[ CAS No. 313546-18-8 ] {[proInfo.proName]}

Name: 313546-18-8|(4-Cyano-2-methylphenyl)boronic acid|95%
Brand: Ambeed
SKU: A274837
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Quality Control of [ 313546-18-8 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 313546-18-8 ]

SDS Specification

Alternatived Products of [ 313546-18-8 ]

Product Details of [ 313546-18-8 ]

CAS No. :	313546-18-8	MDL No. :	MFCD09750473
Formula :	C₈H₈BNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	RGCVYEOTYJCNOS-UHFFFAOYSA-N
M.W :	160.97	Pubchem ID :	16218401
Synonyms :

Calculated chemistry of [ 313546-18-8 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	2.0
Molar Refractivity :	45.95
TPSA :	64.25 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 :	Yes
Log Kp (skin permeation) :	-6.64 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	0.91
Log Po/w (WLOGP) :	-0.45
Log Po/w (MLOGP) :	-0.03
Log Po/w (SILICOS-IT) :	-0.32
Consensus Log Po/w :	0.02

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.72
Solubility :	3.1 mg/ml ; 0.0193 mol/l
Class :	Very soluble
Log S (Ali) :	-1.84
Solubility :	2.3 mg/ml ; 0.0143 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.75
Solubility :	2.86 mg/ml ; 0.0178 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.86

Safety of [ 313546-18-8 ]

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

Application In Synthesis of [ 313546-18-8 ]

* 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 [ 313546-18-8 ]
Downstream synthetic route of [ 313546-18-8 ]

[ 313546-18-8 ] Synthesis Path-Upstream 1~2

1
[ 313546-18-8 ]
[ 185147-08-4 ]

Reference： [1] Journal of Organic Chemistry, 2013, vol. 78, # 23, p. 11794 - 11797

2
[ 41963-20-6 ]
[ 313546-18-8 ]

Reference： [1] Chemistry - A European Journal, 2004, vol. 10, # 1, p. 92 - 100
[2] Tetrahedron, 2011, vol. 67, # 52, p. 10082 - 10088
[3] Chemistry - A European Journal, 2013, vol. 19, # 26, p. 8447 - 8456

[ 313546-18-8 ] Synthesis Path-Downstream 1~85

1
[ 126-30-7 ]
[ 313546-18-8 ]
4-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-3-methyl-benzonitrile [ No CAS ]

Reference： [1]Chemistry - A European Journal,2004,vol. 10,p. 92 - 100

2
C₁₀H₁₂BNO₂ [ No CAS ]
[ 313546-18-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; water; In tetrahydrofuran; at 20℃; for 0.25h;	Using a modification of the procedure by Hall and co-workers,refPreviewPlaceHolder8n-BuLi (1.6 M, 7.5 mL, 12.0 mmol) was added drop-wise to a solution of 4-bromo-3-methylbenzonitrile (2.34 g, 12.0 mmol) in anhydrous THF (24 mL) at -98 C. The mixture was stirred at -98 C for 10 min and trimethylborate (2.0 mL, 18 mmol) was added drop-wise. The reaction mixture was kept at -98 C for 30 min before being warmed to room temperature and stirred for a further 15 min. Aqueous HCl (1 M, 5 mL, 5 mmol) was added and the mixture was stirred for 15 min before being diluted with H2O (20 mL) and extracted with EtOAc (3×20 mL). The combined organic phases were dried (MgSO4) and concentrated in vacuo. Pinacol (1.42 g, 12.0 mmol) and MgSO4 (1.44 g, 12.0 mmol) were added to a solution of the residue dissolved in CH2Cl2 (25 mL). The mixture was stirred for 15 h at room temperature, MgSO4 removed by filtration and the filtrate concentrated in vacuo. The product was purified by column chromatography (5% EtOAc/petroleum ether) to give the boronic ester14 (2.59 g, 89%) as needles (petroleum ether); [Found: C, 69.44; H, 7.68, N, 5.61. C14H18NO2B requires C, 69.17; H, 7.46; N, 5.76%]; mp=139.5-140.5 C (petroleum ether); numax (neat): 2969, 2235, 1347, 1146, 1062 cm-1; deltaH (400 MHz, CDCl3) 7.83 (1H, d, J 8.0 Hz, ArH), 7.41-7.47 (2H, m, ArH), 2.56 (3H, s, Ar-Me), 1.36 (12H, s, 2× CMe2); deltaC (101 MHz, CDCl3) 145.6, 136.1, 132.6, 128.0, 119.0, 113.9, 84.1, 24.8, 21.9; deltaB (96 MHz, CDCl3): 30.7; m/z (EI): 243 (M+, 10), 228 (80), 84 (100); HRMS (EI): M+, found 243.1440. C14H18NO2B requires 243.1431.

Reference： [1]Chemistry - A European Journal,2004,vol. 10,p. 92 - 100
[2]Tetrahedron,2011,vol. 67,p. 10082 - 10088
[3]Chemistry - A European Journal,2013,vol. 19,p. 8447 - 8456

3
[ 41963-20-6 ]
[ 313546-18-8 ]

Reference： [1]Chemistry - A European Journal,2004,vol. 10,p. 92 - 100
[2]Tetrahedron,2011,vol. 67,p. 10082 - 10088
[3]Chemistry - A European Journal,2013,vol. 19,p. 8447 - 8456

4
[ 313546-18-8 ]
[ 673456-15-0 ]

Reference： [1]Chemistry - A European Journal,2004,vol. 10,p. 92 - 100

5
[ 313546-18-8 ]
C₄₈H₆₂B₂N₄O₇ [ No CAS ]

Reference： [1]Chemistry - A European Journal,2004,vol. 10,p. 92 - 100

6
[ 313546-18-8 ]
C₄₇H₅₉B₂N₅O₇ [ No CAS ]

Reference： [1]Chemistry - A European Journal,2004,vol. 10,p. 92 - 100

7
[ 313546-18-8 ]
C₄₉H₆₁B₂N₅O₇ [ No CAS ]

Reference： [1]Chemistry - A European Journal,2004,vol. 10,p. 92 - 100

8
[ 444721-66-8 ]
[ 313546-18-8 ]
[ 760206-08-4 ]

Yield	Reaction Conditions	Operation in experiment
	In 2-[(7bR,11aS)-1,2,7b,8,9,10,11,11a-octahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indol-6-yl]benzaldehyde, trifluoroacetic Acid Salt;	Example 23 4-[(7bR,11aS)-1,2,7b,8,9,10,11,11a-octahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indol-6-yl]-3-methylbenzonitrile, Trifluoroacetic Acid Salt Using 2-methyl-4-cyanophenyl boronic acid and following the procedures in EXAMPLE 7, tert-butyl (7bR,11aS)-6-bromo-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate was converted into the title compound of EXAMPLE 23. 1H NMR (CDCl3): delta 8.70 (broad s, 2H), 7.55 (s, 1H), 7.51 (d, 1H, J=7.7 Hz), 7.26 (app d, 1H), 6.96 (s, 1H), 6.91 (s, 1H), 3.85 (ABq, 2H, JAB=15.7 Hz), 3.66-3.58 (m, 3H), 3.50-3.39 (m, 2H), 3.32-3.12 (m, 3H), 2.97-2.88 (m, 1H), 2.82-2.73 (m, 1H), 2.31 (s, 3H), 2.30-2.22 (m, 2H). LRMS (ES+) 362.4 (M+H)+.
	In 2-[(7bR,11aS)-1,2,7b,8,9,10,11,11a-octahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indol-6-yl]benzaldehyde, trifluoroacetic Acid Salt;	Example 23 4-[(7bR,11aS)-1,2,7b,8,9,10,11,11a-octahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indol-6-yl]-3-methylbenzonitrile, trifluoroacetic acid salt Using 2-methyl-4-cyanophenyl boronic acid and following the procedures in EXAMPLE 7, tert-butyl (7bR,11aS)-6-bromo-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate was converted into the title compound of EXAMPLE 23. 1H NMR (CDCl3): delta 8.70 (broad s, 2H), 7.55 (s, 1H), 7.51 (d, 1H, J=7.7 Hz), 7.26 (app d, 1H), 6.96 (s, 1H), 6.91 (s, 1H), 3.85 (ABq, 2H, JAB=15.7 Hz), 3.66-3.58 (m, 3H), 3.50-3.39 (m, 2H), 3.32-3.12 (m, 3H), 2.97-2.88 (m, 1H), 2.82-2.73 (m, 1H), 2.31 (s, 3H), 2.30-2.22 (m, 2H). LRMS (ES+): 362.4 (M+H)+.

Reference： [1]Patent: US2002/173503,2002,A1
[2]Patent: US2004/186094,2004,A1

9
[ 313688-72-1 ]
[ 313546-18-8 ]
[ 313671-78-2 ]

Yield	Reaction Conditions	Operation in experiment
86%	With Ba(OH)2;Pd(PPh3)4;	Step A Tert-butyl (8aS,12aR)-2-(4-cyano-2-methylphenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.095 g, 86%) was prepared by the general method of Example 319, step A from tert-butyl (8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]pyrido [4,3-b]indole-11(8aH)-carboxylate (0.10 g, 0.25 mmol), <strong>[313546-18-8]4-cyano-2-methylphenylboronic acid</strong> (0.080 g, 0.50 mmol), Pd(PPh3)4 (12 mg, 0.010 mmol), and Ba(OH)2 (0.17 M, 3.0 mL, 0.51 mmol) as a white foam. MS (ESI): 444 (base, M+H).

Reference： [1]Patent: US6548493,2003,B1

10
[ 313669-58-8 ]
[ 313546-18-8 ]
[ 313672-02-5 ]

Yield	Reaction Conditions	Operation in experiment
65%	With Ba(OH)2;Pd(PPh3)4;	Step A Tert-butyl (7aS,11aR)-2-(4-cyano-2-methylphenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (0.073 g, 65%) was prepared by the general method of Example 319, step A from tert-butyl (7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (0.10 g, 0.26 mmol), <strong>[313546-18-8]4-cyano-2-methylphenylboronic acid</strong> (0.088 g, 0.52 mmol), Pd(PPh3)4 (12 mg, 0.010 mmol), and Ba(OH)2 (0.17 M, 3.0 mL, 0.51 mmol) as a white foam. MS (ESI): 430 (base, M+H).

Reference： [1]Patent: US6548493,2003,B1

11
[ 1035454-48-8 ]
[ 313546-18-8 ]
[ 1035454-34-2 ]

Reference： [1]Physical Chemistry Chemical Physics,2008,vol. 10,p. 2686 - 2694

12
[ 1027215-38-8 ]
[ 313546-18-8 ]
[ 1027215-39-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 12.0h;Heating / reflux;	Preparation of Intermediate (4'-Cvano-3,5-difluoro-2'-methyl-biphenyl-4-ylmethyl)-(3-methyl-butyl)- carbamic acid tert-butyl ester (1-1 d):4-Bromo-2,6-difluoro-benzyl)-(3-methyl-butyl)-carbamic acid tert-butyl ester (IUy. 10.0 g) was combined with <strong>[313546-18-8]4-cyano-2-methylphenylboronic acid</strong> (6.0 g), palladium tetrakis(triphenylphosphine) (2.2 g), 1,2-dimethoxy ethane (60 ml) and 2M aqueous sodium carbonate (5.0 ml) under a nitrogen atmosphere. After stirring vigorously while being heated at reflux for 12 hours, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (2 times). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica eluting with ethyl acetate in heptane to provide the title compound (Md).1H NMR (CDCI3): delta 0.87 (d, 6H), 1.3-1.6 (m, 12 H), 2.28 (s, 3H), 3.1-3.3 (m, 2H), 4.5-4.7 (m, 2H), 6.81 (d, 2H), 7.27 (d, 1 H), 7.20 (d, 1H), 7.56 (s, 1 H).

Reference： [1]Patent: WO2008/59335,2008,A1 .Location in patent: Page/Page column 25

13
[ 1027215-42-4 ]
[ 313546-18-8 ]
[ 1027215-43-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 95℃; for 48.0h;	Preparation of Intermediate (^-Cvano-?^'-dimethyl-biphenyl-^ylmethvD-O-methvi-butvD-carbamic acid tert-butyl ester (l-2d):(4-bromo-3-methyl-benzyl)-(3-methyl-butyl)-carbamic acid tert-butyl ester (L2c: 12g) was combined with <strong>[313546-18-8]4-cyano-2-methylphenylboronic acid</strong> (7.2Og), palladium tetrakis(triphenylphosphine) (3.Og), 1 ,2-dimethoxy ethane (100 ml) and 2M aqueous sodium carbonate (50 ml_). After stirring vigorously while being heated at 950C for 48 hours, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (2 times). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica eluting with 10% ethyl acetate in heptane to provide the title compound (l-2d).1H NMR (CDCI3): delta 0.87 (d, 6H), 1.3-1.6 (m, 12 H), 1.99 (s, 3H), 2.06 (s, 3H), 3.1-3.3 (m, 2H), 4.4 (m, 2H), 6.97 (d, 1H), 7.08-7.11 (m, 2H), 7.18 (d, 1 H), 7.50 (d, 1H), 7.55 (s, 1H).

Reference： [1]Patent: WO2008/59335,2008,A1 .Location in patent: Page/Page column 27

14
[ 1027215-46-8 ]
[ 313546-18-8 ]
[ 1027215-47-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 95℃; for 48.0h;	Preparation of Intermediate (3-Chloro-4'-cyano-2'-methyl-biphenyl-4-ylmethyl)-(3-methyl-butyl)-carbamic acid tert-butyl ester (l-3d):To a 250 ml round bottom flask was added (4-bromo-2-chloro-benzyl)-(3-methyl-butyl)-carbamic acid tert-butyl ester (K3c: 12g) followed by the <strong>[313546-18-8]4-cyano-2-methylphenylboronic acid</strong> (7.2Og), 1 ,2- dimethoxy ethane (100 ml_), 2M aqueous sodium carbonate (50 ml) and palladium tetrakis(triphenylphosphine) (3.Og). After heating the reaction mixture at 950C for 48 hours, the mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (2 times). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (l-3d).1H NMR (CDCI3): delta 0.89 (d, 6H), 1.3-1.6 (m, 12 H), 2.28 (s, 3H), 3.2-3.3 (m, 2H), 4.5-4.6 (m, 2H), 7.15 (d, 1 H), 7.28 (bs, 3H), 7.51 (d, 1H), 7.55 (s, 1H).

Reference： [1]Patent: WO2008/59335,2008,A1 .Location in patent: Page/Page column 30

15
[ 847560-46-7 ]
[ 313546-18-8 ]
2-amino-4-(4-cyano-2-methylphenyl)thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 4794 - 4809
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 2845 - 2850

16
[ 1207619-08-6 ]
[ 313546-18-8 ]
[ 1207619-48-4 ]

Yield	Reaction Conditions	Operation in experiment
80%	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In acetonitrile; at 20℃;Reflux;	Intermediate 173: Ethyl 1 -[4-(2-[(4'-cyano-2',3-dimethyl-4-biphenylyl)methyl]oxy}-3,5- difluorophenyl)-1 ,3-thiazol-2-yl]-4-piperidinecarboxylate; To a solution of ethyl 1-[4-(2-[(4-bromo-2-methylphenyl)methyl]oxy}-3,5-difluorophenyl)-1 ,3- thiazol-2-yl]-4-piperidinecarboxylate (Intermediate 135, 0.07 g, 0.127 mmol) and (4-cyano-2- methylphenyl)boronic acid (0.041 g, 0.254 mmol) in acetonitrile (20 ml) was added cesium carbonate (0.083 g, 0.254 mmol) and Palladium tetrakis (7.33 mg, 6.35 mumol). The reaction was then stirred to reflux during one night. TLC (Chex /EtOAc: 80/20) showed that the reaction was incomplete. <strong>[313546-18-8](4-cyano-2-methylphenyl)boronic acid</strong> (0.041 g, 0.254 mmol) and Palladium tetrakis (7.33 mg, 6.35 mumol) was added and the reaction was stirred to reflux during five hours and stirred at room temperature for 48 hours. The reaction was incomplete but treated. The crude reaction was filtered on celite and concentrated in vacuo. Purifcation by flash chromatography on silica was carried out using DCM/MeOH 99/1 gave the title compound (0.06 g, 0.102 mmol, 80 % yield) as an oil. LC/MS: m/z 588 [M+H]+, Rt 4.66 min. 1H NMR (CDCI3, 300 MHz) deltal.10) (d, 1 H), 7.59-7.52 (m, 3H), 7.35-7.28 (d, 3H), 7.16 (brs 1 H), 6.83 (m, 1 H), 5.05 (s, 2H), 4.19 (q, 2H), 4.04 (m, 2H), 3.17 (m, 2H), 2.57 (m, 1 H), 2.47 (s, 3H), 2.33 (s, 3H), 2.06 (m, 2H), 1.90 (m, 2H), 1.30 (t, 3H).

Reference： [1]Patent: WO2010/15652,2010,A2 .Location in patent: Page/Page column 92

17
[ 1207536-99-9 ]
[ 313546-18-8 ]
[ 1207537-06-1 ]

Yield	Reaction Conditions	Operation in experiment
87%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 105℃;	Description 31 : Ethyl 1-(4-(5-methyl-2-(2-methyl-4-(4-cvano-2- methylphenyl)benzyloxy)-phenyl)pyrimidin-2-yl)-piperidine-4-carboxylate (D31); To a solution of ethyl 1-(4-( 5-methyl-2-(2-methyl-4-bromo-benzyloxy)-phenyl)pyrimidin-2-yl)- piperidine-4-carboxylate (D24, 0.4g, 0.763 mmol) in DME (50ml) and water (5ml) were added Pd(PPh3)4 (0.044 g, 0.038 mmol), <strong>[313546-18-8](4-cyano-2-methylphenyl)boronic acid</strong> (0.184 g, 1.144 mmol) and Na2CO3 (0.202 g, 1.907 mmol). The reaction was heated at 1050C overnight and then poured into water. After extraction with CH2CI2, the organic phase was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography on silicagel (CH2CI2 / MeOH, 99/1 ). The title compound was obtained as a colorless oil (0.37g, yield= 87%). LC/MS: 561.1 (M+H), Rt= 4.55min. 1H NMR (CDCI3, ppm): 8.27 (d, 1 H), 7.75 (s, 1 H), 7.58 (s, 1 H), 7.54 (d, 1 H), 7.49 (d, 1 H), 7.33 (d, 1 H), 7.24 (d, 1 H), 7.14 (m, 3H), 7.02 (d, 1 H), 5.14 (s, 2H), 4.79 (Id, 2H), 4.17 (q, 2H), 3.09 (t, 2H), 2.60 (m, 1 H), 2.4 (s, 3H), 2.38 (s, 3H), 2.32 (s, 3H), 2.02 (m, 2H), 1.76 (m, 2H), 1.28 (t, 3H).

Reference： [1]Patent: WO2010/15653,2010,A1 .Location in patent: Page/Page column 53

18
[ 14472-14-1 ]
[ 313546-18-8 ]
[ 1245791-49-4 ]

Reference： [1]Inorganic Chemistry,2010,vol. 49,p. 8601 - 8619
[2]Chemistry - A European Journal,2013,vol. 19,p. 8447 - 8456
[3]Chemistry - A European Journal,2016,vol. 22,p. 1385 - 1391

19
[ 20870-78-4 ]
[ 313546-18-8 ]
[ 1279107-00-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; N,N-dimethyl-formamide; at 90℃; for 15.0h;Sealed;	Step 1 3-Methyl-4-(2-oxo-2,3-dihydro-1H-indol-5-yl)-benzonitrile To a pressure flask was added; 5-bromoindolin-2-one (10.0 g, 47.2 mmol), <strong>[313546-18-8]4-cyano-2-methylphenylboronic acid</strong> (9.11 g, 56.6 mmol) were combined with DMF (370 ml) to give a light brown solution, a solution of sodium carbonate in water (37 ml) was added, while the mixture was degassed with nitrogen, a catalytic amount of Pd(dppf)Cl2*CH2Cl2 was added, and the flask sealed. The reaction mixture was heated to 90 C. for 15 h., water was added, the dark solid was collected, the solid was washed with water, MeOH and 20% EtOAc/hexanes to give 3-methyl-4-(2-oxo-2,3-dihydro-1H-indol-5-yl)-benzonitrile as a dark purple solid (12.1 g, 103%).

Reference： [1]Patent: US2011/71150,2011,A1 .Location in patent: Page/Page column 90-91

20
[ 1279106-97-6 ]
[ 313546-18-8 ]
[ 1279106-99-8 ]

Yield	Reaction Conditions	Operation in experiment
61.6%	With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃; for 4.0h;Inert atmosphere;	Step 1: 2-(2-Chloro-phenyl)-5-(4-cyano-2-methyl-phenyl)-indole-1-carboxylic acid ethyl ester A suspension of ethyl 2-(2-chlorophenyl)-5-iodo-1H-indole-1-carboxylate (100 mg, 235 mmol, Eq: 1.00), <strong>[313546-18-8]4-cyano-2-methylphenylboronic acid</strong> (49.2 mg, 305 mummol, Eq: 1.3), Potassium carbonate (97.4 mg, 705 mummol, Eq: 3) in Dioxane (3.00 ml) and Water (0.6 ml) was purged with nitrogen (10 min) and then 1,1'-bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (19.2 mg, 23.5 mummol, Eq: 0.1) was added and r*n. mixture was heated at 100 C for 4 hr. Filtered through a pad of Celite, washed with DCM, solvent removed in vacuo, the residue redissolved in DCM, washed with water, brine, dried (Magnesium sulfate). Concentrated, chromatographed (silica gel, 10% EtOAc-Hexane) to obtain ethyl 2-(2-chlorophenyl)-5-(4-cyano-2-methylphenyl)-1H-indole-1-carboxylate (60 mg, 145 mummol, 61.6% yield) as a off-white powder. LC/MS: (M+H)=415.

Reference： [1]Patent: US2011/71150,2011,A1 .Location in patent: Page/Page column 89-90

21
[ 1285505-77-2 ]
[ 313546-18-8 ]
[ 1285506-50-4 ]

Yield	Reaction Conditions	Operation in experiment
80%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 80℃; for 12.0h;	Example 57Synthesis of (E)-2'-(3-guanidino-2-methyl-3-oxo-propenyl)-2-methyl-biphenyl-4-carboxamidine<Step 1>Intermediate 1 (100 mg, 0.253 mmol) and 2-methyl-4-cyanophenyl boronic acid (61.0 mg. 0.379 mmol) were dissolved in a mixed solution of dioxane and water (v/v=3/1, 4.0 mL). Pd(PPh3)4 (14.6 mg, 13.0 mumol) and Na2CO3 (107 mg, 1.01 mmol) were added to the solution and then stirred at 80 C. for 12 hours. After cooling it to room temperature, the solvent was eliminated in vacuo and then purified by reversed phase HPLC (0.1% TFA in water/CH3CN) to obtain the objective intermediate (90 mg, 80%).MS: 319

Reference： [1]Patent: US2011/82109,2011,A1 .Location in patent: Page/Page column 30

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[ 1279106-97-6 ]
[ 313546-18-8 ]
[ 1279104-68-5 ]