124289-21-0|3-Bromo-5-methylbenzonitrile| Ambeed

Structure of 124289-21-0

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Quality Control of [ 124289-21-0 ] Purity: 97% SDS Specification

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Product Details of [ 124289-21-0 ]

CAS No. :	124289-21-0
Formula :	C₈H₆BrN
M.W :	196.04
SMILES Code :	BrC1=CC(=CC(=C1)C#N)C
MDL No. :	MFCD08061970
InChI Key :	JRGGBJGKQMUYOK-UHFFFAOYSA-N
Pubchem ID :	14567858

Safety of [ 124289-21-0 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302+H312+H332
Precautionary Statements:	P280

Computational Chemistry of [ 124289-21-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	6
Fraction Csp3	0.12
Num. rotatable bonds	0
Num. H-bond acceptors	1.0
Num. H-bond donors	0.0
Molar Refractivity	43.82
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	23.79 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.19
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	2.7
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.63
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	2.52
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	2.94
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.59

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.2
Solubility	0.124 mg/ml ; 0.00063 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.85
Solubility	0.275 mg/ml ; 0.0014 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-3.73
Solubility	0.0368 mg/ml ; 0.000188 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.58 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	2.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.78

Application In Synthesis of [ 124289-21-0 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 124289-21-0 ]

[ 124289-21-0 ] Synthesis Path-Downstream 1~35

1
[ 124289-21-0 ]
[ 58530-13-5 ]

References: [1]Journal of the Chemical Society,1955,p. 3845,3847.

2
[ 124289-21-0 ]
[ 124289-24-3 ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 10h;Reflux;	Example 46 3-Bromo-5-(bromomethyl)benzonitrile A mixture of <strong>[124289-21-0]3-bromo-5-methylbenzonitrile</strong> (9.80 g, 45.0 mmol), NBS (8.90 g, 45.0 mmol) and BPO (0.40 g) in CCl4 (250 mL) was heated for 10 h at reflux. The reaction mixture was cooled to room temperature and filtered, and the organic phase was washed successively with saturated sodium bicarbonate (100 mL), water (250 mL) and brine (250 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuum to give 12.5 g of crude 3-bromo-5-(bromomethyl)benzonitrile.
	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 10h;Reflux;	Example 46 3-Bromo-5-(bromomethyl)benzonitrile A mixture of <strong>[124289-21-0]3-bromo-5-methylbenzonitrile</strong> (9.80 g, 45.0 mmol), NBS (8.90 g, 45.0 mmol) and BPO (0.40 g) in CCl4 (250 mL) was heated for 10 h at reflux. The reaction mixture was cooled to room temperature and filtered, and the organic phase was washed successively with saturated sodium bicarbonate (100 mL), water (250 mL) and brine (250 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuum to give 12.5 g of crude 3-bromo-5-(bromomethyl)benzonitrile.
	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 10h;Heating; Reflux;	Example 49 3-Bromo-5-(bromomethyl)benzonitrile A mixture of <strong>[124289-21-0]3-bromo-5-methylbenzonitrile</strong> (9.80 g, 45.0 mmol), NBS (8.90 g, 45.0 mmol) and BPO (0.40 g) in CCl4 (250 mL) was heated for 10 h at reflux. The reaction mixture was cooled to room temperature and filtered, and the organic phase was washed successively with saturated sodium bicarbonate (100 mL), water (250 mL) and brine (250 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuum to give 12.5 g of crude 3-bromo-5-(bromomethyl)benzonitrile.

	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 4h;UV-irradiation;	3-Bromo-5-hydroxymethylbenzonitrile(4); 3-Bromo-5-methylbenzonitrile(15g, 76 5mmol) was refluxed with N-bromo succiotaniotamiotade(13 6g, 76 5mmol) and benzoyl peroxiotade(925mg, 3 8mmol) in CCI4(I OOmI) under a light of 500W tungsten lamp After 4hr the mixture was cooled to room temperature, filtered, and concentrated The residue was stirred with sodium acetate(9 41 g, 115mmot) in DMF(100ml) for overnight at room temperature The mixture was diluted with ether, washed with water three times, dried with MgSO4, filtered, and evaporated in vacuo The residue was stirred with ammonium hydroxiotade(30ml) in methanol(IOOml) at room temperature After 3hr , the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography(eluent, ethyl acetate hexane(1 4)) to afford 7 1g(44% overali) of the title compound as a white solid m p 108-109 0C1H-NMR(200MHz, CDCI3) delta 2 03(1 H, t, J=5 6Hz), 4 73(2H, d, J=5 6Hz), 7 60(1 H1 s), 7 70(1 H, s), 7 76(1 H, s) m/z (El) 212 (M+)
	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 10h;Reflux;	Example 46 3-Bromo-5-(bromomethyl)benzonitrileA mixture of <strong>[124289-21-0]3-bromo-5-methylbenzonitrile</strong> (9.80 g, 45.0 mmol), NBS (8.90 g, 45.0 mmol) and BPO (0.40 g) in CCU (250 mL) was heated for 10 h at reflux. The reaction mixture was cooled to room temperature and filtered, and the organic phase was washed successively with saturated sodium bicarbonate (100 mL), water (2 x 50 mL) and brine (2 x 50 mL). The combined organic phases were dried over Na2SC^ and concentrated in vacuum to give 12.5 g of crude 3-bromo-5- (bromomethyl)benzonitrile.

References: [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 3958 - 3978.
[2]Journal of Organic Chemistry,1990,vol. 55,p. 1040 - 1043.
[3]Journal of Organic Chemistry,1990,vol. 55,p. 1040 - 1043.
[4]Patent: US2009/203657,2009,A1 .Location in patent: Page/Page column 53-54.
[5]Patent: US2009/203677,2009,A1 .Location in patent: Page/Page column 57.
[6]Patent: US2009/197871,2009,A1 .Location in patent: Page/Page column 56.
[7]Patent: WO2010/9047,2010,A1 .Location in patent: Page/Page column 85.
[8]Journal of Medicinal Chemistry,2010,vol. 53,p. 2155 - 2170.
[9]Patent: WO2009/100169,2009,A1 .Location in patent: Page/Page column 137.

3
[ 58530-13-5 ]
[ 124289-21-0 ]

References: [1]Journal of Organic Chemistry,1990,vol. 55,p. 1040 - 1043.
[2]Patent: WO2009/100169,2009,A1 .

4
diazotized 3-bromo-5-methyl-aniline [ No CAS ]
[ 124289-21-0 ]

References: [1]Journal of the Chemical Society,1955,p. 3845,3847.

5
[ 2941-78-8 ]
[ 124289-21-0 ]

References: [1]Journal of Organic Chemistry,1990,vol. 55,p. 1040 - 1043.

6
[ 13091-43-5 ]
[ 124289-21-0 ]

References: [1]Journal of Organic Chemistry,1990,vol. 55,p. 1040 - 1043.

7
[ 1611-92-3 ]
[ 141-78-6 ]
[ 124289-21-0 ]

Yield	Reaction Conditions	Operation in experiment
21%	In 1-methyl-pyrrolidin-2-one; hexane;	Reference Example 38 3-Bromo-5-cyanotoluene To a solution of 3,5-dibromotoluene (10.00 g) in 1-methyl-2-pyrrolidone (70 ml) was added copper (I) cyanide (5.20) and the mixture was stirred at 200 C. for 1.5 hours. The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The extract was washed with 1M hydrochloric acid, water and brine, dried over anhydrous magnesium sulfate and then concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=9/1 as an eluant to give the desired compound (1.70 g, yield 21%). 1H NMR (270 MHz, CDCl3) delta ppm: 2.39 (3H, s), 7.40 (1H, s), 7.57 (1H, s), 7.60 (1H, s).

References: [1]Patent: US6555556,2003,B1 .

8
[ 1611-92-3 ]
[ 544-92-3 ]
[ 124289-21-0 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In N,N-dimethyl-formamide; at 153℃; for 6h;	3-Bromo-5-methylbenzonitrile A mixture of 1,3-dibromo-5-methylbenzene (4.97 g, 19.9 mmol), copper (I) cyanide (2.70 g, 30.1 mmol), pyridine (4.85 mL, 60.0 mmol), and N,N-dimethylformamide (35 mL). were heated at 153 C. for 6 h. The reaction was allowed to cool to ambient temperature, poured into a solution of H2O (200 mL) and NH4OH (100 mL), and extracted with methyl tert-butyl ether (100 mL*2). The combined organic extracts were washed with saturated aqueous NH4Cl (200 mL), and the resulting aqueous layer was extracted with methyl tert-butyl ether (50 mL). The combined organic extracts were then washed with saturated aqueous NaHCO3 (200 mL), and the resulting aqueous layer was extracted with methyl tert-butyl ether (50 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The residue was chromatographed on silica gel with hexanes:EtOAc (99:1?1:99) to afford 3-bromo-5-methylbenzonitrile as an off-white solid. 1H NMR (CDCl3, 500 MHz) delta 7.60 (s, 1H), 7.57 (s, 1H), 7.40 (s, 1H), 2.39 (s, 3H).

References: [1]Patent: US2007/60618,2007,A1 .Location in patent: Page/Page column 12.

9
[ 124289-21-0 ]
[ 329203-85-2 ]
3-methyl-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With copper(l) iodide; tetrabutyl ammonium fluoride; triethylamine;bis-triphenylphosphine-palladium(II) chloride; In tetrahydrofuran; N,N-dimethyl-formamide; at 100℃; for 0.25h;Microwave irradiation;	3-Methyl-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]benzonitrile Tetrabutylammonium fluoride (3.2 mL, 1M in THF, 3.2 mmol) was added to a mixture of <strong>[124289-21-0]3-bromo-5-methylbenzonitrile</strong> (394 mg, 2.01 mmol), 2-methyl-4-[(trimethylsilyl)ethynyl]-1,3-thiazole (605 mg, 3.10 mmol), triethylamine (0.60 mL, 4.3 mmol), copper (I) iodide (76 mg, 0.40 mmol), dichlorobis(triphenylphosphine)palladium(II) (138 mg, 0.20 mmol), and N,N-dimethylformamide (4 mL). Nitrogen was bubbled through the resulting mixture for 15 min, and the reaction was heated in a microwave reactor at 100 C. for 15 min. The solvent was removed in vacuo, and the resulting residue was chromatographed on silica gel with hexanes:EtOAc (9:1?1:1) to afford 3-methyl-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]benzonitrile as an off-white solid. 1H NMR (CDCl3, 500 MHz) delta 7.63 (s, 1H), 7.58 (s, 1H), 7.43 (s, 1H), 7.42 (s, 1H), 2.75 (s, 3H), 2.39 (s, 3H). MS (ESI) 239.5 (M++H).

References: [1]Patent: US2007/60618,2007,A1 .Location in patent: Page/Page column 12.

10
3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile [ No CAS ]
[ 124289-21-0 ]

References: [1]Journal of the American Chemical Society,2007,vol. 129,p. 15434 - 15435.

11
[ 1007578-82-6 ]
[ 124289-21-0 ]

Yield	Reaction Conditions	Operation in experiment
52%	With phosphorus pentoxide; In chloroform; for 48h;Reflux;	Example 45 3-Bromo-5-methylbenzonitrile Phosphorous pentoxide (29.8 g, 210.2 mmol) was added to a suspension of 3-bromo-5-methylbenzamide (15.0 g, 70.1 mmol) in CHCl3 and the mixture was kept refluxing for 2 days (monitored by TLC). The reaction was allowed to cool to room temperature, and put into ice water under the condition of stirring. The organic layer was separated and the aqueous layer was extracted with dichloromethane (150 mL*2). The combined extracts were washed with brine, dried over NaSO4. The product, 3-bromo-5-methylbenzonitrile (7.20 g, 52%), was purified by flash column chomatography. 1H NMR (400 MHz, CDCl3) delta 7.60-7.56 (m, 2H), 7.40-7.39 (m, 1H), 2.39 (s, 3H).
52%	With phosphorus pentoxide; In chloroform; for 48h;Reflux;	Example 45 3-Bromo-5-methylbenzonitrile Phosphorous pentoxide (29.8 g, 210.2 mmol) was added to a suspension of 3-bromo-5-methylbenzamide (15.0 g, 70.1 mmol) in CHCl3 and the mixture was kept refluxing for 2 days (monitored by TLC). The reaction was allowed to cool to room temperature, and put into ice water under the condition of stirring. The organic layer was separated and the aqueous layer was extracted with dichloromethane (150 mL*2). The combined extracts were washed with brine, dried over NaSO4. The product, 3-bromo-5-methylbenzonitrile (7.20 g, 52%), was purified by flash column chomatography. 1H NMR (400 MHz, CDCl3) delta 7.60-7.56 (m, 2H), 7.40-7.39 (m, 1H), 2.39 (s, 3H).
52%	With phosphorus pentoxide; In chloroform; for 48h;Heating; Reflux;	Example 48 3-Bromo-5-methylbenzonitrile To a suspension of 3-bromo-5-methylbenzamide (15.0 g, 70.1 mmol) in CHCl3 was added phosphorous pentoxide (29.8 g, 210.2 mmol) and the mixture was kept refluxing for 2 days (monitored by TLC). The reaction was allowed to cool to room temperature, and put into the ice water under the condition of stirring. The organic layer was separated and the aqueous layer was extracted with dichloromethane (150 mL*2). The combined extracts were washed with brine, dried over NaSO4. The product, 3-bromo-5-methylbenzonitrile (7.20 g, 52%), was purified by flash column chromatography. 1H NMR (400 MHz, CDCl3): delta 7.60-7.56 (m, 2H), 7.40-7.39 (m, 1H), 2.39 (s, 3H).

52%

With phosphorus pentoxide; In chloroform; for 48h;Reflux;

Example 45 3-Bromo-5-methylbenzonitrilePhosphorous pentoxide (29.8 g, 210.2 mmol) was added to a suspension of 3-bromo-5- methylbenzamide (15.0 g, 70.1 mmol) in CHCl3 and the mixture was kept refluxing for 2 days (monitored by TLC). The reaction was allowed to cool to room temperature, and put into ice water under the condition of stirring. The organic layer was separated and the aqueous layer was extracted with dichloromethane (150 mL x 2). The combined extracts were washed with brine, dried over NaSOphi The product, 3-bromo-5-methylbenzonitrile (7.20 g, 52%), was purified by flash column chomatography. 1H NMR (400 MHz, CDCl3) delta 7.60-7.56 (m, 2 H), 7.40-7.39 (m, 1 H), 2.39 (s, 3 H).

References: [1]Patent: US2009/203657,2009,A1 .Location in patent: Page/Page column 53.
[2]Patent: US2009/203677,2009,A1 .Location in patent: Page/Page column 56; 57.
[3]Patent: US2009/197871,2009,A1 .Location in patent: Page/Page column 56.
[4]Patent: WO2009/100169,2009,A1 .Location in patent: Page/Page column 137.

12
[ 1205515-03-2 ]
[ 124289-21-0 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrachloromethane; triphenylphosphine; In acetonitrile; for 2h;	3-Bromo-5-methylbenzonitrile(3); A mixture of 3-bromo-5-methylbenzaldehyde oxime(18g, 84mmol), t?phenyiphosphiota?e(88g, 336mmoJ), and carbon tetrachlo?de(16 2ml, 168mmol) in acetonrt?le(160ml) was stirred for 1 hr in an ice-water bath More carbon tetrachlo?de(30ml) was then added and the mixture was stirred for thr The mixture was diluted with ether, washed with water, dried with MgSO4, filtered, and evaporated in vacuo The residue was purified by silica gel column chromatography(eluent, ethyl acetate hexane(1 9)) to afford 15g(93%) of the title compound as a white solid m p 85-86C1H~NMR(200MHz, CDCI3) delta 2 38(3H, s), 7 39(1 H, s), 7 56(1 H, s) 7 58(1H, s) m/z (El) 212 (M+)

References: [1]Patent: WO2010/9047,2010,A1 .Location in patent: Page/Page column 85.

13
[ 1611-92-3 ]
copper(l) cyanide [ No CAS ]
[ 124289-21-0 ]

Yield	Reaction Conditions	Operation in experiment
74%	With pyridine; In N,N-dimethyl-formamide; at 190℃; for 10h;Microwave irradiation;	Intermediate 503-Bromo-5-methylbenzonitrile; A mixture of 1,3-dibromo-5-methylbenzene (1.0 g, 4.0 mmol), copper cyanide (0.179 g, 2.00 mmol), pyridine (0.323 mL, 4.00 mmol), and DMF (15 mL) were heated at 190 C. for 10 h in microwave reactor. The reaction mixture was allowed to cool to r.t., and then poured into a solution of H2O (20 mL) and aq. NH3 solution (25-35% NH3, 10 mL) and the water phase was extracted with EtOAc. The combined organic extracts were dried (Mg2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatograpy (hexane/EtOAc gradient elution) to afford the title compound (0.58 g, 74% yield): 1H NMR (500 MHz, CDCl3) delta ppm 2.39 (s, 3H) 7.41 (s, 1H) 7.58 (s, 1H) 7.60 (s, 1H); MS (EI) m/z 195 M

References: [1]Patent: US2012/165347,2012,A1 .Location in patent: Page/Page column 34.

14
[ 1383985-94-1 ]
[ 124289-21-0 ]
[ 1383983-58-1 ]

Yield	Reaction Conditions	Operation in experiment
16%	With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 130℃; for 0.333333h;Sealed vial; Inert atmosphere;	Example 743-[(1r,4r)-4''-Amino-4-methoxy-5''-methyl-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazol]-6'-yl]-5-methylbenzonitrile; (1r,4r)-6'-Bromo-4-methoxy-5''-methyl-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazol]-4''-amine (Example 19 Method B Step 4, 414 mg, 1.10 mmol), potassium acetate (216 mg, 2.20 mmol), bis(pinacolato)diboron (307 mg, 1.21 mmol) and PdCl2(dppf)-dichloromethane adduct (44.9 mg, 0.06 mmol) were taken up in dioxane (8 mL) in a Biotage 10-20 mL microwave vial. The reaction vessel was sealed and heated at 130 C. for 35+20 min in a Biotage Initiator. The obtained mixture containing (1r,4r)-4-methoxy-5''-methyl-6'44,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazol]-4''-amine mixture was used directly. K2CO3 (2 M aq., 2.20 mL, 4.41 mmol), Pd(Ph3P)4 (63.7 mg, 0.06 mmol) and <strong>[124289-21-0]3-bromo-5-methylbenzonitrile</strong> (Intermediate 50, 216 mg, 1.10 mmol) in dioxane (2 mL) were added. The reaction vessel was sealed and heated at 130 C. for 20 min in a Biotage Initiator. After cooling, the vessel was uncapped, the mixture was diluted with DCM, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The product was purified by preparative chromatography to give the title product compound (62 mg, 16% yield): 1H NMR (600 MHz, DMSO-d6) delta ppm 0.97 (td, 1H) 1.11-1.30 (m, 2H) 1.35-1.52 (m, 3H) 1.83 (d, 2H) 2.18 (s, 3 H) 2.39 (s, 3H) 2.90-2.97 (m, 1H) 2.97-3.11 (m, 2H) 3.20 (s, 3H) 6.53 (br. s, 2H) 6.82 (s, 1 H) 7.39 (d, 1H) 7.52 (d, 1H) 7.59 (s, 1H) 7.67 (s, 1H) 7.77 (s, 1H); MS (ES+) m/z 413 [M+H]1.

References: [1]Patent: US2012/165347,2012,A1 .Location in patent: Page/Page column 88.

15
[ 24544-04-5 ]
[ 124289-21-0 ]
[ 1395093-32-9 ]

Yield	Reaction Conditions	Operation in experiment
59%		To a250 mL 3-neck round bottom flask was added 2,6-diisopropylaniline (2.365 g, 13.34 mmol) and 70 mL toluene. The solution was cooled in an ice bath under nitrogen and trimethylaluminum (2.0 M in toluene, 9.34 mL, 18.68 mmol) was added dropwise via dropping funnel. The reaction mixture was stirred at room temperature for 2 hours. Next, <strong>[124289-21-0]3-bromo-5-methylbenzonitrile</strong> (3.4 g, 17.34 mmol) in 30 mL toluene was added and the reaction mixture was heated to 70 C overnight under nitrogen. The reaction mixture was cooled in an ice bath and was poured onto a stirring slurry of silica gel in 2: 1 dichloromethane/methanol (v/v). The silica gel was filtered off and washed with dichloromethane and methanol. The filtrate was evaporated leaving a solid.Hexane was added to the solvent and the solid was filtered off and washed with hexane (2.92 g, 59%).

References: [1]Patent: WO2012/116231,2012,A2 .Location in patent: Page/Page column 134.

16
[ 557-21-1 ]
2-(3-bromo-5-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ No CAS ]
[ 124289-21-0 ]

Yield	Reaction Conditions	Operation in experiment
20%	With copper(II) nitrate trihydrate; cesium fluoride; In methanol; water; at 100℃; for 5h;Sealed flask;	To a sealable vessel was added 2-(3-bromo-5- methylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (26.1 g, 88 mmol), copper(II)nitrate trihydrate (42.5 g, 176 mmol), zinc cyanide (31.0 g, 264 mmol), cesium fluoride (13.35 g, 88 mmol), 125 mL methanol, and 50 mL water. The vessel was sealed and heated to 100 C for 5 hours. The reaction mixture was cooled and an insoluble tan solid was filtered and washed with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography eluting with 5 and 10 % ethyl acetate/hexane (3.4 g, 20%)

References: [1]Science,2014,vol. 343,p. 853 - 857.
[2]Patent: WO2015/35325,2015,A1 .Location in patent: Paragraph 00125.
[3]Patent: WO2012/116231,2012,A2 .Location in patent: Page/Page column 133-134.

17
[ 591-17-3 ]
[ 124289-21-0 ]

References: [1]Patent: WO2012/116231,2012,A2 .

18
[ 124289-21-0 ]
[ 1395093-33-0 ]

References: [1]Patent: WO2012/116231,2012,A2 .

19
[ 124289-21-0 ]
[ 1395093-34-1 ]

References: [1]Patent: WO2012/116231,2012,A2 .

20
[ 124289-21-0 ]
C₄₄H₄₈N₄OPt [ No CAS ]

References: [1]Patent: WO2012/116231,2012,A2 .

21
[ 556-96-7 ]
[ 124289-21-0 ]

References: [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 10573 - 10576.
Angew. Chem.,2013,vol. 125,p. 10767 - 10770,4.
[2]Patent: WO2009/100169,2009,A1 .

22
[ 124289-21-0 ]
[ 1177558-49-4 ]