[ CAS No. 40273-45-8 ] {[proInfo.proName]}

Name: 40273-45-8|2-Bromo-3-fluoropyridine|98%
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Quality Control of [ 40273-45-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 40273-45-8 ]

Product Details of [ 40273-45-8 ]

CAS No. :	40273-45-8	MDL No. :	MFCD04114128
Formula :	C₅H₃BrFN	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	IFGLECYAEGYLSJ-UHFFFAOYSA-N
M.W :	175.99	Pubchem ID :	2762803
Synonyms :

Calculated chemistry of [ 40273-45-8 ]

Physicochemical Properties

Num. heavy atoms :	8
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	31.89
TPSA :	12.89 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) :	-5.97 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.71
Log Po/w (XLOGP3) :	1.98
Log Po/w (WLOGP) :	2.4
Log Po/w (MLOGP) :	1.68
Log Po/w (SILICOS-IT) :	2.54
Consensus Log Po/w :	2.06

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.73
Solubility :	0.325 mg/ml ; 0.00185 mol/l
Class :	Soluble
Log S (Ali) :	-1.88
Solubility :	2.34 mg/ml ; 0.0133 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.15
Solubility :	0.124 mg/ml ; 0.000703 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.83

Safety of [ 40273-45-8 ]

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

Application In Synthesis of [ 40273-45-8 ]

* 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 [ 40273-45-8 ]
Downstream synthetic route of [ 40273-45-8 ]

[ 40273-45-8 ] Synthesis Path-Upstream 1~2

1
[ 39856-58-1 ]
[ 40273-45-8 ]

Reference： [1] Tetrahedron, 1983, vol. 39, # 12, p. 2009 - 2021
[2] Journal of Medicinal Chemistry, 1984, vol. 27, # 9, p. 1182 - 1185

2
[ 372-47-4 ]
[ 40273-45-8 ]

Reference： [1] Tetrahedron, 1983, vol. 39, # 12, p. 2009 - 2021

[ 40273-45-8 ] Synthesis Path-Downstream 1~88

1
[ 372-47-4 ]
[ 40273-45-8 ]

Reference： [1]Tetrahedron,1983,vol. 39,p. 2009 - 2021

2
[ 1445-73-4 ]
[ 40273-45-8 ]
[ 90606-76-1 ]

Reference： [1]Journal of Medicinal Chemistry,1984,vol. 27,p. 1182 - 1185

3
[ 109-65-9 ]
[ 40273-45-8 ]
[ 40273-48-1 ]

Reference： [1]Tetrahedron,1986,vol. 42,p. 2253 - 2262

4
[ 39856-58-1 ]
[ 40273-45-8 ]

Reference： [1]Tetrahedron,1983,vol. 39,p. 2009 - 2021
[2]Journal of Medicinal Chemistry,1984,vol. 27,p. 1182 - 1185

5
[ 40273-45-8 ]
[ 372-47-4 ]

Reference： [1]Tetrahedron,1986,vol. 42,p. 2253 - 2262

6
[ 40273-45-8 ]
[ 372-47-4 ]
[ 107399-23-5 ]

Reference： [1]Tetrahedron,1986,vol. 42,p. 2253 - 2262

7
[ 40273-45-8 ]
[ 96-22-0 ]
[ 372-47-4 ]
[ 40273-44-7 ]
[ 40273-43-6 ]

Reference： [1]Tetrahedron,1986,vol. 42,p. 2253 - 2262

8
[ 40273-45-8 ]
[ 96-22-0 ]
[ 372-47-4 ]
[ 107399-24-6 ]

Reference： [1]Tetrahedron,1986,vol. 42,p. 2253 - 2262

9
[ 40273-45-8 ]
[ 96-22-0 ]
[ 40273-44-7 ]

Reference： [1]Tetrahedron,1986,vol. 42,p. 2253 - 2262
[2]Tetrahedron,1983,vol. 39,p. 2009 - 2021

10
[ 40273-45-8 ]
[ 90606-81-8 ]

Reference： [1]Journal of Medicinal Chemistry,1984,vol. 27,p. 1182 - 1185

11
[ 807618-13-9 ]
[ 40273-45-8 ]
[ 1104082-44-1 ]

Yield	Reaction Conditions	Operation in experiment
	(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; copper(l) iodide; In ISOPROPYLAMIDE; at 80℃;	Synthesis of Example 19: Intermediate 19a): [Show Image] A flame dried Schlenk flask was charged with <strong>[40273-45-8]2-bromo-3-fluoropyridine</strong> (500 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (70 mg), copper(I) iodide (32 mg), and dry N,N-dimethylacetamide (4 ml). The resulting mixture was degassed with alternating vacuum/argon purges. Then 1-tert-butoxycarbonylpiperidin-4-yl)(iodo)zinc (3.99 mmol, prepared as described above) was added. The mixture was degassed once again and then heated to 80 C overnight. The mainpart of N,N-dimethylacetamide was then evaporated and the remainder was taken up in a mixture of EtOAc and water (each with 75 ml). The mixture was then filtered through Celite and transferred into a separatory funnel. The phases were separated and the water layer was extracted with EtOAc (3 x 25 ml). The combined organic layer was washed with water and brine (75 ml each), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography to furnish the desired compound in form of a brownish oil.
	With copper(l) iodide;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl acetamide; at 80℃;Inert atmosphere of argon;	A 500 ml flask was charged with <strong>[40273-45-8]2-bromo-3-fluoropyridine</strong> (10.0 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1.39 g), copper(I) iodide (0.65 g), and dry N,N-dimethylacetamide (80 ml). The resulting mixture was degassed with alternating vacuum/argon purges. Then 1-tert-butoxycarbonylpiperidin-4-yl)(iodo)zinc (79.7 mmol) was added. The mixture was degassed once again and then heated to 80C overnight. The main part of N,N-dimethylacetamide was then evaporated and the remainder was taken up in a mixture of EtOAc and water (500 ml each). This was then filtered through Celite and transferred into a separatory funnel. The phases were separated and the water layer was extracted with EtOAc (3 x 250 ml). The combined organic layer was washed with water and brine (500 ml each), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by chromatography to furnish the desired compound in form of a brown solid.

Reference： [1]Patent: EP2019100,2009,A1 .Location in patent: Page/Page column 43
[2]Patent: EP2210885,2010,A1 .Location in patent: Page/Page column 29

12
[ 40273-45-8 ]
C₁₇H₂₆BNO₃*4H₂O [ No CAS ]
[ 146141-10-8 ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 5243 - 5263

13
[ 40273-45-8 ]
[ 1025699-99-3 ]
[ 1150263-10-7 ]

Yield	Reaction Conditions	Operation in experiment
	With diisopropylamine;palladium diacetate; trisodium tris(3-sulfophenyl)phosphine; In N,N-dimethyl acetamide; water; at 80℃; for 18h;	Step C: Methyl 3-C3 -fluoropyridin-2-yl)-5-('5-methvlpvridin-2-v?benzoate; To a solution of methyl 3-(5-methylpyridin-2-yl)-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)benzoate (0.80 g, 2.27 mmol) in iV,7V-dimethylformamide (6.8 mL) and water (2.3 mL) were added <strong>[40273-45-8]2-bromo-3-fluoropyridine</strong> (0.44 g, 2.49 mmol), palladium acetate (25.4 mg, 0.11 mmol), 3,3',3"-phosphinidynetris(benzenesulfonic acid) trisodium salt (0.19 g, 0.34 mmol) and diisopropylamine (0.81 mL, 5.66 mmol). The reaction mixture was heated to 80 C. After 18 h, the mixture was cooled to ambient temperature and the solid was filtered off. Purification by reverse phase HPLC (C- 18, 95% water/ acetonitrile ? 5% water/ acetonitrile with 0.1% trifluoroacetic acid) gave the title compound. MS 323.0 (M+l).

Reference： [1]Patent: WO2009/58298,2009,A1 .Location in patent: Page/Page column 167-168

14
[ 40273-45-8 ]
[ 1239205-57-2 ]

Yield	Reaction Conditions	Operation in experiment
50%		To a solution of 2 bromo-3-fluoro pyrdine (300 mg, 1.67 mmol) in CH2Cl2 (40 mL) was added m-chloroperbenzoic acid (520 mg, 3.5 mmol) at 0 C. After the reaction mixture was stirred for 30 min, sat. NaHCO3 was added. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and concentrated. Purification of the residue by column chromatography [CH2Cl2/MeOH (10:1 v/v)]gave 2-bromo-3-fluoro-2H-pyridin-1-ol (50%) as colorless oil which was used without further purification. MS (ESI) m/z=195 (MH+).

Reference： [1]Patent: US2010/204265,2010,A1 .Location in patent: Page/Page column 130

15
[ 40273-45-8 ]
[ 79099-07-3 ]
[ 1239205-63-0 ]

Yield	Reaction Conditions	Operation in experiment
65%		To a solution of 2-bromo-3-fluoropyrdine (0.52 g, 2.97 mmol) in THF at -50 C. was added n-BuLi (2.5M solution in THF, 5.60 mmol). After 10 min 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (450 mg, 2.25 mmol) in THF (30 mL). The resulting suspension was stirred at room temperature for 12 hours. The reaction mixture was cooled and quenched with ice-water (100 mL) and the mixture was extracted with EtOAc (50 mL). The combined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography on silica gel (20% EtOAc/hexanes) to yield the title Compound (65%). 1H NMR (d6-DMSO, 300 MHz) delta 1.47 (s, 9H), 2.27 (m, 2H), 2.45 (dd, 1H, J=6.6, 6.0 Hz), 3.30 (m, 2H), 3.72 (t, 1H, J=6.4 Hz), 4.09 (m, 2H), 7.29 (m, 1H), 7.46 (m, 1H), 8.38 (m, 1H); MS (ESI) m/z=297 (MH+).

Reference： [1]Patent: US2010/204265,2010,A1 .Location in patent: Page/Page column 135; 136

16
[ 40273-45-8 ]
[ 1048970-17-7 ]
[ 1239205-08-3 ]

Yield	Reaction Conditions	Operation in experiment
79%	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 90℃; for 2h;Inert atmosphere;	A mixture of 3,6-dihydro-2H-pyridine-1-N-Boc-boronic acid pinacolato ester (8.00 g, 25.9 mmol), <strong>[40273-45-8]2-bromo-3-fluoropyridine</strong> (4.14 g, 23.5 mmol), Pd(dppf)Cl.CH2Cl2 (1.15 g, 1.4 mmol) in 2 M Na2CO3 (35.28 mL, 70.6 mmol) and 1,4-dioxane (100 mL) was degassed twice and stirred at 90 C. for 2 hours. The mixture was concentrated on silica and flash column chromatography (1:1 EtOAc/hexane) afforded 3-fluoro-3',6'-dihydro-2'H-[2,4']bipyridinyl-1'-carboxylic acid tert-butyl ester as a pale yellow oil (5.2 g, 79%). 1H NMR (CDCl3, 300 MHz) delta 1.50 (s, 9H), 2.69 (m, 2H), 3.64 (t, 2H, J=5.40 Hz), 4.15 (d, 2H, J=3.00 Hz), 6.53 (m, 1H), 7.18 (m, 1H), 7.39 (m, 1H), 8.39 (m, 1H); MS (ESI) m/z=223.1 (MH+-t-Bu).

Reference： [1]Patent: US2010/204265,2010,A1 .Location in patent: Page/Page column 89

17
[ 40273-45-8 ]
[ 1206621-28-4 ]
[ 1206621-13-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; for 16h;Inert atmosphere; Reflux;	A mixture of Lambda/-{(1 S)-2,2-dimethyl-1-[((1 S,4S)-5-[5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-2-pyridinyl]carbonyl}-2,5-diazabicyclo[2.2.1]hept-2-yl)carbonyl]propyl}- 1 H-indole-2-carboxamide (150 mg, 0.26 mmol), <strong>[40273-45-8]2-bromo-3-fluoropyridine</strong> (69 mg, 0.38 mmol), Pd(dppf)CI2 (15 mg, 0.018 mmol), sodium carbonate (55 mg, 0.52 mmol) in dry 1 ,4-dioxane (2 ml.) and water (1 ml.) was refluxed for 16 h under a nitrogen atmosphere. The solution was concentrated and the resulting residue was purified by reverse phase HPLC. Concentration of the desired fractions containing product afforded the title compound (21 mg) as a pale brown solid. LCMS (m/z): 555.3 (M+H). 1 H NMR (400 MHz, CDCI3) delta ppm: 0.90 - 1.10 (m, 9 H), 1.80 - 2.25 (m, 2 H), 3.50 - 4.30 (m, 4 H), 4.15 - 5.10 (m, 3 H), 7.00 - 7.75 (m, 8 H), 7.95 - 8.70 (m, 3 H), 9.00 - 9.30 (m, 1 H), 9.40 - 9.70 (m, 1 H)

Reference： [1]Patent: WO2010/11914,2010,A1 .Location in patent: Page/Page column 98-99

18
potassium (RS)-(4-(ethoxycarbonyl)cyclohex-1-enyl)trifluoroborate [ No CAS ]
[ 40273-45-8 ]
[ 1339126-40-7 ]

Yield	Reaction Conditions	Operation in experiment
89%	With (1,3-diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium(II) dichloride; potassium carbonate;Reflux;	4-Aryl- and 4-heteroaryl-cvclohex-3-enecarboxylic acid ester intermediates of formula (V)General procedure (I): To a mixture of potassium (RS)-(4-(ethoxycarbonyl)cyclohex-l-enyl)trifluoroborate (1 eq), an aryl or heteroaryl halide (1.2 eq) and potassium carbonate (3 eq) in an alcohol such as ethanol or methanol (0.2 M) is added (l,3-diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium (II) chloride (0.02 eq). The mixture is stirred at reflux for 1-20 h. After cooling to room temperature the solvent is evaporated. The residue is triturated in an organic solvent such as tert-butyl methyl ether or ethyl acetate. The precipitates are removed by filtration. The filtrate is concentrated to dryness. Purification by flash-chromatography gives a 4-aryl- or 4-heteroaryl-cyclohex-3-enecarboxylic acid ester intermediate of formula (V).(RS)-4-(3-Fluoro-pyridin-2-yl)-cyclohex-3-enecarboxylic acid ethyl ester The title compound was obtained as colorless oil in 89% yield from <strong>[40273-45-8]2-bromo-3-fluoropyridine</strong> according to general procedure (I). MS m/e: 250 ([M+H]+)
89%	With (1,3-diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium(II) dichloride; potassium carbonate;Reflux;	General procedure: 4-Aryl- and 4-heteroaryl-cyclohex-3-enecarboxylic acid ester intermediates of formula (V) General Procedure (I): To a mixture of potassium (RS)-(4-(ethoxycarbonyl)cyclohex-1-enyl)trifluoroborate (1 eq), an aryl or heteroaryl halide (1.2 eq) and potassium carbonate (3 eq) in an alcohol such as ethanol or methanol (0.2 M) is added (1,3-diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium (II) chloride (0.02 eq). The mixture is stirred at reflux for 1-20 h. After cooling to room temperature the solvent is evaporated. The residue is triturated in an organic solvent such as tert-butyl methyl ether or ethyl acetate. The precipitates are removed by filtration. The filtrate is concentrated to dryness. Purification by flash-chromatography gives a 4-aryl- or 4-heteroaryl-cyclohex-3-enecarboxylic acid ester intermediate of formula (V). The title compound was obtained as colorless oil in 89% yield from <strong>[40273-45-8]2-bromo-3-fluoropyridine</strong> according to general procedure ( I). MS m/e: 250 ([M+H]+).
76%	With potassium carbonate;[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride;Reflux;	General Procedure (III):To a mixture of potassium (RS)-(4-(ethoxycarbonyl)cyclohex-1-enyl)trifluoroborate (1 eq), an aryl halide (1.2 eq) and potassium carbonate (3 eq) in an alcohol such as ethanol or methanol (0.2 M) is added (1,3-diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium (II) chloride (0.02 eq). The mixture is stirred at reflux for 1-20 h. After cooling to room temperature the solvent is evaporated. The residue is triturated in an organic solvent such as tert-butyl methyl ether or ethyl acetate. The precipitates are removed by filtration. The filtrate is concentrated to dryness. Purification by flash-chromatography gives 4-aryl-cyclohexenyl carboxylic acid ester intermediates of formula (V).4-Aryl-cyclohex-3-enecarboxylic acid ester 8(RS)-4-(4-Fluoro-pyridin-2-yl)-cyclohex-3-enecarboxylic acid ethyl ester The title compound was obtained as light yellow oil in 76% yield from 2-chloro-4-fluoropyridine according to the general procedure (III). MS m/e: 250 ([M+H]30 )

Reference： [1]Patent: WO2013/50334,2013,A1 .Location in patent: Page/Page column 35
[2]Patent: US2014/221350,2014,A1 .Location in patent: Paragraph 0151-0152
[3]Patent: US2011/251183,2011,A1 .Location in patent: Page/Page column 18-19; 20

19
[ 40273-45-8 ]
[ 185099-67-6 ]
3-(3-fluoro-pyridin-2-yl)-3-hydroxy-8-aza-bicyclo[3.2.1 ]octane-8-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Synthesis 53-(3-Fluoro-pyridin-2-yl)-3-hydroxy-8-aza-bicyclo[3.2.1 ]octane-8-carboxylic acid tert-butyl estern-Butyl lithium (2.5M, 1 mL, 2.5 mmol) was added dropwise to a solution of 2-bromo-3- fluoro-pyridine (0.4 g, 2.27 mmol) in diethyl ether (8 mL), under nitrogen at -78C and stirred for 1 hour. 3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.51 g, 2.27 mmol) in diethyl ether (5 mL) was added dropwise at -78C and the reaction mixture stirred for 0.5 hours before warming to room temperature. The reaction mixture was poured onto ice, acidified with acetic acid and extracted into ethyl acetate. The remaining aqueous solution was basified with 1 M sodium hydroxide, extracted with DCM and the combined organics were dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. Methanol (10 mL) and sodium borohydride (0.14 g) were added to the residues and stirred for 2 hours to reduce any unreacted ketone. The solvent was removed by evaporation under vacuum, DCM added to the residues and the organics washed with water and brine, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 5-10% ethyl acetate/cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.25 g). LCMS m/z 323 [M+H]+. R.T. = 4.67 min (Analytical Method 3).

Reference： [1]Patent: WO2011/135276,2011,A1 .Location in patent: Page/Page column 74

20
[ 40273-45-8 ]
[ 185099-67-6 ]
3-(3-fluoro-pyridin-2-yl)-8-aza-bicyclo[3.2.1]octan-3-ol hydrochloride [ No CAS ]

Reference： [1]Patent: WO2011/135276,2011,A1

21
[ 40273-45-8 ]
[ 1352794-85-4 ]

Reference： [1]Patent: WO2011/159839,2011,A2

22
[ 40273-45-8 ]
[ 1352792-71-2 ]

Reference： [1]Patent: WO2011/159839,2011,A2

23
[ 40273-45-8 ]
[ 1352794-84-3 ]

Reference： [1]Patent: WO2011/159839,2011,A2

24
[ 40273-45-8 ]
[ 126747-14-6 ]
[ 1352794-83-2 ]

Yield	Reaction Conditions	Operation in experiment
89%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 80℃; for 12h;Sealed;	[00266] Step A: 4-(3-Fluoropyridin-2-yl)benzonitrileA mixture of <strong>[40273-45-8]2-bromo-3-fluoropyridine</strong> (1.05g, 6.0mmol), 4- cyanophenylboronic acid (0.882g, 6.0 mmol), Pd(PPh3)4 (0.138g, 0.12mmol), and aqueous sodium carbonate solution (2M, 6mL), in dioxane (6mL) was degassed for 15 minutes. The mixture was sealed, heated to 80C for 12 hours, washed with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated and purified by chromatography to yield 4-(3-fluoropyridin-2-yl)benzonitrile (1.16g, 89%).

Reference： [1]Patent: WO2011/159839,2011,A2 .Location in patent: Page/Page column 82

25
[ 40273-45-8 ]
[ 5419-55-6 ]
[ 67-63-0 ]
lithium (3-fluoropyridin-2-yl)triisopropoxyborate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%		General procedure: 3-Chloro-2-bromopyridine (68.5 g, 0.356 mol) and triisopropylborate (83 mL, 0.356 mol) were dissolved in a mixture of toluene and THF (900 mL/225 mL). The resulting solution was cooled to -77 C, followed by slow addition (85 min.) of n-BuLi/hexane (130 mL, 0.338 mol). Temperature was controlled below -70 C and a brown solution resulted. The reaction mixture was stirred for an additional 135 min., then the cooling bath was removed and allowed to stir at ambient (turned into a greenish-brown mixture) until the temperature reached 0 C (1.5 h). The reaction was quenched with 100 mL of i-propanol, and left overnight. The reaction mixture was concentrated under reduced pressure at ~ 45 C until dry. Acetone (600 mL) was added and the flask was kept on a rotary evaporator until a homogeneous suspension resulted. The solid was collected by filtration under N2 after cooling to room temperature, washed with acetone, dried in air with aspiration for 2 h to give 61.2 g (53 % yield) of white powder.

Reference： [1]Tetrahedron Letters,2012,vol. 53,p. 4873 - 4876

26
[ 40273-45-8 ]
[ 1395284-98-6 ]
[ 1395285-83-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; at 120℃; for 0.166667h;Inert atmosphere; microwave irradiation;	To a microwave vial (5 mL), 3-amino-N-(4-((1R,3R,4R,5S)-3-(tert-butyldimethylsilyloxy)-4-hydroxy-4,5-dimethylcyclohexyl)pyridin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (40 mg, 0.067 mmol), <strong>[40273-45-8]2-bromo-3-fluoropyridine</strong> (17.70 mg, 0.101 mmol), PdCl2(dppf) (7.36 mg, 10.06 mumol), DME (0.503 ml) and 2M Na2CO3 solution (0.168 ml) were added. The reaction mixture was degassed by N2 stream for 10 min. The reaction mixture was heated in a microwave at 120 C. for 10 min. To the reaction mixture, anhydrous sodium sulfate was added to remove water and diluted with EtOAc. The mixture was filtered and concentrated in vacuo to yield 5-amino-N-(4-((1R,3R,4R,5S)-3-(tert-butyldimethylsilyloxy)-4-hydroxy-4,5-dimethylcyclohexyl)pyridin-3-yl)-3'-fluoro-2,2'-bipyridine-6-carboxamide. LCMS (m/z): 566.2 (MH+), Rt=0.95 min. The crude product was dissolved in MeOH and THF (1:1, 1 mL) followed by 0.5 mL of 3N HCl solution. After 1 h, the mixture was basified with Na2CO3 solution and worked up with EtOAc. The concentrated crude product was purified via prep HPLC. The pure fractions were lyophilized to yield 5-amino-N-(4-((1R,3R,4R,5S)-3,4-dihydroxy-4,5-dimethylcyclohexyl)pyridin-3-yl)-3'-fluoro-2,2'-bipyridine-6-carboxamide as the TFA salt (3.9 mg). LCMS (m/z): 452.1 (MH+), Rt=0.47 min. 1H-NMR (DMSO, 400 MHz)-delta 10.44 (s, 1H), 9.28 (s, 1H), 8.53 (d, J=4 Hz, 1H), 8.45 (d, J=4 Hz, 1H), 8.12 (d, J=8 Hz, 1H), 7.78 (m, 1H), 7.72 (m, 1H), 7.52 (m, 2H), 7.43 (d, J=8 Hz, 1H), 7.29 (bs, 2H), 3.12 (m, 1H), 2.49 (m, 1H), 1.78 (m, 1H), 1.61 (m, 2H), 1.53 (m, 1H), 1.31 (m, 1H), 0.92 (s, 3H), 0.77 (d, J=8 Hz, 3H).

Reference： [1]Patent: US2012/225061,2012,A1 .Location in patent: Page/Page column 107

27
[ 288-13-1 ]
[ 40273-45-8 ]
[ 1339392-76-5 ]

Yield	Reaction Conditions	Operation in experiment
53%	With copper(l) iodide; potassium carbonate; L-proline; In dimethyl sulfoxide; at 90℃; for 72h;microwave irradiation; Inert atmosphere;	a) 3-f Iuoro-2-(1 H-pyrazol-1 -yl)pyridineA microwave vessel was charged with pyrazole (202 mg, 2.97 mmol, 1.0 eq), copper (I) iodide (113 mg, 0.59 mmol, 0.2 eq), L-Proline (137 mg, 1.19 mmol, 0.4 eq), 2-bromo-3- fluoropyridine (628 mg, 3.57 mmol, 1.2 eq) and K2C03 (1.23 g, 8.90 mmol, 3.0 eq). It was then evacuated and back-filled with nitrogen (3 cycles). Anhydrous DMSO (3 mL) was added and the mixture stirred at 90C for 72 h. The reaction was then diluted with water (30 mL) and extracted with EtOAc (5 x 15 mL). The combined organic extracts were washed with water (2 x 50 mL), dried (MgS04) and concentrated in vacuo. Chromatography on silica gel (12-100% EtOAc in petrol) afforded a clear liquid (256 mg, 53%); 1H NMR (400 MHz, DMSO-cfe) delta ppm 8.44-8.43 (m, 1H), 8.38 (dt, J=4.6, 1.1 Hz, 1 H), 8.05-7.98 (m, 1H), 7.86-7.85 (m, 1 H), 7.55-7.50 (m, 1 H), 6.60 (dd, J=2.7, 1.8 Hz, 1 H); m/z (ES+APCI)+: 164 [M+H]+.

Reference： [1]Patent: WO2012/127212,2012,A1 .Location in patent: Page/Page column 113-114

28
[ 40273-45-8 ]
[ 1400873-45-1 ]

Reference： [1]Patent: WO2012/127212,2012,A1

29
[ 40273-45-8 ]
[ 1341900-28-4 ]

Reference： [1]Patent: WO2012/127212,2012,A1

30
[ 40273-45-8 ]
[ 1400874-08-9 ]

Reference： [1]Patent: WO2012/127212,2012,A1

31
[ 40273-45-8 ]
[ 1400874-09-0 ]

Reference： [1]Patent: WO2012/127212,2012,A1

32
[ 40273-45-8 ]
[ 141-32-2 ]
C₁₂H₁₃BrFNO₂ [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2013,p. 448 - 452

33
[ 831235-64-4 ]
[ 40273-45-8 ]
[ 1423778-53-3 ]