[ CAS No. 505083-04-5 ] {[proInfo.proName]}

Name: 505083-04-5|(3-Fluoro-4-(methoxycarbonyl)phenyl)boronic acid|97%
Brand: Ambeed
SKU: A180558
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Quality Control of [ 505083-04-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 505083-04-5 ]

Product Details of [ 505083-04-5 ]

CAS No. :	505083-04-5	MDL No. :	MFCD04115665
Formula :	C₈H₈BFO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YZYGXFXSMDUXJT-UHFFFAOYSA-N
M.W :	197.96	Pubchem ID :	2782818
Synonyms :

Calculated chemistry of [ 505083-04-5 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	3
Num. H-bond acceptors :	5.0
Num. H-bond donors :	2.0
Molar Refractivity :	47.51
TPSA :	66.76 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.95 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	0.78
Log Po/w (WLOGP) :	-0.29
Log Po/w (MLOGP) :	0.63
Log Po/w (SILICOS-IT) :	-0.42
Consensus Log Po/w :	0.14

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.68
Solubility :	4.16 mg/ml ; 0.021 mol/l
Class :	Very soluble
Log S (Ali) :	-1.76
Solubility :	3.42 mg/ml ; 0.0173 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.65
Solubility :	4.44 mg/ml ; 0.0224 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.91

Safety of [ 505083-04-5 ]

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

Application In Synthesis of [ 505083-04-5 ]

* 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 [ 505083-04-5 ]
Downstream synthetic route of [ 505083-04-5 ]

[ 505083-04-5 ] Synthesis Path-Upstream 1~2

1
[ 603122-52-7 ]
[ 505083-04-5 ]

Reference： [1] Journal of Medicinal Chemistry, 2008, vol. 51, # 6, p. 1925 - 1944
[2] Patent: WO2004/94363, 2004, A1, . Location in patent: Page 19-20
[3] Patent: WO2005/9941, 2005, A1, . Location in patent: Page 20
[4] Patent: WO2004/94382, 2004, A1, . Location in patent: Page 20

2
[ 179232-29-2 ]
[ 505083-04-5 ]

Reference： [1] Patent: WO2004/94382, 2004, A1,

[ 505083-04-5 ] Synthesis Path-Downstream 1~87

1
[ 603122-52-7 ]
[ 505083-04-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium periodate; ammonium acetate; In water; acetone; at 20℃; for 18h;	Combine methyl 4-bromo-2-fluorobenzoate (3.66 g, 15.75 mmol), 4,4, 5,5, 4', 4', 5', 5'-octamethyl-2, 2 -BI-1, 3,2-dioxaborolanyl (5.0 g, 19.68 mmol) and potassium acetate (4.63 g, 47.19 mmol) in DMSO (40 mL) and purge the solution with argon. Add PDCL2 (1, 1 -BIS (DIPHENYLPHOSPHINO) ferrocene) 2 (10 mol %, 1. 35 g) and purge the solution with argon again. Heat the reaction to 80C for 3 hours and cool to room temperature. Wash the reaction with water and extract with ethyl acetate and concentrate. Redissolve the resulting black oil in 1: 2 ethyl acetate: hexanes, filter through a short plug of silica gel, and concentrate to get 2-FLUORO-4- (4, 4,5, 5-TETRAMETHYL-1, 3,2- dioxaborolan-2-yl) benzoic acid methyl ester as a yellow oil. Dissolve the resulting yellow oil in acetone (100 mL) and combine with NAI04 (10.1 g, 47.25 mmol), NH40Ac (3.63 g, 47.25 mmol), and water (50 mL) at room temperature. Stir at room temperature for 18 hours, transfer to a separatory funnel and extract with ethyl acetate several times. Dry the combined organics over MGSO4, filter and concentrate to yield 3.0 g of 3-fluoro-4-carbomethoxybenzene boronic acid as an off- white solid. The boronic acid obtained above (800 mg, 4.04 mmol) and 2,6- CTIFLUOROBROMOBCNZENE (1.17 g, 6.06 mmol) are coupled according to the procedure described in Method G to give 380 mg of the title compound. MS (ES) : M/Z 251. 1 (M- H).
	With ammonium acetate; sodium periodate; In water; acetone; at 20℃; for 18h;	Combine methyl 4-bromo-2-fluorobenzoate (3.66 g, 15.75 mmol), 4,4, 5,5, 4', 4', 5', 5'-octamethyl-2, 2 -BI-1, 3,2-dioxaborolanyl (5.0 g, 19.68 mmol) and potassium acetate (4.63 g, 47. 19 mmol) in dimethylsulfoxide (40 mL) and purge the solution with argon. Add PDCL2 (1, 1 -BIS (diphenylphosphino) ferrocene) 2 (10 mol %, 1.35 g) and purge the solution with argon again. Heat the reaction to 80C for 3 hours and cool to room temperature. Wash the reaction with water and extract with ethyl acetate and concentrate. The resulting black oil is re-dissolved in 1: 2 ethyl acetate: hexanes, filtered through a short plug of silica gel, and concentrated. 2-FLUORO-4- (4, 4,5, 5-tetramethyl- 1, 3,2-dioxaborolan-2-yl) benzoic acid methyl ester is obtained as a yellow oil. Dissolve the resulting yellow oil in acetone (100 mL) and combine with NAI04 (10.1 g, 47.25 mmol), NH40Ac (3.63 g, 47.25 mmol), and water (50 mL) at room temperature. Stir at room temperature for 18 hours, transfer to a separatory funnel and extract with ethyl acetate several times. Dry the combined organics over magnesium sulfate, filter and concentrate to yield 3.0 g of 3-fluoro-4-carbomethoxybenzene boronic acid as an off-white solid. The boronic acid obtained above (800 mg, 4.04 mmol) and 2,6- difluorobromobenzene (1.17 g, 6.06 mmol) are coupled according to the procedure described in Method G to give 380 mg of the title compound. MS (M/E) : 251. 1 (M-).
	With sodium periodate; ammonium acetate; In water; acetone; at 20℃; for 18h;	Dissolve the resulting yellow oil in acetone (100 mL) and combine with NAI04 (10.1 g, 47.25 mmol), NH40Ac (3.63 g, 47.25 mmol), and water (50 mL) at room temperature. Stir at room temperature for 18 hours, transfer to a separator funnel and extract with ethyl acetate several times. Dry the combined organics over MGS04, filter and concentrate to yield 3.0 g of 3-FLUORO-4-CARBOMETHOXYBENZENE boronic acid as an off- white solid

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 1925 - 1944
[2]Patent: WO2004/94363,2004,A1 .Location in patent: Page 19-20
[3]Patent: WO2005/9941,2005,A1 .Location in patent: Page 20
[4]Patent: WO2004/94382,2004,A1 .Location in patent: Page 20

Yield	Reaction Conditions	Operation in experiment
		(1) [3-Fluoro-4-(methoxycarbonyl)phenyl]boronic Acid (+)ESI-MS (m/z): 197 (M-H)-

3
[ 505083-04-5 ]
[ 643093-72-5 ]
[ 643091-31-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane;	EXAMPLE 16 To a solution of 4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenyl trifluoromethanesulfonate (300 mg) in 1,2-dimethoxyethane (5 ml) was added <strong>[505083-04-5][3-fluoro-4-(methoxycarbonyl)phenyl]boronic acid</strong> (125 mg), tetrakis(triphenylphosphine)palladium (53 mg) and aqueous solution of sodium carbonate (2M, 0.6 ml), and the mixture was stirred at 80 C. for 2 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=3/1) to give methyl 4'-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-3-fluoro-1,1'-biphenyl-4-carboxylate (230 mg). (+)ESI-MS (m/z): 528 (M+H)+

Reference： [1]Patent: US2004/6143,2004,A1

4
[ 643093-71-4 ]
[ 505083-04-5 ]
[ 643091-31-0 ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 1925 - 1944

5
[ 505083-04-5 ]
[ 1003-98-1 ]
[ 942203-32-9 ]

Yield	Reaction Conditions	Operation in experiment
37%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 80℃; for 16h;Inert atmosphere;	Example (III-1) Preparation of Starting Materials of the Formula (III) Under an atmosphere of inert gas (argon), 4.5 ml of a saturated sodium carbonate solution and 0.1 g (0.1 mmol) of tetrakis(triphenylphosphine)palladium(0) are added to a suspension consisting of 0.9 g (4.8 mmol) of 2-bromo-4-fluoroaniline and 1.0 g (5.1 mmol) of [3-fluoro-4-(methoxycarbonyl)phenyl]-boronic acid in 5 ml of toluene and 0.5 ml of ethanol. The reaction mixture is stirred at 80 C. for 16 hours and then poured into 10 ml of water and extracted with 20 ml of toluene. The combined organic phases are dried over magnesium sulphate, filtered and concentrated under reduced pressure. Column chromatography (gradient cyclohexane/ethyl acetate) gives 0.5 g (1.76 mmol, 37% of theory) of methyl 2'-amino-3,5'-difluorobiphenyl-4-carboxylate [log P (pH 2.3) 2.73].

Reference： [1]Patent: US2009/76113,2009,A1 .Location in patent: Page/Page column 19-20

6
[ 505083-04-5 ]
[ 1146089-80-6 ]
[ 1146089-90-8 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 95℃; for 16h;	Preparation 40: 3-[6-(4-Methoxycarbonyl-3-fluorophenyl)pyridin-3-yloxy]azetidine-l- carboxylic acid tert-butyl esterTo a degassed solution of 2-bromo-5-[l-(3-isopropyl-[l,2,4]oxadiazol-5- ylmethyl)azetidin-3-yloxy]pyridine (23.5 mmol), 4-boronic acid-2-fluorobenzoic acid methyl ester (25.8 mmol) and cesium carbonate (70.4 mmol) in dioxane/water (4:1) 75 mL was added Pd(Cl)2(dppf).DCM (2.3 mmol). The stirred mixture was heated to 95 0C for 16 h. The reaction mixture was cooled, concentrated and re -dissolved in ethyl acetate. The solution was filtered <n="28"/>through celite and washed with saturated aqueous sodium carbonate (x2) and brine. The solution was dried (MgSO4) and concentrated. Flash chromatography afforded the title compound: RT = 3.93 min; m/z (ES+) = 404.29 [M+H]+.
	With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 95℃; for 16h;	Preparation 12: 3-[6-(4-Methoxycarbonyl-3-fluorophenyl)pyridin-3-yloxy]azetidine-l- carboxylic acid tert-butyl esterTo a degassed solution of 2-bromo-5-[l-(3-isopropyl-[l,2,4]oxadiazol-5- ylmethyl)azetidin-3-yloxy]pyridine (23.5 mmol), 4-boronic acid-2-fluorobenzoic acid methyl ester (25.8 mmol) and cesium carbonate (70.4 mmol) in dioxane/water (4:1) 75 mL was added Pd(Cl)2(dppf).DCM (2.3 mmol). The stirred mixture was heated to 950C for 16 h. The reaction mixture was cooled, concentrated and re -dissolved in ethyl acetate. The solution was filtered through celite and washed with saturated aqueous sodium carbonate (x2) and brine. The solution was dried (MgSO4) and concentrated. Flash chromatography afforded the title compound: RT = 3.93 min; m/z (ES+) = 404.29 [M+H]+ (LCMS protocol 3).

Reference： [1]Patent: WO2009/50522,2009,A1 .Location in patent: Page/Page column 26
[2]Patent: WO2009/50523,2009,A1 .Location in patent: Page/Page column 22

7
[ 505083-04-5 ]
[ 603122-39-0 ]
[ 603123-03-1 ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 4804 - 4822

8
[ 505083-04-5 ]
[ 1246382-91-1 ]
[ 497-19-8 ]
[ 1246382-93-3 ]

Yield	Reaction Conditions	Operation in experiment
	In 1,4-dioxane; water;	Step 2: 3'-Chloro-3-fluoro-4'-(3,3,3-trifluoro-2-hydroxy-2-isoquinolin-5-yl-1-methyl-propyl)-biphenyl-4-carboxylic acid methyl ester To a suspension of trifluoromethanesulfonic acid 3-chloro-4-(3,3,3-trifluoro-2-hydroxy-2-isoquinolin-5-yl-1-methyl-propyl)-phenyl ester (86 mg), 3-fluoro-4-methoxycarbonylphenyl-boronic acid (50 mg) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]dichloromethane adduct (7 mg) in dioxane (0.5 ml) under argon were added water (0.4 ml) and a 2 M aqueous sodium carbonate solution (0.25 ml). The mixture was stirred at 80 C. for 5 h. The mixture was filtered and to the filtrate was added water. The mixture was extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>2:3) to give the title compound (12 mg) as a colorless solid.

Reference： [1]Patent: US2010/249139,2010,A1

9
[ 505083-04-5 ]
[ 1134915-79-9 ]
[ 1246382-93-3 ]
3'-chloro-3-fluoro-4'-[3,3,3-trifluoro-2-hydroxy-2-(6-methoxy-pyridin-3-yl)-1-methyl-propyl]-biphenyl-4-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 176 3'-Chloro-3-fluoro-4'-[3,3,3-trifluoro-2-hydroxy-2-(6-methoxy-pyridin-3-yl)-1-methyl-propyl]-biphenyl-4-carboxylic acid methyl ester In analogy to Example 150, step 2, 3-(4-bromo-2-chloro-phenyl)-1,1,1-trifluoro-2-(6-methoxy-pyridin-3-yl)-butan-2-ol (Example 175, step 3) was reacted with <strong>[505083-04-5]3-fluoro-4-methoxycarbonylphenylboronic acid</strong> to give the title compound as a colorless foam. MS (m/e)=498.2 [M+H+].

Reference： [1]Patent: US2010/249139,2010,A1

10
[ 505083-04-5 ]
[ 1246383-19-6 ]
[ 1246380-45-9 ]
3'-chloro-4'-[2-(5-cyano-4-methyl-thiophen-2-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-3-fluoro-biphenyl-4-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 3: 3'-Chloro-4'-[2-(5-cyano-4-methyl-thiophen-2-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-3-fluoro-biphenyl-4-carboxylic acid The compound was prepared in analogy to Example 60, step 2, from 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-thiophene-2-carbonitrile and <strong>[505083-04-5]3-fluoro-4-methoxycarbonylphenylboronic acid</strong> (CAS Reg. No. 505083-04-5). The resulting ester was hydrolyzed by addition of aqueous LiOH solution (1N) to the reaction mixture.

Reference： [1]Patent: US2010/249139,2010,A1

11
[ 505083-04-5 ]
[ 1246682-91-6 ]
[ 1246685-19-7 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; copper diacetate; In dichloromethane; for 96h;Molecular sieves;	Copper(II)acetate (657 mg), <strong>[505083-04-5]3-fluoro-4-methoxycarbonylphenylboronic acid</strong> (CAS Reg. 505083-04-5, 716 mg), and pyridine (0.3 ml) were added to a solution of 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (Example 85, 500 mg) in DCM (20 ml). The mixture was stirred with molecular sieves under air atmosphere for 4 days and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, 2:1 EtOAc/heptane) to give the title compound (400 mg) as a light yellow oil. MS (m/e)=567.1 [M+H+].

Reference： [1]Patent: US2010/249124,2010,A1 .Location in patent: Page/Page column 55

12
[ 505083-04-5 ]
5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one [ No CAS ]
3'-chloro-3-fluoro-4'-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl)-propyl]-biphenyl-4-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 80℃; for 2h;	5-[2-(4-Bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (500 mg, obtained in Example 116, step 8), 3-fluoro-4-methoxycarbonyl-phenylboronic acid (320 mg, [CAS Reg. No. 505083-04-5]) and dichloro(1,1'-bis(diphenyl-phosphino)ferrocene)palladium(II)dichloromethane adduct (39 mg) were dissolved in dioxane (9 mL) and water (5 mL). To the reaction mixture was added 2.0 M aqueous Na2CO3 (0.81 mL). The mixture was heated to 80 C. for 2 hours. The reaction mixture was cooled, poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a colorless foam (440 mg, 76%). MS (m/e)=555.2 [(M+NH4+)+], MS (m/e)=506.1 [(M-CH3O-)+].

Reference： [1]Patent: US2010/249124,2010,A1 .Location in patent: Page/Page column 65

13
[ 505083-04-5 ]
[ 1246685-13-1 ]
C₂₇H₂₃ClF₄N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 0.333333h;Sealed tube;	A mixture of 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (40 mg), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (7 mg), Cs2CO3 (82 mg) and <strong>[505083-04-5]3-fluoro-4-methoxycarbonylphenylboronic acid</strong> (CAS Reg. No. 505083-04-5, 33 mg) in dioxane (2 ml) was heated at 80 C. for 20 min in a sealed tube. 1N aqueous LiOH solution (1 ml) was added and stirred for 20 min at room temperature. The mixture was acidified with HCOOH and then purified by prep. HPLC (C18-column, solvent gradient 30-98% CH3CN in 0.1% HCOOH[aq]) to give the title compound (32 mg) as a yellow solid. MS (m/e)=537.2[M+H+].

Reference： [1]Patent: US2010/249124,2010,A1 .Location in patent: Page/Page column 51

14
[ 505083-04-5 ]
[ 1253055-62-7 ]
[ 1253055-65-0 ]

Yield	Reaction Conditions	Operation in experiment
70%	With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,4-dioxane; at 150℃; for 3h;Microwave irradiation;	General Procedure GP3: Suzuki Coupling; The 4-chloropyridine (1.0 eq.) is taken up in dioxane, boronic acid (2.0 eq.), K3PO4 (1.2 eq.), Pd2(dba)3 (0.1 eq.) and Dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphan ("X-Phos", 0.3 eq.) are added and the reaction mixture is stirred either for 3-16 h under reflux or alternatively for 60-180 min at 150ºC under microwave radiation. In case the conversion of the starting material is not complete, additional amounts of boronic acid and Pd-catalyst are added and the reaction is re-run.; A-31) 4-[3-(6-Amino-pyridin-3-ylethynyl)-2-methyl-pyridin-4-yl]-2-fluoro-benzoic acid methyl ester; The title compound is synthesized according to general procedure GP3 starting from 500 mg (2.1 mmol) 5-(4-chloro-2-methyl-pyridin-3-ylethynyl)-pyridin-2-ylamine using 812 mg (4.1 mmol) 3-fluoro-4-methoxycarbonylphenyl boronic acid, 188 mg (0.21 mmol) Pd2(dba)3, 293 mg (0.62 mmol) X-Phos and 567 mg (2.5 mmol) K3PO4 in 4 mL dioxane. The reaction mixture is stirred for 180 min at 150 ºC under microwave irradiation. The product is purified by chromatography on silica gel using an DCM/MeOH-gradient (99:1 to 90:10, 20 min). Yield: 52 mg (70 %).

Reference： [1]Patent: WO2010/122069,2010,A1 .Location in patent: Page/Page column 15; 27

15
[ 505083-04-5 ]
[ 1321612-97-8 ]
[ 1321613-05-1 ]

Yield	Reaction Conditions	Operation in experiment
72%	With caesium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; ethanol; water; at 80℃;	A-86) 4-[5-(6-Amino-2-methyl-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-fluoro- benzoic acid methyl esterThe title compound is synthesized according to general procedure GP4 starting from 3.90 g (14.3 mmol) 4-chloro-6-ethyl-5-(6-amino-2-methyl-pyridin-3-ylethynyl)-pyrimidine using 3.38 g (18.6 mmol) 3-fluoro-4-methoxycarbonylphenyl boronic acid, 502 mg (0.71 mmol) bis-(triphenylphoshine)palladium(II) chloride, 10.7 mL (21.5 mmol) of an aqueous 2 M CS2CO3 solution and 10 mL EtOH in 100 mL DME. The reaction mixture is stirred over night at 80C. The solvent is removed under reduced pressure and the residue is taken up in water and ethylacetate. The aqueous phase is extracted twice with ethylacetate. The combined organic layers are dried over MgSC^ filtered over celite and the solvent is removed under reduced pressure. After drying 4.0 g (72 %) of the desired product is obtained.
72%	With potassium carbonate; caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; water; at 80℃; for 4h;Reflux;	General Procedure 4 (GP4): Suzuki CouplingThe 4-chloropyrimidine (1.0 eq.) is dissolved in DME/water (20:1 v/v), boronic acid (1.3 eq.), K2CO3 (2.0 eq.) and Pd(PPh3)4 (0.2 eq.) are added and the reaction mixture is stirred for 4 h under reflux. In case the conversion of the starting material is not complete, additional amounts of boronic acid and Pd-catalyst are added and the reaction is run over night under reflux. After cooling to RT water is added. The precipitate is filtered off. In cases where the product is not precipitated it is extracted with diethylether, the organic phase is dried, filtered off, and the solvent removed under reduced pressure. The obtained product can either be used without further purification or is purified by chromatography A-50) 4-[5-(6-Amino-2-methyl-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-fluoro-benzoic acid methyl ester The title compound is synthesized in analogy to general procedure GP4 starting from 3.9 g (14.3 mmol) 5-(6-Amino-2-methyl-pyridin-3-ylethynyl)-4-chloro-6-ethyl-pyrimidine using 3.7 g (18.6 mmol) 3-fluoro-4-methoxycarbonylphenyl boronic acid, 502 g (0.71 mmol) bis-(triphenylphoshine)palladium(II) chloride, 10.7 mL (21.5 mmol) of an aqueous 2 M Cs2CO3 and 10 mL EtOH in 100 mL DME. The reaction mixture is stirred over night at 80 C. The reaction mixture is filtered over celite and the solvent is removed under reduced pressure. The crude product is triturated with water and ethylacetate. The phases are separated and the aqueous is extracted twice with ethylacetate. The combined organic layers are dried over Mg2SO4 and the solvent is evaporated under reduced pressure. The crude is stirred with cyclohexane and filtered off. After drying 4.0 g (72%) of the desired product is obtained as solid material, which is used without further purification in the next step.

Reference： [1]Patent: WO2011/92198,2011,A1 .Location in patent: Page/Page column 52
[2]Patent: US2012/28952,2012,A1 .Location in patent: Page/Page column 7; 19-20

16
[ 505083-04-5 ]
[ 1321612-97-8 ]
[ 1321613-06-2 ]

Reference： [1]Patent: WO2011/92198,2011,A1

17
[ 505083-04-5 ]
[ 1131222-65-5 ]
C₂₃H₂₅FN₂O₃ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 2452 - 2468

18
[ 505083-04-5 ]
[ 1382994-99-1 ]
[ 1382995-42-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In 1,4-dioxane; water; at 100℃;Inert atmosphere;	Example 623'-Chloro-3-fluoro-6'-methoxy-2'-methyl-5'-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-carboxamide Step 1. Methyl 3'-acetyl-5'-chloro-3-fluoro-2'-methoxy-6'-methylbiphenyl-4-carboxylat A mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (1.0 g, 3.6 mmol) and <strong>[505083-04-5][3-fluoro-4-(methoxycarbonyl)phenyl]boronic acid</strong> (0.85 g, 4.3 mmol) in 1,4-dioxane (12 mL) and 10% sodium carbonate in water (5.73 mL, 5.40 mmol) was bubbled with N2 to degas. After tetrakis(triphenylphosphine)palladium(0) (166 mg, 0.144 mmol) was added, the mixture was bubbled with N2 for 5 min. more and heated at 100 C. overnight. The mixture was cooled to room temperature and diluted with ethyl acetate. The layers were separated and the aq. layer was extracted with more ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to give crude product.

Reference： [1]Patent: US2012/157430,2012,A1 .Location in patent: Page/Page column 53

19
[ 505083-04-5 ]
[ 1350915-20-6 ]
[ 1392315-11-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate monohydrate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; for 2h;Inert atmosphere; Reflux;	Example AlPreparation of 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-amino- 5a,5b,8,8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l l,l la,l lb,12,13,13a,13b-octadecahydro-lH- cyclopenta[a]chrysen-9-yl)-2-fluorobenzoic acid. Step 1. Preparation of (lR,3aS,5aR,5bR,7aR,l laS.l lbR,13aR,13bR)-benzyl 9-(3- fluoro-4-(methoxycarbonyl)phenyl)-5a,5b,8, 8, 11 a-pentamethyl- l-(prop-l-en-2 -yl)- 2,3,3a,4,5,5a,5b,6,7,7a,8,l l,l la,l lb,12,13,13a,13b-octadecahydro-lH- cyclopenta[a]chrysene-3a-carboxylate.A suspension of (lR,3aS,5aR,5bR,7aR,l laR,l lbR,13aR,13bR)-benzyl 5a,5b,8, 8, 11 a-pentamethyl- 1 -(prop- 1 -en-2-yl)-9-(trifluoromethylsulfonyloxy)- 2,3,3a,4,5,5a,5b,6,7,7a,8,l l,l la,l lb,12,13,13a,13b-octadecahydro-lH- cyclopenta[a]chrysene-3a-carboxylate (4.0 g, 5.91 mmol), 3-fluoro-4- (methoxycarbonyl)phenylboronic acid (1.287 g, 6.50 mmol), sodium carbonate monohydrate (2.198 g, 17.73 mmol), and Pd(PPh3)4 (0.205 g, 0.177 mmol) in 1,4- dioxane (24 mL) and water (6 mL) was flushed with 2 and the mixture was heated to reflux. After 2 h of heating, the mixture was cooled to rt. The mixture was diluted with water (40 mL) and was extracted with dichloromethane (3 x 40 mL). The combined organic layers were dried with Na2S04. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM and was filtered through a pad of celite and silica gel, washing with a 25% EtOAc in hexanes solution. The filtrate was concentrated under reduced pressure to give the title compound (3.59 g, 5.27 mmol, 89% yield) as a dark grey foam. The crude product was used in the next step with no additional purification. XH NMR (500 MHz, CHLOROFORM-d) delta ppm 7.80 (1 H, t, J=7.8 Hz), 7.29 - 7.42 (5 H, m), 6.96 (1 H, d, J=7.9 Hz), 6.91 (1 H, d, J=11.9 Hz), 5.28 - 5.33 (1 H, m), 5.16 (1 H, d, J=12.5 Hz), 5.09 (1 H, d, J=12.2 Hz), 4.73 (1 H, s), 4.59 (1 H, br. s.), 3.92 (3 H, s), 3.03 (1 H, td, J=10.8, 4.7 Hz), 2.20 - 2.33 (2 H, m), 2.09 (1 H, dd, J=17.1, 6.4 Hz), 1.81 - 1.97 (2 H, m), 1.68 (3 H, s), 0.96 (3 H, s), 0.92 (3 H, s), 0.92 (3 H, s), 0.91 (3 H, s), 0.81 (3 H, s), 0.79 - 1.75 (17 H, m).

Reference： [1]Patent: WO2012/106190,2012,A1 .Location in patent: Page/Page column 339-341
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 7289 - 7313

20
[ 505083-04-5 ]
1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ No CAS ]
methyl 3'-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5'-chloro-3-fluoro-2'-methoxy-6'-methylbiphenyl-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In water; acetonitrile; at 95℃; for 2h;	A mixture of 1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (60 mg, 0.15 mmol, chiral pure, first peak from Example 20, Step 2), <strong>[505083-04-5][3-fluoro-4-(methoxycarbonyl)phenyl]boronic acid</strong> (from Combi-Blocks, 0.041 g, 0.20 mmol), sodium carbonate (36 mg, 0.34 mmol) and [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (6 mg, 0.007 mmol) in acetonitrile (1.2 mL)/water (0.3 mL) was vacuumed and then refilled with N2. The reaction was stirred at 95 C. for 2 hours. Then solvent was removed and the crude mixture was purified by silica gel chromatography, eluting with 0 to 70% EtOAc in CH2Cl2, to give the desired product (54 mg, 75%). LCMS calculated for C24H24ClFN5O3 (M+H)+: m/z=484.2; Found: 484.1

Reference： [1]Patent: US2013/59835,2013,A1 .Location in patent: Paragraph 0736

21
[ 505083-04-5 ]
3'-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5'-chloro-3-fluoro-2'-methoxy-6'-methylbiphenyl-4-carboxylic acid [ No CAS ]

Reference： [1]Patent: US2013/59835,2013,A1

22
[ 505083-04-5 ]
3'-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5'-chloro-3-fluoro-2'-methoxy-n,n,6'-trimethylbiphenyl-4-carboxamide trifluoroacetate [ No CAS ]

Reference： [1]Patent: US2013/59835,2013,A1

23
[ 505083-04-5 ]
[ 1313726-84-9 ]
[ 1350426-32-2 ]

Yield	Reaction Conditions	Operation in experiment
71%	With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water;	Intermediate 19 :2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[l,2,3]triazolo[4,5-b]pyridin-5- yl)benzoic acid Step-1 : Methyl 2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-ri,2,31triazolor4,5-blpyridin-5- vDbenzoate: The title compound was prepared by following the procedure described for example 1 using intermediate 7 (0.300 g, 1.01 mmol), 3-fluoro-4- methoxycarbonylphenylboronic acid (0.257 g, 1.29 mmol), potassium carbonate (0.466 g, 13.37 mmol), dioxan (6 ml), water (1.2 ml) and tetrakis (triphenylphosphine)palladium(O) (0.093 g, 0.081 mmol). Brown colour solid (0.300 g, 71%). 'H-NMR (delta ppm, DMSO-d6, 400 MHz): 8.88 (dd, J = 4.2,1.8 Hz, 1H), 8.74 (d, J = 8.7 Hz, 1H), 8.38 (dd, J = 8.4,1.0 Hz, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.24 (s, 1H), 8.22 (m, 1H), 8.07-8.00 (m, 3H), 7.83 (dd, J = 8.7,2.0 Hz, 1H), 7.63 (m, 1H), 6.24 (s, 2H), 3.89 (s, 3H).

Reference： [1]Patent: WO2013/144737,2013,A2 .Location in patent: Paragraph 252

24
[ 505083-04-5 ]
[ 16308-68-2 ]
3-methoxybenzenediazonium tetrafluoroborate [ No CAS ]
methyl 2-fluoro-4-(1-(3-methoxyphenyl)-3-((phenoxycarbonyl)oxy)propyl)benzoate [ No CAS ]

Reference： [1]Organic Letters,2013,vol. 15,p. 5008 - 5011

25
[ 505083-04-5 ]
5-bromo-3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]sulfanyl}pyridin-2-amine [ No CAS ]
methyl 4-(6-amino-5-[1-(2,6-dichloro-3-fluorophenyl)ethyl]sulfanyl}pyridin-3-yl)-2-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50.6%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 16h;Inert atmosphere;	To a solution of 10a (2.2 g, 5.55 mmol) and <strong>[505083-04-5][3-fluoro-4-(methoxycarbonyl)phenyl]boronic acid</strong> (1.10 g, 5.55 mmol) in 44 mL of DME was added 11 mL of 1.5 M Na2CO3, followed by Pd(PPh3)2Cl2 (195 mg, 0.28 mmol) under argon. The resulting mixture was stirred at 80 C for 16 h and extracted with EA. The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column chromatography (CH2Cl2/EA, 10:1) and further recrystallized from CH2Cl2 to afford 34b as a white solid (1.80 g, 50.6% yield). 1H NMR (400 MHz, DMSO-d6) delta 8.41 (t, J = 2.8 Hz, 1H), 7.86 (dt, J = 1.2, 8.0 Hz, 1H), 7.62-7.53 (m, 1.5H), 7.45 (dd, J = 1.6, 12.8 Hz, 1H), 7.39-7.32 (m, 2.5H), 6.62 (d, J = 3.2 Hz, 2H), 5.11-5.02 (m, 1H), 3.85 (s, 3H), 1.81 (dd, J = 1.6, 7.6 Hz, 3H).

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 6804 - 6820

26
[ 505083-04-5 ]
sodium carbonate monohydrate [ No CAS ]
[ 1350915-20-6 ]
[ 1392315-11-5 ]

Yield	Reaction Conditions	Operation in experiment
89%	In 1,4-dioxane; water;	Step 1. Preparation of (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-benzyl 9-(3-fluoro-4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate A suspension of (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-benzyl 5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-9-(trifluoromethylsulfonyloxy)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate (4.0 g, 5.91 mmol), <strong>[505083-04-5]3-fluoro-4-(methoxycarbonyl)phenylboronic acid</strong> (1.287 g, 6.50 mmol), sodium carbonate monohydrate (2.198 g, 17.73 mmol), and Pd(PPh3)4 (0.205 g, 0.177 mmol) in 1,4-dioxane (24 mL) and water (6 mL) was flushed with N2 and the mixture was heated to reflux. After 2 h of heating, the mixture was cooled to rt. The mixture was diluted with water (40 mL) and was extracted with dichloromethane (3*40 mL). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM and was filtered through a pad of celite and silica gel, washing with a 25% EtOAc in hexanes solution. The filtrate was concentrated under reduced pressure to give the title compound (3.59 g, 5.27 mmol, 89% yield) as a dark grey foam. The crude product was used in the next step with no additional purification. 1H NMR (500 MHz, CHLOROFORM-d) delta ppm 7.80 (1H, t, J=7.8 Hz), 7.29-7.42 (5H, m), 6.96 (1H, d, J=7.9 Hz), 6.91 (1H, d, J=11.9 Hz), 5.28-5.33 (1H, m), 5.16 (1H, d, J=12.5Hz), 5.09 (1H, d, J=12.2Hz), 4.73 (1H, s), 4.59 (1H, br. s.), 3.92 (3H, s), 3.03 (1H, td, J=10.8, 4.7 Hz), 2.20-2.33 (2H, m), 2.09 (1H, dd, J=17.1, 6.4 Hz), 1.81-1.97 (2H, m), 1.68 (3H, s), 0.96 (3H, s), 0.92 (3H, s), 0.92 (3H, s), 0.91 (3H, s), 0.81 (3H, s), 0.79-1.75 (17H, m).

Reference： [1]Patent: US2014/221361,2014,A1 .Location in patent: Page/Page column

27
[ 505083-04-5 ]
1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ No CAS ]
methyl 3'-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5'-chloro-3-fluoro-2'-methoxy-6'-methylbiphenyl-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In water; acetonitrile; at 95℃; for 2h;Inert atmosphere;	Step 1. Methyl 3'-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5'-chloro-3-fluoro-2'-methoxy-6'-methylbiphenyl-4-carboxylate A mixture of 1-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (60 mg, 0.15 mmol, chiral pure, first peak from Example 20, Step 2), <strong>[505083-04-5][3-fluoro-4-(methoxycarbonyl)phenyl]boronic acid</strong> (from Combi-Blocks, 0.041 g, 0.20 mmol), sodium carbonate (36 mg, 0.34 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (6 mg, 0.007 mmol) in acetonitrile (1.2 mL) water (0.3 mL) was vacuumed and then refilled with N2. The reaction was stirred at 95 C. for 2 hours. Then solvent was removed and the crude mixture was purified by silica gel chromatography, eluting with 0 to 70% EtOAc in CH2Cl2, to give the desired product (54 mg, 75%). LCMS calculated for C24H24ClFN5O3 (M+H)+: m/z=484.2. Found: 484.1

Reference： [1]Patent: US2014/249132,2014,A1 .Location in patent: Paragraph 0273

28
[ 505083-04-5 ]
(6-chloro-8-fluoroimidazo[1,2-a]pyridin-3-yl)(quinolin-6-yl)methanone [ No CAS ]
methyl 2-fluoro-4-(8-fluoro-3-(quinoline-6-carbonyl)imidazo[1,2-a]pyridin-6-yl)benzoate [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 507 - 512

29
[ 505083-04-5 ]
6-(1-(6-bromo-8-fluoroimidazo[1,2-a]pyridin-3-yl)cyclopropyl)quinoline [ No CAS ]
methyl 2-fluoro-4-(8-fluoro-3-(1-(quinolin-6-yl)cyclopropyl)imidazo[1,2-a]pyridin-6-yl)benzoate [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 507 - 512

30
[ 505083-04-5 ]
6-((6-bromo-8-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)quinoline [ No CAS ]
methyl 2-fluoro-4-(8-fluoro-3-(quinolin-6-ylmethyl)imidazo[1,2-a]pyridin-6-yl)benzoate [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 507 - 512

31
[ 505083-04-5 ]
2-fluoro-4-(5-((1-(3,3,3-trifluoro-2,2-dimethylpropyl)piperidin-4-yl)methoxy)pyridin-2-yl)benzoic acid [ No CAS ]