[ CAS No. 872365-91-8 ]

Name: 872365-91-8|2-Bromo-6-(difluoromethyl)pyridine|95%
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Quality Control of [ 872365-91-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 872365-91-8 ]

CAS No. :	872365-91-8	MDL No. :	MFCD16140194
Formula :	C₆H₄BrF₂N	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZTBGDNNRDRISQZ-UHFFFAOYSA-N
M.W :	208.00	Pubchem ID :	10104489
Synonyms :

Calculated chemistry of [ 872365-91-8 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.17
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	37.0
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) :	-5.77 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.99
Log Po/w (XLOGP3) :	2.53
Log Po/w (WLOGP) :	3.3
Log Po/w (MLOGP) :	2.18
Log Po/w (SILICOS-IT) :	2.9
Consensus Log Po/w :	2.58

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.1
Solubility :	0.165 mg/ml ; 0.000792 mol/l
Class :	Soluble
Log S (Ali) :	-2.45
Solubility :	0.743 mg/ml ; 0.00357 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.49
Solubility :	0.0673 mg/ml ; 0.000324 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.79

Safety of [ 872365-91-8 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P301+P312-P302+P352-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 872365-91-8 ]

* 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 [ 872365-91-8 ]
Downstream synthetic route of [ 872365-91-8 ]

[ 872365-91-8 ] Synthesis Path-Upstream 1~2

1
[ 34160-40-2 ]
[ 872365-91-8 ]

Yield	Reaction Conditions	Operation in experiment
89%	With diethylamino-sulfur trifluoride In dichloromethane at 20℃; for 18 h;	Step 3. Preparation of 2-bromo-6-(difluoromethyl)pyridine To a solution of 6-bromopicolinaldehyde (2.10 g, 11.29 mmol) in dichloromethane (20 mL) was added diethylaminosulfur trifluoride (1.94 mL, 14.68 mmol) at 0 °C. The reaction mixture was allowed to warm to ambient temperature and stirred for 18 h, and then poured into an ice cold solution of saturated sodium bicarbonate (300 mL). The mixture was extracted with ethyl acetate (2 ^χ 120 mL). The combined organic phase was washed with saturated sodium bicarbonate (80 mL), brine (2 ^χ 50 mL), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo afforded the title compound as a brown oil (2.17 g, 89percent yield): H NMR (300 MHz, CDCI₃) δ 7.75-7.70 (m, 1 H), 7.65-7.60 (m, 2H), 6.60 (t, J = 55.1 Hz, 1 H).
80%	With diethylamino-sulfur trifluoride In dichloromethane at 0 - 25℃; for 12 h; Inert atmosphere	DAST (17.76 mL, 134.40 mmol) was added dropwise to 6-bromopicolinaldehyde (10 g, 53.76 mmol) in DCM (150 mL) cooled to 0 °C over a period of 10 minutes. The resulting mixture was stirred at 25 °C for 12 hours. The reaction mixture was quenched with water (20 mL) and basified by the addition of NaHC0₃ (sat. aq.). The aqueous phase was extracted with DCM (3 x 150 mL), the organic layer was dried over Na₂S0₄, filtered and evaporated to afford a brown liquid. The crude product was purified by flash silica chromatography, elution gradient 0 to 8percent EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 2-bromo-6-(difluoromethyl)pyridine (Intermediate 43; 9.00 g, 80percent) as a colourless liquid. H NMR (400 MHz, CDCb, 22 °C) δ 6.59 (IH, t), 7.58 - 7.65 (2H, m), 7.71 (IH, t). m/z (ES+), [M+H]+ = 208/210.
68%	With diethylamino-sulfur trifluoride In dichloromethane at 0 - 20℃;	Preparation 29 Synthesis of 2-bromo-6-difluoromethyl-pyridine Add diethylaminosulfur trifluoride (31.5 mL, 0.238 mol) dropwise over 20 min to a stirring cooled solution of 6-bromo-pyridine-2-carbaldehyde (30.40 g, 0. 158 mol) in dichloromethane (600 mL) at 0° C. and warm to room temperature overnight. Divide the reaction mixture in two batches of equal volume for ease of working up. Slowly add, using extreme caution, a saturated aqueous solution of sodium bicarbonate over 30 min. Wash the aqueous layer once with dichloromethane. Dry the combined organic layers over sodium sulfate, filter, and concentrate. Purify resulting crude material by silica gel chromatography, gradient eluding from 1:99 to 10:90 using ethyl acetate:iso-hexane, to give the title compound (22.60 g, 68percent) and a second fraction (9.4 g, 90percent wt/wt purity, 26percent) which are used with our further purification. ¹H NMR (CDCl₃) δ 6.59 (t, 1H), 7.61 (m, 2H), 7.73(t, 1H).

1.87 g

With diethylamino-sulfur trifluoride In dichloromethane for 2 h; Cooling with ice

Step 1: Synthesis of 2-bromo-6-(difluoromethyl)pyridine (0396) 3.81 g (23.6 mmol) of (diethylamino)sulfur trifluoride were added with ice cooling to a mixed solution of 2.00 g (10.8 mmol) of 6-bromopicolinaldehyde and 40 ml methylene chloride. After completion of the addition, said reaction mixture liquid was stirred for 2 hours with ice cooling. After completion of the stirring, the reaction was stopped by addition of 30 ml of saturated aqueous sodium hydrogen carbonate solution, and said reaction liquid was extracted with methylene chloride (2×30 ml). The organic layer obtained was washed with water, then dried with anhydrous sodium sulfate, and the solvent distilled off under reduced pressure. The residue obtained was purified by silica gel chromatography (n-hexane:ethyl acetate=10:0 to 8:2), and 1.87 g of the desired compound were obtained as a white solid. (0397) ¹H-NMR (CDCl₃, Me₄Si, 300 MHz): δ 7.73-7.58 (m, 3H), 6.58 (t, 1H, J=56 Hz).

Reference： [1] Patent: WO2017/201468, 2017, A1, . Location in patent: Page/Page column 236
[2] Patent: WO2017/80979, 2017, A1, . Location in patent: Page/Page column 124; 125
[3] Patent: US2009/253750, 2009, A1, . Location in patent: Page/Page column 9
[4] Patent: US2016/221998, 2016, A1, . Location in patent: Paragraph 0396; 0397

2
[ 872365-91-8 ]
[ 1315611-68-7 ]

Yield	Reaction Conditions	Operation in experiment
770 mg	With copper(I) oxide; ammonium hydroxide; potassium carbonate; N,N`-dimethylethylenediamine In ethylene glycol for 22 h; Reflux	Step 2: Synthesis of (6-difluoromethyl)pyridin-2-amine (0398) 13 ml of aqueous ammonia (28 wt. percent) and 250 mg (1.81 mmol) of potassium carbonate were added at room temperature to a mixed solution of 1.86 g (8.94 mmol) of 2-bromo-6-(fluoromethyl)pyridine, 64 mg (0.447 mmol) of copper(1) oxide, 80 mg (0.908 mmol) of N,N′-dimethylethylenediamine and 18 ml ethylene glycol. After completion of the addition, said reaction mixture liquid was stirred for 22 hours with heating under reflux. After completion of the stirring, the reaction was stopped by addition of 30 ml of water, and said reaction liquid was extracted with ethyl acetate (2×20 ml). The organic layer obtained was washed with water, then dried with anhydrous sodium sulfate, and the solvent distilled off under reduced pressure. The residue obtained was purified by silica gel chromatography (n-hexane:ethyl acetate=9:1 to 6:4), and 770 mg of the desired compound were obtained as a colorless liquid. (0399) ¹H-NMR (CDCl₃, Me₄Si, 300 MHz): δ 7.53 (dd, 1H, J=7.2 Hz, 8.1 Hz), 6.94 (d, 1H, J=7.2 Hz), 6.57 (d, 1H, J=8.1 Hz), 6.42 (t, 1H, J=56 Hz), 4.58 (brs, 2H).

Reference： [1] Patent: US2016/221998, 2016, A1, . Location in patent: Paragraph 0398; 0399

[ 872365-91-8 ] Synthesis Path-Downstream 1~51

1
[ 34160-40-2 ]
[ 872365-91-8 ]

Yield	Reaction Conditions	Operation in experiment
89%	With diethylamino-sulfur trifluoride; In dichloromethane; at 20℃; for 18h;	Step 3. Preparation of 2-bromo-6-(difluoromethyl)pyridine To a solution of 6-bromopicolinaldehyde (2.10 g, 11.29 mmol) in dichloromethane (20 mL) was added diethylaminosulfur trifluoride (1.94 mL, 14.68 mmol) at 0 C. The reaction mixture was allowed to warm to ambient temperature and stirred for 18 h, and then poured into an ice cold solution of saturated sodium bicarbonate (300 mL). The mixture was extracted with ethyl acetate (2 chi 120 mL). The combined organic phase was washed with saturated sodium bicarbonate (80 mL), brine (2 chi 50 mL), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo afforded the title compound as a brown oil (2.17 g, 89% yield): H NMR (300 MHz, CDCI3) delta 7.75-7.70 (m, 1 H), 7.65-7.60 (m, 2H), 6.60 (t, J = 55.1 Hz, 1 H).
80%	With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 25℃; for 12h;Inert atmosphere;	DAST (17.76 mL, 134.40 mmol) was added dropwise to 6-bromopicolinaldehyde (10 g, 53.76 mmol) in DCM (150 mL) cooled to 0 C over a period of 10 minutes. The resulting mixture was stirred at 25 C for 12 hours. The reaction mixture was quenched with water (20 mL) and basified by the addition of NaHC03 (sat. aq.). The aqueous phase was extracted with DCM (3 x 150 mL), the organic layer was dried over Na2S04, filtered and evaporated to afford a brown liquid. The crude product was purified by flash silica chromatography, elution gradient 0 to 8% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 2-bromo-6-(difluoromethyl)pyridine (Intermediate 43; 9.00 g, 80%) as a colourless liquid. H NMR (400 MHz, CDCb, 22 C) delta 6.59 (IH, t), 7.58 - 7.65 (2H, m), 7.71 (IH, t). m/z (ES+), [M+H]+ = 208/210.
68%	With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 20℃;	Preparation 29 Synthesis of 2-bromo-6-difluoromethyl-pyridine Add diethylaminosulfur trifluoride (31.5 mL, 0.238 mol) dropwise over 20 min to a stirring cooled solution of 6-bromo-pyridine-2-carbaldehyde (30.40 g, 0. 158 mol) in dichloromethane (600 mL) at 0 C. and warm to room temperature overnight. Divide the reaction mixture in two batches of equal volume for ease of working up. Slowly add, using extreme caution, a saturated aqueous solution of sodium bicarbonate over 30 min. Wash the aqueous layer once with dichloromethane. Dry the combined organic layers over sodium sulfate, filter, and concentrate. Purify resulting crude material by silica gel chromatography, gradient eluding from 1:99 to 10:90 using ethyl acetate:iso-hexane, to give the title compound (22.60 g, 68%) and a second fraction (9.4 g, 90% wt/wt purity, 26%) which are used with our further purification. 1H NMR (CDCl3) delta 6.59 (t, 1H), 7.61 (m, 2H), 7.73(t, 1H).

1.87 g

With diethylamino-sulfur trifluoride; In dichloromethane; for 2h;Cooling with ice;

Step 1: Synthesis of 2-bromo-6-(difluoromethyl)pyridine (0396) 3.81 g (23.6 mmol) of (diethylamino)sulfur trifluoride were added with ice cooling to a mixed solution of 2.00 g (10.8 mmol) of 6-bromopicolinaldehyde and 40 ml methylene chloride. After completion of the addition, said reaction mixture liquid was stirred for 2 hours with ice cooling. After completion of the stirring, the reaction was stopped by addition of 30 ml of saturated aqueous sodium hydrogen carbonate solution, and said reaction liquid was extracted with methylene chloride (2×30 ml). The organic layer obtained was washed with water, then dried with anhydrous sodium sulfate, and the solvent distilled off under reduced pressure. The residue obtained was purified by silica gel chromatography (n-hexane:ethyl acetate=10:0 to 8:2), and 1.87 g of the desired compound were obtained as a white solid. (0397) 1H-NMR (CDCl3, Me4Si, 300 MHz): delta 7.73-7.58 (m, 3H), 6.58 (t, 1H, J=56 Hz).

Reference： [1]Patent: WO2017/201468,2017,A1 .Location in patent: Page/Page column 236
[2]Patent: WO2017/80979,2017,A1 .Location in patent: Page/Page column 124; 125
[3]Patent: US2009/253750,2009,A1 .Location in patent: Page/Page column 9
[4]Patent: US2016/221998,2016,A1 .Location in patent: Paragraph 0396; 0397

2
[ 773837-37-9 ]
[ 872365-91-8 ]
copper(l) cyanide [ No CAS ]
6-(difluoromethyl)picolinonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
720 mg	In N,N-dimethyl acetamide; at 120 - 125℃; for 168h;Inert atmosphere; Sealed tube;	Step 1: 2-Bromo-6-(difluoromethyl)pyridine (CAS 872365-91-8, 1 g) was dissolved under argon in N,N-dimethylacetamide (10 ml), then copper (I) cyanide (340 mg) and sodium cyanide (193 mg) were added. The reaction mixture was stirred in a sealed tube for 24 h at 120C and for 6 days at 125C. After cooling to room temperature, the reaction mixture was poured onto saturated aqueous NaHC03. AcOEt was added and the solids were removed by filtration. The organic layer was concentrated and the product was purified by flash chromatography (silica gel, 0% to 100% EtOAc in n-heptane) to give 6- (difluoromethyl)picolinonitrile (720 mg) as a colorless semisolid.

Reference： [1]Patent: WO2016/1266,2016,A1 .Location in patent: Page/Page column 49

3
[ 1166829-70-4 ]
[ 872365-91-8 ]
ethyl 2-(4-(6-(difluoromethyl)pyridin-2-yl)cyclohex-3-enyl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 110℃; for 20h;Inert atmosphere;	To the reaction mixture of <strong>[872365-91-8]2-bromo-6-(difluoromethyl)pyridine</strong> (1.55 g, 7.45 mmol), ethyl 2-(4-(4,4 ,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)cyclohex-3 -en-iyl)acetate (2.52 g, 8.57 mmol) in 1,4-Dioxane (20 mL) was added K2C03 (7.45 mL, 22.36 mmol) solution and the resulting mixture was purged with nitrogen stream for 3mm, followed by addition of Pd(Ph3P)4 (0.43 1 g, 0.373 mmol) and the reaction mixture was further purged with nitrogen stream and then heated at 110 C under nitrogen for 20 h. The reaction mixture was diluted with brine and ethyl acetate. The organic layer was separated, dried over MgSO4. The filtrate was concentrated in vacuo.and the residue was purified via silica gel flash column chromatography, eluting with 0-20% ethyl acetate inhexane to give Intermediate 231A (oil, 2.2 g, 7.45 mmol, 99% yield). LC-MS Anal.Calc?d for C,6H,9F2N02, 295.14, found [M+H] 296.2 . T = 1.10 mm (Method A). ?HNMR (400MHz, METHANOL-d4) oe: 7.92 - 7.80 (m, 1H), 7.60 (dd, J=8.0, 0.8 Hz, 1H),7.47 (d, J7.7 Hz, 1H), 6.71 (dd, J3.1, 2.0 Hz, 1H), 6.65 - 6.44 (m, 1H), 4.20 - 4.08 (m,2H), 2.79 - 2.65 (m, 1H), 2.56 - 2.39 (m, 2H), 2.36 (d, J=7.0 Hz, 2H), 2.20 - 1.92 (m, 3H),1.48 (dtd,J=13.0, 10.6, 5.5 Hz, 1H), 1.30- 1.22 (m, 3H)

Reference： [1]Patent: WO2016/73774,2016,A2 .Location in patent: Paragraph 0482

4
[ 872365-91-8 ]
[ 1315611-68-7 ]

Yield	Reaction Conditions	Operation in experiment
770 mg	With copper(I) oxide; ammonium hydroxide; potassium carbonate; N,N`-dimethylethylenediamine; In ethylene glycol; for 22.0h;Reflux;	Step 2: Synthesis of (6-difluoromethyl)pyridin-2-amine (0398) 13 ml of aqueous ammonia (28 wt. %) and 250 mg (1.81 mmol) of potassium carbonate were added at room temperature to a mixed solution of 1.86 g (8.94 mmol) of 2-bromo-6-(fluoromethyl)pyridine, 64 mg (0.447 mmol) of copper(1) oxide, 80 mg (0.908 mmol) of N,N?-dimethylethylenediamine and 18 ml ethylene glycol. After completion of the addition, said reaction mixture liquid was stirred for 22 hours with heating under reflux. After completion of the stirring, the reaction was stopped by addition of 30 ml of water, and said reaction liquid was extracted with ethyl acetate (2×20 ml). The organic layer obtained was washed with water, then dried with anhydrous sodium sulfate, and the solvent distilled off under reduced pressure. The residue obtained was purified by silica gel chromatography (n-hexane:ethyl acetate=9:1 to 6:4), and 770 mg of the desired compound were obtained as a colorless liquid. (0399) 1H-NMR (CDCl3, Me4Si, 300 MHz): delta 7.53 (dd, 1H, J=7.2 Hz, 8.1 Hz), 6.94 (d, 1H, J=7.2 Hz), 6.57 (d, 1H, J=8.1 Hz), 6.42 (t, 1H, J=56 Hz), 4.58 (brs, 2H).

Reference： [1]Patent: US2016/221998,2016,A1 .Location in patent: Paragraph 0398; 0399

5
[ 872365-91-8 ]
5-(2-chloropyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole [ No CAS ]
5-(6’-(difluoromethyl)-[2,2’-bipyridin]-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49.3%	With tetrakis(triphenylphosphine) palladium(0); hexamethyldistannane; In 1,4-dioxane; at 110℃; for 36h;Inert atmosphere;	To a stirred solution of compound 1A (200 mg, 0.785 mmol) and 2-bromo-6- (trifluoromethyl)pyridine (195 mg, 0.864 mmol) in 1,4-dioxane (2 mL) was added hexamethylditin (0.326 mL, 1.571 mmol) and the reaction mixture was purged with nitrogen for 5 minutes. Then Pd(PPh3)4 (0.09 1 g, 0.079 mmol) was added and the mixture was again purged for 10 minutes. It was then heated at 110 C for 16 h. The reaction mixture was filtered through syringe filter and the filtrate was concentrated. The crude residue was purified by preparative HPLC (condition N) to give 6-(6?-(trifluoromethyl)-[2,2?-bipyridinj-3- yl)imidazo[1,2-ajpyridine-3-carbonitrile 14(0.15 g, 0.411 mmol, 52.3 %yield) as a yellow solid. Compound 2W was synthesized by reacting 21C and 2-bromo-6- (difluoromethyl)pyridine (95 mg, 0.45 8 mmol) employing the experimental procedure described in Scheme-2 (Method B). The cmde residue was purified by silica gel chromatography (24 g RediSep column, eluted with a gradient of 5-10% methanol in chloroform) to yield 5 -(6?-(difluoromethyl)- [2,2?-bipyridinj -3 -yl)- 1 -((2- (trimethylsilyl)ethoxy)methyl)-1H-indazole 2W (93 mg, 0.205 mmol, 49.3 % yield). LCMS:+ .m/z = 453.7 [M+Hj ; ret. time 1.1 mm; condition B.

Reference： [1]Patent: WO2016/133838,2016,A1 .Location in patent: Paragraph 0210; 0338

6
[ 872365-91-8 ]
5-(2-chloropyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole [ No CAS ]
5-(6’-(difluoromethyl)-[2,2’-bipyridin]-3-yl)-1H-indazole [ No CAS ]

Reference： [1]Patent: WO2016/133838,2016,A1

7
[ 872365-91-8 ]
6-(6‘-methyl-[2,2‘-bipyridin]-3-yl)-[1,2,4]triazolo[1,5-a]pyridine [ No CAS ]
6-(6’-(difluoromethyl)-[2,2’-bipyridin]-3-yl)imidazo[1,2-b]pyridazine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62.9%		To a stirred solution of 2-bromo-4-fluoropyridine (0.3 g, 1.71 mmol) in 1,4-dioxane (5 mL) was added hexamethylditin (0.43 mL, 2. immol). The reaction mixture was purged with N2 for 10 mm. and to it was added Pd(Ph3P)4 (0.20 g, 0.17 mmol). The reaction mixture was purged once again with N2 for another 10 mm and heated at 110 C for 2 h. Then, after cooling to room temperature, compound 1A (0.43 g, 1.7lmmol) was added and the mixture was purged with N2 for 5 mm., followed by the addition of Pd(Ph3P)4 (0.2 g, 0.17 mmol). The reaction was again heated at 110 C for 18 h. The reaction mixture was concentrated under vacuum to give a crude residue, which was purified by preparative HPLC (Condition N) to provide 6-(4?-fluoro- [2,2?-bipyridinj -3-yl)imidazo [1,2-al pyridine-3 -carbonitrile 16 (0.38 mg, 0.89 mmol, 52.3 % yield). LC-MS: m/z = 317.1 [M+Hf?; ret.time 1.41 mm; condition C. ?H NMR (400 MHz, DMSO-d6) 3 ppm 8.93 - 8.89 (m, 1H), 8.60 - 8.57 (m, 1H), 8.27 - 8.19 (m, 3H), 8.03 - 7.97 (m, 1H), 7.77 - 7.72 (m, 1H), 7.42 - 7.37 (m, 1H), 7.34 - 7.27 (m, 1H). Compound 49 was synthesized by reacting 4 (reference: WO 2015157093 Al and WO 2014055955 Al) and <strong>[872365-91-8]2-bromo-6-(difluoromethyl)pyridine</strong> employing the experimental procedure described in Scheme 4 (Method-D). The crude residue was purified by preparative HPLC (condition-H) to yield 6-(6?-(difluoromethyl)- [2,2?-bipyridinj -3 -yl)imidazo[ 1,2- bjpyridazine-3-carbonitrile 49 (242 mg, 0.0604 mmol, 62.9 % yield). LCMS: m/z = 349.1 [M+Hf?; ret. time 1.53 mm. condition C. ?H NMR (400 MHz, DMSO-d6) oe ppm ppm 8.92 (dd, J4.6, 1.7 Hz, 1H), 8.36 (dd, J8.l, 1.0 Hz, 1H), 8.25 (d, J=9.3 Hz, 1H), 8.21 - 8.18 (m, 2H), 8.16 (t, J=7.8 Hz, 1H), 7.74 (dd, J=7.7, 4.8 Hz, 1H), 7.61 (d, J7.8 Hz, 1H), 7.43 (d, J9.5 Hz, 1H), 6.26 (s, 1H).

Reference： [1]Patent: WO2016/133838,2016,A1 .Location in patent: Paragraph 0212; 0244

8
[ 872365-91-8 ]
N-(2-((2-acetamidopyridin-4-yl)ethynyl)-4-chloropyridin-3-yl)-2,2,2-trifluoroacetamide [ No CAS ]
N-(4-(7-chloro-3-(6-(difluoromethyl)pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)pyridin-2-yl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere; Sealed tube;	A mixture of Example 61C (1.273 g, 3.33 mmol) and cesium carbonate (2.167 g, 6.65 mmol) was evacuated and backfilled with N2, then DMF (13.30 mL) and <strong>[872365-91-8]2-bromo-6-(difluoromethyl)pyridine</strong> (1.384 g, 6.65 mmol) were added. The mixture was sparged with N2 for 5 min, then 2nd generation XPhos precatalyst (0.131 g, 0.166 mmol) was added. The reaction was sparged with N2 for 2 min, then it was sealed and stirred at 120 C. for 2 h. The reaction was cooled to room temperature, diluted with THF (20 mL), filtered through Celite (washed with 60 mL THF followed by 100 mL 20% MeOH-CH2Cl2), and concentrated in vacuo. The residue was suspended in CH2Cl2 (25 mL) and the solids were collected by vacuum filtration (washed with 10 mL CH2Cl2) to provide crude Example 125A, which was used without further purification. LC-MS m/z 414 [M+H]+.

Reference： [1]Patent: US2016/176871,2016,A1 .Location in patent: Paragraph 0685-0686

9
[ 872365-91-8 ]
4-(3-(6-(difluoromethyl)pyridin-2-yl)-6-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)pyridin-2-amine [ No CAS ]

Reference： [1]Patent: US2016/176871,2016,A1

10
[ 872365-91-8 ]
N-(4-{3-[6-(difluoromethyl)pyridin-2-yl]-6-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl}pyridin-2-yl)-2-(dimethylamino)acetamide [ No CAS ]

Reference： [1]Patent: US2016/176871,2016,A1

11
[ 872365-91-8 ]
N-(2-((2-acetamidopyridin-4-yl)ethynyl)-5-methoxypyridin-3-yl)-2,2,2-trifluoroacetamide [ No CAS ]
N-(4-(3-(6-(difluoromethyl)pyridin-2-yl)-6-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)pyridin-2-yl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In acetonitrile; at 110℃; for 2h;Inert atmosphere; Sealed tube;	A mixture of Example 48B (0.360 g, 0.952 mmol) and cesium carbonate (0.620 g, 1.903 mmol) was evacuated and backfilled with N2, then MeCN (9.52 mL) and <strong>[872365-91-8]2-bromo-6-(difluoromethyl)pyridine</strong> (0.396 g, 1.903 mmol) were added. The mixture was sparged with N2 for 5 min, then tetrakis(triphenylphosphine)palladium(0) (0.055 g, 0.048 mmol) was added. The reaction was sparged with N2 for 1 min, then it was sealed and stirred at 110 C. for 2 h. The reaction was cooled to room temperature, diluted with 10% MeOH-CH2Cl2 (10 mL), and filtered through Celite (washed with 10% MeOH-CH2Cl2). The filtrate was concentrated in vacuo. The crude material was purified by flash chromatography (24 g silica gel with 5 g prepacked load cartridge; linear gradient 0-10% MeOH-CH2Cl2) to provide Example 117A (194 mg, 50%) as an off-white solid. LC-MS m/z 410 [M+H]+; 1H NMR (400 MHz, DMSO-d6) delta 12.00 (s, 1H), 10.49 (s, 1H), 8.35-8.30 (m, 2H), 8.27 (dd, J=5.3, 0.6 Hz, 1H), 8.24 (d, J=2.7 Hz, 1H), 8.05 (t, J=7.9 Hz, 1H), 7.54 (d, J=7.6 Hz, 1H), 7.37 (d, J=2.6 Hz, 1H), 7.21 (dd, J=5.1, 1.6 Hz, 1H), 6.66 (t, J=55.4 Hz, 1H), 3.90 (s, 3H), 2.08 (s, 3H).

Reference： [1]Patent: US2016/176871,2016,A1 .Location in patent: Paragraph 0674-0675

12
[ 872365-91-8 ]
2-chloro-4-phenoxypyrrolo[2,1-f][1,2,4]triazine [ No CAS ]
2-(6-(difluoromethyl)pyridin-2-yl)-4-phenoxypyrrolo[2,1-f][1,2,4]triazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
19.91%		To a sealed tube, was added <strong>[872365-91-8]2-bromo-6-(difluoromethyl)pyridine</strong> (200 mg, 0.962 mmol), hexamethylditin (0.199 mL, 0.962 mmol) and DMF (5 mL).The solution was degassed with argon and tetrakis(triphenylphosphine)palladium(0)(1 11 mg, 0.096 mmol) was added. The reaction mixture was stirred at 110 C for 4 h. An aliquot of the reaction mixture was diluted with methanol and analyzed by LCMS to ensure completeconversion. To the reaction mixture, was added 2-chloro-4-phenoxypyrrolo[2,1- J][1,2,4]triazine (547 mg, 2.227 mmol) and tetrakis(triphenylphosphine)palladium(0)(257 mg, 0.223 mmol). The solution was degassed with argon and stirred at 110C for 18 h. An aliquot of the reaction mixture was diluted with methanol and analyzed by LCMS to ensure complete conversion. The reaction mixture was partitioned between water andethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated. The crude residue was purified by silica gel column chromatography using hexane-ethyl acetate to get 2-(6-(difluoromethyl)pyridin-2-yl)-4-phenoxypyrrolo[2, 1- J][1,2,4]triazine (150 mg, 0.443 mmol, 19.91 % yield) as a pale brown solid. LCMS m/z 339.2 (M+H); rt 3.1 mm; Conditions E.

Reference： [1]Patent: WO2017/15425,2017,A1 .Location in patent: Page/Page column 78; 79

13
[ 872365-91-8 ]
N-{2-[6-(difluoromethyl)pyridin-2-yl]-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-4-yl}-3-fluoropyridin-4-amine [ No CAS ]

Reference： [1]Patent: WO2017/15425,2017,A1

14
[ 872365-91-8 ]
ethyl 2-(6-(difluoromethyl)pyridin-2-yl)-4-((3-fluoropyridin-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazine-5-carboxylate [ No CAS ]

Reference： [1]Patent: WO2017/15425,2017,A1

15
[ 872365-91-8 ]
(2-(6-(difluoromethyl)pyridin-2-yl)-4-((3-fluoropyridin-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methanol [ No CAS ]

Reference： [1]Patent: WO2017/15425,2017,A1

16
[ 872365-91-8 ]
(2-(6-(difluoromethyl)pyridin-2-yl)-4-((3-fluoropyridin-4-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl methanesulfonate [ No CAS ]

Reference： [1]Patent: WO2017/15425,2017,A1

17
[ 872365-91-8 ]
ethyl 2-chloro-4-phenoxypyrrolo[2,1-f][1,2,4]triazine-5-carboxylate [ No CAS ]
ethyl 2-(6-(difluoromethyl)pyridin-2-yl)-4-phenoxypyrrolo[2,1-f][1,2,4]triazine-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66.7%	With tetrakis(triphenylphosphine) palladium(0); hexamethyldistannane; In 1,4-dioxane; at 110℃; for 16h;Sealed tube; Inert atmosphere;	In a sealed tube, was taken ethyl 2-chloro-4-phenoxypyrrolo[2, 1 -J] [1 ,2,4]triazine-5-carboxylate (0.5 g, 1.574 mmol), <strong>[872365-91-8]2-bromo-6-(difluoromethyl)pyridine</strong> (0.192 mL, 1.574mmol), hexamethylditin (0.326 mL, 1.574 mmol) and dioxane (15 mL). The solution wasdegassed with argon and tetrakis(triphenylphosphine)palladium(0)(0. 182 g, 0.157 mmol)was added. The reaction mixture was stirred at 110 C for 16 h. An aliquot of thereaction mixture was diluted with methanol and analyzed by LCMS to ensure complete conversion. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated. Crude residue was purified by silica gel column chromatography (hexane-ethyl acetate) to getethyl 2-(6-(difluoromethyl)pyridin-2-yl)-4-phenoxypyrrolo[2, 1 -J] [1 ,2,4]triazine-5 - carboxylate (1.6 g, 3.90 mmol, 66.7% yield) as an off white solid. LCMS m/z 411.2 (M+H); rt 1.18 mm; Conditions B.

Reference： [1]Patent: WO2017/15425,2017,A1 .Location in patent: Page/Page column 105; 106; 293

18
[ 872365-91-8 ]
ethyl 2-chloro-4-phenoxypyrrolo[2,1-f][1,2,4]triazine-5-carboxylate [ No CAS ]
ethyl 4-phenoxy-2-(6-(trifluoromethyl)pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51.9%		In a 100 mL sealed tube was taken a solution of 2-bromo-6- (trifluoromethyl)pyridine (0.53 g, 2.36 mmol) in dioxane (20 mL), added hexamethylditin (1.15g, 3.53 mmol), PdCl2 (dppf)-CH2Cl2Adduct (0.096 g, 0.117 mmol), and heated to110 C for 1 h. To the reaction mixture was added ethyl 2-chloro-4-phenoxypyrrolo[2, 1-f][1,2,4]triazine-5-carboxylate (0.5 g, 1.574 mmol) and PdC12(dppf)-CH2Cl2Adduct(0.064 g, 0.079 mmol) and heated to 110 C overnight. The reaction mixture wasconcentrated under reduced pressure. To the residue was added ethyl acetate, filteredthrough Celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with 0-20% ethyl acetate in petroleumether) to yield the intermediate 64A (0.35g, 0.8 17 mmol, 5 1.9%). LCMS m/z 429.2 (M+H); rt 3.49 mm; Conditions E.

Reference： [1]Patent: WO2017/15425,2017,A1 .Location in patent: Page/Page column 298; 299

19
[ 872365-91-8 ]
2-chloro-4-phenoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine [ No CAS ]
2-(6-(difluoromethyl)pyridin-2-yl)-4-phenoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo [2,3-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35.5%		To <strong>[872365-91-8]2-bromo-6-(difluoromethyl)pyridine</strong> (0.6 g, 2.88 mmol) and hexamethylditin (0.7 18 mL, 3.46 mmol) was added 1,4-dioxane (15 mL). The reaction mixture was degassed and then added tetrakis(triphenylphosphine)palladium(0) (0.333 g, 0.288 mmol). The mixture was stirred at 110 CC under microwave irradiation for 90 mm.LCMS indicated completion of reaction. The reaction mixture was cooled to room temperature, filtered through a pad of cilte and concentrated. To the resulting crude stannyl intermediate was added 2-chloro-4-phenoxy-7-((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-djpyrimidine (1.084 g, 2.88 mmol) and 1,4-dioxane (15 mL). To the resulting reaction mixture was added tetrakis(triphenylphosphine)palladium(0) (0.333 g,0.288 mmol)) and heated to 110 C in 100 mL sealed tube for 12 h. The mixture was cooled to room temperature and filtered through a pad of cilte. The filtrate was conecntrated. The resulting crude compound was purified by silica gel chromatography (10-15% ethyl acetate in petroleum ether) to get 2-(6-(difluoromethyl)pyridin-2-yl)-4- phenoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d pyrimidine (0.6 g, 1.024mmol, 35.5 % yield) as a pale yellow liquid. LCMS m/z 469.2 (M+H); ft 3.03 mm; conditions E.

Reference： [1]Patent: WO2017/19757,2017,A1 .Location in patent: Page/Page column 50; 51

20
[ 872365-91-8 ]
2-(6-(difluoromethyl)pyridin-2-yl)-9-(4-methoxybenzyl)-6-phenoxy-9H-purine [ No CAS ]

Reference： [1]Patent: WO2017/35118,2017,A1

21
[ 872365-91-8 ]
2-(6-(difluoromethyl)pyridin-2-yl)-N-(3-fluoropyridin-4-yl)-9-(4-methoxybenzyl)-9H-purin-6-amine [ No CAS ]

Reference： [1]Patent: WO2017/35118,2017,A1

22
[ 872365-91-8 ]
2-(6-(difluoromethyl)pyridin-2-yl)-N-(3-fluoropyridin-4-yl)-9H-purin-6-amine dihydrochloride [ No CAS ]

Reference： [1]Patent: WO2017/35118,2017,A1

23
[ 872365-91-8 ]
N-(2-chloro-5-fluoropyridin-4-yl)-2-(6-(difluoromethyl)pyridin-2-yl)-9-(4-methoxybenzyl)-9H-purin-6-amine [ No CAS ]

Reference： [1]Patent: WO2017/35118,2017,A1

24
[ 872365-91-8 ]
N-(4-((2-(6-(difluoromethyl)pyridin-2-yl)-9-(4-methoxybenzyl)-9H-purin-6-yl)amino)-5-fluoropyridin-2-yl)acetamide [ No CAS ]

Reference： [1]Patent: WO2017/35118,2017,A1

25
[ 872365-91-8 ]
[ 661-69-8 ]
2-(difluoromethyl)-6-(trimethylstannyl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 110℃; for 1.5h;Inert atmosphere; Microwave irradiation;	To a nitrogen purged solution of <strong>[872365-91-8]2-bromo-6-(difluoromethyl)pyridine</strong> (600 mg, 2.88 mmol) in 1,4-dioxane (10 mL) in a 30 mL microwave vial, was added hexamethylditin (0.424 mL, 2.045 mmol) and tetrakis(triphenylphosphine)palladium(0)(79 mg, 0.068 mmol). The resulting solution was purged with nitrogen for five mm, subjected to microwave irradiation at 110 C for 1.5 h. The cmde trimethylstannylpyridine intermediate was filtered through a pad of Celite. The filtrate was purged with nitrogen and used in the next step without purification. To the nitrogen purged solution of 2-(difluoromethyl)-6-(trimethylstannyl)pyridine (842 mg, 2.88 mmol)in a 100 mL sealed tube, 2-chloro-9-(4-methoxybenzyl)-6-phenoxy-9H-Purine (500 mg,1.363 mmol), tetrakis(triphenylphosphine)palladium(0) (79 mg, 0.068 mmol) was added. The resulting solution was heated at 110 CC for 15 h. An aliquot of the reaction mixture was analyzed by LCMS to ensure completion of reaction. The reaction mixture was concentrated and the residue was purified by silica gel chromatography using 30-100%ethyl acetate in hexanes to get 2-(6-(difluoromethyl)pyridin-2-yl)-9-(4-methoxybenzyl)-6- phenoxy-9H-Purine (350 mg, 0.762 mmol, 55.9 %yield) as off brown solid. LCMS: m/z 460.0 (M+H); ft 4.15 mm; conditions E.
	With tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 105℃; for 14h;Inert atmosphere;	To a microwave vial were added <strong>[872365-91-8]2-bromo-6-(difluoromethyl)pyridine</strong> (310 mg, 1.490 mmol), 1,1,1,2,2,2-hexamethyldistannane (CAS: 661-69-8, Sigma-Aldrich) (586 mg, 1.788 mmol) and 1,4-dioxane (6 mL). The reaction mixture was purged with nitrogen for 2 mm. and Pd(Ph3P)4 (172 mg, 0.149 mmol) was added. The mixture was purgedagain with nitrogen and heated at 105 C for 14 h. The reaction was then cooled to RT, passed through a pad of Celite and washed with EtOAc. The filtrate was concentrated. The crude product was used for the next step. MS (ES): m/z = 275.9 [M+Hf HPLC Ret.Time 0.54 mi (HPLC Method C).

Reference： [1]Patent: WO2017/35118,2017,A1 .Location in patent: Page/Page column 44; 45
[2]Patent: WO2018/132279,2018,A1 .Location in patent: Page/Page column 44; 45

26
[ 67-56-1 ]
[ 201230-82-2 ]
[ 872365-91-8 ]
[ 1379375-24-2 ]