 mL). The aqueous mixture was neutralized with NaOH, and extracted with CH₂Cl₂ (4 x 100 mL). The combined extracts were dried (Na₂SO₄), filtered and EPO <DP n="52"/>concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (EtOAc/hexanes, 1 :5 in v/v) followed by recrystallization from EtOAc/hexanes, affording a white solid (35.4 g, 71percent). ¹H NMR (CDCl₃) δ 2.64 (s, 3H), 7.19 (d, IH, J= 8.4 Hz), 7.63 (d, IH, J= 8.4 Hz).
14%	With hydrogen bromide; sodium nitrite In water at 20℃;	6-Amino-3-bromo-2-methylpyridine (25.0 g, 134 mmol) was dissolved in 150 ml of 48percent HBr solution. Sodium nitrite (11.04 g, 160 mmol) was dissolved in 25 ml water and added dropwise at room temperature and stirred over night. The reaction was diluted with 200 ml of water and extracted three times with 100 ml of ethyl acetate. The combined organic layers were washed three times with 100 ml of 1 N HCI solution, dried over MgSO4, filtered and evaporated. The resulting solid was stirred in 250 ml of diethyl ether and filtered. The ether filtrate was evaporated to give a solid (4.61 g, 14percent yield). 1H NMR (400 MHz, DMF-d7) δ 7.97 (d, J= 8.3 Hz, 1 H), 7.47 (app dd, J = 8.3, 0.5 Hz, 1 H), 2.57 (s, 3H); LC/MS, tr = 2.53 minutes (5 to 95percent acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50 0C), ES-MS m/z 250 (M+H).
14%	With hydrogen bromide; sodium nitrite In water at 20℃;	6-Amino-3-bromo-2-methylpyridine (25.0 g, 134 mmol) was dissolved in 150 ml of48percent HBr solution. Sodium nitrite (11.04 g, 160 mmol) was dissolved in 25 ml water and addeddropwise at room temperature and stirred over night. The reaction was diluted with 200 ml ofwater and extracted three times with 100 ml of ethyl acetate. The combined organic layers werewashed three times with 100 ml of 1N HCI solution, dried over MgSO₄, filtered and evaporated.The resulting solid was stirred in 250 ml of diethyl ether and filtered. The ether filtrate wasevaporated to give a solid (4.61 g, 14percent yield). ¹H NMR (400 MHz, DMF-d₇) 5 7.97 (d, J= 8.3 Hz,1H), 7.47 (app dd, J = 8.3, 0.5 Hz, 1H), 2.57 (s, 3H); LC/MS, t_r = 2.53 minutes (5 to 95percentacetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50 °C), ES-MS m/z250 (M+H).

Reference： [1] Patent: WO2007/22371, 2007, A2, . Location in patent: Page/Page column 50-51
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 11, p. 4889 - 4905
[3] Patent: WO2006/18735, 2006, A2, . Location in patent: Page/Page column 75; 76
[4] Patent: WO2006/18727, 2006, A2, . Location in patent: Page/Page column 91

4
[ 853569-71-8 ]
[ 39919-65-8 ]

Yield	Reaction Conditions	Operation in experiment
79%	Stage #1: With hydrogen bromide In water at 35℃; Stage #2: With bromine In water at 2℃; for 0.666667 h;	5-Bromo-2-amino-6-picoline hydrobromide (29.4 kg, 76.5 wgt percent purity,84 mol, 1.00 eq) was dissolved into 48percent hydrobromic acid (162.0 kg, 961 mol, 11.44 eq) at <35 °C. The solution was cooled to 2 °C and bromine (43.0 kg, 269 mol, 3.20 eq) was charged over 40 min. A 40 wt percent solution of sodium nitrite (28.9 kg, 419 mol, 4.99 eq) was charged over 50 min at -1 to 5 °C. The contents were held one hour and the pH was adjusted to 13.1 using 50percent aqueous sodium hydroxide (120.0 kg). The contents were warmed to 20 °C over one hour and toluene (78.0 kg) was charged. The mixture was stirred for 30 min and allowed to settle overnight. The organic phase was clarified by filtration and washed twice with saturated aqueous sodium chloride solution (51.1 kg). This produced 96.0 kg of 2,5-dibromo-6-picoline solution (17.3 wgt percent) or 79percent yield.

Reference： [1] Patent: WO2005/51954, 2005, A2, . Location in patent: Page/Page column 38; 39

5
[ 42753-71-9 ]
[ 853569-71-8 ]
[ 39919-65-8 ]

Yield	Reaction Conditions	Operation in experiment
68%	Stage #1: With hydrogen bromide In water at 35℃; Stage #2: With bromine In water at 0 - 5℃; for 0.75 h;	5-Bromo-2-amino-6-picoline (7.0 kg) and 5-bromo-2-amino-6-picolinehydrobromide (7.0 kg) (based on the starting material analyses, this was equal to 11 kg or 41 mol of starting material) are dissolved into 48percent hydrobromic acid (107.0 kg, 635 mol, 15.49 eq) at <35 °C. The solution was cooled to 2 °C and bromine (27.3 kg, 171 mol, 4.17 eq) was charged over 45 min at 0-5 °C. A solution of sodium nitrite (8.1 kg, 117 mol, 2.86 eq) in 20 L of water was charged over 1.5 hours at -1 to 5 °C. The contents were held one hour and the pH was adjusted to 12.5 using 50percent aqueous sodium hydroxide (70.0 kg). The contents were warmed to 20 °C over one hour and the solids were collected in a polypropylene bag on a centrifuge. The solids were washed with water (75 L) to produce 12.0 kg of moist 2,5-dibromo-6-picoline, determined to be 83 wgt percent product (68 percent yield). Part of this was dried for the purposes of recording the ¹³C NMR spectrum: ¹³C NMR (400 MHz, CDC1₃) 5 158.8, 141.9, 139.4, 126.7, 120.6, 24.7.

Reference： [1] Patent: WO2005/51954, 2005, A2, . Location in patent: Page/Page column 38; 39

6
[ 54923-31-8 ]
[ 39919-65-8 ]

Reference： [1] Patent: US2010/222345, 2010, A1, . Location in patent: Page/Page column 95

7
[ 1824-81-3 ]
[ 39919-65-8 ]

Reference： [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 11, p. 4889 - 4905

8
[ 39919-65-8 ]
[ 68-12-2 ]
[ 926293-55-2 ]

Yield	Reaction Conditions	Operation in experiment
76%	Stage #1: With n-butyllithium In hexanes; diethyl ether at -78℃; for 1 h; Stage #2: at -78 - 20℃; for 2 h;	Under N₂, to a solution of 2,5-dibromo-6-methylpyridine (35.5 g, 141.1 mmol) in anhydrous Et₂O (600 mL), cooled to -78 ⁰C, was added BuLi (2.5 M in hexanes, 64.8 mL, 162 mmol) slowly, forming a yellow suspension. After addition the mixture was stirred at that temperature for 1 h, and then anhydrous DMF (18.3 g, 250 mmol) was added. After the mixture was stirred at -78 ⁰C for 1 h, it was brought to room temperature and stirred for an additional 1 h. Aqueous HCl (0.5 N, 300 mL) was added and the organic layer was collected. The aqueous layer was extracted with EtOAc (3 x 150 mL). The combined extracts were dried (Na₂SO₄), filtered and the solvent was removed. The residue was purified by flash chromatography on silica gel (EtOAc/hexanes, 1 :3 in v/v) followed by recrystallization form CH₂Cl₂/hexanes, affording a pale yellow solid (21.5 g, 76percent). ¹H NMR (CDCl₃) δ 2.87 (s, 3H), 7.51 (d, IH, J= 8.1 Hz), 7.93 (d, IH, J= 8.1 Hz), 10.30 (s, IH).
51%	Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 1 h; Stage #2: at 20℃; for 1 h;	Add to the reaction flask3,6-dibromo-2-methylpyridine (1.0 g, 3.9 mmol)And anhydrous ether (10 mL) were cooled to -78°C,N-BuLi (1.6 M in hexanes, 2.4 mL, 3.9 mmol) was added dropwise,After stirring for 1 hour, anhydrous DMF (307 mg, 4.2 mmol) was added,The reaction was stirred at room temperature for 1 hour. Saturated ammonium chloride solution (10 mL) was added,Ethyl acetate (20 mL x 3). Combine organic phase,Saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, suction filtration,Concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether = 1: 10)The resulting residue was purified to give the title compound (0.4 g, white solid) in 51percent yield.
42.5%	Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1 h; Inert atmosphere Stage #2: at -78 - 25℃; for 1 h; Inert atmosphere	To a solution of 3,6-dibromo-2-methylpyridine (60 g, 239 mmol) in THF (600 mL) and was added -BuLi (100 mL, 251 mmol) at -78 °C. The mixture was then stirred for 1 h at -78 °C under N₂ atmosphere. DMF (20.4 mL, 263 mmol) was added dropwise to the mixture. The mixture was then stirred for 1 h at -78 °C under N₂ atmosphere. The reaction mixture was warmed to 25 °C and 1 M aq. HC1 solution (300 mL) was added. The reaction mixture was combined with five additional crade reaction mixtures (performed at scales of 30 g, 120 mmol and 4 x 50 g, 199 mmol of 3,6-dibromo-2-methylpyridine using the same reagent and solvent stoichiometry as above) and worked up together. The reaction mixture was extracted with EtOAc (800 mL x 4). The combined organic layers were washed with H₂0 (300 mL x 3), dried over Na₂S04, filtered, and concentrated to give 6-bromo-2-methylnicotinaldehyde (260 g, 492 mmol, 42.5percent combined yield) as a red oil. NMR (400 MHz, CHLOROFORM-d) δ 10.28 (s, 1H), 7.92 (d, .7=7.9 Hz, 1H), 7.64 (s, 1H), 2.88 - 2.83 (m, 3H). LCMS [M+H]⁺ = 200.1, 202.1.

Reference： [1] Patent: WO2007/22371, 2007, A2, . Location in patent: Page/Page column 51
[2] Patent: CN106608879, 2017, A, . Location in patent: Paragraph 0310-0313
[3] Patent: WO2017/145050, 2017, A1, . Location in patent: Page/Page column 25-26

9
[ 557-21-1 ]
[ 39919-65-8 ]
[ 1173897-86-3 ]

Reference： [1] Patent: EP2080761, 2009, A1, . Location in patent: Page/Page column 36

10
[ 39919-65-8 ]
[ 1173897-86-3 ]

Yield	Reaction Conditions	Operation in experiment
49%	at 110℃; for 4 h; sealed vessel	3,6-Dibromo-2-methylpyridine(4.9 g, 19.53 mmol), copper(I)cyanide (1.75 g, 19.53 mmol) and N,N-dimethylformamide (20 mL) were combined in a sealable vessel with a stirbar. The resulting mixture was sealed, stirred vigorously and heated at 110 ⁰C for 4 h. The resulting mixture was diluted with ethyl acetate, poured into a separatory funnel containing water and the layers were separated. The water layer was extracted with ethyl acetate twice. The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was purified by silica gel chromatography (10 percent ethyl acetate in hexanes) to give the title compound as a white solid (1.88 g, 9.54 mmol, 49 percent yield). MS (ESI) m/z 197.3 [M]⁺.

Reference： [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 13, p. 5323 - 5333
[2] Patent: WO2010/62571, 2010, A1, . Location in patent: Page/Page column 108
[3] Patent: WO2016/54807, 2016, A1, . Location in patent: Page/Page column 75

11
[ 39919-65-8 ]
[ 1173897-86-3 ]

Reference： [1] Patent: WO2013/149996, 2013, A1,
[2] Patent: WO2013/149997, 2013, A1,
[3] Patent: US2014/315908, 2014, A1,
[4] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2016, vol. 55B, # 9, p. 1117 - 1130

[ 39919-65-8 ] Synthesis Path-Downstream 1~88

1
[ 39919-65-8 ]
[ 87286-77-9 ]

Yield	Reaction Conditions	Operation in experiment
35%	With sodium hydroxide; N-benzyl-N,N,N-triethylammonium chloride; sodium formate;palladium; In ethanol;	EXAMPLE 4 5-Bromo-6,6'-dimethyl-2,2'-bipyridine (4) According to: G. R. Newkome et al., J. Inorg. Nucl. Chem. 43, 1529 (1981) <strong>[39919-65-8]2,5-Dibromo-6-methylpyridine</strong> (1.25 g, 5.0 mmoles), sodium formate (0.51 g, 7.5 mmoles), 10percent palladium on carbon (30 mg), benzyltriethylammonium chloride (0.20 g, 0.88 mmoles) and 8percent sodium hydroxide solution (2.0 ml) were refluxed for two days. The mixture was filtered and the aqueous phase was extracted with methylene chloride. The organic phase was dried, the solvent was evaporated and the product was purified by means of flash chromatography (silica, methylene chloride). The main product was a monobromo substituted compound. Yield: 35percent UV (in ethanol): 296 nm, 251 nm, 245 nm 1 H-NMR (400 MHz, CDCl3): 2.61 (s, 3H); 2.73 (s, 3H); 7.16 (d, 1H, J=7.6 Hz); 7.67 (t, 1H, 7.6 Hz); 7.88 (d, 1H, J=8.5 Hz); 8.12 (d, 1H, J=8.5 Hz); 8.19 (d, 1H, J=7.6 Hz)

Reference： [1]Patent: US5216134,1993,A
[2]Helvetica Chimica Acta,1992,vol. 75,p. 1578 - 1592

2
[ 39919-65-8 ]
5,5'-dibromo-6,6'-dimethyl-2,2'-dipyridyl ditelluride [ No CAS ]

Reference： [1]Synthetic Communications,2003,vol. 33,p. 977 - 988

3
[ 39919-65-8 ]
5,5'-dibromo-6,6'-dimethyl-2,2'-dipyridyl diselenide [ No CAS ]

Reference： [1]Synthetic Communications,2003,vol. 33,p. 977 - 988

4
[ 39919-65-8 ]
[ 144342-57-4 ]

Reference： [1]Helvetica Chimica Acta,1992,vol. 75,p. 1578 - 1592

5
[ 42753-71-9 ]
[ 853569-71-8 ]
[ 39919-65-8 ]

Yield	Reaction Conditions	Operation in experiment
68%		5-Bromo-2-amino-6-picoline (7.0 kg) and 5-bromo-2-amino-6-picolinehydrobromide (7.0 kg) (based on the starting material analyses, this was equal to 11 kg or 41 mol of starting material) are dissolved into 48percent hydrobromic acid (107.0 kg, 635 mol, 15.49 eq) at <35 °C. The solution was cooled to 2 °C and bromine (27.3 kg, 171 mol, 4.17 eq) was charged over 45 min at 0-5 °C. A solution of sodium nitrite (8.1 kg, 117 mol, 2.86 eq) in 20 L of water was charged over 1.5 hours at -1 to 5 °C. The contents were held one hour and the pH was adjusted to 12.5 using 50percent aqueous sodium hydroxide (70.0 kg). The contents were warmed to 20 °C over one hour and the solids were collected in a polypropylene bag on a centrifuge. The solids were washed with water (75 L) to produce 12.0 kg of moist 2,5-dibromo-6-picoline, determined to be 83 wgt percent product (68 percent yield). Part of this was dried for the purposes of recording the 13C NMR spectrum: 13C NMR (400 MHz, CDC13) 5 158.8, 141.9, 139.4, 126.7, 120.6, 24.7.

Reference： [1]Patent: WO2005/51954,2005,A2 .Location in patent: Page/Page column 38; 39

6
[ 853569-71-8 ]
[ 39919-65-8 ]

Yield	Reaction Conditions	Operation in experiment
79%		5-Bromo-2-amino-6-picoline hydrobromide (29.4 kg, 76.5 wgt percent purity,84 mol, 1.00 eq) was dissolved into 48percent hydrobromic acid (162.0 kg, 961 mol, 11.44 eq) at <35 °C. The solution was cooled to 2 °C and bromine (43.0 kg, 269 mol, 3.20 eq) was charged over 40 min. A 40 wt percent solution of sodium nitrite (28.9 kg, 419 mol, 4.99 eq) was charged over 50 min at -1 to 5 °C. The contents were held one hour and the pH was adjusted to 13.1 using 50percent aqueous sodium hydroxide (120.0 kg). The contents were warmed to 20 °C over one hour and toluene (78.0 kg) was charged. The mixture was stirred for 30 min and allowed to settle overnight. The organic phase was clarified by filtration and washed twice with saturated aqueous sodium chloride solution (51.1 kg). This produced 96.0 kg of 2,5-dibromo-6-picoline solution (17.3 wgt percent) or 79percent yield.

Reference： [1]Patent: WO2005/51954,2005,A2 .Location in patent: Page/Page column 38; 39

7
[ 42753-71-9 ]
[ 39919-65-8 ]

Yield	Reaction Conditions	Operation in experiment
71%		To a solution of 2-amino-5-bromo-6-methylpyridine (37.6 g, 200 mmol) in aqueous HBr (48percent, 200 mL), cooled at 0 0C, was added bromine (64.0 g, 400 mmol), forming a yellow suspension. A solution OfNaNO2 (34.5 g, 500 mmol) in water (40 mL) was then added drop- wise. After addition the mixture was brought to room temperature and stirred for 1.5 h, and was poured into ice (200 mL). The aqueous mixture was neutralized with NaOH, and extracted with CH2Cl2 (4 x 100 mL). The combined extracts were dried (Na2SO4), filtered and EPO <DP n="52"/>concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (EtOAc/hexanes, 1 :5 in v/v) followed by recrystallization from EtOAc/hexanes, affording a white solid (35.4 g, 71percent). 1H NMR (CDCl3) delta 2.64 (s, 3H), 7.19 (d, IH, J= 8.4 Hz), 7.63 (d, IH, J= 8.4 Hz).
14%	With hydrogen bromide; sodium nitrite; In water; at 20℃;	6-Amino-3-bromo-2-methylpyridine (25.0 g, 134 mmol) was dissolved in 150 ml of 48percent HBr solution. Sodium nitrite (11.04 g, 160 mmol) was dissolved in 25 ml water and added dropwise at room temperature and stirred over night. The reaction was diluted with 200 ml of water and extracted three times with 100 ml of ethyl acetate. The combined organic layers were washed three times with 100 ml of 1 N HCI solution, dried over MgSO4, filtered and evaporated. The resulting solid was stirred in 250 ml of diethyl ether and filtered. The ether filtrate was evaporated to give a solid (4.61 g, 14percent yield). 1H NMR (400 MHz, DMF-d7) delta 7.97 (d, J= 8.3 Hz, 1 H), 7.47 (app dd, J = 8.3, 0.5 Hz, 1 H), 2.57 (s, 3H); LC/MS, tr = 2.53 minutes (5 to 95percent acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50 0C), ES-MS m/z 250 (M+H).
14%	With hydrogen bromide; sodium nitrite; In water; at 20℃;	6-Amino-3-bromo-2-methylpyridine (25.0 g, 134 mmol) was dissolved in 150 ml of48percent HBr solution. Sodium nitrite (11.04 g, 160 mmol) was dissolved in 25 ml water and addeddropwise at room temperature and stirred over night. The reaction was diluted with 200 ml ofwater and extracted three times with 100 ml of ethyl acetate. The combined organic layers werewashed three times with 100 ml of 1N HCI solution, dried over MgSO4, filtered and evaporated.The resulting solid was stirred in 250 ml of diethyl ether and filtered. The ether filtrate wasevaporated to give a solid (4.61 g, 14percent yield). 1H NMR (400 MHz, DMF-d7) 5 7.97 (d, J= 8.3 Hz,1H), 7.47 (app dd, J = 8.3, 0.5 Hz, 1H), 2.57 (s, 3H); LC/MS, tr = 2.53 minutes (5 to 95percentacetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50 °C), ES-MS m/z250 (M+H).

Reference： [1]Patent: WO2007/22371,2007,A2 .Location in patent: Page/Page column 50-51
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 4889 - 4905
[3]Patent: WO2006/18735,2006,A2 .Location in patent: Page/Page column 75; 76
[4]Patent: WO2006/18727,2006,A2 .Location in patent: Page/Page column 91

8
[ 39919-65-8 ]
3-bromo-6-hydrazinyl-2-methylpyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With hydrazine; In propan-1-ol; at 65℃;Heating / reflux;	<strong>[39919-65-8]3,6-dibromo-2-methylpyridine</strong> (4.5 g, 17.93 mmol) was dissolved in 13.5 ml of 1- propanol and heated to 65 0C. Hydrazine monohydrate (5.22 ml, 108 mmol) was added and the reaction was heated to reflux over night. The reaction was evaporated and re-dissolved in 300 ml of diethyl ether. The ether solution was decanted away from the oily layer of excess hydrazine, dried over Na2SO4, filtered and evaporated to give a solid (2.5 g, 69percent yield). 1H NMR (400 MHz, DMF-d7) delta 7.56 (d, J= 8.9 Hz, 1H), 7.46 (br s, 1H), 6.62 (d, J= 8.9 Hz, 1H), 4.25 (br s, 2H), 2.38 (s, 3H); LC/MS, tr = 0.63 minutes (5 to 95percent acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 500C), ES-MS m/z 202 (M+H).
69%	With hydrazine; In propan-1-ol; at 65℃;Heating / reflux;	<strong>[39919-65-8]3,6-dibromo-2-methylpyridine</strong> (4.5 g, 17.93 mmol) was dissolved in 13.5 ml of 1-propanol and heated to 65 °C. Hydrazine monohydrate (5.22 ml, 108 mmol) was added and thereaction was heated to reflux over night. The reaction was evaporated and re-dissolved in 300ml of diethyl ether. The ether solution was decanted away from the oily layer of excesshydrazine, dried over Na2SO4, filtered and evaporated to give a solid (2.5 g, 69percent yield). 1H NMR(400 MHz, DMF-d7) 8 7.56 (d, J= 8.9 Hz, 1H), 7.46 (br s, 1H), 6.62 (d, J= 8.9 Hz, 1H), 4.25 (br s,2H), 2.38 (s, 3H); LC/MS, tr = 0.63 minutes (5 to 95percent acetonitrile/water over 5 minutes at 1ml/min, at 254 nm, at 50°C), ES-MS m/z202 (M+H).

Reference： [1]Patent: WO2006/18735,2006,A2 .Location in patent: Page/Page column 76
[2]Patent: WO2006/18727,2006,A2 .Location in patent: Page/Page column 92

9
[ 39919-65-8 ]
[ 1094166-05-8 ]

Reference： [1]Journal of Organic Chemistry,2009,vol. 74,p. 939 - 942

10
[ 39919-65-8 ]
[ 1173897-86-3 ]

Reference： [1]Patent: WO2013/149996,2013,A1
[2]Patent: WO2013/149997,2013,A1
[3]Patent: US2014/315908,2014,A1
[4]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2016,vol. 55B,p. 1117 - 1130

11
[ 557-21-1 ]
[ 39919-65-8 ]
[ 1173897-86-3 ]

Yield	Reaction Conditions	Operation in experiment
	tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 100 - 140℃; for 30h;	A mixture of <strong>[39919-65-8]3,6-dibromo-2-methylpyridine</strong> (200 mg), zinc cyanide (140 mg) and tetrakis(triphenylphosphine)palladium (0) (92.4 mg) in DMF (4 ml) was heated at 100 °C for 10h. Then, an excess of tetrakis(triphenylphosphine)palladium (0) (93 mg) was added. The mixture was heated at 140 °C for 20h. After cooling, the reaction was filtered through a pad of celite, diluted with EtOAc and washed with H2O (x 3). The combined aqueous layers were then washed with EtOAc (x 3). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under vacuum to give 314 mg of a brown sticky solid. This was purified on Biotage using hexane/EtOAc 8:2 as eluent to give 89 mg of the title compound as a white solid. [ES MS] m/z 197 (MH+).

Reference： [1]Patent: EP2080761,2009,A1 .Location in patent: Page/Page column 36

12
[ 39919-65-8 ]
potassium 6-bromo-2-methylpyridin-3-yltrifluoroborate [ No CAS ]

Reference： [1]Organic Letters,2009,vol. 11,p. 4330 - 4333

13
[ 39919-65-8 ]
[ 1215183-86-0 ]

Yield	Reaction Conditions	Operation in experiment
75%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 70℃; for 16h;	To a solution of <strong>[39919-65-8]3,6-dibromo-2-methylpyridine</strong> (498 mg, 1.98 mmol) in carbon tetrachloride (10 mL) was added NBS (712 mg, 4.00 mmol), AIBN (66 mg, 0.40 mmol) successively at room temperature. The resulting mixture was then stirred at 70° C. for 16 h. The insoluable solids in the reaction mixture were removed by filtration and rinsed with dichloromethane (20 mL*3). The combined filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with ethyl acetate in petroleum ether (5percent to 15percent gradient) to yield 3,6-dibromo-2-(dibromomethyl)pyridine as light yellow oil (610 mg, 75percent). MS: m/z=409.6 [M+H]+.
	With N-Bromosuccinimide;2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 70℃;	22.1. 3,6-Dibromo-2-(dibromomethyl)pyridine (84) To a solution of <strong>[39919-65-8]3,6-dibromo-2-methylpyridine</strong> (5.34 g, 21 mmol) in CCl4 (50 mL) was added N-bromosuccinimide (7.57 g, 42 mmol) and 2,2'-azobis(2-methylpropionitrile) (0.70 g, 4.3 mmol). The mixture was heated at 70° C. overnight and cooled to room temperature. The solid was removed by filtration and the filtrate was concentrated under reduced pressure. The product was obtained after flash chromatography eluding with 0-10percent EtOAc in hexane (8.17 g).
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃;	To a solution of <strong>[39919-65-8]3,6-dibromo-2-methylpyridine</strong> (5.2 g, 21 mmol) in CC14 (50 mL) was added N-bromosuccinimide (7.57 g, 42 mmol) and 2,2'-azobis(2-methylpropionitrile) (0.70 g, 4.3 mmol). The mixture was heated at 80 °C overnight and cooled to room temperature. The solid was removed by filtration and the filtrate was concentrated under reduced pressure. The product (42A) was obtained after flash chromatography eluding with 0-10 percent EtOAc in hexane (7.36 g). MS (m/z): 409.66 [M+H]+

With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃;

[0236] Synthesis of 3,6-dibromo-2-(dibromomethyl)pyridine (1A): To a solution of 3,6- dibromo-2-methylpyridine (5.2 g, 21 mmol) in CCl4(50 mL) was added N- bromosuccinimide (7.57 g, 42 mmol) and 2,2'-azobis(2-methylpropionitrile) (0.70 g, 4.3 mmol). The mixture was heated at 80 °C overnight and cooled to room temperature. The solid was removed by filtration and the filtrate was concentrated under reduced pressure. The product (1 A) was obtained after flash chromatography. MS (m z): 409.66 [M+H]+

Reference： [1]Patent: US2016/75711,2016,A1 .Location in patent: Paragraph 0682-0683
[2]Patent: US2010/81680,2010,A1 .Location in patent: Page/Page column 66
[3]Patent: WO2014/110297,2014,A1 .Location in patent: Paragraph 0278
[4]Patent: WO2016/33243,2016,A1 .Location in patent: Paragraph 0236

14
copper(l) cyanide [ No CAS ]
[ 39919-65-8 ]
[ 1173897-86-3 ]

Yield	Reaction Conditions	Operation in experiment
49%	In N,N-dimethyl-formamide; at 110℃; for 4h;sealed vessel;Product distribution / selectivity;	<strong>[39919-65-8]3,6-Dibromo-2-methylpyridine</strong>(4.9 g, 19.53 mmol), copper(I)cyanide (1.75 g, 19.53 mmol) and N,N-dimethylformamide (20 mL) were combined in a sealable vessel with a stirbar. The resulting mixture was sealed, stirred vigorously and heated at 110 0C for 4 h. The resulting mixture was diluted with ethyl acetate, poured into a separatory funnel containing water and the layers were separated. The water layer was extracted with ethyl acetate twice. The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was purified by silica gel chromatography (10 percent ethyl acetate in hexanes) to give the title compound as a white solid (1.88 g, 9.54 mmol, 49 percent yield). MS (ESI) m/z 197.3 [M]+.
	In N,N-dimethyl-formamide; at 120℃; for 4h;	To a solution of 3, 6-dibromo-2-methylpyridine (200 mg, 0.8 mmol) in DMF (3 mL) was added CuCN (72 mg, 0.80 mmol) . The resulting mixture was heated at 120 for 4 h, then cooled and concentrated. The residue was partitioned between DCM (5 mL) and water (10 mL) , and the organic layer was concentrated. The residue was purified by column chromatography on silica gel (PE: EtOAc 10:1) to afford the title compound. MS: m/z 197.2/199.2 (M + 1) .1H NMR (400 MHz, CDCl3) delta 7.96 (d, J 8.0 Hz, 1H) , 7.41 (d, J 8.0 Hz, 1H) , 2.72 (s, 3H) .

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 5323 - 5333
[2]Patent: WO2010/62571,2010,A1 .Location in patent: Page/Page column 108
[3]Patent: WO2016/54807,2016,A1 .Location in patent: Page/Page column 75

15
[ 39919-65-8 ]
[ 1008361-77-0 ]

Yield	Reaction Conditions	Operation in experiment
73%	With trimethylsilyl iodide; sodium iodide; at 95℃; for 16h;Inert atmosphere;	Sodium iodide (2 eq., 13 mmol, 1 .96 g) and <strong>[39919-65-8]2,5-dibromo-6-methylpyridine</strong> (1 .64 g, 6.5 mmol) were combined in propionitrile (16 ml_) and the resulting slurry was stirred under nitrogen for 5 min. lodotrimethylsilane (0.2 eq., 1 .3 mmol, 0.185 ml_) was added and the reaction mixture was heated at 955C with stirring under nitrogen for 16 h. The slurry was cooled to room temperature, diluted with a 1 :1 mixture of ethyl acetate and water. The mixture was stirred for 15 min and the aqueous and organic phases were then separated. The organic layer was washed sequentially with equal volume of saturated aqueous sodium bicarbonate solution, sodium thiosulfate (5percent aqueous solution) and brine. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduce pressure to afford the desired product which was purified by flash chromatography on silica gel using an elution of 4percent ethyl acetate in hexanes to afford the title compound as an oil (1 .42 g, Yield: 73percent). 1 H NMR (400 MHz, CDCI3) delta 7.41 (2H, s), 2.63 (3H, s). LC-MS: tR = 3.53 [M+H]+= 298/300 (method 3)
72%	With trimethylsilyl iodide; sodium iodide; at 95℃; for 16h;Inert atmosphere;	Sodium iodide (2 eq., 16 mmol, 2.40 g) and <strong>[39919-65-8]2,5-dibromo-6-methylpyridine</strong> (2.0 g, 8.0 mmol) were combined in propionitrile ( 20 ml_) and the resulting slurry was stirred under nitrogen for 5 min. lodotrimethylsilane (0.2 eq., 1 .6 mmol, 0.23 ml_) was added and the reaction mixture was heated at 955C with stirring under nitrogen for 16 h. The slurry was cooled to room temperature, diluted with a 1 :1 mixture of ethylacetate and water. The mixture was stirred for 15 min and the aqueous and organic phases were then separated. The organic layer was washed sequentially with equal volume of saturated aqueous sodium bicarbonate solution, sodium thiosulfate (5percent aqueous solution) and brine. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduce pressure to afford the desired product which was purified by flash chromatography on silica gel using an elution of 4percent ethylacetate in hexanes afforded the title compound as an oil (1 .72 g, 72percent). 1 H NMR (400 MHz, CDCI3) delta 7.41 (2H, s), 2.63 (3H, s). LC-MS: tR = 3.53 [M+H]+= 298/300 (method 3)
72%	With trimethylsilyl iodide; sodium iodide; at 95℃; for 16h;Inert atmosphere;	Sodium iodide (2 eq., 16 mmol, 2.40 g) and <strong>[39919-65-8]2,5-dibromo-6-methylpyridine</strong> (2.0 g, 8.0 mmol) were combined in propionitrile (20 mL) and the resulting slurry was stirred under nitrogen for 5 min. Iodotrimethylsilane (0.2 eq., 1.6 mmol, 0.23 mL) was added and the reaction mixture was heated at 95°C with stirring under nitrogen for 16 h. The slurry was cooled to RT, diluted with a 1:1 mixture of ethyl acetate and water. The mixture was stirred for 15 min and the aqueous and organic phases were then separated. The organic layer was washed sequentially with saturated aqueous sodium bicarbonate solution, sodium thiosulfate (5percent aqueous solution) and brine. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford the desired product which was purified by flash chromatography over silica gel using an elution of 4percent ethyl acetate in hexane to give 1.72 g (Yield: 72percent) of the title compound 12 as an oil. 1H NMR (400 MHz, CDCl3): delta 7.41 (2H, s), 2.63 (3H, s); ESI-MS: m/z 298 [M + H]+

	With acetyl chloride; sodium iodide; In acetonitrile;Reflux;	To a solution of <strong>[39919-65-8]3,6-dibromo-2-methylpyridine</strong> (2.0 g, 8.0 mmol) in acetonitrile (40 mL) was added sodium iodide (4.8 g, 31.9 mmol), followed by acetyl chloride (0.85 mL, 12.0 mmol). The reaction was heated at reflux overnight, then was cooled to room temperature and quenched with water and basified with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (2.x.) and the combined extracts were washed with brine and dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified via chromatography (5percent ethyl acetate/hexane), providing the product, 3-bromo-6-iodo-2-methylpyridine.
	With trimethylsilyl iodide; sodium iodide; at 95℃; for 24h;Inert atmosphere;	A. 3-Bromo-6-iodo-2-methylpyridine Sodium iodide (2 equiv) and <strong>[39919-65-8]3,6-dibromo-2-methylpyridine</strong> (1 equiv) were combined in propionitrile and the resulting slurry was treated with iodotrimethylsilane (0.2 equiv) and heated to 95° C., with stirring, under nitrogen for 24 h. The slurry was cooled to room temperature, diluted with a 1:1 mixture of ethyl acetate and water and the aqueous and organic phases were separated. The organic layer was washed with saturated aqueous sodium bicarbonate solution, sodium thiosulfate (5percent aqueous solution), and saturated aqueous sodium chloride solution. The organic phase was dried, filtered, and concentrated under reduced pressure to afford the desired product, as an oil, which crystallized to a solid. MS (ESI) m/z 297.8 [M]+, 299.8 [M+2]+.

Reference： [1]Patent: WO2013/149996,2013,A1 .Location in patent: Page/Page column 68
[2]Patent: WO2013/149997,2013,A1 .Location in patent: Page/Page column 55
[3]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2016,vol. 55B,p. 1117 - 1130
[4]Patent: US2010/222345,2010,A1 .Location in patent: Page/Page column 95
[5]Patent: US2014/315908,2014,A1 .Location in patent: Paragraph 0302-0304

16
[ 39919-65-8 ]
6-methyl-5-vinylpyridine-2-carbonitrile [ No CAS ]

Reference： [1]Patent: WO2013/149996,2013,A1
[2]Patent: WO2013/149997,2013,A1
[3]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2016,vol. 55B,p. 1117 - 1130

17
[ 39919-65-8 ]
5-formyl-6-methylpyridine-2-carbonitrile [ No CAS ]

Reference： [1]Patent: WO2013/149996,2013,A1
[2]Patent: WO2013/149997,2013,A1
[3]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2016,vol. 55B,p. 1117 - 1130

18
[ 39919-65-8 ]
2,4,6-trivinylcyclotriboroxane*pyridine complex [ No CAS ]
[ 1122090-67-8 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 110 - 130

19
[ 1824-81-3 ]
[ 39919-65-8 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 4889 - 4905

20
[ 39919-65-8 ]
[ 1610628-29-9 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 4889 - 4905
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 4889 - 4905

21
[ 39919-65-8 ]
[ 1289130-65-9 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 4889 - 4905

22
[ 39919-65-8 ]
[ 1610628-28-8 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 4889 - 4905

23
[ 39919-65-8 ]
[ 68-12-2 ]
[ 137778-18-8 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 4889 - 4905

24
[ 1616113-93-9 ]
[ 39919-65-8 ]
(2R,3R,4R,5R,6R)-2-(4-(5-bromo-6-methylpyridin-2-yl)-2-methylphenyl)-6-((pivaloyloxy)methyl)tetrahydro-2H-pyran-3,4,5-triyl tris(2,2-dimethylpropanoate) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
159 mg	With caesium carbonate; In acetonitrile; at 130℃; for 0.5h;Inert atmosphere; Microwave irradiation;	Step I: (2R,3R,4R,5R,6R)-2-(4-(5-bromo-6-methylpyridin-2-yl)-2-methylphenyl)-6- ((pivaloyloxy)methyl)tetrahydro-2H-pyran-3,4,5-triyl tris(2,2-dimethylpropanoate) A 5 ml microwave vial is charged with Intermediate R (150 mg, 0.209 mmol) , 3,6- dibromo-2-methyl-pyridine (43.8 mg, 0.174 mmol), Siliacat DPP-Pd (70 mg, 0.017 mmol) and CS2CO3 (171 mg, 0.523 mmol) in CH3CN (2.0 mL). The vial is capped under nitrogen and irradiated at 130°C for 30 min in the microwave. The reaction mixture is diluted with EtOAc passed on a 500 mg silica cartridge and eluted with EtOAc. The resulting mixture was concentrated under reduced pressure the residue (159 mg) is used as such in the next step.

Reference： [1]Patent: WO2014/100158,2014,A1 .Location in patent: Page/Page column 184

25
[ 39919-65-8 ]
[ 1215183-85-9 ]

Reference： [1]Patent: WO2014/110297,2014,A1
[2]Patent: WO2014/134566,2014,A2
[3]Patent: US2016/75711,2016,A1
[4]Patent: WO2016/33243,2016,A1
[5]Patent: WO2019/161280,2019,A1

26
2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N-((S)-2-(3,5-difluorophenyl)-1-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)-3-(4-methoxy-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)pyridin-2-yl)ethyl)acetamide [ No CAS ]
[ 39919-65-8 ]
[ 1215183-86-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃;	[0410] To a solution of <strong>[39919-65-8]3,6-dibromo-2-methylpyridine</strong> (5.2 g, 21 mmol) in CC14 (50 mL) was added N-bromosuccinimide (7.57 g, 42 mmol) and 2,2?-azobis(2-methylpropionitrile) (0.70 g, 4.3 mmol). The mixture was heated at 80 °C overnight and cooled to room temperature. The solid was removed by filtration and the filtrate was concentrated under reduced pressure. The product (5A) was obtained after flash chromatography eluding with 0-10 percent EtOAc in hexane (7.36 g). MS (mlz): 409.66 [M+H]

Reference： [1]Patent: WO2014/134566,2014,A2 .Location in patent: Paragraph 0410

27
[ 39919-65-8 ]
[ 1228014-21-8 ]

Reference： [1]Patent: US2014/315908,2014,A1
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 5323 - 5333

28
[ 39919-65-8 ]
5-bromo-6-methylpicolinimidohydrazide [ No CAS ]

Reference： [1]Patent: US2014/315908,2014,A1

29
[ 39919-65-8 ]
[ 1228014-23-0 ]

Reference： [1]Patent: US2014/315908,2014,A1

30
[ 39919-65-8 ]
1-ethyl-7-(2-methyl-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one [ No CAS ]

Reference： [1]Patent: US2014/315908,2014,A1

31
[ 39919-65-8 ]
[ 1228013-15-7 ]

Reference： [1]Patent: US2014/315908,2014,A1

32
[ 39919-65-8 ]
7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 5323 - 5333

33
[ 39919-65-8 ]
[ 1228014-22-9 ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 5323 - 5333

34
[ 39919-65-8 ]
[ 1228014-23-0 ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 5323 - 5333

35
[ 39919-65-8 ]
C₂₆H₃₂N₈O₃ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 5323 - 5333

36
[ 39919-65-8 ]
C₂₆H₃₂N₈O₃ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 5323 - 5333

37
[ 39919-65-8 ]
6-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 5323 - 5333

38
[ 39919-65-8 ]
[ 98-80-6 ]
[ 53546-08-0 ]

Yield	Reaction Conditions	Operation in experiment
92.7%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In water; toluene; for 16h;Inert atmosphere; Reflux;	Phenylboronic acid (24.3 g, 199.25 mmol), <strong>[39919-65-8]2,5-dibromo-6-methylpyridine</strong> (10 g, 39.85 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (654 mg, 1.5 mmol), and potassium phosphate tribasic (27.5 g, 119.5 mmol), 300 mL of toluene and 30 mL of water were placed in a 1 L round-bottom flask. Nitrogen was bubbled directly into the mixture for 30 min after which tris(dibenzylideneacetone)dipalladium(0) (364 mg, 0.398 mmol) was added. Nitrogen was bubbled for another 15 min then the reaction mixture was heated to reflux for 16 h under nitrogen. After the reaction was completed, the mixture was cooled and the organic layer was separated. The organic layer was washed with a saturated brine solution and dried over magnesium sulfate. The solution was filtered and the solvent removed under vacuum. The crude was purified by column chromatography using silica gel as the stationary phase and 10percent-20percent ethyl acetate in hexanes as the mobile phase. 9.0 g of desired product was obtained after purification (92.7percent yield)

Reference： [1]Patent: US2015/307535,2015,A1 .Location in patent: Paragraph 0224; 0225

39
[ 39919-65-8 ]
C₇₂H₅₆Cl₂Ir₂N₄ [ No CAS ]

Reference： [1]Patent: US2015/307535,2015,A1

40
[ 39919-65-8 ]
3,6-dibromo-2-(1,3-dioxolan-2-yl)pyridine [ No CAS ]

Reference： [1]Patent: US2016/75711,2016,A1

41
[ 39919-65-8 ]
3-bromo-6-cyclopropyl-2-(1,3-dioxolan-2-yl)pyridine [ No CAS ]

Reference： [1]Patent: US2016/75711,2016,A1

42
[ 39919-65-8 ]
3-bromo-6-cyclopropylpyridine-2-carbaldehyde [ No CAS ]

Reference： [1]Patent: US2016/75711,2016,A1

43
[ 39919-65-8 ]
tert-butyl ((5-bromo-6-methylpyridin-2-yl)methyl)carbamate [ No CAS ]

Reference： [1]Patent: WO2016/54807,2016,A1

44
[ 39919-65-8 ]
tert-butyl ((6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-methyl)carbamate [ No CAS ]

Reference： [1]Patent: WO2016/54807,2016,A1

45
[ 39919-65-8 ]
tert-butyl ((6-methyl-5-(4-(S-methylsulfonimidoyl)phenyl)pyridin-2-yl)methyl)carbamate [ No CAS ]

Reference： [1]Patent: WO2016/54807,2016,A1

46
[ 39919-65-8 ]
(6-methyl-5-(4-(S-methylsulfonimidoyl)phenyl)pyridin-2-yl)methanamine trifluoroacetate [ No CAS ]

Reference： [1]Patent: WO2016/54807,2016,A1

47
[ 848192-96-1 ]
[ 39919-65-8 ]
1-(5-bromo-6-methyl-2-pyridyl)-3-(trifluoromethyl)azetidin-3-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
13.0%	With N-ethyl-N,N-diisopropylamine; at 130℃; for 4h;	2,5 -dibromo-6-methylpyridine (1 .30 g, 5.18 mmo 1) and 3 -(trifluoromethyl)azetidin-3 -ol hydrochloride (1.00 g, 5.63 mmol) were added to a small RB flask with stirrer bar. N,Ndiisopropylethylamine (0.90 mL, 5.2 mmol) was added and the mixture heated to 130Cfor 4 hours. The mixture was cooled, diluted with dichloromethane (5OmL) and washed with sodium bicarbonate solution (5OmL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. Chromatography (silica, DCM gradient to 15% EtOAc in DCM) gave the title compound as a white solid (210 mg, 13.0% yield). 1H NMR (400 MHz, DMSO-d6) oe 7.70 (d, J= 8.7 Hz, 1H), 7.32 (s, 1H), 6.32 (dd, J= 8.7,0.7 Hz, 1H), 4.19 (dd, J 9.6, 1.0 Hz, 2H), 3.93 (dt, J= 9.4, 1.3 Hz, 2H), 2.42 (s, 3H). LC/MS Method 3: RT 2.02 minutes, mlz 313/315.

Reference： [1]Patent: WO2016/50975,2016,A1 .Location in patent: Page/Page column 181

48
[ 39919-65-8 ]
[ 411235-57-9 ]
3-bromo-6-cyclopropyl-2-methylpyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; at 120℃; for 0.5h;Inert atmosphere; Microwave irradiation;	3-Bromo-6-cyclopropyl-2-methylpyridine (B4.1) (0359) A mixture of <strong>[39919-65-8]3,6-dibromo-2-methylpyridine</strong> (250 mg, 1 mmol), cyclopropylboronic acid (86 mg, 1 mmol), Cs2CO3 (975 mg, 3 mmol), Pd(PPh3)4(160 mg, 0.2 mmol) and dioxane (5 mL) was stirred at 120° C. under N2 with microwave for 30 min. The mixture was filtered with MeOH (15 mL), the filtrate was purified by Prep-TLC (silica gel, UV254, PE) to afford the title compound (100 mg, 47percent) as a clear oil. 1H NMR (400 MHz, CDCl3) delta ppm 0.95-0.98 (m, 4H), 1.36-1.99 (m, 1H), 2.56 (s, 3H), 6.76 (d, 1H), 7.59 (d, 1H).
47%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; at 120℃; for 0.5h;Inert atmosphere; Microwave irradiation;	A mixture of 3 ,6-d i bromo-2-methylpyridine (250 mg, 1 mmol), cyclopropylboronic acid (86 mg, 1 mmol), C52CO3 (975mg, 3 mmol), Pd(PPh3)4 (160 mg, 0.2 mmol) and dioxane (5 mL) was stirred at 120 °Cunder N2 with microwave for 30 mm. The mixture was filtered with MeOH (15 mL), thefiltrate was purified by Prep-TLC (silica gel, UV254, PE) to afford the title compound (100mg, 47percent) as a clear oil. 1H NMR(400 MHz, CDCI3) O ppm 0.95 - 0.98 (m, 4H), 1.36 -1.99 (m, 1H), 2.56 (5, 3H), 6.76 (d, 1H), 7.59 (d, 1H).

Reference： [1]Patent: US2016/176882,2016,A1 .Location in patent: Paragraph 0358; 0359
[2]Patent: WO2017/221100,2017,A1 .Location in patent: Paragraph 00168

49
[ 39919-65-8 ]
5-((3aS,4R,9bR)-3a,4,5,9b-tetrahydro-8-methyl-3H-cyclopenta[c]quinolin-4-yl)-6-methylpyridine-2-carbonitrile [ No CAS ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2016,vol. 55B,p. 1117 - 1130

50
[ 39919-65-8 ]
5-fluoro-4-(5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)-N-(6-methyl-5-(piperazin-1-ylmethyl)pyridin-2-yl)pyrimidin-2-amine [ No CAS ]

Reference： [1]Patent: CN106608879,2017,A

51
[ 39919-65-8 ]
1-((6-bromo-2-methylpyridin-3-yl)methyl)-4-ethylpiperazine [ No CAS ]

Reference： [1]Patent: CN106608879,2017,A

52
[ 39919-65-8 ]
N-(5-((4-ethylpiperazin-1-yl)methyl)-6-methylpyridin-2-yl)-5-fluoro-4-(5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-amine [ No CAS ]

Reference： [1]Patent: CN106608879,2017,A

53
[ 39919-65-8 ]
1-((6-bromo-2-methylpyridin-3-yl)methyl)-4-methylpiperazine [ No CAS ]

Reference： [1]Patent: CN106608879,2017,A

54
[ 39919-65-8 ]
5-fluoro-4-(5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)-N-(6-methyl-5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)pyrimidin-2-amine [ No CAS ]

Reference： [1]Patent: CN106608879,2017,A

55
[ 39919-65-8 ]
N-(5-((4-ethylpiperazin-1-yl)methyl)-6-methylpyridin-2-yl)-5-fluoro-4-(5-fluoro-1-methyl-2,3-dihydro-1H-benzo[d]pyrrole[1,2-a]imidazol-7-yl)pyrimidin-2-amine [ No CAS ]

Reference： [1]Patent: CN106608879,2017,A

56
[ 39919-65-8 ]
[ 1446819-39-1 ]

Reference： [1]Patent: CN106608879,2017,A

57
[ 39919-65-8 ]
4-((6-((5-fluoro-4-(5-fluoro-1,1-dimethyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester [ No CAS ]

Reference： [1]Patent: CN106608879,2017,A

58
[ 39919-65-8 ]
2-(4'-ethoxy-6-methyl-6'-oxo-1',6'-dihydro-[2,3'-bipyridin]-5-yl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-2-fluoro-5-(trifluoromethyl)phenyl)acetamide [ No CAS ]

Reference： [1]Patent: WO2017/145050,2017,A1

59
[ 39919-65-8 ]
(6-bromo-2-methylpyridin-3-yl)methanol [ No CAS ]

Reference： [1]Patent: WO2017/145050,2017,A1

60
[ 39919-65-8 ]
6-bromo-3-(bromomethyl)-2-methylpyridine [ No CAS ]

Reference： [1]Patent: WO2017/145050,2017,A1

61
[ 39919-65-8 ]
2-(6-bromo-2-methylpyridin-3-yl)acetonitrile [ No CAS ]

Reference： [1]Patent: WO2017/145050,2017,A1

62
[ 39919-65-8 ]
2-(6-bromo-2-methylpyridin-3-yl)acetic acid [ No CAS ]

Reference： [1]Patent: WO2017/145050,2017,A1

63
[ 39919-65-8 ]
2-(6-bromo-2-methylpyridin-3-yl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-2-fluoro-5-(trifluoromethyl)phenyl)acetamide [ No CAS ]

Reference： [1]Patent: WO2017/145050,2017,A1

64
[ 39919-65-8 ]
2-(4'-ethoxy-6'-((4-methoxybenzyl)oxy)-6-methyl-[2,3'-bipyridin]-5-yl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-2-fluoro-5-(trifluoromethyl)phenyl)acetamide [ No CAS ]

Reference： [1]Patent: WO2017/145050,2017,A1

65
[ 39919-65-8 ]
2-(2-aminophenylamino)-5-bromo-6-methylpyridine [ No CAS ]

Reference： [1]Patent: CN107216328,2017,A

66
[ 39919-65-8 ]
1-(5-bromo-6-methyl-2-pyridyl)-1H-benzotriazole [ No CAS ]

Reference： [1]Patent: CN107216328,2017,A

67
[ 39919-65-8 ]
2-methyl-3-bromo-9H-pyrido[2,3-b]indole [ No CAS ]

Reference： [1]Patent: CN107216328,2017,A
[2]Patent: CN108218862,2018,A

68
[ 88-74-4 ]
[ 39919-65-8 ]
2-(2-nitrophenylamino)-5-bromo-6-methylpyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66.3%	With copper(l) iodide; potassium tert-butylate; In N,N-dimethyl-formamide; at 110℃; for 7h;Catalytic behavior;	The synthetic process steps are:(1)The compound of <strong>[39919-65-8]2,5-dibromo-6-methylpyridine</strong> (2.70 g, 10.76 mmol)And o-nitroaniline (1.78 g, 12.91 mmol) were dissolved in DMF (30 mL)Was added t-BuOK (3.62 g, 32.28 mmol)5percent Pd / C (474.68 mg, 2.96 mmol),Drain the air and protect it with nitrogen,The mixture was stirred at 120 ° C for 5 h, cooled, dissolved in 20 mL of water,Extracted with EtOAc, and the extract was washed successively with water and saturated brine, dried over anhydrous Na2SO4,Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography,To give the product 2- (2-nitrophenylamino) -5-bromo-6-methylpyridine,The yield was 65percent; step 1)The reaction temperature was 110 ° C,Reaction time 7h, the reaction solvent is DMF,CuI as the catalyst, KOBu-t is the acid removal agent,The yield of 2- (2-nitrophenylamino) -5-bromo-6-methylpyridine was 66.3percent.

Reference： [1]Patent: CN107216328,2017,A .Location in patent: Paragraph 0053; 0058; 0064; 0069; 0074; 0079

69
[ 74-93-1 ]
[ 39919-65-8 ]
3-bromo-2-methyl-6-(methylthio)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	In N,N-dimethyl-formamide; at 20℃; for 6h;	Step 1: Synthesis of 3-bromo-2-methyl-6-(methylthio)pyridine To a stirred solution of 5-bromo-2-chloropyrimidine (0.3 g, 1.19 mmol) in DMF (10 mL) was added methyl mercaptan (0.4 mL, 1.19 mmol) at room temperature and stirred for 6 h at room temperature. Completion of reaction was monitored by TLC. Reaction mixture was quenched by addition of water, extracted with EtOAc. Organic portions were combined, dried over Na2SO4, evaporated under reduced pressure to obtain crude which was purified by column chromatography using silica gel (100-200 mesh); eluent 1percent ethyl acetate/hexane to obtain pure product 3-bromo-2-methyl-6-(methylthio)pyridine (0.200 g, 76percent) as light yellow oil. MS: 219.1[M++1]

Reference： [1]Patent: US2017/291910,2017,A1 .Location in patent: Paragraph 0667-0669

70
[ 39919-65-8 ]
2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(methylthio)pyridine [ No CAS ]

Reference： [1]Patent: US2017/291910,2017,A1

71
[ 39919-65-8 ]
2-((S)-1-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)ethoxy)-5-(2-methyl-6-(methylthio)pyridin-3-yl)thiazolo[5,4-b]pyridine [ No CAS ]

Reference： [1]Patent: US2017/291910,2017,A1

72
[ 39919-65-8 ]
2-((S)-1-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)ethoxy)-5-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)thiazolo[5,4-b]pyridine [ No CAS ]

Reference： [1]Patent: US2017/291910,2017,A1

73
[ 39919-65-8 ]
(1S,3S)-3-((6-(5-((((3-fluorobutyl)(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid trifluoroacetate [ No CAS ]

Reference： [1]Patent: US2017/360759,2017,A1
[2]Patent: US2017/360759,2017,A1

74
[ 39919-65-8 ]
(1S,3S)-3-((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid [ No CAS ]

Reference： [1]Patent: US2017/360759,2017,A1
[2]Patent: US2017/360759,2017,A1

75
[ 39919-65-8 ]
3-bromo-2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridine [ No CAS ]

Reference： [1]Patent: US2017/360759,2017,A1
[2]Patent: US2017/360759,2017,A1
[3]Patent: US2019/185446,2019,A1
[4]Patent: WO2019/126093,2019,A1
[5]Patent: WO2019/126094,2019,A1

76
[ 39919-65-8 ]
C₂₁H₃₁BN₄O₄ [ No CAS ]

Reference： [1]Patent: US2017/360759,2017,A1
[2]Patent: US2017/360759,2017,A1
[3]Patent: US2019/185446,2019,A1
[4]Patent: WO2019/126093,2019,A1
[5]Patent: WO2019/126094,2019,A1

77
[ 39919-65-8 ]
2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-ol [ No CAS ]

Reference： [1]Patent: US2017/360759,2017,A1
[2]Patent: US2017/360759,2017,A1
[3]Patent: US2019/185446,2019,A1
[4]Patent: WO2019/126093,2019,A1
[5]Patent: WO2019/126094,2019,A1

78
[ 39919-65-8 ]
isopropyl (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate [ No CAS ]

Reference： [1]Patent: US2017/360759,2017,A1
[2]Patent: US2017/360759,2017,A1
[3]Patent: US2019/185446,2019,A1
[4]Patent: WO2019/126093,2019,A1
[5]Patent: WO2019/126094,2019,A1

79
[ 39919-65-8 ]
isopropyl (1S,3S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate [ No CAS ]

Reference： [1]Patent: US2017/360759,2017,A1
[2]Patent: US2017/360759,2017,A1
[3]Patent: US2019/185446,2019,A1
[4]Patent: WO2019/126093,2019,A1
[5]Patent: WO2019/126094,2019,A1

80
[ 39919-65-8 ]
isopropyl (1S,3S)-3-((2-methyl-6-(1-methyl-5-((((4-nitrophenoxy)carbonyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate [ No CAS ]

Reference： [1]Patent: US2017/360759,2017,A1
[2]Patent: US2017/360759,2017,A1

81
[ 39919-65-8 ]
isopropyl (1S,3S)-3-((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate [ No CAS ]

Reference： [1]Patent: US2017/360759,2017,A1
[2]Patent: US2017/360759,2017,A1

82
[ 39919-65-8 ]
(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(((1R,2R)-2-methylcyclopropyl)methyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid trifluoroacetate [ No CAS ]

Reference： [1]Patent: US2017/360759,2017,A1
[2]Patent: US2017/360759,2017,A1

83
[ 39919-65-8 ]
C₂₇H₃₉N₅O₅ [ No CAS ]

Reference： [1]Patent: US2017/360759,2017,A1
[2]Patent: US2017/360759,2017,A1

84
[ 39919-65-8 ]
(1R,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(((1S,2S)-2-methylcyclopropyl)methyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid trifluoroacetate [ No CAS ]

Reference： [1]Patent: US2017/360759,2017,A1
[2]Patent: US2017/360759,2017,A1

85
[ 39919-65-8 ]
C₂₇H₃₉N₅O₅ [ No CAS ]

Reference： [1]Patent: US2017/360759,2017,A1
[2]Patent: US2017/360759,2017,A1

86
[ 39919-65-8 ]
C₂₅H₃₅F₂N₅O₅ [ No CAS ]

Reference： [1]Patent: US2017/360759,2017,A1
[2]Patent: US2017/360759,2017,A1

87
[ 39919-65-8 ]
C₂₆H₃₈FN₅O₅ [ No CAS ]

Reference： [1]Patent: US2017/360759,2017,A1
[2]Patent: US2017/360759,2017,A1

88
[ 6089-04-9 ]
[ 39919-65-8 ]
3-bromo-2-methyl-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In acetonitrile; at 20℃; for 14h;Inert atmosphere;	Example 1 (1S,3S)-3-((6-(5-(((cyclopentyl(methyl)carbamoyl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylic acid 1A 3-bromo-2-methyl-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine To a solution of <strong>[39919-65-8]2,5-dibromo-6-methyl-pyridine</strong> (5 g, 21.11 mmol) and 2-(prop-2-yn-1-yloxy) tetrahydro-2H-pyran (4.44 g, 31.7 mmol) in MeCN (42.2 mL) was added Et3N (8.83 mL, 63.3 mmol). The solution was degassed under N2, then trans-dichlorobis (triphenylphosphine) palladium (II) chloride (0.74 g, 1.06 mmol) and CuI (0.20 g, 1.06 mmol) were added. The reaction was stirred at rt for 14 h, after which the reaction mixture was filtered through a Celite plug and the plug was washed with EtOAc (2×10 mL). The filtrate was concentrated in vacuo and the residue was chromatographed (SiO2; continuous gradient from 0% to 100% EtOAc in Hexanes for 20 min) to give the title compound as a white solid (6.0 g, 20.3 mmol, 96% yield). 1H NMR (400 MHz, CDCl3) delta 8.65 (d, J=2.0 Hz, 1H), 7.80 (dd, J=8.3, 2.3 Hz, 1H), 7.35 (dd, J=8.4, 0.4 Hz, 1H), 4.91 (t. J=3.3 Hz, 1H), 4.61-4.45 (m, 2H), 3.98-3.81 (m, 1H), 3.66-3.44 (m, 1H), 1.92-1.73 (m, 2H), 1.72-1.52 (m, 2H). LCMS, [M+H]+=298.0.
96%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In acetonitrile; at 20℃; for 14h;Inert atmosphere;	To a solution of <strong>[39919-65-8]2,5-dibromo-6-methyl-pyridine</strong> (5 g, 21.11 mmol) and 2-(prop-2-yn-1-yloxy) tetrahydro-2H-pyran (4.44 g, 31.7 mmol) in MeCN (42.2 mL) was added Et3N (8.83 mL, 63.3 mmol). The solution was degassed under N2, then (Ph3P)2PdCl2 (0.74 g, 1.06 mmol) and CuI (0.20 g, 1.06 mmol) were added. The reaction was stirred at RT for 14 h, after which the reaction mixture was filtered through a Celite plug and the plug was washed with EtOAc (2×10 mL). The combined filtrates were concentrated in vacuo and the residue was chromatographed (SiO2; continuous gradient from 0% to 100% EtOAc in hexanes for 20 min) to give the title compound as a white solid (6.0 g, 20.3 mmol, 96% yield). 1H NMR (400 MHz, CDCl3) delta 8.65 (d, J=2.0 Hz, 1H), 7.80 (dd, J=8.3, 2.3 Hz, 1H), 7.35 (dd, J=8.4, 0.4 Hz, 1H), 4.91 (t, J=3.3 Hz, 1H), 4.61-4.45 (m, 2H), 3.98-3.81 (m, 1H), 3.66-3.44 (m, 1H), 1.92-1.73 (m, 2H), 1.72-1.52 (m, 2H). LCMS, [M+H]+=298.0.
96%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In acetonitrile; at 20℃; for 14h;Inert atmosphere;	To a solution of <strong>[39919-65-8]2,5-dibromo-6-methyl-pyridine</strong> (5 g, 21.11 mmol) and 2-(prop-2- yn-l-yloxy) tetrahydro-2H-pyran (4.44 g, 31.7 mmol) in MeCN (42.2 mL) was added Et3N (8.83 mL, 63.3 mmol). The solution was degassed under N2, then (Ph3P)2PdCh (0.74 g, 1.06 mmol) and Cul (0.20 g, 1.06 mmol) were added. The reaction was stirred at RT for 14 h, after which the reaction mixture was filtered through a plug of Celite and the plug was washed with EtOAc (2 X 10 mL). The combined filtrates were concentrated in vacuo and the residue was chromatographed (S1O2; continuous gradient from 0% to 100% EtOAc in Hexanes for 20 min) to give the title compound as a white solid (6.0 g, 20.3 mmol, 96 % yield). NMR (400 MHz, CDCl3) d 8.65 (d, 7=2.0 Hz, 1H), 7.80 (dd, 7=8.3, 2.3 Hz, 1H), 7.35 (dd, 7=8.4, 0.4 Hz, 1H), 4.91 (t, 7=3.3 Hz, 1H), 4.61 - 4.45 (m,2H), 3.98 - 3.81 (m, 1H), 3.66 - 3.44 (m, 1H), 1.92 - 1.73 (m, 2H), 1.72 - 1.52 (m, 2H). LCMS, [M+H]+ = 298.0.

96%

With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In acetonitrile; at 20℃; for 14h;Inert atmosphere;

To a solution of <strong>[39919-65-8]2,5-dibromo-6-methyl-pyridine</strong> (5 g, 21.11 mmol) and 2-(prop-2-yn-1-yloxy) tetrahydro-2H-pyran (4.44 g, 31.7 mmol) in MeCN (42.2 mL) was added Et3N (8.83 mL, 63.3 mmol). The solution was degassed under N2, then (Ph3P)2PdCh (0.74 g, 1.06 mmol) and Cul (0.20 g, 1.06 mmol) were added. The reaction was stirred at RT for 14 h, after which the reaction mixture was filtered through a plug of Celite and the plug was washed with EtOAc (2 X 10 mL). The combined filtrates were concentrated in vacuo the residue was chromatographed (SiCh; continuous gradient from 0% to 100% EtOAc in hexanes over 20 min) to give the title compound as a white solid (6.0 g, 20.3 mmol, 96 % yield). NMR (400 MHz, CDCh) d 8.65 (d, J=2.0 Hz, 1H), 7.80 (dd, =8.3,2.3 Hz, 1H), 7.35 (dd, J=8.4, 0.4 Hz, 1H), 4.91 (t, J=3.3 Hz, 1H), 4.61 -4.45 (m, 2H), 3.98 -3.81 (m, 1H), 3.66 -3.44 (m, 1H), 1.92 -1.73 (m, 2H), 1.72 -1.52 (m,2H). LCMS, [M+H]+ = 298.0.

Reference： [1]Patent: US2017/360759,2017,A1 .Location in patent: Paragraph 0788-0790
[2]Patent: US2019/185446,2019,A1 .Location in patent: Paragraph 0458; 0505-0507
[3]Patent: WO2019/126093,2019,A1 .Location in patent: Page/Page column 100
[4]Patent: WO2019/126094,2019,A1 .Location in patent: Page/Page column 103

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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. 39919-65-8 ] {[proInfo.proName]}

Quality Control of [ 39919-65-8 ]

Related Doc. of [ 39919-65-8 ]

Product Details of [ 39919-65-8 ]

Safety of [ 39919-65-8 ]

Application In Synthesis of [ 39919-65-8 ]

[ 39919-65-8 ] Synthesis Path-Upstream 1~11

[ 39919-65-8 ] Synthesis Path-Downstream 1~88

Related Functional Groups of [ 39919-65-8 ]

Bromides

Related Parent Nucleus of [ 39919-65-8 ]

Pyridines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 39919-65-8 ]

Related Parent Nucleus of
[ 39919-65-8 ]