[ CAS No. 100367-39-3 ] {[proInfo.proName]}

Name: 100367-39-3|4-Bromo-2-methoxypyridine|98%
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Quality Control of [ 100367-39-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 100367-39-3 ]

Product Details of [ 100367-39-3 ]

CAS No. :	100367-39-3	MDL No. :	MFCD08277268
Formula :	C₆H₆BrNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YFTGMMXMLPTTAY-UHFFFAOYSA-N
M.W :	188.02	Pubchem ID :	14062309
Synonyms :

Calculated chemistry of [ 100367-39-3 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.17
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	38.43
TPSA :	22.12 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.98 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.82
Log Po/w (XLOGP3) :	2.06
Log Po/w (WLOGP) :	1.85
Log Po/w (MLOGP) :	1.33
Log Po/w (SILICOS-IT) :	2.04
Consensus Log Po/w :	1.82

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.73
Solubility :	0.349 mg/ml ; 0.00186 mol/l
Class :	Soluble
Log S (Ali) :	-2.15
Solubility :	1.32 mg/ml ; 0.00702 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.01
Solubility :	0.185 mg/ml ; 0.000986 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.73

Safety of [ 100367-39-3 ]

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

Application In Synthesis of [ 100367-39-3 ]

* 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 [ 100367-39-3 ]
Downstream synthetic route of [ 100367-39-3 ]

[ 100367-39-3 ] Synthesis Path-Upstream 1~13

1
[ 128071-98-7 ]
[ 124-41-4 ]
[ 100367-39-3 ]

Yield	Reaction Conditions	Operation in experiment
83%	at 155℃; for 5 h; Sealed tube	A heterogeneous reaction mixture of 4-bromo-2- fluoropyridine (2.64 mL, 25.6 mmol) and NaOMe (8.29 g, 153 mmol) in MeOH (36.5 mL) was reacted in a pressure tube at 155 °C for 5 h. The reaction mixture was cooled to rt and the solids were filtered and washed with EtOAc. The filtrate was concentrated to a pale yellow oil with some white solids. The oil yellow was decanted and diluted with water and the solution was extracted with EtOAc (2x). The combined organic layers were washed with water and brine, dried over MgS0₄, filtered, and concentrated to obtain II (4.43 g, 21.20 mmol, 83percent yield) as a yellow oil. LC-MS Anal. Calc'd for C₆H₆BrNO: 188.02, found [M+H] 187.9, 189.9. 1H NMR (400 MHz, CDC1₃) δ 7.98 (d, J=5.5 Hz, 1H), 7.02 (dd, J=5.5, 1.5 Hz, 1H), 6.94 (d, J=1.8 Hz, 1H), 3.92 (s, 3H).

Reference： [1] Patent: WO2015/171722, 2015, A1, . Location in patent: Page/Page column 67

2
[ 20265-39-8 ]
[ 100367-39-3 ]

Reference： [1] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 24, p. 3537 - 3541
[2] Patent: WO2012/24615, 2012, A1, . Location in patent: Page/Page column 56

3
[ 14432-12-3 ]
[ 100367-39-3 ]

Reference： [1] Patent: WO2012/24615, 2012, A1,

4
[ 20773-98-2 ]
[ 100367-39-3 ]

Reference： [1] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 24, p. 3537 - 3541
[2] Patent: WO2012/24615, 2012, A1,

5
[ 14395-39-2 ]
[ 100367-39-3 ]

Reference： [1] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 24, p. 3537 - 3541
[2] Patent: WO2012/24615, 2012, A1,

6
[ 1628-89-3 ]
[ 100367-39-3 ]

Reference： [1] Patent: WO2012/24615, 2012, A1,

7
[ 1628-89-3 ]
[ 100367-39-3 ]
[ 13472-59-8 ]
[ 19230-59-2 ]

Reference： [1] Journal of Organic Chemistry, 1988, vol. 53, # 7, p. 1367 - 1371
[2] Journal of Organic Chemistry, 1988, vol. 53, # 7, p. 1367 - 1371

8
[ 1628-89-3 ]
[ 100367-39-3 ]
[ 13472-59-8 ]
[ 19230-59-2 ]

Reference： [1] Journal of Organic Chemistry, 1988, vol. 53, # 7, p. 1367 - 1371
[2] Journal of Organic Chemistry, 1988, vol. 53, # 7, p. 1367 - 1371

9
[ 1628-89-3 ]
[ 100367-39-3 ]
[ 13472-59-8 ]
[ 19230-59-2 ]

Reference： [1] Journal of Organic Chemistry, 1988, vol. 53, # 7, p. 1367 - 1371
[2] Journal of Organic Chemistry, 1988, vol. 53, # 7, p. 1367 - 1371

10
[ 100367-39-3 ]
[ 73183-34-3 ]
[ 408502-23-8 ]

Reference： [1] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 24, p. 3537 - 3541
[2] Advanced Synthesis and Catalysis, 2010, vol. 352, # 11-12, p. 2002 - 2010
[3] Patent: WO2012/24615, 2012, A1, . Location in patent: Page/Page column 56
[4] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 836 - 848
[5] European Journal of Organic Chemistry, 2012, # 3, p. 595 - 603
[6] Patent: WO2014/78257, 2014, A1, . Location in patent: Page/Page column 120; 121
[7] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 12, p. 2496 - 2500

11
[ 100367-39-3 ]
[ 219715-34-1 ]

Reference： [1] Organic Letters, 2014, vol. 16, # 6, p. 1744 - 1747

12
[ 100367-39-3 ]
[ 36953-37-4 ]

Yield	Reaction Conditions	Operation in experiment
88%	Stage #1: With hydrogenchloride; water In 1,4-dioxane at 50 - 90℃; Stage #2: With sodium hydroxide In 1,4-dioxane; water	Y. l-Methyl-S-^λ.S.S-tetramethyl-lJ^-dioxaborolan^-vnpyridin^qHl-one; Step a: 4-Bromopyridin-2(lH)-one; To a solution of 4-bromo-2-methoxypyridine (1.0 g, 5.3 mmol) in 1,4-dioxane(26 mL) was added 4M HCl aqueous solution (13 mL). The reaction was heated at 90 ⁰C for 5 hours and then at 50 ⁰C overnight. The solution was neutralized with IN NaOH solution to pH 8-9 and extracted with ethyl acetate. The organics were dried over MgSO₄ and concentrated to yield 4-bromopyridin-2(lH)-as a white solid (490 mg, 53 percent). The aqueous layer was also concentrated, and then the residue was stirred with CH₂CI₂ and filtered. The filtrate was concentrated to yield additional 4-bromopyridin-2(lH)- (320 mg, 35 percent). ESI-MS m/z calc. 173.0, found 174.3 (M+l)⁺. Retention time 0.32 minutes. ¹H NMR (400 MHz, DMSO-t/6) δ 11.87 (s, IH), 7.36 (d, J = 7.0 Hz, IH), 6.64 (d, J = 2.0 Hz, IH), 6.37 (dd, J = 2.0, 7.0 Hz, IH).

Reference： [1] Patent: WO2008/141119, 2008, A2, . Location in patent: Page/Page column 97
[2] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 21, p. 6262 - 6267

13
[ 100367-39-3 ]
[ 1211534-25-6 ]

Yield	Reaction Conditions	Operation in experiment
86%	With N-chloro-succinimide In N,N-dimethyl-formamide at 20℃;	To a solution of II (2.00 g, 10.6 mmol) in DMF (21 mL) was added NCS (2.98 g, 22.3 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was quenched with water, diluted with EtOAc, and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with brine, dried over MgS0₄, and concentrated. The crude product was purified by silica chromatography to provide 1J (2.15 g, 9.18 mmol, 86percent yield) as a white solid. LC-MS Anal. Calc'd for C₆H₅BrClNO: 220.92, found [M+H] 223.8. 1H NMR (400 MHz, CDC1₃) δ 8.15 (s, 1H), 7.05 (s, 1H), 3.91 (s, 3H).

Reference： [1] Patent: WO2015/171722, 2015, A1, . Location in patent: Page/Page column 67; 68

[ 100367-39-3 ] Synthesis Path-Downstream 1~88

1
[ 1628-89-3 ]
[ 100367-39-3 ]
[ 13472-59-8 ]
[ 19230-59-2 ]

Reference： [1]Journal of Organic Chemistry,1988,vol. 53,p. 1367 - 1371
[2]Journal of Organic Chemistry,1988,vol. 53,p. 1367 - 1371

2
3-tributylstannanyl-7-trifluoromethyl-imidazo[1,2-<i>a</i>]pyrimidine [ No CAS ]
[ 100367-39-3 ]
[ 876601-11-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 1175 - 1179

3
[ 100367-39-3 ]
[ 876601-30-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 1175 - 1179

4
[ 100367-39-3 ]
3-(2-chloro-pyridin-4-yl)-7-trifluoromethyl-imidazo[1,2-<i>a</i>]pyrimidine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 1175 - 1179

5
[ 100367-39-3 ]
[ 408502-24-9 ]

Reference： [1]Bioorganic and medicinal chemistry letters,2002,vol. 12,p. 3537 - 3541

6
[ 100367-39-3 ]
[ 408502-25-0 ]

Reference： [1]Bioorganic and medicinal chemistry letters,2002,vol. 12,p. 3537 - 3541

7
[ 100367-39-3 ]
1-[3-(4-methylpiperazin-1-yl)-propyl]-4-(3-thiophen-3-yl-pyrazolo[1,5-a]pyrimidin-6-yl)-1H-pyridin-2-one [ No CAS ]

Reference： [1]Bioorganic and medicinal chemistry letters,2002,vol. 12,p. 3537 - 3541

8
[ 20773-98-2 ]
[ 100367-39-3 ]

Reference： [1]Bioorganic and medicinal chemistry letters,2002,vol. 12,p. 3537 - 3541
[2]Patent: WO2012/24615,2012,A1

9
[ 14395-39-2 ]
[ 100367-39-3 ]

Reference： [1]Bioorganic and medicinal chemistry letters,2002,vol. 12,p. 3537 - 3541
[2]Patent: WO2012/24615,2012,A1

Yield	Reaction Conditions	Operation in experiment
		Step 2 4-Bromo-2-methoxypyridine(5-5) A saturated solution of NaNO2(817 mg, 11.5 mmol) cooled to 0 C. was added dropwise to a stirred suspension of 5-4(J. Heterocycl. Chem. (1985), 22(1), 145-7) (1.2 g, 10 mmol) NaBr(391 mg, 38 mmol) and CuSO4(750 mg, 29 mmol) in 9 M H2SO4(3 ml) cooled to -5 C. in ice/salt water bath. The reaction was stirred 20 min at -5 C. and allowed to warm to rt before it was poured unto ice and made basic with 50% NaOH. The resulting mixture was extracted into ethyl acetate. The extracts were combined, dried over MgSO4 and concentrated to give a tan oil which was chromatographed on silica gel. Elution with 50% Hexanes/CH2Cl2 to 100% CH2Cl2 provided 5-5 as a colorless gum. 1H NMR(400 MHz, CDCl) delta7.98(d, 1H, J=6 Hz), 7.02 (dd, 1H, J=6, 2 Hz), 6.94 (d, 1H, J=2 Hz), 3.92 (s, 3H).

11
[ 100367-39-3 ]
[ 6783-05-7 ]
[ 1039826-82-8 ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 90℃; for 1h;	c) (£)-2-Methoxy-4-styrylpyridine; Chemical Formula: C 14H13NOExact Mass: 21 1.10 Molecular Weight: 21 1.26 [00182] <strong>[100367-39-3]4-Bromo-2-methoxypyridine</strong> (1 85 g, 9.84 mmol), (£)-phenylvinylboronic acid (4.3 g, 30 mmol), K2CO3 (4.0 g, 30 mmol) and [1, 1 '-Bis- (diphosphenylphosphino)ferrocene]dichloropalladium(II) (PdCl2dppf) (400 mg, 0.5 mmol) were stirred in DMSO (15 mL) under vacuum for 30 min. The flask was flushed <n="108"/>with nitrogen and the mixture was heated at 90 0C for 30 min. Upon cooling, the mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5chi), dried, concentrated, and the residue was purified by column chromatography (silica gel, hexanes/ethyl acetate, 97 3 to 75:25) to provide the title compound (1 93 g, 93%) as an orange oil: 1H NMR (300 MHz, CDCl3) delta 8.12 (d, J= 5.2 Hz, IH), 7.51 (m, 2H), 7.40-7.22 (m, 4H), 7.02-6.94 (m, 2H), 6.78 (s, IH), 3.95 (s, 3H).
93%	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 90℃; for 0.5h;	<strong>[100367-39-3]4-Bromo-2-methoxypyridine</strong> (1.85 g, 9.84 mmol), (E)-phenylvinylboronic acid (4.3 g, 30 mmol), K2CO3 (4.0 g, 30 mmol) and PdCl2(dppf) (400 mg, 0.5 mmol) were stirred in DMSO (15 mL) under vacuum for 30 min. The flask was flushed with nitrogen and the mixture was heated to 90 0C for 30 min. Upon cooling, the mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5chi), dried, concentrated, and the residue was purified by flash column chromatography (silica gel, hexanes/ethyl acetate, 97:3 to 75:25) to provide the title compound (1.93 g, 93%) as an orange oil: 1H NMR (300 MHz, CDCl3) delta 8.12 (d, J= 5.2 Hz, IH), 7.51 (m, 2H), 7.40- 7.22 (m, 4H), 7.02-6.94 (m, 2H), 6.78 (s, IH), 3.95 (s, 3H).

Reference： [1]Patent: WO2008/86404,2008,A1 .Location in patent: Page/Page column 106-107
[2]Patent: WO2009/89482,2009,A1 .Location in patent: Page/Page column 79

12
[ 100367-39-3 ]
[ 36953-37-4 ]

Yield	Reaction Conditions	Operation in experiment
88%		Y. l-Methyl-S-^lambda.S.S-tetramethyl-lJ^-dioxaborolan^-vnpyridin^qHl-one; Step a: 4-Bromopyridin-2(lH)-one; To a solution of <strong>[100367-39-3]4-bromo-2-methoxypyridine</strong> (1.0 g, 5.3 mmol) in 1,4-dioxane(26 mL) was added 4M HCl aqueous solution (13 mL). The reaction was heated at 90 0C for 5 hours and then at 50 0C overnight. The solution was neutralized with IN NaOH solution to pH 8-9 and extracted with ethyl acetate. The organics were dried over MgSO4 and concentrated to yield 4-bromopyridin-2(lH)-as a white solid (490 mg, 53 %). The aqueous layer was also concentrated, and then the residue was stirred with CH2CI2 and filtered. The filtrate was concentrated to yield additional 4-bromopyridin-2(lH)- (320 mg, 35 %). ESI-MS m/z calc. 173.0, found 174.3 (M+l)+. Retention time 0.32 minutes. 1H NMR (400 MHz, DMSO-t/6) delta 11.87 (s, IH), 7.36 (d, J = 7.0 Hz, IH), 6.64 (d, J = 2.0 Hz, IH), 6.37 (dd, J = 2.0, 7.0 Hz, IH).

Reference： [1]Patent: WO2008/141119,2008,A2 .Location in patent: Page/Page column 97
[2]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 6262 - 6267

13
[ 100367-39-3 ]
[ 5720-07-0 ]
[ 1173157-41-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 95℃; for 2h;	A suspension of <strong>[100367-39-3]4-bromo-2-methoxypyridine</strong> (1.22 g, 6.49 mmol), 4- methoxyphenyl boronic acid (1.97 g, 13.0 mmol), PdCl2(dppf) (530 mg, 0.649 mmol) and K2Ctheta3 (1.79 g, 13.0 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under Ar and stirred at 95 0C for 2 h. The suspension was cooled, H2O was added, and the suspension was filtered to afford a light colored solid. Flash chromatography (silica gel, hexanes/(l :l EtOAc/hexanes), 100:0 to 0:100) afforded 1.10 g of a white powder.

Reference： [1]Patent: WO2009/89482,2009,A1 .Location in patent: Page/Page column 203

14
[ 100367-39-3 ]
[ 98546-51-1 ]
[ 1173157-47-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 95℃; for 16h;	A suspension of <strong>[100367-39-3]4-bromo-2-methoxypyridine</strong> (1.225 g, 6.511 mmol), A- methylthiophenyl boronic acid (2.188 g, 13.02 mmol), PdCl2(dppf) (531 mg, 0.651 mmol) <n="207"/>Attorney's Docket 2882.023B and K2CO3 (1.797 g, 13.02 mmol) in DMSO (10 niL) was degassed under reduced pressure for 25 min. The suspension was put under N2 and stirred at 95 0C for 16 h. The suspension was cooled, H2O was added, and the suspension was filtered to afford a light colored solid. Flash chromatography (silica gel, hexanes/(l :l EtOAc/hexanes), 100:0 to 0 : 100) afforded 1.10 g of a white powder

Reference： [1]Patent: WO2009/89482,2009,A1 .Location in patent: Page/Page column 205-206

15
[ 100367-39-3 ]
[ 208399-66-0 ]
[ 1234690-71-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; In dimethyl sulfoxide; at 90℃; for 2h;Inert atmosphere;	A suspension of <strong>[100367-39-3]4-bromo-2-methoxypyridine</strong> (341 mg, 1.82 mmol), 4-methyloxy- 2-methylphenyl boronic acid (452 mg, 2.72 mmol), Pd(PPh3)2Cl2 (133 mg, 0.182 mmol) and K2CO3 (503 mg, 3.64 mmol) in DMSO (10 mL) was degassed under reduced pressure for 1 h. The suspension was put under Ar and stirred at 90 0C for 2 h. The suspension was cooled, H2O was added, and the suspension was filtered to afford a light colored solid. Flash chromatography (silica gel, hexanes/(l :l EtOAc/hexanes), 100:0 to 0:100) afforded 235 mg of a white powder.

Reference： [1]Patent: WO2009/89482,2009,A1 .Location in patent: Page/Page column 212

16
[ 100367-39-3 ]
(2-fluoro-4-methoxyphenyl)boronic acid [ No CAS ]
[ 1173157-90-8 ]

Yield	Reaction Conditions	Operation in experiment
57%	With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; In dimethyl sulfoxide; at 90℃; for 3h;Inert atmosphere;	<strong>[100367-39-3]4-Bromo-2-methoxypyridine</strong> (1.39 g, 7.42 mmol), 2-fluoro- 4methoxyphenylboronic acid (2.40 g, 14.1 mmol), K2CO3 (2.05 g, 14.8 mmol) and bis(triphenylphosphine) palladium(II)chloride (Pd(PPhS)2Cl2) (52 mg, 0.74 mmol) were stirred in DMSO (8.5 mL) under vacuum for 20 min. The flask was flushed with argon and the mixture was heated to 900C for 3 h. Upon cooling, the mixture was diluted with brine, and the aqueous solution was extracted with CH2Cl2 (3 x 50 mL). The combined organic extracts were washed with water (3 x 20 mL), dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography (40+M Biotage column, CH2C12/(8O:18:2 CH2Cl2/MeOH/NH4OH), 100:0 to 80:20) provided the title compound (0.98 g, 57%) as a yellow oil: 1H NMR (500 MHz, CDCl3) delta 8.20 (d, J= 5.4 Hz, IH), 7.42-7.38 (m, IH), 7.07 (d, J= 5.4 Hz, IH), 6.93 (s, IH), 6.80 (dd, J= 8.6, 2.5 Hz, IH), 6.74 (dd, J= 12.6, 2.5 Hz, IH), 3.99 (s, 3H), 3.85 (s, 3H).

Reference： [1]Patent: WO2009/89482,2009,A1 .Location in patent: Page/Page column 229

17
[ 100367-39-3 ]
[ 386704-04-7 ]
[ 1173155-95-7 ]

Yield	Reaction Conditions	Operation in experiment
72%	With copper(l) iodide; 3,4,7,8-Tetramethyl-o-phenanthrolin; caesium carbonate; In toluene; for 16h;Reflux;	4-BromoBromo-2-methoxypyridine (3.06 g, 16.2 mmol), (6- (trifluoromethyl)pyridin-3-yl)methanol (2.74 g, 15.5 mmol), 3,4,7,8- tetramethylphenanthroline (0.36 g, 0.15 mmol), CuI (0.14 g, 0.74 mmol) and Cs2CO3 (7.57 g, 23.2 mmol) were combined in toluene (15 mL) and heated to reflux under a nitrogen <n="138"/>Attorney's Docket 2882.023B atmosphere for 16 h. Upon cooling the mixture was purified by flash column chromagraphy (silica gel, hexanes/EtOAc, 1 :0 to 1 :1) to provide the title compound (3.19 g, 72%) as a red oil: 1H NMR (300 MHz, CDCl3) delta 8.78 (s, IH), 8.02 (d, J= 5.9 Hz, IH), 7.95 (d, J= 8.1 Hz, IH), 7.32 (d, J= 8.0 Hz, IH), 6.55 (dd, J= 5.9, 2.2 Hz, IH), 6.26 (d, J = 2.2 Hz, IH), 5.16 (s, 2H), 3.93 (s, 3H).
72%	With copper(l) iodide; caesium carbonate; In toluene; for 16h;Inert atmosphere; Reflux;	<strong>[100367-39-3]4-Bromo-2-methoxypyridine</strong> (3.06 g, 16.2 mmol), (6-(trifluoromethyl)pyridin-3-yl)methanol (2.74 g, 15.5 mmol), 3,4,7,8-tetramethylphenanthroline (0.36 g, 0.15 mmol), CuI (0.14 g, 0.74 mmol) and Cs2CO3 (7.57 g, 23.2 mmol) were combined in toluene (15 mL) and heated to reflux under a nitrogen atmosphere for 16 h. Upon cooling the mixture was purified by flash column chromography (silica gel, hexanes/EtOAc, 1:0 to 1:1) to provide the title compound (3.19 g, 72%) as a red oil: 1H NMR (300 MHz, CDCl3) delta 8.78 (s, 1H), 8.02 (d, J=5.9 Hz, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 6.55 (dd, J=5.9, 2.2 Hz, 1H), 6.26 (d, J=2.2 Hz, 1H), 5.16 (s, 2H), 3.93 (s, 3H).
72%	With 3,4,7,8-Tetramethyl-o-phenanthrolin; caesium carbonate;copper(l) iodide; In toluene; for 16h;Inert atmosphere; Reflux;	<strong>[100367-39-3]4-Bromo-2-methoxypyridine</strong> (3.06 g, 16.2 mmol), (6-(trifluoromethyl)pyridin-3-yl)methanol (2.74 g, 15.5 mmol), 3,4,7,8-tetramethylphenanthroline (0.36 g, 0.15 mmol), CuI (0.14 g, 0.74 mmol) and Cs2CO3 (7.57 g, 23.2 mmol) were combined in toluene (15 mL) and heated to reflux under a nitrogen atmosphere for 16 h. Upon cooling the mixture was purified by flash column chromagraphy (silica gel, hexanes/EtOAc, 1:0 to 1:1) to provide the title compound (3.19 g, 72%) as a red oil: 1H NMR (300 MHz, CDCl3) delta 8.78 (s, 1H), 8.02 (d, J=5.9 Hz, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 6.55 (dd, J=5.9, 2.2 Hz, 1H), 6.26 (d, J=2.2 Hz, 1H), 5.16 (s, 2H), 3.93 (s, 3H).

72%	With 3,4,7,8-Tetramethyl-o-phenanthrolin; caesium carbonate;copper(l) iodide; In toluene; for 16h;Reflux; Inert atmosphere;	<strong>[100367-39-3]4-Bromo-2-methoxypyridine</strong> (3.06 g, 16.2 mmol), (6-(trifluoromethyl)pyridin-3-yl)methanol (2.74 g, 15.5 mmol), 3,4,7,8-tetramethylphenanthroline (0.36 g, 0.15 mmol), CuI (0.14 g, 0.74 mmol) and Cs2CO3 (7.57 g, 23.2 mmol) were combined in toluene (15 mL) and heated to reflux under a nitrogen atmosphere for 16 h. Upon cooling the mixture was purified by flash column chromagraphy (silica gel, hexanes/EtOAc, 1:0 to 1:1) to provide the title compound (3.19 g, 72%) as a red oil: 1H NMR (300 MHz, CDCl3) delta 8.78 (s, 1H), 8.02 (d, J=5.9 Hz, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 6.55 (dd, J=5.9, 2.2 Hz, 1H), 6.26 (d, J=2.2 Hz, 1H), 5.16 (s, 2H), 3.93 (s, 3H).
72%	With copper(l) iodide; 3,4,7,8-tetramethyl-phenanthroline; caesium carbonate; In toluene; for 16h;Reflux; Inert atmosphere;	<strong>[100367-39-3]4-Bromo-2-methoxypyridine</strong> (3.06 g, 16.2 mmol), (6-(trifluoromethyl)pyridin-3-yl)methanol (2.74 g, 15.5 mmol), 3,4,7,8-tetramethylphenanthroline (0.36 g, 0.15 mmol), Cut (0.14 g, 0.74 mmol) and Cs2CO3 (7.57 g, 23.2 mmol) were combined in toluene (15 mL) and heated to reflux under a nitrogen atmosphere for 16 h. Upon cooling the mixture was purified by flash column chromatography (silica gel, hexanes/EtOAc, 1:0 to 1:1) to provide the title compound (3.19 g, 72%) as a red oil: 1H NMR (300 MHz, CDCl3) delta 8.78 (s, 1H), 8.02 (d, J=5.9 Hz, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 6.55 (dd, J=5.9, 2.2 Hz, 1H), 6.26 (d, J=2.2 Hz, 1H), 5.16 (s, 2H), 3.93 (s, 3H).

Reference： [1]Patent: WO2009/89482,2009,A1 .Location in patent: Page/Page column 136-137
[2]Patent: US2011/3738,2011,A1 .Location in patent: Page/Page column 33
[3]Patent: US2011/3739,2011,A1 .Location in patent: Page/Page column 23
[4]Patent: US2011/3793,2011,A1 .Location in patent: Page/Page column 34
[5]Patent: US2012/157460,2012,A1 .Location in patent: Page/Page column 29-30

18
[ 100367-39-3 ]
[ 1194488-90-8 ]
[ 1229244-21-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In propan-1-ol; at 80℃; for 14h;Inert atmosphere;	To a rc-PrOeta solution (0.15 M) of l-(l,l-dimethylethyl) 3-ethyl 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-l,3(2H)-pyridinedicarboxylate (1 eq.) from the previous step and Arene 1 (1 eq.) was added sodium carbonate (2 M aq. solution, 3 eq.). The suspension was evacuated and back-filled with N2. Finally, [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.03 eq.) was added in one rapid portion and the reaction suspension was heated at 80 0C for 14 h. The reaction was then quenched with the addition of diethyl ether and sat. aq. NH4Cl. The aqueous layer was separated and back- extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of column chromatography (SiO2, 95:5 (v/v) Hex : EtOAc -> EtOAc) afforded the title compound as a white solid.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3970 - 3975
[2]Patent: WO2009/135299,2009,A1 .Location in patent: Page/Page column 112

19
[ 100367-39-3 ]
[ 4248-19-5 ]
[ 849353-31-7 ]

Reference： [1]Tetrahedron Letters,2010,vol. 51,p. 4445 - 4448

20
[ 100367-39-3 ]
[ 1254319-24-8 ]
[ 1254319-43-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); In water; acetonitrile; at 85℃; for 18h;Inert atmosphere of nitrogen;	(S)-tert-Buty{ 4-( 1 -amino- 1 -oxo-3-(4-(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2- yl)phenyl)propan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 16, step (i), 250 mg) and <strong>[100367-39-3]4-bromo-2-methoxypyridine</strong> (91 mg) in acetonitrile (8 mL) were treated with aqueous sodium carbonate solution (2M, 0.5 mL) and nitrogen was bubbled through the mixture. 1,1 delta(Di-tert-butylphosphino)ferrocene palladium dichloride (5 mg) was added and the mixture was heated at 85C for 18 h. The mixture was evaporated onto silica and purified by chromatography on silica eluting with ethyl acetate to afford the sub-titled compound (214 mg).m/e (MultiMode+) 499 [M+Eta]+

Reference： [1]Patent: WO2010/128324,2010,A1 .Location in patent: Page/Page column 108

21
2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine [ No CAS ]
[ 100367-39-3 ]
[ 1173156-60-9 ]

Yield	Reaction Conditions	Operation in experiment
98%		a) 2'-Methoxy-6-methyl-3,4'-bipyridine (CAS Registry Number 1173156-60-9) (WO 2009/089482 to Guzzo et al., which is hereby incorporated by reference in its entirety) 2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.5 g, 16 mmol) and <strong>[100367-39-3]4-bromo-2-methoxypyridine</strong> (2.0 g, 11 mmol) were reacted according to Example 3 (step a) to provide the title compound (2.1 g, 98%) as a brown solid: 1H NMR (300 MHz, CDCl3) delta 8.75 (d, J=2.1 Hz, 1H), 8.23 (d, J=5.4 Hz, 1H), 7.78 (dd, J=8.0, 2.4 Hz, 1H), 7.24 (d, J=8.1, 1H), 7.08 (dd, J=5.4, 1.5 Hz, 1H), 6.84 (d, J=1.0, 1H), 3.98 (s, 3H), 2.61 (s, 3H).

Reference： [1]Patent: US2011/3737,2011,A1

22
[ 100367-39-3 ]
3,4,7,8-tetramethyl-phenanthroline [ No CAS ]
[ 386704-04-7 ]
[ 1173155-95-7 ]

Yield	Reaction Conditions	Operation in experiment
72%	With CuI; caesium carbonate; In toluene;	a) 2-Methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridine <strong>[100367-39-3]4-Bromo-2-methoxypyridine</strong> (3.06 g, 16.2 mmol), (6-(trifluoromethyl)pyridin-3-yl)methanol (2.74 g, 15.5 mmol), 3,4,7,8-tetramethylphenanthroline (0.36 g, 0.15 mmol), CuI (0.14 g, 0.74 mmol) and Cs2CO3 (7.57 g, 23.2 mmol) were combined in toluene (15 mL) and heated to reflux under a nitrogen atmosphere for 16 h. Upon cooling the mixture was purified by flash column chromatography (silica gel, hexanes/EtOAc, 1:0 to 1:1) to provide the title compound (3.19 g, 72%) as a red oil: 1H NMR (300 MHz, CDCl3) delta 8.78 (s, 1H), 8.02 (d, J=5.9 Hz, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 6.55 (dd, J=5.9, 2.2 Hz, 1H), 6.26 (d, J=2.2 Hz, 1H), 5.16 (s, 2H), 3.93 (s, 3H).

Reference： [1]Patent: US2011/3737,2011,A1

23
[ 100367-39-3 ]
[ 98546-51-1 ]
[ 1173157-45-3 ]

Yield	Reaction Conditions	Operation in experiment
71%		a) 4-(4-(Methylthio)phenyl)pyridin-2(1H)-one (CAS Registry Number 1173157-45-3) (WO 2009/089482 to Guzzo et al., which is hereby incorporated by reference in its entirety) A suspension of <strong>[100367-39-3]4-bromo-2-methoxypyridine</strong> (1.225 g, 6.511 mmol), 4-methylthiophenyl boronic acid (2.188 g, 13.02 mmol), PdCl2(dppf) (531 mg, 0.651 mmol), and K2CO3 (1.797 g, 13.02 mmol) in DMSO (10 mL) was degassed under reduced pressure for 25 min. The suspension was put under N2 and stirred at 95 C. for 16 h. The suspension was cooled, H2O was added, and the suspension was filtered to afford a light colored solid. Flash chromatography (silica gel, hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded 1.10 g of a white powder. The white powder was diluted with concentrated HCl solution (50 mL) and stirred at reflux for 24 h. The reaction was cooled and concentrated under reduced pressure. The residue was neutralized with saturated NaHCO3 solution, and the solid was collected by filtration. The solid was washed with H2O to afford the title compound (1.103 g, 71%) as a tan solid: 1H NMR (300 MHz, DMSO-d6) delta 7.65 (d, J=8.4 Hz, 2H), 7.43 (d, J=6.9 Hz, 1H), 7.34 (d, J=8.4 Hz, 2H), 6.57 (d, J=1.7 Hz, 1H), 6.50 (dd, J=6.9, 1.7 Hz, 1H), 3.34 (s, 3H).

Reference： [1]Patent: US2011/3793,2011,A1 .Location in patent: Page/Page column 58

24
[ 100367-39-3 ]
[ 98546-51-1 ]
[ 1260494-11-8 ]

Reference： [1]Patent: US2011/3793,2011,A1

25
[ 100367-39-3 ]
[ 1259034-68-8 ]
[ 1259034-66-6 ]

Yield	Reaction Conditions	Operation in experiment
	With copper(l) iodide; diethylamine;bis-triphenylphosphine-palladium(II) chloride; In N,N-dimethyl-formamide; at 120℃; for 0.75h;Irradiation;	A mixture of (S)-3-((S)-1-(4-ethynylphenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1 ,3-oxazinan-2-one (10 mg, 0.027 mmol), <strong>[100367-39-3]4-bromo-2-methoxypyridine</strong> (10 mg, 2 equiv), CuI (0.5 mg, 10%mol), Pd(PPh3)2CI2 (1.9 mg, 10%mol), diethylamine (1 mL), dry DMF (1 mL) was degassed, refilled with nitrogen gas (3x). The mixture was then heated in the microwave for 45 min at 120 0C. LC-MS found the reaction was30 complete. The mixture was filtered, concentrated, acidified with 5% aq HCI andpurified by prep HPLC to afford (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-((2- methoxypyridin-4-yl)ethynyl)phenyl)ethyl)-6-phenyl-1 ,3-oxazinan-2-one (1.4mg).BOST_1499943 1 - 105 - LC-MS Method 1 tR = 1.92 min, m/z 485 (M+1 ); 1H NMR (CD3OD) 7.41-7.27(m, 7H), 6.97(m, 4H), 5.55(q, 1 H), 3.92(s, 3H), 3.04(m, 1 H), 2.49(m, 2H), 2.21 (m, 1 H), 2.14(s, 2H), 1.53(d, 3H), 1.28(t, 1 H), 1.26(s, 3H), 0.96(s, 3H).

Reference： [1]Patent: WO2011/2910,2011,A1 .Location in patent: Page/Page column 105-106

26
[ 100367-39-3 ]
[ 1259034-68-8 ]
[ 1259034-70-2 ]

Yield	Reaction Conditions	Operation in experiment
34%	With copper(l) iodide; triethylamine;bis-triphenylphosphine-palladium(II) chloride; In N,N-dimethyl-formamide; at 20 - 100℃; for 4h;Inert atmosphere;	CuI (68 mg), Pd(PPh3)2CI2 (125 mg), and NEt3 (0.82 mL) were addedsuccessively to a flask charged with a stir bar, 4-bromo-1-methyl-1 H-pyridin-2-oneBOST 1499943 1 - 106 - (0.38 g), 3-[(S)-1-(4-ethynyl-phenyl)-ethyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl- [1 ,3]oxazinan-2-one (0.61 g), and N,N-dimethylformamide (3 ml.) and kept at room temperature under argon atmosphere. The resulting mixture was heated to 100 0C and stirred at this temperature for 4 h. After cooling the mixture to ambient temperature, 5 water was added and the resulting mixture was extracted with ethyl acetate. Thecombined organic extracts were washed with water and brine and dried (MgSO4). The solvent was evaporated and the residue was chromatographed on silica gel twice (first chromatography: ethyl acetate/methanol 1 :0->4:1 ; second chromatography:dichloromethane/methanol 19:1 ->9:1 ) to afford the title compound as an oil which 10 crystallized from ethyl acetate. Yield: 0.27 g (34% of theory); LC-MS (Method 1 ): tR = 3.41 min; Mass spectrum (ESI+): m/z = 485 [M+H]+.

Reference： [1]Patent: WO2011/2910,2011,A1 .Location in patent: Page/Page column 106-107

27
[ 100367-39-3 ]
[ 111-83-1 ]
[ 1303543-49-8 ]