[ CAS No. 73112-16-0 ] {[proInfo.proName]}

Name: 73112-16-0|2,6-Dibromo-4-methylpyridine|98%
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SKU: A120920
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Quality Control of [ 73112-16-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 73112-16-0 ]

Product Details of [ 73112-16-0 ]

CAS No. :	73112-16-0	MDL No. :	MFCD11036225
Formula :	C₆H₅Br₂N	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	OHBIPNNTWKNAGC-UHFFFAOYSA-N
M.W :	250.92	Pubchem ID :	11288174
Synonyms :

Calculated chemistry of [ 73112-16-0 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.17
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	0.0
Molar Refractivity :	44.6
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) :	-5.51 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.35
Log Po/w (XLOGP3) :	3.27
Log Po/w (WLOGP) :	2.92
Log Po/w (MLOGP) :	2.33
Log Po/w (SILICOS-IT) :	3.18
Consensus Log Po/w :	2.81

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.95
Solubility :	0.0282 mg/ml ; 0.000112 mol/l
Class :	Soluble
Log S (Ali) :	-3.22
Solubility :	0.153 mg/ml ; 0.000609 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.12
Solubility :	0.019 mg/ml ; 0.0000757 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	1.78

Safety of [ 73112-16-0 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338-P310	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 73112-16-0 ]

* 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 [ 73112-16-0 ]
Downstream synthetic route of [ 73112-16-0 ]

[ 73112-16-0 ] Synthesis Path-Upstream 1~3

1
[ 4664-16-8 ]
[ 73112-16-0 ]

Reference： [1] Synthesis, 2000, # 12, p. 1665 - 1667
[2] Journal of the American Chemical Society, 1947, vol. 69, p. 1147,1148
[3] Journal of the Chemical Society, 1955, p. 631,635

2
[ 856835-83-1 ]
[ 73112-16-0 ]

Reference： [1] Journal of the Chemical Society, 1955, p. 631,635

3
[ 73112-16-0 ]
[ 38439-33-7 ]

Reference： [1] Journal of the American Chemical Society, 1947, vol. 69, p. 1147,1148

[ 73112-16-0 ] Synthesis Path-Downstream 1~80

1
[ 73112-16-0 ]
[ 2785-29-7 ]
[ 856835-83-1 ]

Reference： [1]Journal of the Chemical Society,1955,p. 631,635

2
[ 73112-16-0 ]
[ 38439-33-7 ]

Reference： [1]Journal of the American Chemical Society,1947,vol. 69,p. 1147,1148

3
[ 4664-16-8 ]
[ 73112-16-0 ]

Reference： [1]Synthesis,2000,p. 1665 - 1667
[2]Journal of the American Chemical Society,1947,vol. 69,p. 1147,1148

4
[ 73112-16-0 ]
[ 17997-47-6 ]
[ 72036-41-0 ]

Reference： [1]Synthesis,2000,p. 1665 - 1667

5
[ 73112-16-0 ]
[ 189195-41-3 ]
5,4',5''-trimethyl-[2,2';6',2'']terpyridine [ No CAS ]

Reference： [1]Synthesis,2000,p. 1665 - 1667

6
[ 73112-16-0 ]
[ 259807-95-9 ]
6,4',6''-trimethyl-[2,2';6',2'']terpyridine [ No CAS ]

Reference： [1]Synthesis,2000,p. 1665 - 1667

7
[ 73112-16-0 ]
[ 301652-23-3 ]
[ 33354-75-5 ]

Reference： [1]Synthesis,2000,p. 1665 - 1667

8
[ 856835-83-1 ]
[ 73112-16-0 ]

Reference： [1]Journal of the Chemical Society,1955,p. 631,635

9
[ 73112-16-0 ]
[ 20154-03-4 ]
2-bromo-4-methyl-6-(3-trifluoromethyl-1H-pyrazol-1-yl)-pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide;	1A Preparation of 2-bromo-4-methyl-6-(3-trifluoromethyl-1H-pyrazol-1-yl)-pyridine A mixture of <strong>[73112-16-0]2,6-dibromo-4-methylpyridine</strong> (33 mmol, obtained according to the method disclosed by WO 94/22833), 3-trifluoromethyl-1H-pyrazole (21 mmol), potassium carbonate (45 mmol) and N,N-dimethylformamide ((50 mL) is heated at 90 C. for 4 hours. The reaction mixture is partitioned between ethyl acetate ands water. The separated organic phase is washed with brine, dried over sodium sulfate and evaporated in vacuo to provide an oily residue which is purified by flash chromatography. To yield 1.9 g of the title compound.
	With potassium carbonate; In N,N-dimethyl-formamide;	1A Preparation of 2-bromo-4-methyl-6-(3-trifluoromethyl-1H-pyrazol-1-yl)-pyridine A mixture of <strong>[73112-16-0]2,6-dibromo-4-methylpyridine</strong> (33 mmol, obtained according to the method disclosed by WO 94/22833), 3-trifluoromethyl-1H-pyrazole (21 mmol), potassium carbonate (45 mmol) and N,N-dimethylformamide ((50mL) is heated at 90 C for 4 hours. The reaction mixture is partitioned between ethyl acetate ands water. The separated organic phase is washed with brine, dried over sodium sulfate and evaporated in vacuoto provide an oily residue which is purified by flash chromatography. To yield 1.9 g of the title compound.

Reference： [1]Patent: US6448204,2002,B1
[2]Patent: EP1101764,2001,A1

Yield	Reaction Conditions	Operation in experiment
25%		This material was mixed with tribromomethane (100 ml) and phosphoryl bromide (24 g) and heated to reflux for 3 hours. After cooling, the reaction mixture was quenched carefully with an aqueous 50% solution of sodiumhydroxide and the mixture extracted twice each with dichloromethane (100 ml). The solvent was removed in vacuo and the crude product purified by flash silica gel column chromatography using hexane/ethyl acetate (7/3). 2,6-Dibromo-4-methylpyridine (6.9 g; 25%) was obtained.
25%		This was mixed with 24 g phosphorylbromide in 100 ml bromoforme and heated to reflux for 3 hours. After cooling the reaction mixture was hydrolyzed carefully with a 50% aqueous solution of sodium hydroxide and extracted 2 times with 100 ml dichloromethane. The solvent was removed in vacuo and the crude product purified by flash silica gel column chromatography using hexane/ethyl acetate 7/3. 2,6-Dibromo-4-methylpyridine (6.9 g, 25%) was obtained as a colourless solid melting point 77 C.

11
[ 73112-16-0 ]
[ 1158984-38-3 ]

Yield	Reaction Conditions	Operation in experiment
85%	With hydrazine; In water; dimethyl sulfoxide; at 20 - 120℃; for 21h;	<strong>[73112-16-0]2,6-Dibromo-4-methylpyridine</strong> (D2, 1.279g, 5.098mmol) was dissolved in anhydrous dimethylsulfoxide (12ml) and stirred at room temperature. Hydrazine monohydrate (0.99ml, 20.39mmol, 4eq.) was added slowly and the mixture was then stirred at room temperature for 3 hours and then at 12O0C for 18 hours. The mixture was cooled to room temperature and poured into water and the resulting precipitate was collected by filtration, washed with water and dried to give the title compound (881 mg, 85%) as a beige coloured solid. LCMS (method A): major peak, Rt = 1.60mins; MH+ 202, 204.

Reference： [1]Patent: WO2009/68652,2009,A1 .Location in patent: Page/Page column 24

12
4-methyl-pyridine-2,6-diol; hydrochloride [ No CAS ]
[ 73112-16-0 ]

Yield	Reaction Conditions	Operation in experiment
16%		theta-Hydroxy^-methyl^-oxo-i ^-dihydro-S-pyridinecarbonitrile hydrochloride (D1 , 5g, 30.94mmol) and phosphorus oxybromide (25g, 87.2mmol) were heated together at 13O0C for 6 hours. The mixture was cooled in ice and water was added cautiously and the mixture was then basified with 2M sodium hydroxide solution and extracted with dichloromethane. The organic phase was separated and evaporated to give a pale brown solid. This was purified by silica gel chromatography (CombiFlash Companion, Redisep 8Og silica gel column) eluting with cyclohexane-dichloromethane mixtures (100%-70% cyclohexane). Fractions which contained the major component were combined and evaporated to give the title compound (1.279g, 16%) as a colourless solid. LCMS (method A): single peak, Rt = 3.09mins; MH+ 250, 252, 254.

Reference： [1]Patent: WO2009/68652,2009,A1 .Location in patent: Page/Page column 24

13
[ 73112-16-0 ]
[ 1300740-00-4 ]

Reference： [1]Patent: WO2011/52805,2011,A1

14
[ 73112-16-0 ]
C₅₉H₃₄Br₆N₁₂ [ No CAS ]

Reference： [1]Patent: WO2011/52805,2011,A1

15
[ 73112-16-0 ]
4,7-bis-pinacolato-diborane-2,1,3-benzothiadiazole [ No CAS ]
[ 1300740-01-5 ]

Yield	Reaction Conditions	Operation in experiment
54%	With Aliquat 336; potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; toluene; at 80℃; for 168h;Inert atmosphere;	<Example 2> (Synthesis of aromatic compound P2)Aromatic compound P2 was synthesized according to the following reaction formula. [Chemical Formula 119]Aromatic compound P2[0139] First, compound 2(l,4-bis-(2-bromo-4-methylpyridm-6-yl)-3,4-diaminobenzene) to be used as the starting material was synthesized via 4,7-bis-(2-bromo-4-methylpyridin-6-yl)-2, 1 ,3-benzothiadiazole.[0140] Specifically, 4.930 g of <strong>[73112-16-0]2,6-dibromo-4-methylpyridine</strong> (0.0196 mol) and 0.762 g of 4,7-bis-pinacolato-diborane-2,l ,3-benzothiadiazole (0.00196 mol) were dissolved in 120 ml of toluene to obtain a toluene solution. To the toluene solution there were added 10 ml of an aqueous solution dissolving 10 g of K2C03, and 0.032 g of trioctylmethylammonium chloride (trade name: Aliquat336 by Aldrich Co., hereunder referred to as "Aliquat336"). After deaerating the solution with argon, 0.1132 g of tetrakis-(triphenylphosphin)-Pd(0)(0.098 mmol) was added and the mixture was heated at 80C for 1 week. This was followed by column purification (dichloromethane/hexane/ethyl acetate) to obtain 0.507 g of 4,7-bis-(2-bromo-4-methylpyridin-6-yl)-2, 1 ,3-benzothiadiazole at a yield of 54% .Results of NMR analysis and MS analysis of 4,7-bis-(2-bromo-4-methylpyridin-6-yl)-2, 1 ,3-benzothiadiazole-NMR (250 MHz, CD2C12): delta = 8.684 ppm (s, 2H); 8.625 ppm (s, 2H); 7.385 ppm (s, 2H); 2.484 ppm (s, 6H)MS(FD, 8 kV) Found: m/z 476.2 (M ), Calculated: m/z: 476.19 (M+)

Reference： [1]Patent: WO2011/52805,2011,A1 .Location in patent: Page/Page column 74-76

16
[ 73112-16-0 ]
[ 312693-05-3 ]
[ 1353577-81-7 ]

Reference： [1]Synthesis,2011,p. 3496 - 3506

17
[ 73112-16-0 ]
[ 62673-31-8 ]
[ 25927-33-7 ]

Reference： [1]Synthesis,2011,p. 3496 - 3506

18
[ 73112-16-0 ]
[(2,5-dimethoxyphenyl)methyl]zinc halide [ No CAS ]
[ 1353577-87-3 ]

Reference： [1]Synthesis,2011,p. 3496 - 3506

19
[ 73112-16-0 ]
[(2-methoxyphenyl)methyl]zinc halide [ No CAS ]
[ 1353577-83-9 ]

Reference： [1]Synthesis,2011,p. 3496 - 3506

20
[ 73112-16-0 ]
[(3,4,5-trimethoxyphenyl)methyl]zinc halide [ No CAS ]
[ 1353577-88-4 ]

Reference： [1]Synthesis,2011,p. 3496 - 3506

21
[ 73112-16-0 ]
[(3-methoxyphenyl)methyl]zinc halide [ No CAS ]
[ 1353577-84-0 ]

Reference： [1]Synthesis,2011,p. 3496 - 3506

22
[ 73112-16-0 ]
[(4-fluorophenyl)methyl]zinc halide [ No CAS ]
[ 1353577-82-8 ]

Reference： [1]Synthesis,2011,p. 3496 - 3506

23
[ 73112-16-0 ]
[(4-methoxyphenyl)methyl]zinc halide [ No CAS ]
[ 1353577-85-1 ]

Reference： [1]Synthesis,2011,p. 3496 - 3506

24
[ 73112-16-0 ]
[4-(methylsulfanyl)phenyl]methylzinc halide [ No CAS ]
[ 1353577-86-2 ]

Reference： [1]Synthesis,2011,p. 3496 - 3506

25
[ 73112-16-0 ]
(R)-methyl 5-hydroxy-5-(5-(4-methyl-6-(4-(trifluoromethyl)pyridin-2-ylamino)pyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate [ No CAS ]

Reference： [1]Patent: WO2012/151137,2012,A1

26
[ 73112-16-0 ]
[ 1407501-09-0 ]

Reference： [1]Patent: WO2012/151137,2012,A1

27
[ 73112-16-0 ]
[ 1407501-44-3 ]
[ 1407501-42-1 ]
[ 1407501-46-5 ]

Reference： [1]Patent: WO2012/151137,2012,A1

28
[ 73112-16-0 ]
[ 1407502-54-8 ]

Reference： [1]Patent: WO2012/151137,2012,A1

29
[ 73112-16-0 ]
[ 1407502-60-6 ]

Reference： [1]Patent: WO2012/151137,2012,A1

30
[ 73112-16-0 ]
[ 1407500-66-6 ]

Reference： [1]Patent: WO2012/151137,2012,A1

31
[ 73112-16-0 ]
[ 1407500-81-5 ]

Reference： [1]Patent: WO2012/151137,2012,A1

32
[ 73112-16-0 ]
[ 106447-97-6 ]
[ 1407500-61-1 ]

Yield	Reaction Conditions	Operation in experiment
92%	With sodium t-butanolate;dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); In 1,4-dioxane; at 75℃;Inert atmosphere;	Preparative Example 1 - 6-bromo-4-methyI-N-[4-(trifluoromethyl)pyridin-2-yl]pyridin-2- amine (PrepEx-1) PrepEx-1[00184] N2 was bubbled through a solution of 4-(trifluoromemyl)pyridin-2 -amine (12.0 g, 74.0 mmol) and <strong>[73112-16-0]2,6-dibromo-4-methylpyridine</strong> (18.57 g, 74.0 mmol) in 1,4-dioxane (240 mL) for five minutes. Sodium tert-butoxide (7.83 g, 81 mmol) and l,l'-bis(di-terf- butylphosphino)ferrocene palladium dichloride (1.204 g, 1.851 mmol) were added and the solution was heated to 75 C; the mixture was stirred using a magnetic stirrer. Upon completion, the reaction mixture was cooled and then partitioned between EtOAc (200 mL) and 5% aqueous ammonium chloride solution (200 mL). The layers were separated and the aqueous layer was extracted with EtOAc (200 mL). The combined organic layers were washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (gradient of 0-40% EtOAc/hexane) to provide 6- bromo-4-methyl-N-[4-(trifluoromethyl)pyridin-2-yl]pyridin-2-amine (22.5 g, 67.7 mmol, 92%). MS ESI calcd for C12H9BrF3N3 [M + H]+ 332, found 332. 1H NMR (600 MHz, CDC13) delta 8.39 (s, 1H), 7.73 (s, 1H), 7.54 (s, 1H), 7.33 (s, 1H), 7.05 (s, 1H), 6.92 (d, J= 2.7 Hz, 1H), 2.31 (d, J = 3.6 Hz, 3H) ppm.
92%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium t-butanolate; In 1,4-dioxane; at 75℃;Inert atmosphere;	N2 was bubbled through a solution of 4-(trifluoromethyl)pyridin-2-amine (12.0 g, 74.0 mmol) and <strong>[73112-16-0]2,6-dibromo-4-methylpyridine</strong> (18.57 g, 74.0 mmol) in 1,4-dioxane (240 mL) for five minutes. Sodium tert-butoxide (7.83 g, 81 mmol) and l,l'-bis(di-tert- butylphosphino)ferrocene palladium dichloride (1.204 g, 1.851 mmol) were added and the solution was heated to 75 C; the mixture was stirred using a magnetic stirrer. Upon completion, the reaction mixture was cooled and then partitioned between EtOAc (200 mL) and 5% aqueous ammonium chloride solution (200 mL). The layers were separated and the aqueous layer was extracted with EtOAc (200 mL). The combined organic layers were washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (gradient of 0-40% EtOAc/hexane) to provide 6- bromo-4-methyl-N-[4-(trifluoromethyl)pyridin-2-yl]pyridin-2-amine (22.5 g, 67.7 mmol, 92%). MS ESI calc'd for CizHgBrFs s [M + H]+ 332, found 332. XH NMR (600 MHz, CDC13) delta 8.39 (s, 1H), 7.73 (s, 1H), 7.54 (s, 1H), 7.33 (s, 1H), 7.05 (s, 1H), 6.92 (d, J= 2.7 Hz, 1H), 2.31 (d, J = 3.6 Hz, 3H) ppm.
	With sodium t-butanolate;dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); In 1,4-dioxane; at 25 - 75℃; for 12.25h;Inert atmosphere;	Intermediate 4. 6-Bromo-4-methyl-N-[4-(trifluoromethyl)pyridine-2-yl]pyridine-2-amine; To a flask containing 2,6-dibromo-4-methyl pyridine (13.9 g, 55.5 mmol) and 2-amino-4- trifluoromethyl pyridine (9.0 g, 55.5 mmol) was added nitrogen sparged dioxane (180 mL).Sodium tert-butoxide (5.87 g, 61.1 mmol) and l,l'-bis(di-tert-butylphsophino)ferrocene palladium dichloride (0.905 g, 1.4 mmol) were then added, and the slurry was evacuated and refilled with nitrogen. The mixture was stirred at 25 C for 15 minutes and then heated to 75 C for 12 hours. The reaction was cooled to 25 C, water (20 mL) was added, and the mixture was extracted with ethyl actetate (2 x 200 mL ). The combined extracts were dried over Na2S04, filtered, concentrated in vacuo. The residue was purified via chromatography on silica gel to afford 6-bromo-4-methyl-N-[4-(trifluoromethyl)pyridine-2-yl]pyridine-2-amine as a white solid. MS ESI calc'd. for C12H10BrF3N3 [M+H]+ 332 and 334, found 332 and 334. 1H NMR (600 MHz,DMSO-d6) delta 10.40 (s, 1H), 8.46 (d, J= 6.0 Hz, 1H), 7.90 (s, 1H), 7.60 (s, 1H), 7.18 (d, JHz, 1H), 7.00 (s, 1H), 2.25 (s, 3H).

	With sodium t-butanolate;dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); In 1,4-dioxane; at 25 - 75℃; for 12.25h;Inert atmosphere;	Sodium terf-butoxide (5.87 g, 61.1 mmol) and l, -bis(di-iert-butylphosphino)ferrocene palladium dichloride (0.905 g, 1.4 mmol) were added to a solution of 2,6-dibromo-4-methyl pyridine (13.9 g, 55.5 mmol) and 2-amino-4-trifluoromethyl pyridine (9.0 g, 55.5 mmol) in nitrogen sparged dioxane (180 mL). The slurry was evacuated and refilled with nitrogen. The mixture was stirred at 25 C for 15 minutes and then heated to 75 C for 12 hours. The reaction mixture was cooled to 25 C, water (20 mL) was added, and the mixture was extracted with ethyl acetate (2 x 200 mL). The combined extracts were dried over sodium sulfate, filtered, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford 6-bromo-4-memyl-N-[4-(trifluoromemyl)pyridine-2-yl]pyridine-2 -amine as a white solid. MS ESI calc'd. for Ci2H10BrF3N3 [M+H]+ 332 and 334, found 332 and 334. 1H NMR (600 MHz, DMSO-d6) delta 10.40 (s, 1H), 8.46 (d, J= 6.0 Hz, 1H), 7.90 (s, 1H), 7.60 (s, 1H), 7.18 (d, J= 6.0 Hz, 1H), 7.00 (s, 1H), 2.25 (s, 3H).
	With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); sodium t-butanolate; In 1,4-dioxane; at 25 - 75℃; for 12.25h;Inert atmosphere;	To a flask containing 2,6-dibromo-4-methyl pyridine (13.9 g, 55.5 mmol) and 2- amino-4-trifluoromethyl pyridine (9.0 g, 55.5 mmol) was added nitrogen sparged dioxane (180 mL). Sodium tert-butoxide (5.87 g, 61.1 mmol) and 1 , l'-bis(di-tert-butylphsophino)ferrocene palladium dichloride (0.905 g, 1.4 mmol) were then added, and the slurry was evacuated and refilled with nitrogen. The mixture was stirred at 25 C for 15 minutes and then heated to 75 C for 12 hours. The reaction was cooled to 25 C, water (20 mL) was added, and the mixture was extracted with ethyl actetate (2 x 200 mL ). The combined extracts were dried over a2S04, filtered, concentrated in vacuo. The residue was purified via chromatography on silica gel to afford 6-bromo-4-methyl-N-[4-(trifluoromethyl)pyridine-2-yl]pyridine-2-amine as a white solid. MS ESI calc'd. for Ci2H10BrF3 3 [M+H]+ 332 and 334, found 332 and 334. XH NMR (600 MHz, DMSO-d6) delta 10.40 (s, 1H), 8.46 (d, J= 6.0 Hz, 1H), 7.90 (s, 1H), 7.60 (s, 1H), 7.18 (d, J= 6.0 Hz, 1H), 7.00 (s, 1H), 2.25 (s, 3H).
	With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); sodium t-butanolate; In 1,4-dioxane; at 25 - 75℃; for 12h;Inert atmosphere;	Preparative Example 2.1 6-Bromo-4-methyl-N-[4-(trifluoromethyl)pyridine-2-yl]pyridine-2- Sodium tert-butoxide (5.87 g, 61.1 mmol) and l, l'-bis(di-/ert- butylphsophino)ferrocene palladium dichloride (0.91 g, 1.4 mmol) were added to a solution of 2,6-dibromo-4-methyl pyridine (13.9 g, 55.5 mmol) and 2-amino-4-trifluoromethyl pyridine (9.0 g, 55.5 mmol) in nitrogen sparged dioxane (180 mL). The slurry was evacuated and refilled with nitrogen. The mixture was stirred at 25 C for 15 minutes and then heated to 75 C for 12 hours. The reaction mixture was cooled to 25 C, water (20 mL) was added, and the mixture was extracted with EtOAc (2 x 200 mL). The combined extracts were dried over sodium sulfate, filtered, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford 6-bromo-4-methyl-N-[4-(trifluoromethyl)pyridine-2- yl]pyridine-2-amine as a white solid. MS ESI calc'd. for Ci2HioBrF3 3 [M+H]+ 332 and 334, found 332 and 334. NMR (600 MHz, DMSO-d6) delta 10.40 (s, 1H), 8.46 (d, J= 6.0 Hz, 1H), 7.90 (s, 1H), 7.60 (s, 1H), 7.18 (d, J= 6.0 Hz, 1H), 7.00 (s, 1H), 2.25 (s, 3H).
	With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); sodium t-butanolate; In 1,4-dioxane; at 25 - 75℃; for 12h;Inert atmosphere;	Preparative Example 4.1 6-Bromo-4-methyl-N-[4-(trifluoromethyl)pyridine-2-yl]pyridine-2-amine Sodium ie/t-butoxide (5.87 g, 61.1 mmol) and l,l'-bis(di-ie/t- butylphsophino)ferrocene palladium dichloride (0.91 g, 1.4 mmol) were added to a solution of 2,6-dibromo-4-methyl pyridine (13.9 g, 55.5 mmol) and 2-amino-4-trifluoromethyl pyridine (9.0 g, 55.5 mmol) in nitrogen sparged dioxane (180 mL). The slurry was evacuated and refilled with nitrogen. The mixture was stirred at 25 C for 15 minutes and then heated to 75 C for 12 hours. The reaction mixture was cooled to 25 C, water (20 mL) was added, and the mixture was extracted with EtOAc (2 x 200 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford 6-bromo-4-methyl-N-[4-(trifluoromethyl)pyridine-2- yl]pyridine-2-amine as a white solid. MS ESI calc'd. for Ci2HioBrF3N3 [M+H]+ 332 and 334, found 332 and 334. 1H NMR (600 MHz, DMSO-d6) delta 10.40 (s, 1H), 8.46 (d, / = 6.0 Hz, 1H), 7.90 (s, 1H), 7.60 (s, 1H), 7.18 (d, / = 6.0 Hz, 1H), 7.00 (s, 1H), 2.25 (s, 3H).

Reference： [1]Patent: WO2012/151137,2012,A1 .Location in patent: Page/Page column 47
[2]Patent: WO2014/74422,2014,A1 .Location in patent: Paragraph 00164
[3]Patent: WO2012/154518,2012,A1 .Location in patent: Page/Page column 45
[4]Patent: WO2012/154520,2012,A1 .Location in patent: Page/Page column 39
[5]Patent: WO2013/192128,2013,A1 .Location in patent: Page/Page column 55
[6]Patent: WO2013/192125,2013,A1 .Location in patent: Page/Page column 103
[7]Patent: WO2014/48065,2014,A1 .Location in patent: Page/Page column 77

33
[ 73112-16-0 ]
[ 10201-73-7 ]
[ 1407500-69-9 ]

Yield	Reaction Conditions	Operation in experiment
50%	With sodium t-butanolate;dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); In 1,4-dioxane; at 80℃; for 1.5h;Microwave irradiation;	Step 2: To a solution of 4-methoxypyridin-2-amine (620 mg, 5 mmol) and 2,6- dibromo-4-methylpyridine (1123 mg, 5.25 mmol) in dioxane (18 mL) was added l,l'-bis(di- tertbutylphosphino) ferrocene palladium dichloride (280 mg, 0.5 mmol) and sodium tert- butoxide (437 mg, 5.25 mmol). Then the mixture stirred under microwave irradiation for 1.5 hours at 80C. Then the mixture was poured into water (50 mL), and extracted with EtOAc (100 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried and concentrated. The residue purified by silica gel chromatography using a solvent system of 75% petroleum ether/EtOAc. The product containing fractions were collected and concentrated to give 6-bromo-N-(4-methoxypyridin-2-yl)-4-methylpyridin-2-amine (627 mg, 50 %). MS ESI calcd for CI2H12BrN30 [M + H]+ 294, found 294.
50%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium t-butanolate; In 1,4-dioxane; at 80℃; for 1.5h;Microwave irradiation;	To a solution of 4-methoxypyridin-2-amine (620 mg, 5 mmol) and 2,6- dibromo-4-methylpyridine (1 123 mg, 5.25 mmol) in dioxane (18 mL) was added l, l'-bis(di- tertbutylphosphino) ferrocene palladium dichloride (280 mg, 0.5 mmol) and sodium tert- butoxide (437 mg, 5.25 mmol). Then the mixture stirred under microwave irradiation for 1.5 hours at 80C. Then the mixture was poured into water (50 mL), and extracted with EtOAc (100 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried and concentrated. The residue purified by silica gel chromatography using a solvent system of 75% petroleum ether/EtOAc. The product containing fractions were collected and concentrated to give 6-bromo-N-(4-methoxypyridin-2-yl)-4-methylpyridin-2-amine (627 mg, 50 %). MS ESI calc'd for C12H12BrN30 [M + H]+ 294, found 294.

Reference： [1]Patent: WO2012/151137,2012,A1 .Location in patent: Page/Page column 51
[2]Patent: WO2014/74422,2014,A1 .Location in patent: Paragraph 00166

34
[ 73112-16-0 ]
[ 4248-19-5 ]
[ 1206249-13-9 ]

Yield	Reaction Conditions	Operation in experiment
82%	With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 1,1'-bis(di-tertbutylphosphino)ferrocene; In 2-methyltetrahydrofuran; at 70℃; for 4h;Inert atmosphere;	Preparative Example 3 - Tert-butyl (6-bromo-4-methylpyridin-2-yl)carbamate (PrepEx-3)[00186] Into a flask were added tert-butyl carbamate (5.6 g, 47.8 mmol) and <strong>[73112-16-0]2,6-dibromo-4-methyl-pyridine</strong> (12 g, 47.8 mmol) followed by degassed 2-MeTHF (120 mL). Solid sodium tert-butoxide (4.6 g, 47.8 mmol) was then added followed bytris(dibenzylideneacetone)dipalladium(0) (1.1 g, 1.2 mmol) and l,l'-bis(di-tert- butylphosphino)ferrocene (1.1 g, 2.4 mmol), and the solution evacuated and refilled with nitrogen 3 times. The solution was heated to 70 C for 4 h and then cooled to rt. The mixture was treated with water (20 mL) and EtOAc (100 mL) and filtered through Celite. The organic solution was washed with brine (100 mL) and then concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography to afford tert-butyl (6-bromo-4- methylpyridin-2-yl)carbamate (11.2 g, 82%) as a white solid. MS ESI calcd for CnH15BrN202 [M + H]+ 287, found 287. 1H NMR (600 MHz, CDC13) delta 7.70 (s, 1H), 7.13 (s, 1H), 6.95 (s, 1H), 2.29 (s, 3H), 1.49 (s, 9H) ppm.
	With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); sodium t-butanolate; In 2-methyltetrahydrofuran; at 70 - 80℃; for 7h;Inert atmosphere;	Step 1 : <strong>[73112-16-0]2,6-dibromo-4-methylpyridine</strong> (300 mg, 1.20 mmol), tert-butyl carbamate (168 mg, 1.44 mmol), sodium ie/t-butoxide (138 mg, 1.44 mmol) and l,l'-bis(di-tert- butylphosphino)ferrocene palladium dichloride (39.0 mg, 0.06 mmol) were dissolved in nitrogen sparged 2-MeTHF. The system was evacuated and purged with nitrogen (3X) then placed into 70C oil bath. After 3 hours, the temperature was increased to 80C for 4 hours. The reaction mixture was diluted with EtOAc and brine. The product was extracted with EtOAc, washed with brine, dried and concentrated under reduced pressure to afford crude iert-butyl {4-methyl-6- [(trimethylsilyl)ethynyl]pyridin-2-yl} carbamate. Copper (I) iodide (0.13 g, 0.7 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.24 g, 0.35 mmol) were added to the crude product and then dissolved in nitrogen sparged dimethylacetamide. The system was evacuated and purged with nitrogen (3X). Triethylamine (1.5 mL, 10.45 mmol) and trimethylsilylactylene (1.5 mL, 10.45 mmol) were added and the solution was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (25 mL) and brine. The product was extracted with EtOAc (25 mL), washed with brine, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (5% EtOAc). The fractions were concentrated under reduced pressure, suspended in hexanes, filtered in vacuo and dried to afford iert-butyl {4-methyl-6-[(trimethylsilyl)ethynyl]pyridin-2-yl} carbamate. MS ESI calcd. for Ci6H25N202Si [M + H]+ 305, found 305.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium t-butanolate; In toluene; at 60℃; for 4h;Inert atmosphere;	Sodium tert-butoxide (0.15 g, 1.56 mmol) and l,l'-bis(di-tert- butylphsophino)ferrocene palladium dichloride (0.078 g, 0.12 mmol) were added to a mixture of 2,6-dibromo-4-methyl pyridine (0.301 g, 1.2 mmol) and tert-butyl carbamate (0.141 g, 1.2 mmol) in nitrogen sparged toluene (3 mL). The slurry was evacuated and refilled with nitrogen. After stirring at 60 C for 4 hours, the solution was cooled to 25 C, water (1 mL) was added and then the mixture extracted with ethyl actetate (2 x 50 mL), dried ( a2S04), filtered and concentrated in reduced pressure. The residue was chromatographed on silica gel to afford tert- butyl (6-bromo-4-methylpyridin-2-yl)carbamate as a white solid (0.3 g, 1.05 mmol). 'H NMR (600 MHz, CDC13) delta 7.7 (s, 1H), 7.13 (s, 1H), 6.95 (s, 1H), 2.29 (s, 3H), 1.49 (s, 9H).

Reference： [1]Patent: WO2012/151137,2012,A1 .Location in patent: Page/Page column 48
[2]Patent: WO2014/48065,2014,A1 .Location in patent: Page/Page column 86
[3]Patent: WO2014/176210,2014,A1 .Location in patent: Paragraph 00247

35
[ 73112-16-0 ]
trans-4-((1R or 1S)-1-hydroxy-1-(4-methyl-6-(4-(trifluoromethyl)pyridin-2-ylamino)-2,3'-bipyridin-6'-yl)ethyl)cyclohexanecarboxylic acid [ No CAS ]

Reference： [1]Patent: WO2012/154518,2012,A1

36
[ 73112-16-0 ]
methyl trans-4-((1R or 1S)-1-hydroxy-1-(4-methyl-6-(4-(trifluoromethyl)pyridin-2-ylamino)-2,3'-bipyridin-6'-yl)ethyl)cyclohexanecarboxylate [ No CAS ]

Reference： [1]Patent: WO2012/154518,2012,A1

37
[ 73112-16-0 ]
methyl trans-4-[1-(5-{6-[(4-cyclopropylpyridin-2-yl)amino]-4-methylpyridin-2-yl}-1,3-thiazol-2-yl)-1-hydroxypropyl]cyclohexanecarboxylate [ No CAS ]