[ CAS No. 870238-67-8 ] {[proInfo.proName]}

Name: 870238-67-8|2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile|97%
Brand: Ambeed
SKU: A214282
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Quality Control of [ 870238-67-8 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 870238-67-8 ]

SDS Specification

Alternatived Products of [ 870238-67-8 ]

Product Details of [ 870238-67-8 ]

CAS No. :	870238-67-8	MDL No. :	MFCD16996321
Formula :	C₁₃H₁₅BFNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DMJGKVYFBOCENL-UHFFFAOYSA-N
M.W :	247.07	Pubchem ID :	51350951
Synonyms :

Calculated chemistry of [ 870238-67-8 ]

Physicochemical Properties

Num. heavy atoms :	18
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.46
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	67.59
TPSA :	42.25 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-5.87 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	2.73
Log Po/w (WLOGP) :	2.42
Log Po/w (MLOGP) :	1.45
Log Po/w (SILICOS-IT) :	2.26
Consensus Log Po/w :	1.77

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.27
Solubility :	0.132 mg/ml ; 0.000534 mol/l
Class :	Soluble
Log S (Ali) :	-3.27
Solubility :	0.132 mg/ml ; 0.000535 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.37
Solubility :	0.0106 mg/ml ; 0.0000429 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.91

Safety of [ 870238-67-8 ]

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

Application In Synthesis of [ 870238-67-8 ]

* 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 [ 870238-67-8 ]
Downstream synthetic route of [ 870238-67-8 ]

[ 870238-67-8 ] Synthesis Path-Upstream 1~3

1
[ 105942-08-3 ]
[ 73183-34-3 ]
[ 870238-67-8 ]

Yield	Reaction Conditions	Operation in experiment
73%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In dimethyl sulfoxide at 80℃; for 4 h; Inert atmosphere	Under nitrogen, 4-bromo-2-fluorobenzonitrile (4.0 g, 20 mmol), bis(pinacolato)diboron (3.8 g, 30 mmol) and potassium acetate (6.1 g, 60 mmol) were suspended in DMSO (50 mL), Pd(dppf)Cl₂(1.5 g, 0.2 mmol) was added. The mixture was stirred at 80° C. for 4 hours. The mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL×3). The organic layers were combined, washed with water (50 mL×3) and saturated brine (50 mL) in sequence, dried over anhydrous sodium sulfate, then filtrated, the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (petroleum ether:ethyl acetate=50:1 to 10:1) to give compound 56-a (3.6 g, yield: 73percent). (0367) ¹H-NMR (400 MHz, CD₃OD) δ: 7.62 (m, 3H), 1.35 (s, 12H) ppm

Reference： [1] Patent: US2015/336982, 2015, A1, . Location in patent: Paragraph 0365; 0366; 0367
[2] Patent: WO2009/32861, 2009, A1, . Location in patent: Page/Page column 45; 46
[3] Patent: WO2010/59658, 2010, A1, . Location in patent: Page/Page column 149

2
[ 843663-18-3 ]
[ 76-09-5 ]
[ 870238-67-8 ]

Yield	Reaction Conditions	Operation in experiment
85.6%	at 20 - 40℃;	Step 2. A suspension of the crude 3-fluoro-4-cyanophenyl boronic acid (9.2 Kg, 55.8 mol) in cyclohexane (150 L) was treated with pinacol (13.2 Kg, 111.6 mol, 2.0 equiv) at room temperature, and the resulting reaction mixture was warmed to 40° C. for 4 h. When TLC and LC/MS showed that the reaction was deemed complete, the reaction mixture was cooled down to room temperature before being washed with water (2*75 L). The organic layer was then dried over magnesium sulfate (MgSO₄) and concentrated under the reduced pressure to afford 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (19, 11.8 Kg, 13.8 Kg theoretical, 85.6percent yield) as a light yellow solid.

Reference： [1] Patent: US2009/291956, 2009, A1, . Location in patent: Page/Page column 25; 26

3
[ 57381-51-8 ]
[ 25015-63-8 ]
[ 870238-67-8 ]
[ 394-47-8 ]

Reference： [1] Heterocycles, 2010, vol. 80, # 1, p. 213 - 218

[ 870238-67-8 ] Synthesis Path-Downstream 1~37

1
[ 870238-67-8 ]
methyl 3-(2-(3-bromophenyl)-2-(tert-butoxycarbonyl)-ethyl)-benzoate [ No CAS ]
[ 898803-05-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 100℃;	77B: 3-[2-tert-Butoxycarbonylamino-2-(4'-cyano-3'-fluoro-biphenyl-3-yl)-ethyl]-benzoic acid methyl ester: Compound 77A (0.54 g, 1.62 mmol) was treated with di-tert-butyldicarbonate (0.35 g, 1.62 mmol) and triethylamine (1 mL) in anhydrous THF (10 mL). The reaction mixture was allowed to stir at rt for 4 h, quenched with water (100 mL) and organics extracted with ethyl acetate (2×25 mL), dried (MgSO4), filtered and evaporated to afford methyl 3-(2-(3-bromophenyl)-2-(tert-butoxycarbonyl) ethyl) benzoate (oil, 0.48 g). The oil was re-dissolved in dioxane (25 mL) and to this solution was added <strong>[870238-67-8]2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile</strong> (0.25 g), potassium phosphate (0.5 g) and degassed for 0.5 h. Tetrakis(triphenylphosphine) palladium (0) catalyst was added and the reaction mixture was heated at 100 C. overnight. The reaction mixture was diluted with water (100 mL) and the organics extracted with ethyl acetate (2×25 mL) dried (MgSO4), filtered and evaporated to a yellow oil. Purification via column chromatography on silica gel (gradient elution 10-100% ethylacetate:hexane) afforded 0.20 g of compound 77B as a colorless solid. 1HNMR(CDCl3 400): 7.83 (1H, J=6.4 Hz, d), 7.80 (1H, s), 7.60 (1H, t), 7.40-7.17 (6H, m), 6.60 (2H, m), 5.10 (1H, bs), 4.90 (1H, bs), 3.85 (3H, s), 3.07 (2H, J=7.1 Hz, d), 1.34 (9H, s). LC/MS m/z 497.30 (M+H)+.

Reference： [1]Patent: US2006/154915,2006,A1 .Location in patent: Page/Page column 34

2
[ 3934-20-1 ]
[ 870238-67-8 ]
[ 1129540-59-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 90℃;in a sealed tube; Inert atmosphere;	General procedure B: Suzuki coupling of 2,4-dicholoripyrimidine with arylboronate ester or arylboronic acid.[0114] A mixture of <strong>[870238-67-8]2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile</strong> (2.47 g, 10 mmol), 2,4-dichloropyrimidine (1.64 g, 11 mmol), Pd(PPh3)4 (0.58 g, 0.50 mmol), K2CO3 (15 mL of 2 M aq. solution) and DME (30 mL) was purged with Ar for 10 min, then heated in a sealed tube at 90C overnight. The reaction mixture was cooled down to room temperature, extracted with EtOAc (2x). The combined organic solution was dried over <n="48"/>anhydrous MgSO4 and concentrated in vacuo to give an oil. Purification of this material by column chromatography on silica gel (25 % EtOAc / hexane) provided the desired product as an off-white solid. 1H NMR (CDCl3, 400 MHz) delta 8.85 (d, 1H), 8.09 (d, 1H), 8.06 (d, 1H), 7.87 (dd, 1H), 7.75 (d, 1H).

Reference： [1]Patent: WO2009/32861,2009,A1 .Location in patent: Page/Page column 46; 47

3
[ 105942-08-3 ]
[ 73183-34-3 ]
[ 870238-67-8 ]

Yield	Reaction Conditions	Operation in experiment
89%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; dimethyl sulfoxide; at 105℃; for 3.0h;Inert atmosphere;	A mixture of 4-bromo-2-fluorobenzonitrile (1.0 g, 5.0 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.3 g, 5.0 mmol), potassium acetate (5.9 g, 20.0 mmol) and Pd(dppf)Cl2 (2.0 g, 1.0 mmol) in DMSO (50 ml.) and 1,4-dioxane (10 ml.) was heated at 105 C under N2 for 3 h. [82] The mixture was diluted with EtOAc (200 ml.) and washed with water (100 ml. x 3). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and the residue was purified by column chromatography (Pet. ether/EtOAc= 100/0 to 50/1) to give the title compound (1.1 g, 89%) as a white solid, which was used directly in the next step.
73%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In dimethyl sulfoxide; at 80℃; for 4.0h;Inert atmosphere;	Under nitrogen, 4-bromo-2-fluorobenzonitrile (4.0 g, 20 mmol), bis(pinacolato)diboron (3.8 g, 30 mmol) and potassium acetate (6.1 g, 60 mmol) were suspended in DMSO (50 mL), Pd(dppf)Cl2 (1.5 g, 0.2 mmol) was added. The mixture was stirred at 80 C. for 4 hours. The mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL×3). The organic layers were combined, washed with water (50 mL×3) and saturated brine (50 mL) in sequence, dried over anhydrous sodium sulfate, then filtrated, the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (petroleum ether:ethyl acetate=50:1 to 10:1) to give compound 56-a (3.6 g, yield: 73%). (0367) 1H-NMR (400 MHz, CD3OD) delta: 7.62 (m, 3H), 1.35 (s, 12H) ppm
	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dichloromethane; dimethyl sulfoxide; at 100℃;in a sealed tube;	Example 12-Fluoro-4-(2-(4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylamino)pyrimidin-4-yl)benzonitrilePart I: 2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile <n="47"/>General procedure A: Preparation of arylboronate ester from aryl halide.[0113] A mixture of 4-bromo-2-fluorobenzonitrile (4.00 g, 20 mmol), bis(pinacolato)diboron (6.60 g, 26 mmol), Pd(dppf)Cl2(CH2Cl2) (0.82 g, 1.0 mmol), KOAc (5.89 g, 60 mmol) and DMSO (20 mL) was heated in a sealed tube at 100C overnight. The reaction mixture was cooled down to room temperature, diluted with water and extracted with ethyl acetate (2x). The combined organic solution was dried over anhydrous MgSO4 and concentrated in vacuo to give an oil. Purification of this material by column chromatography on silica gel (5% EtOAc / hexane) provided the desired product as a yellow solid. 1H NMR (CDCl3, 400 MHz) delta 7.68 (d, 1H), 7.64 (d, 1H), 7.62 (d, 1H), 1.37 (s, 12H).

With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; dimethyl sulfoxide; at 110℃;Inert atmosphere;

Intermediate 68; 2-Fluoro-4-(4A5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile; A mixture of 4-bromo-2-fluorobenzonitrile (30 g, 150 mmol), bis(pinacolato)diboron (49.5 g, 195 mmol), potassium acetate (29.4 g, 300 mmol), and Pd(dppf)CI2«CH2CI2 (12.2 g,15.0 mmol) in DMSO and 1 ,4-dioxane (65 ml.) was heated overnight at 1 10 0C under nitrogen. The reaction mixture was cooled to room temperature, filtered throughKieselguhr, and concentrated. The resilting residue was purified by SiO2 chromatography(100:1 petroleum ethe?EtOAc) to afford the title compound (35 g) as a white solid. LC-MS (ES) m/z = 247 [M+H]+.

Reference： [1]Patent: WO2019/243491,2019,A1 .Location in patent: Page/Page column 81-82
[2]Patent: US2015/336982,2015,A1 .Location in patent: Paragraph 0365; 0366; 0367
[3]Patent: WO2009/32861,2009,A1 .Location in patent: Page/Page column 45; 46
[4]Patent: WO2010/59658,2010,A1 .Location in patent: Page/Page column 149

4
[ 843663-18-3 ]
[ 76-09-5 ]
[ 870238-67-8 ]

Yield	Reaction Conditions	Operation in experiment
85.6%	In cyclohexane; at 20 - 40℃;	Step 2. A suspension of the crude 3-fluoro-4-cyanophenyl boronic acid (9.2 Kg, 55.8 mol) in cyclohexane (150 L) was treated with pinacol (13.2 Kg, 111.6 mol, 2.0 equiv) at room temperature, and the resulting reaction mixture was warmed to 40 C. for 4 h. When TLC and LC/MS showed that the reaction was deemed complete, the reaction mixture was cooled down to room temperature before being washed with water (2*75 L). The organic layer was then dried over magnesium sulfate (MgSO4) and concentrated under the reduced pressure to afford 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (19, 11.8 Kg, 13.8 Kg theoretical, 85.6% yield) as a light yellow solid.

Reference： [1]Patent: US2009/291956,2009,A1 .Location in patent: Page/Page column 25; 26

5
[ 870238-67-8 ]
[ 69249-22-5 ]
[ 1197377-47-1 ]

Yield	Reaction Conditions	Operation in experiment
82.3%	With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 20 - 86℃;Inert atmosphere;	Example 25 4-(3-Amino-1,2,4-triazin-6-yl)-2-fluorobenzonitrile (20) A mixture of <strong>[69249-22-5]6-bromo-1,2,4-triazin-3-amine</strong> (17, 100.0 g, 571.47 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (19, 145.43 g, 588.61 mmol, 1.03 equiv) in 1,4-dioxane (1200 mL) was stirred at room temperature for 10 min before potassium carbonate (K2CO3, 355.4 g, 2572 mmol) in water (600 mL) was added to give a deep red solution. The mixture was degassed by bubbling with nitrogen for 10 min before 1,1'-bis(diphenyl phosphino)ferrocene dichloropalladium(II) complex with dichloromethane (1:1) (Pd(dppf)2Cl2, 14.14 g, 17.14 mmol, 0.03 equiv) was added at room temperature. The resulting reaction mixture was degassed by bubbling with nitrogen for 10 min and then heated at 86 C. under nitrogen. After 2 h, HPLC showed that the reaction was deemed complete, and the reaction mixture was cooled to room temperature and then to 0-5 C. with an ice-water bath. 1,4-Dioxane (400 mL) was added to the cooled reaction mixture before a solution of 3.3 M aqueous hydrochloric acid solution (HCl, 1900 mL) was added dropwise with stirring to adjust pH to 0.40-0.93. The mixture was stirred at room temperature for 30 min and filtered. The solid collected was stirred with 1,4-dioxane (260 mL) and then added 1N HCl (400 mL). The mixture was stirred at room temperature for 10 min and filtered. The filtrate was combined with the filtrate obtained earlier and washed with ethyl acetate (EtOAc, 22 L). The combined ethyl acetate extracts was extracted with 1 N aqueous hydrochloric acid solution (HCl, 3200 mL). The combined aqueous solution was then treated with activated charcoal (20 g) and stirred at room temperature for 30 min. The mixture was filtered through a celite bed and the filtrate was cooled to 0-5 C. with an ice-water bath. A solution of 50% of sodium hydroxide in water (NaOH, 240 mL, 4500 mmol) was added dropwise at 5-12 C. to adjust pH to 10.6-11.6. The mixture was stirred at 0-5 C. for 30 min and then filtered. The solids collected were washed with aqueous ammonium hydroxide (1 to 3 of 28% concentrated NH4OH to water, 1900 mL) and dried under vacuum at 40-45 C. to constant weight to afford 4-(3-amino-1,2,4-triazin-6-yl)-2-fluorobenzonitrile (20, 101.2 g, 122.9 g theoretical, 82.3% yield) as a off-white powder.

Reference： [1]Patent: US2009/291956,2009,A1 .Location in patent: Page/Page column 25; 26

6
[ 57381-51-8 ]
[ 25015-63-8 ]
[ 870238-67-8 ]
[ 394-47-8 ]

Reference： [1]Heterocycles,2010,vol. 80,p. 213 - 218

7
[ 870238-67-8 ]
[ 944804-72-2 ]
[ 1221541-29-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 1559 - 1564

8
[ 122862-58-2 ]
[ 870238-67-8 ]
[ 1227910-34-0 ]

Yield	Reaction Conditions	Operation in experiment
43%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃;Inert atmosphere;	Intermediate 40; 4-{2-Amino-6-r(cvclohexylmethyl)aminol-4-pyrimidinyl}-2-fluorobenzonitrile; To beta-chloro-Lambda/^cyclohexylmethyl^^-pyrimidinediamine^i ^ g, 5 mmol), 2-fluoro-4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (1.48 g, 6 mmol) and Pd(PPh3)4 (289 mg, 0.25 mmol) in 1 ,4-dioxane (40 mL) was added a solution of Na2CO3 (636 mg, 6 mmol) in water (10 mL), and the resulting mixture was degassed and then re-charged with nitrogen (3X). The reaction mixture was stirred overnight at 100 0C. The reaction was cooled to room temperature, and the organic layer was separated and concentrated. The resulting residue was purified by SiO2 chromatography (eluent: 1/2 EtOAc/petroleum ether) to afford the title compound (0.7 g, 43%) as a white solid. LC-MS (ES) m/z = 326 [M+H]+.

Reference： [1]Patent: WO2010/59658,2010,A1 .Location in patent: Page/Page column 127

9
[ 870238-67-8 ]
[ 122862-39-9 ]
[ 1227910-46-4 ]

Yield	Reaction Conditions	Operation in experiment
66%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 95℃;Inert atmosphere;	Intermediate 44; 4-{2-Amino-6-r(2-phenylethyl)aminol-4-pyrimidinyl}-2-fluorobenzonitrile; To a mixture of 6-chloro-Lambda/4-(2-phenylethyl)-2,4-pyrimidinediamine_(0.9 g, 3.6 mmol), 2- fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (1.06 g, 4.3 mmol) and Pd(PPh3)4 (289 mg, 0.25 mmol) in 1 ,4-dioxane (20OmL) was added a solution of Na2CO3 (320 mg, 3 mmol) in water (20 mL), and the resulting mixture was degassed and re- charged with N2 (3X). The resulting reaction mixture was stirred overnight at 95 0C, then allowed to cool to room temperature. The organic layer was separated and concentrated, and the resulting crude product was purified by flash chromatography on SiO2 (gradient: 1 :5 to 2:1 EtO Ac/petroleum ether) to afford the title compound (0.8g, 66%) as light yellow solid. LC-MS (ES) m/z = 334 [M+H]+.

Reference： [1]Patent: WO2010/59658,2010,A1 .Location in patent: Page/Page column 132

10
[ 870238-67-8 ]
[ 6307-36-4 ]
C₁₂H₉FN₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃;Inert atmosphere; Sealed tube;	Example 3; 6-r2-Amino-6-(methylthio)-4-pyrimidinyll-1/-/-indazol-3-amine; To 2-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (16.5 g, 66.6 mmol) and 4-chloro-6-(methylthio)-2-pyrimidinamine (11.7 g, 66.6 mmol) were added 1 ,4- dioxane (300 ml.) and saturated aqueous NaHCO3 (150 ml.) and the mixture was degassed with nitrogen gas for 15 minutes into a sealable tube. Pd(Ph3P)4 (2.3 g, 2.0 mmol) was added, the tube was sealed, and the reaction mixture was stirred overnight at 100 C. The mixture was cooled to room temperature and poured onto water where a precipitate was formed. The mixture was filtered and the solid was transferred to a sealable tube. Dioxane (300 ml.) was added followed by hydrazine monohydrate (32.7 ml_, 666 mmol) and the reaction mixture was stirred overnight at 100 0C into the sealed tube. The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was poured onto water and filtered again. The aqueous filtrate was poured onto a separatory funnel and extracted with EtOAc (3X). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. To the resulting residue was added 1 ,4-dioxane (100 ml.) and the mixture was sonicated for 30 minutes. The solids were filtered affording the crude title compound (11.5 g) as a yellow solid. The filtrate was concentrated and the resulting residue was dissolved in dioxane and purified via flash chromatography on SiO2 (gradient: 99:1 :0.1 CHCI3/CH3OH/NH4OH to 90:10:1 CHCI3/CH3OH/NH4OH) to afford the title compound (4.5 g) as a pale yellow solid. LC-MS (ES) m/z = 273 [M+H]+. 1H NMR (400 MHz, DMSOd6): delta 2.53 (s, 3H), 5.41 (s, 2H), 6.70 (s, 2H), 7.06 (s, 1 H), 7.58 (dd, J = 8.5, 1.1 Hz, 1 H), 7.74 (d, J = 8.6 Hz, 1 H), 7.98 (s, 1 H), 1 1.60 (s, 1 H).

Reference： [1]Patent: WO2010/59658,2010,A1 .Location in patent: Page/Page column 88-89

11
[ 870238-67-8 ]
[ 122862-11-7 ]
[ 1227910-73-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In 1,4-dioxane; water; at 100℃; for 16.0h;Inert atmosphere;	Intermediate 70; 4-(2-Amino-6-[(2-chlorophenyl)methyl1amino}-4-PVrimidinyl)-2-fluorobenzonitrile; A mixture of 6-chloro-Lambda/4-[(2-chlorophenyl)methyl]-2,4-pyrimidinediamine (1.2 g, 4.46 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (1.32 g, 5.35 mmol) in 1 ,4-dioxane (14.6 ml.) and a solution of NaHCOs (3.12 mmol) in water (20 ml.) was protected with N2. Pd(Ph3P)4 (100 mg, 0.087 mmol) was added, and the reaction mixture was heated at 100 0C for 16 hours. The mixture was decanted to remove the solids, and the resulting solution was concentrated to dryness. The crude material was purified by SiO2 chromatography (1 :2 THF:petroleum ether) to afford the title compound (800 mg) as a yellow solid. LC-MS (ES) m/z = 354 [M+H]+.

Reference： [1]Patent: WO2010/59658,2010,A1 .Location in patent: Page/Page column 149-150

12
[ 870238-67-8 ]
[ 1227910-85-1 ]
[ 1227910-86-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 110℃; for 3.5h;Inert atmosphere;	Intermediate 73; 4-(2-Amino-6-{ri-(phenylmethyl)cvclopropyllamino}-4-pyrimidinyl)-2-fluorobenzonitrile; A mixture of 6-chloro-Lambda/4-[1-(phenylmethyl)cyclopropyl]-2,4-pyrimidinediamine (185 mg, 0.67 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (247 mg, 1 mmol), Pd(PPh3)4 (81 mg, 0.07 mmol) and Na2CO3 (178 mg, 1.68 mmol) in 1 ,4-dioxane (30 ml.) and water (10 ml.) was stirred and heated at 1 10 0C for 3.5 hours under nitrogen. Then the mixture was cooled to room temperature and concentrated. The resulting residue was portioned between EtOAc and water. The aqueous was extracted with EtOAc (2 x 50 ml_), and the organics were dried (MgSO4), filtered, concentrated to dryness, and purified by SGC using a petroleum ether to 4:1 petroleum ether/ EtOAc to 1 :1 petroleum ether/EtOAc as eluent to afford the title compound (124 mg) as a brown oil solid. LC-MS (ES) m/z = 360 [M+H]+.

Reference： [1]Patent: WO2010/59658,2010,A1 .Location in patent: Page/Page column 156-157

13
[ 870238-67-8 ]
[ 1227910-89-5 ]
[ 1227910-90-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 140℃; for 0.5h;microwave irradiation;	Intermediate 77; 4-{2-Amino-6-r(1 ,1-dimethyl-2-phenylethyl)aminol-4-pyrimidinyl}-2-fluorobenzonitrile; A mixture of 6-chloro-Lambda/4-(1 ,1-dimethyl-2-phenylethyl)-2,4-pyrimidinediamine (338 mg, 1.22 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (452 mg, 1.83 mmol), Pd(PPh3)4 (139 mg, 0.12 mmol) and Na2CO3 (323 mg, 3.05 mmol) in 1 ,4- dioxane (6 ml.) and water (2 ml.) was stirred and heated at 140 0C for 30 min in a Biotage Initiator microwave synthesizer. The reaction mixture was cooled to room temperature and concentrated to dryness, and the resulting residue was partitioned between EtOAc and water. The aqueous layer was extracted by EtOAc (3 X 50 ml_), and the combined organic layers were dried over Na2SO4, filtered and concentrated to dryness. Purification by RPHPLC with CH3CN in water (0.01 % ammonium hydrogen carbonate)(gradient: from 70% to 80% in 7.5 min, flow rate: 30 mL/min), afforded the title compound (210 mg) as a white solid. LC-MS (ES) m/z = 362 [M+H]+.

Reference： [1]Patent: WO2010/59658,2010,A1 .Location in patent: Page/Page column 159

14
[ 870238-67-8 ]
[ 1227910-95-3 ]
[ 1227910-96-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 140℃; for 0.666667h;microwave irradiation;	Intermediate 83; 4-(2-Amino-6-{methvir(1 f?)-1-methyl-2-phenylethyllamino}-4-pyrimidinyl)-2- fluorobenzonitrile; To a mixture of 6-chloro-Lambda/4-methyl-Lambda/4-[(1 /?)-1-methyl-2-phenylethyl]-2,4- pyrimidinediamine (0.4 g, 1.45 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)benzonitrile (0.46 g, 1.88 mmol) and Na2CO3 (0.38 g, 3.63 mmol) in 1 ,4-dioxane (6 ml.) and water (3 ml.) was added Pd(PPh3)4 (16 mg, 0.015 mmol), the reaction mixture was heated at 140 0C under microwave conditions with stirring for 40 minutes. The mixture was filtered and concentrated, and the resulting residue was purified by reverse phase chromatography using CH3CN in water from 45% to 55% (0.5% ammonium hydrogen carbonate in water) to afford the title compound (0.42 g) as a yellow solid. LC- MS (ES) m/z = 362 [M+H]+.

Reference： [1]Patent: WO2010/59658,2010,A1 .Location in patent: Page/Page column 162-163

15
[ 870238-67-8 ]
[ 147406-83-5 ]
[ 1227910-98-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 120℃; for 16.0h;Inert atmosphere;	Intermediate 85; 4-[2-Amino-6-(2,3-dihydro-1 /-/-inden-1-ylamino)-4-pyrimidinyl1-2-fluorobenzonitrile; A mixture of 6-chloro-Lambda/4-(2,3-dihydro-1/-/-inden-1-yl)-2,4-pyrimidinediamine (700 mg, 2.69 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (797 mg, 3.23 mmol) in 1 ,4-dioxane (150 ml.) and a solution of NaHCO3 (903 mg, 10.76 mmol) in water (50 ml.) was protected with nitrogen. Pd(Ph3P)4 (31 mg, 0.0269mmol) was added, and the reaction mixture was heated at 120 0C for 16 hours. The mixture was decanted to remove the solids, and the solution was concentrated to dryness. The crude material was purified by SiO2 chromatography eluting with 1 :1 THF:petroleum ether to afford the title compound (500 mg) as a yellow solid. LC-MS (ES) m/z = 246 [M+H]+.

Reference： [1]Patent: WO2010/59658,2010,A1 .Location in patent: Page/Page column 164

16
[ 870238-67-8 ]
[ 1227911-91-2 ]
[ 1227911-92-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 140℃; for 1.0h;microwave irradiation;	Intermediate 158; 4-(2-Amino-6-{2-r4-(4-chlorophenyl)-1 /-/-imidazol-2-yll-4-morpholinyl}-4-Pyrimidinyl)-2- fluorobenzonitrile; A mixture of 4-chloro-6-{2-[4-(4-chlorophenyl)-1 H-imidazol-2-yl]-4-morpholinyl}-2- pyrimidinamine (300 mg, 0.767 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)benzonitrile (246 mg, 0.997 mmol), Na2CO3 (203 mg, 1.917 mmol) and Pd(PPh3)4 (89 mg, 0.077 mmol) in 1 ,4-dioxane (6 ml.) and water (2 ml.) was heated at 140 0C under microwave condition with stirring for 1 hour. The mixture was filtered, washed with EtOAc (150 ml_), evaporated, and then chromatographed to afford the title compound (305 mg). LC-MS (ES) m/z = 476 [M+H]+.

Reference： [1]Patent: WO2010/59658,2010,A1 .Location in patent: Page/Page column 227

17
[ 870238-67-8 ]
[ 1227911-98-9 ]
[ 1227911-99-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 140℃; for 1.0h;microwave irradiation;	Intermediate 164; 4-{2-Amino-6-[2-(4,5,6,7-tetrahvdro-1 /-/-benzimidazol-2-yl)-4-morpholinyl1-4-pyrimidinyl}-2- fluorobenzonitrile; A mixture of 4-chloro-6-[2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)-4-morpholinyl]-2- pyrimidinamine (208 mg, 0.623 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (200 mg, 0.809 mmol), Na2CO3 (165 mg, 1.557 mmol) and Pd(PPh3)4 (72 mg, 0.062 mmol) in 1 ,4-dioxane (6 mL) and water (2 mL) was heated at 140 0C under microwave condition with stirring for 1 hour. The mixture was filtered, washed by EtOAc(150 mL), evaporated, and chromatographed (PE-EtOAc, 3:1 ) to afford the title compound (150 mg) as a yellow solid. LC-MS(ES) m/z = 420 [M+H]+ .

Reference： [1]Patent: WO2010/59658,2010,A1 .Location in patent: Page/Page column 230

18
[ 870238-67-8 ]
[ 1227912-04-0 ]
[ 1227912-05-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 140℃; for 1.0h;microwave irradiation;	Intermediate 171; 4-{2-Amino-6-r2-(4-phenyl-1 /-/-imidazol-2-yl)-4-morpholinyll-4-pyrimidinyl}-2- fluorobenzonitrile; A mixture of crude 4-chloro-6-[2-(4-phenyl-1 /-/-imidazol-2-yl)-4-morpholinyl]-2- pyrimidinamine, 2-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (765 mg, 3.10 mmol), Na2CO3 (631 mg, 5.96 mmol) and Pd(PPh3)4 (275 mg, 0.238 mmol) in 1 ,4-dioxane (6 ml.) and water (2 ml.) was heated at 140 0C under microwave conditions with stirring for 1.0 hour. The mixture was filtered, washed by EtOAc (150 ml_), and concentrated to afford the crude title compound (1.3 g) as a yellow solid. This material was combined with another batch of crude title compound (100 mg). The combined material was washed by EtOAc (150 ml_), and concentrated. The resulting residue was purified by silica gel chromatography using EtOAc in petroleum ether from 50% to 70% to afford the title compound (400 mg) as a light yellow solid. LC-MS (ES) m/z = 442 [M+H]+.

Reference： [1]Patent: WO2010/59658,2010,A1 .Location in patent: Page/Page column 233-234

19
[ 870238-67-8 ]
[ 1227912-10-8 ]
[ 1227912-11-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 140℃; for 1.0h;microwave irradiation;	Intermediate 177; 4-(2-Amino-6-{2-r4-(3-chlorophenyl)-1 /-/-imidazol-2-yll-4-morpholinyl}-4-Pyrimidinyl)-2- fluorobenzonitrile; A mixture of 4-chloro-6-{2-[4-(3-chlorophenyl)-1 H-imidazol-2-yl]-4-morpholinyl}-2- pyrimidinamine (1.1 g, 2.81 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile (0.903 g, 3.65 mmol), Na2CO3 (0.745 g, 7.03 mmol) and Pd(PPh3)4 (0.325 g, 0.281 mmol) in 1 ,4-dioxane (4 ml.) and water (1 ml.) was heated at 140 0C under microwave condition with stirring for 1 hour. The reaction mixture was filtered, washed by ethyl acetate (100 ml.) and concentrated to afford the crude title compound (310 mg) as a yellow solid. LC-MS (ES) m/z = 476 [M+H]+.

Reference： [1]Patent: WO2010/59658,2010,A1 .Location in patent: Page/Page column 237

21
[ 870238-67-8 ]
[ 1159489-37-8 ]
[ 1161498-16-3 ]

Yield	Reaction Conditions	Operation in experiment
	With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); potassium carbonate; In water; acetonitrile; at 80℃; for 2.5h;Inert atmosphere;	General procedure: To 1-1.1 (3.00 g, 8.74 nunol) in acetonitrile (50 mL) R3 (2.82 g, 9.18 mmol) and potassiwuphosphate solution (2 moVL, 8. 74 mL) are added. The mixture is purged with argon, [1, 1'-Bis(di-tert-butylphosphino)ferrocene]palladium dichloride (0.57 g, 0.87 mmol) is addedand then the reaction mixture is heated to 80 C for 2.5 h. Ethyl acetate and half saturated brine areadded to the reaction mixture. The organic layer is dried over MgS04 and concentrated. Yield 97%mlz 461/444 [M+NH4)+ /[M+H]+, rt 1.12 min, LC-MS Method V01 1_SOI.

Reference： [1]Patent: WO2014/140081,2014,A1 .Location in patent: Page/Page column 49; 50; 51; 52

22
[ 870238-67-8 ]
[ 869570-00-3 ]
[ 1161498-16-3 ]

Yield	Reaction Conditions	Operation in experiment
	With dichloro[1,1?-bis[bis(1,1-dimethylethyl)phosphino]ferrocene-P,P?]palladium; potassium carbonate; In water; acetonitrile; at 80℃; for 2.5h;Inert atmosphere;	General procedure: To I-1.1 (3.00 g, 8.74 mmol) in acetonitrile (50 mL) R3 (2.82 g, 9.18 mmol) and potassium phosphate solution (2 mol/L, 8.74 mL) are added. The mixture is purged with argon, [1,1?-Bis(di-tert-butylphosphino)ferrocene]palladium dichloride (0.57 g, 0.87 mmol) is added and then the reaction mixture is heated to 80 C. for 2.5 h. Ethyl acetate and half saturated brine are added to the reaction mixture. The organic layer is dried over MgSO4 and concentrated. Yield 97% m/z 461/444 [M+NH4]+/[M+H]+, rt 1.12 min, LC-MS Method V011_S01. The following intermediates as shown in TableS are synthesized in a similar fashion from the appropriate intermediate: During the synthesis of 1-1.2.3, 1-1.2.6 and 1-1.2.7 an aq. solution of sodium carbonate (2 mol/L) is used instead of the potassium phosphate solution and for 1-1.2.4 an aq. solution of potassium carbonate (2 mol/L) is used.

Reference： [1]Patent: US2014/275155,2014,A1 .Location in patent: Paragraph 0252; 0253; 0254

23
[ 16234-14-3 ]
[ 870238-67-8 ]
C₁₃H₅ClFN₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87.5%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 2.0h;Inert atmosphere;	Under nitrogen, compound 56-a (1.0 g, 4 mmol), 2,4-dichlorotheino[3,2-d]pyrimidine (1.0 g, 4.9 mmol) and potassium carbonate (1.38 g, 10 mmol) were suspended in 1,4-dioxane (20 mL) and water (4 mL), Pd(PPh3)4 (490 mg, 0.6 mmol) was added. The mixture was heated to 100 C. and stirred for 2 hours. The mixture was concentrated under reduced pressure, the residue was treated with water (20 mL), extracted with dichloromethane (20 mL×3). The organic layers were combined, washed with water (10 mL×3) and saturated brine (10 mL) in sequence, dried over anhydrous sodium sulfate, then filtrated, the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (petroleum ether:ethyl acetate=3:1) to give light yellow solid 56 (1.0 g, yield: 87.5%). LC-MS (ESI): m/z=290 [M+H]+.

Reference： [1]Patent: US2015/336982,2015,A1 .Location in patent: Paragraph 0365; 0368

24
[ 870238-67-8 ]
2-fluoro-4-(2-(phenylamino)thieno[3,2-d]pyrimidin-4-yl)benzonitrile [ No CAS ]

Reference： [1]Patent: US2015/336982,2015,A1

25
[ 870238-67-8 ]
azetidin-1-yl(3-bromoimidazo[1,2-b]pyridazin-2-yl)methanone [ No CAS ]
4-[2-(azetidin-1-ylcarbonyl)imidazo[1,2-b]pyridazin-3-yl]-2-fluorobenzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (bis(tricyclohexyl)phosphine)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 100℃; for 20.0h;	Compound C9 (1.90 g, 6.76 mmcl) was combined with 6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)[1 ,2,4]triazolo[1 ,5-a]pyridine (1.82 g, 7.43 mmol), [1 1?-bis(dicyclohexylphosphino)ferrocene]dichloropalladium(II) (51.4 mg, 68.0 pmol), and1,4-dioxane (34 mL). Aqueous sodium carbonate solution (3 M, 9.0 mL, 27 mmol) was added, and the reaction mixture was purged with nitrogen for 15 minutes, then heated at 100 C for 20 hours. The reaction mixture was cooled to room temperature and the supernatant was immediately filtered through a pad of diatomaceous earth, rinsing with10% methanol in ethyl acetate. Remaining solids were partitioned between half- saturated aqueous sodium chloride solution (25 mL) and 10% methanol in ethyl acetate by stirring for 5 minutes; this mixture was also filtered through diatomaceous earth. The combined filtrates were diluted with saturated aqueous sodium chloride solution (25 mL) and additional 10% methanol in ethyl acetate. The aqueous layer was extracted threetimes with 10% methanol in ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was adsorbed onto diatomaceous earth (4-fold the weight of the crude product) using dichloromethane and methanol, and subjected to chromatography on silica gel (Gradient: 0% to 20% methanol in ethylacetate). The resulting material (1.83 g) was mixed with methanol (20 mL) and heated to 72 C for 20 minutes; after cooling, the mixture was filtered and washed with methanol to afford the product as an off-white solid. This material was found to be crystalline via powder X-ray diffraction. Yield: 1.66 g, 5.20 mmol, 77%. ; Using the methodology described above for Examples 1 -9, Examples 10-25 were synthesized. See Table 1 for specific methods employed, as well as characterization data for these Examples.

Reference： [1]Patent: WO2016/20786,2016,A1 .Location in patent: Page/Page column 60; 61; 65; 70

26
[ 870238-67-8 ]
N-(5-bromopyrazin-2-yl)cyclopropanecarboxamide [ No CAS ]
N-(5-(4-cyano-3-fluorophenyl)pyrazin-2-yl)cyclopropanecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46.3%	With 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii)dichloride-chloroform adduct; caesium carbonate; In 1,4-dioxane; water; at 95℃; for 12.0h;	[0096] A mixture of Pd(dppf)2 CHCI3 adduct (0.217 g, 0.266 mmol), aqueous cesium carbonate solution (2M, 10.62 mL, 21.25 mmol), N-(5-bromopyrazin-2-yl)cyclopropanecarboxamide (1.35 g, 5.58 mmol), and 2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile (1.312 g, 5.31 mmol) was dissolved in anhydrous dioxane (26.6 mL). The reaction was heated at 95C for 12 hours. The cooled reaction was diluted in deionized water (200 mL) and triturated to give a solid which was collected by vacuum filtration, washed with deionized water, followed by hexanes. The residue was purified via normal phase column chromatography on (Thomson Single Step 80 g) using a gradient of 20-100% EtO Ac/Heptanes on the Teledyne ISCO CombiFlash Purification system. The collected fractions were concentrated and dried in vacuo to afford the title compound (693.6 mg, 46.3 % yield).

Reference： [1]Patent: WO2016/57338,2016,A1 .Location in patent: Paragraph 0095-0096

27
[ 59489-71-3 ]
[ 870238-67-8 ]
4-(5-aminopyrazin-2-yl)-2-fluorobenzonitrile [ No CAS ]