144649-99-0|5-Bromo-2-methoxybenzonitrile| Ambeed

Structure of 144649-99-0

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Quality Control of [ 144649-99-0 ] Purity: 97% SDS Specification

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Product Details of [ 144649-99-0 ]

CAS No. :	144649-99-0
Formula :	C₈H₆BrNO
M.W :	212.04
SMILES Code :	N#CC1=CC(Br)=CC=C1OC
MDL No. :	MFCD00143429
InChI Key :	LOASAXVECBZCRJ-UHFFFAOYSA-N
Pubchem ID :	4418560

Safety of [ 144649-99-0 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H312-H332-H320
Precautionary Statements:	P261-P264-P270-P271-P280-P301+P312+P330-P302+P352+P312-P304+P340+P312-P305+P351+P338-P337+P313-P501

Computational Chemistry of [ 144649-99-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.12
Num. rotatable bonds	1
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	45.35
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	33.02 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.15
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	2.3
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.33
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.	1.86
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	2.47
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.22

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.94
Solubility	0.243 mg/ml ; 0.00114 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.	-2.63
Solubility	0.496 mg/ml ; 0.00234 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	-3.47
Solubility	0.0718 mg/ml ; 0.000339 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.	-5.96 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	0.0
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)	1.74

Application In Synthesis of [ 144649-99-0 ]

* 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 [ 144649-99-0 ]

[ 144649-99-0 ] Synthesis Path-Downstream 1~35

1
[ 144649-99-0 ]
[ 144650-00-0 ]

Yield	Reaction Conditions	Operation in experiment
43%		A 1 M solution of lithium bis-hexamethylsilazide (220 mmol, 220 mL) in tetrahydrofuran was transferred into a 3 neck round bottom flask. The solution was cooled to 0° C. and treated dropwise with <strong>[144649-99-0]5-bromo-2-methoxy-benzonitrile</strong> (100 mmol 21.21 g) in tetrahydrofuran over 20 minutes. The reaction mixture was allowed to stir at 0° C. for 30 minutes, then allowed to stir at room temperature for 4 hours. The reaction mixture was cooled to 0° C. and treated with 2 M hydrochloric acid (350 mL) dropwise. The reaction mixture was allowed to stir for 15 hours at room temperature and poured into a separating funnel. The layers were separated and the organics were washed with 2 M hydrochloric acid (100 mL). The aqueous layer was treated with 2 M NaOH solution (400 mL). The aqueous layer was extracted with 3.x.200 mL of chloroform. The organics were dried with MgSO4, filtered, and evaporated to give a dark yellow solid. This was triturated with diethyl ether to provide the title compound as a yellow solid. Yield 9.8 g, 43percent. Analytical LCMS method 2, retention time 0.40 min, M+H=229. 1H NMR: (CDCl3) delta: 7.71 (d, 1H), 7.46 (dd, 1H), 6.83 (d, 1H), 5.48 (br, s, 3H), 3.86 (s, 3H).
	silica gel; In methanol; dichloromethane;	EXAMPLE II A mixture of 4.0 g <strong>[144649-99-0]5-bromo-2-methoxybenzonitrile</strong>, 5 g 3A molecular sieves and 60 mL of anhydrous methanol was saturated with HCl gas at 0° C. and allowed to stand at 0° C. for 24 h. The solvent was removed in vacuo and the residue taken up in 75 mL of anhydrous methanol and saturated with ammonia gas at room temperature. The reaction mixture was then heated at 80° C. for 4 h in a sealed tube. The sovent was removed in vacuo, the reaction mixture was diluted with 3N HCl and washed with ethyl acetate to remove unreacted nitrile. The aqueous layer was made basic with 50percent NaOH and the product was extracted three times with 10percent methanol in methylene chloride. The combined organic extracts were dried over potassium carbonate and the solvents removed in vacuo to afford 5-bromo-2-methoxybenzamidine as a glassy solid.
	silica gel; In methanol; dichloromethane;	EXAMPLE II STR32 A mixture of <strong>[144649-99-0]5-Bromo-2-methoxy-benzonitrile</strong> (4.0 g), 3A molecular sieves (5 g) and anhydrous methanol (60 mL) was saturated with HCl gas at room temperature and allowed to stand at room temperature for 24 h. The solvent was removed in, vacuo and the residue taken up in 75 mL of anhydrous methanol and saturated with ammonia gas at room temperature. The reaction mixture was then heated at 80° C. for 4 h in a sealed tube. The solvent was removed in vacuo, the reaction mixture was diluted with 3N HCl and washed with ethyl acetate to remove unreacted nitrile. The aqueous layer was made basic with 50percent NaOH and the product was extracted three times with 10percent methanol in methylene chloride. The combined organic extracts were dried over magnesium sulfate and the sovents removed in vacuo to afford 5-Bromo-2-methoxy-benzamidine as a glassy solid.

	In methanol; dichloromethane;	EXAMPLE II STR35 A mixture of <strong>[144649-99-0]5-Bromo-2-methoxy-benzonitrile</strong> (4.0 g), 3A molecular selves (5 g) and anhydrous methanol (60 mL) was saturated with HCl gas at room temperature and allowed to stand at room temperature for 24 h. The solvent was removed in vacuo and the residue taken up in 75 mL of anhydrous methanol and saturated with ammonia gas at room temperature. The reaction mixture was then heated at 80° C. for 4 h in a sealed tube. The sovent was removed in vacuo, the reaction mixture was diluted with 3N HCl and washed with ethyl acetate to remove unreacted nitrile. The aqueous layer was made basic with 50percent NaOH and the product was extracted three times with 10percent methanol in methylene chloride. The combined organic extracts were dried over magnesium sulfate and the sovents removed in vacuo to afford 5-Bromo-2-methoxy-benzamidine as a glassy solid. STR36
	silica gel; In methanol; dichloromethane;	EXAMPLE II STR22 A mixture of <strong>[144649-99-0]5-Bromo-2-methoxy-benzonitrile</strong> (4.0 g), 3A molecular sieves (5 g) and anhydrous methanol (60 mL) was saturated with HCl gas at room temperature and allowed to stand at room temperature for 24 h. The solvent was removed in vacuo and the residue taken up in 75 mL of anhydrous methanol and saturated with ammonia gas at room temperature. The reaction mixture was then heated at 80° C. for 4 h in a sealed tube. The solvent was removed in vacuo, the reaction mixture was diluted with 3N HCl and washed with ethyl acetate to remove unreacted nitrile. The aqueous layer was made basic with 50percent NaOH and the product was extracted three times with 10percent methanol in methylene chloride. The combined organic extracts were dried over magnesium sulfate and the solvents removed in vacuo to afford 5-Bromo-2-methoxy-benzamidine as a glassy solid.

References: [1]Patent: US2009/247519,2009,A1 .Location in patent: Page/Page column 144.
[2]Journal of Medicinal Chemistry,1995,vol. 38,p. 2251 - 2255.
[3]Patent: US2003/18025,2003,A1 .
[4]Patent: US5633376,1997,A .
[5]Patent: US5681956,1997,A .
[6]Patent: US5159083,1992,A .

2
[ 144649-99-0 ]
[ 1026583-40-3 ]

References: [1]Journal of Medicinal Chemistry,1995,vol. 38,p. 2251 - 2255.

3
[ 144649-99-0 ]
[ 144650-02-2 ]

References: [1]Journal of Medicinal Chemistry,1995,vol. 38,p. 2251 - 2255.

4
[ 144649-99-0 ]
Benzyl-[2-(5-bromo-2-methoxy-phenyl)-3H-imidazol-4-ylmethyl]-methyl-amine [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1995,vol. 38,p. 2251 - 2255.

5
[ 5720-07-0 ]
[ 144649-99-0 ]
4,4'-dimethoxy-3-cyanobiphenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%		Example 58 3-(4.6-Diamino-[1,3,5]triazin-2-yl)-biphenyl-4,4'-diol One equivalent of 5-bromo-2-methoxy-benznitrile (1 mmol) was reacted with 4-methoxyphenylboronic acid (1.05 mmol), following General Procedure G, to give 4,4'-dimethoxy-3-cyanobiphenol in 90percent yield.

References: [1]Patent: US2003/187007,2003,A1 .

6
[ 25016-01-7 ]
[ 144649-99-0 ]

Yield	Reaction Conditions	Operation in experiment
97%	With formic acid; hydroxylamine hydrochloride; sodium acetate; for 15h;Reflux;	5-Bromo-2-methoxybenzaldehyde (20.00 mmol, 4.30 g) was dissolved in formic acid (20 mL) and treated with hydroxylamine hydrochloride (21.00 mmol, 1.45 g) and sodium acetate (26.00 mmol, 2.13 g). The reaction mixture was heated at reflux for 15 hours. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate (250 mL). The organics were washed with saturated sodium bicarbonate solution (2.x.200 mL) and then dried with MgSO4. The organics were filtered and evaporated under reduced pressure to yield the title compound as a white solid. Yield=4.10 g, 97percent. Analytical LCMS method 2, retention time 6.07 min, M+H=214, 216. 1H NMR: (CDCl3) delta: 7.66-7.61 (m, 2H), 6.87 (d, 1H), 3.92 (s, 3H).
	With sodium hydroxide; formic acid; hydroxylamine hydrochloride; sodium formate;	EXAMPLE I A mixture of 6.45 g 5-bromo-o-anisaldehyde, 2.2 g of hydroxylamine hydrochloride, 4.1 g of sodium formate and 20 mL formic acid were heated at 100° C. with stirring for 1 h. The reaction mixture was poured onto ice water and the mixture was made basic by the careful addition of 50percent sodium hydroxide. The product was extracted with ether, the ether extracts were dried over magnesium sulfate and the solvent was removed in vacuo. The residue was crystallized from ether/hexane to afford 5-bromo-2-methoxybenzonitrile.
	With sodium hydroxide; hydroxylamine hydrochloride; sodium acetate; acetic anhydride; acetic acid;	EXAMPLE I STR31 A mixture of 5-Bromo-o-anisaldehyde (6.45 g), hydroxylamine hydrochloride (2.2 g), sodium acetate (4.1 g) and acetic acid (20 mL) was heated at 100° C. with stirring for 1 h. Acetic anhydride was added (20 mL) and the mixture was refluxed for 8 h. The reaction mixture was poured onto ice water and the mixture was made basic by the careful addition of 50percent sodium hydroxide. The product was extracted with ether, the ether extracts were dried over magnesium sulfate and the solvent was removed in vacuo. The residue was crystallized from ether/hexane to afford 5-Bromo-2-methoxy-benzonitrile.

With sodium hydroxide; hydroxylamine hydrochloride; sodium acetate; acetic anhydride; acetic acid;

EXAMPLE I STR21 A mixture of 5-Bromo-o-anisaldehyde (6.45 g), hydroxylamine hydrochloride (2.2 g), sodium acetate (4.1 g) and acetic acid (20 mL) was heated at 100° C. with stirring for 1 h. Acetic anhydride was added (20 mL) and the mixture was refluxed for 8 h. The reaction mixture was poured onto ice water and the mixture was made basic by the careful addition of 50percent sodium hydroxide. The product was extracted with ether, the ether extracts were dried over magnesium sulfate and the sovent was removed in vacuo. The residue was crystallized from ether/hexane to afford 5-Bromo-2-methoxybenzonitrile.

References: [1]Science China Chemistry,2015,vol. 58,p. 747 - 750.
[2]Patent: US2009/247519,2009,A1 .Location in patent: Page/Page column 143.
[3]Patent: US2003/18025,2003,A1 .
[4]Patent: US5633376,1997,A .
[5]Patent: US5159083,1992,A .

7
[ 144649-99-0 ]
[ 911210-48-5 ]

Yield	Reaction Conditions	Operation in experiment
		16.23 ml of n-butyllithium solution (1.6M in hexane) are added dropwise to a solution of 5.00 g of <strong>[144649-99-0]5-bromo-2-methoxybenzonitrile</strong> in 90 ml of dry tetrahydrofuran at -78°C. After stirring at this temperature for 45 minutes, 6.71 ml of triisopropylborate are added, and the mixture is then slowly warmed to -20°C. 50 ml of 1 N HCl are added to the reaction mixture. The phase is separated and the aqueous phase is extracted three more times with 100 ml of diethyl ether each time. The combined organic phases are dried with sodium sulphate, filtered and evaporated. The remaining oil is mixed with pentane, and the precipitate which separates out is filtered off with suction and washed once with a little dichloromethane. Drying under high vacuum affords the title compound as a white solid. Rt = 2.74.
		16.23 ml of n-butyllithium solution (1.6M in hexane) are added dropwise to a solution of 5.00 g of <strong>[144649-99-0]5-bromo-2-methoxybenzonitrile</strong> in 90 ml of dry tetrahydrofuran at -78° C. After stirring at this temperature for 45 minutes, 6.71 ml of triisopropylborate are added, and the mixture is then slowly warmed to -20° C. 50 ml of 1N HCl are added to the reaction mixture. The phase is separated and the aqueous phase is extracted three more times with 100 ml of diethyl ether each time. The combihled organic phases are dried with sodium sulphate, filtered and evaporated. The remaining oil is mixed with pentane, and the precipitate which separates out is filtered off with suction and washed once with a little dichloromethane. Drying under high vacuum affords the title compound as a white solid. Rt=2.74.
		16.23 ml of n-butyllithium solution (1.6M in hexane) are added dropwise to a solution of 5.00 g of <strong>[144649-99-0]5-bromo-2-methoxybenzonitrile</strong> in 90 ml of dry tetrahydrofuran at -78°C. After stirring at this temperature for 45 minutes, 6.71 ml of triisopropylborate are added, and the mixture is then slowly warmed to -200C. 50 ml of 1 N HCI are added to the reaction mixture. The phase is separated and the aqueous phase is extracted three more times with 100 ml of diethyl ether each time. The combined organic phases are dried with sodium sulphate, filtered and evaporated. The remaining oil is mixed with pentane, and the precipitate which separates out is filtered off with suction and washed once with a little dichloromethane. Drying under high vacuum affords the title compound as a white solid. Rt = 2.74.

References: [1]Patent: EP1987834,2008,A2 .Location in patent: Page/Page column 35.
[2]Patent: US2009/306064,2009,A1 .Location in patent: Page/Page column 53.
[3]Patent: WO2006/103273,2006,A1 .Location in patent: Page/Page column 42.

8
[ 24424-99-5 ]
[ 144649-99-0 ]
[ 334015-82-6 ]

Yield	Reaction Conditions	Operation in experiment
27%	With sodium tetrahydroborate; nickel dichloride; In ethanol; at 0 - 20℃; for 3h;	Example 38 1,1-Dimethylethyl [5-bromo-2-(methyloxy)phenyl]methyl}carbamate NaBH4 (2.9 g, 75.5 mmol) was cautiously added in several portions to a solution of NiCl2 (2.6 g, 19.8 mmol), Boc2O (8.2 g, 37.7 mmol) and <strong>[144649-99-0]5-bromo-2-(methyloxy)benzonitrile</strong> (4.0 g, 18.9 mmol) in dry EtOH (70 mL) at 0° C. Once the reaction had subsided, the mixture was left to stir at room temperature for 3 h. Ethanol was removed under reduced pressure and the residue was dissolved in EtOAc and saturated solution of NaHCO3, then filtered and repeatedly washed with EtOAc. The combined organic phases were dried using Na2SO4. The crude product was purified by flash column chromatography (PE/EA=20:1) to give 1.6 g of the product, 1,1-dimethylethyl [5-bromo-2-(methyloxy)phenyl]methyl}-carbamate. (Yield: 27percent). 1H NMR (400 MHz, CDCl3): delta 7.36-7.33 (m, 2H), 6.74 (d, J=8.8 Hz, 1H), 4.97 (br, 1H), 4.27 (d, J=4.8 Hz, 1H), 3.82 (s, 3H), 1.45 (s, 9H); 13C NMR (400 MHz, CDCl3): delta 156.5, 155.8, 131.7, 131.1, 129.3, 111.8, 79.5, 55.5, 39.9, 26.4. HPLC: retention time: 6.592 min; purity: 97.9percent.
25%	With sodium tetrahydroborate; ethanol;nickel dichloride; at 0 - 20℃;	Example 35 1,1-Dimethylethyl[5-bromo-2-(methyloxy)phenyl]methyl}carbamate NaBH4 (2.9 g, 75.5 mmol) was cautiously added in several portions to a solution of NiCl2 (2.6 g, 19.8 mmol), Boc2O (8.2 g, 37.7 mmol) and <strong>[144649-99-0]5-bromo-2-(methyloxy)benzonitrile</strong> (4.0 g, 18.9 mmol) in dry EtOH (70 mL) at 0° C. Once the reaction had subsided, the mixture was left to stir at room temperature for 3 h. Ethanol was removed under reduced pressure and the residue was dissolved in EtOAc and saturated solution of NaHCO3, then filtered and the aqueous layer was repeatedly washed with EtOAc. The combined organic phases were dried Na2SO4. The crude product was purified by flash column chromatography to give the captioned the product (1.5 g yield: 25percent). 1H NMR (400 MHz, CDCl3) delta 7.36-7.33 (m, 2H), 6.74 (d, J=8.8 Hz, 1H), 4.97 (br, 1H), 4.27 (d, J=4.8 Hz, 1H), 3.82 (s, 3H), 1.45 (s, 9H); 13C NMR (400 MHz, CDCl3) delta 156.5, 155.8, 131.7, 131.1, 129.3, 111.8, 79.5, 55.5, 39.9, 26.4. HPLC: retention time.
25%	With sodium tetrahydroborate; ethanol; nickel dichloride; at 0 - 20℃; for 3h;	Example 35 1,1-Dimethylethyl [5-bromo-2-(methyloxy)phenyl] methyl} carbamateNaBH4 (2.9 g, 75.5 mmol) was cautiously added in several portions to a solution OfNiCl2 (2.6 g, 19.8 mmol), BoC2O (8.2 g, 37.7 mmol) and <strong>[144649-99-0]5-bromo-2-(methyloxy)benzonitrile</strong> (4.0 g, 18.9 mmol) in dry EtOH (70 mL) at 0 0C. Once the reaction had subsided, the mixture was left to stir at room temperature for 3 h. Ethanol was removed under reduced pressure and the residue was dissolved in EtOAc and saturated solution of NaHCpsi3, then filtered and the aqueous layer was repeatedly washed with EtOAc. The combined organic phases were dried Na2SO4. The crude product was purified by flash column chromatography to give the captioned the product (1.5g yield: 25percent). 1H NMR (400 MHz, CDCl3) delta 7.36-7.33 (m, 2 H), 6.74 (d, J=8.8 Hz, 1 H), 4.97 (br, 1 H), 4.27(d, J=4.8 Hz, 1 H), 3.82 (s, 3 H), 1.45 (s, 9 H); 13C NMR (400 MHz, CDCl3) delta 156.5, 155.8, 131.7, 131.1, 129.3, 111.8, 79.5, 55.5, 39.9, 26.4. HPLC: retention time.

With sodium tetrahydroborate; nickel dichloride; In ethanol; at 0 - 20℃;

Example 35 1,1-Dimethylethyl [5-bromo-2-(methyloxy)phenyl]methyl}carbamate NaBH4 (2.9 g, 75.5 mmol) was cautiously added in several portions to a solution of NiCl2 (2.6 g, 19.8 mmol), Boc2O (8.2 g, 37.7 mmol) and <strong>[144649-99-0]5-bromo-2-(methyloxy)benzonitrile</strong> (4.0 g, 18.9 mmol) in dry EtOH (70 mL) at 0° C. Once the reaction had subsided, the mixture was left to stir at room temperature for 3 h. Ethanol was removed under reduced pressure and the residue was dissolved in EtOAc and saturated solution of NaHCO3, then filtered and the aqueous layer was repeatedly washed with EtOAc. The combined organic phases were dried Na2SO4. The crude product was purified by flash column chromatography to give the captioned the product (1.5 g yield: 25percent). 1H NMR (400 MHz, CDCl3) delta 7.36-7.33 (m, 2H), 6.74 (d, J=8.8 Hz, 1H), 4.97 (br, 1H), 4.27 (d, J=4.8 Hz, 1H), 3.82 (s, 3H), 1.45 (s, 9H); 13C NMR (400 MHz, CDCl3) delta 156.5, 155.8, 131.7, 131.1, 129.3, 111.8, 79.5, 55.5, 39.9, 26.4. HPLC: retention time.

References: [1]Patent: US2009/197871,2009,A1 .Location in patent: Page/Page column 54.
[2]Patent: US2009/203677,2009,A1 .Location in patent: Page/Page column 54.
[3]Patent: WO2009/100169,2009,A1 .Location in patent: Page/Page column 133.
[4]Patent: US2009/203657,2009,A1 .Location in patent: Page/Page column 51.

9
[ 6609-56-9 ]
[ 144649-99-0 ]

Yield	Reaction Conditions	Operation in experiment
96%	With N-Bromosuccinimide; iodine; In acetonitrile; for 12h;Darkness;	General procedure: To a reaction tube charged with NBS (1.5 equiv, 0.3 mmol), catalyst (10 molpercent, 0.02 mmol) and CH3CN (1.0 mL),was added para-chloroanisole 1a (0.2 mmol). After being stirred at room temperature for 12 h in dark, the reaction was quenched by saturated aq. solution of Na2S2O3 (2 mL). The resulting mixture was extracted by ethyl acetate (3 5 mL). The combined organic extracts were washed by brine (10 mL), dried over Na2SO4 and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and the residuewas purified by flash chromatography on a silica gel column with petroleum ether/dichloromethane (5:1) as the eluent to give 4.3.1. 2-Bromo-4-chloroanisole (2a)
71%	With bromine; In chloroform; for 29h;Reflux;	Example 34 5-Bromo-2-(methyloxy)benzonitrile Br2 (13.7 g, 86.0 mmol) in CHCl3 (20 mL) was added to a solution of 2-(methyloxy)benzonitrile (10.9 g, 81.9 mmol) in CHCl3 (50 mL). The mixture was refluxed for 29 h. The reaction was allowed to cool to room temperature, and washed with saturated sodium bisulfite (50 mL), and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate. Evaporation of the solvent afforded 5-bromo-2-(methyloxy)benzonitrile (12.4 g, 71percent).
71%	With bromine; In chloroform; for 29h;Reflux;	Example 34 5-Bromo-2-(methyloxy)benzonitrile Bromine (13.7 g, 86.0 mmol) in CHCl3 (20 mL) was added to a solution of 2-(methyloxy)benzonitrile (10.9 g, 81.9 mmol) in CHCl3 (50 mL). The mixture was refluxed for 29 h. The reaction was allowed to cool to room temperature, and washed with saturated sodium bisulfite (50 mL), and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate. Evaporation of the solvent afforded 5-bromo-2-(methyloxy)benzonitrile (12.4 g, 71percent).

71%	With bromine; In chloroform; for 29h;Heating;	Example 37 5-Bromo-2-(methyloxy)benzonitrile Bromine (13.7 g, 86.0 mmol) in CHCl3 (20 mL) was added to the solution of 2-(methyloxy)benzonitrile (10.9 g, 81.9 mmol) in CHCl3 (50 mL). The mixture was refluxed for 29 h. The reaction was allowed to cool to room temperature, and washed with saturated sodium bisulfite (50 mL), and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate. Evaporation of the solvent afforded 5-bromo-2-(methyloxy)benzonitrile (12.4 g, 71percent).
71%	With bromine; In chloroform; for 29h;Reflux;	Example 34 5-Bromo-2-(methyloxy)benzonitrile <n="134"/>Br2 (13.7 g, 86.0 mmol) in CHCl3 (20 mL) was added to a solution of 2-(methyloxy)benzonitrile (10.9 g, 81.9 mmol) in CHCl3 (50 mL). The mixture was refluxed for 29 h. The reaction was allowed to cool to room temperature, and washed with saturated sodium bisulfite (50 mL), and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate. Evaporation of the solvent afforded 5-bromo-2-(methyloxy)benzonitrile (12.4 g, 71percent).

References: [1]Tetrahedron,2017,vol. 73,p. 7105 - 7114.
[2]Patent: US2009/203657,2009,A1 .Location in patent: Page/Page column 51.
[3]Patent: US2009/203677,2009,A1 .Location in patent: Page/Page column 54.
[4]Patent: US2009/197871,2009,A1 .Location in patent: Page/Page column 53-54.
[5]Patent: WO2009/100169,2009,A1 .Location in patent: Page/Page column 132-133.

10
[ 144649-99-0 ]
[ 623-47-2 ]
[ 956125-10-3 ]

Yield	Reaction Conditions	Operation in experiment
63%		<strong>[144649-99-0]5-Bromo-2-methoxy-benzonitrile</strong> (25.00 mmol, 5.73 g) was dissolved in ethanol (35 mL) and treated with ethyl propiolate (28.75 mmol, 2.93 g). The reaction mixture was heated at 60° C. for 30 minutes and then treated with a solution of potassium hydroxide (28.75 mmol, 1.63 g) in ethanol (35 mL). The reaction mixture was then heated at reflux for 3 hours and then allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure and taken up in water 300 mL. The mixture was adjusted to pH 4 with conc hydrochloric acid and the resultant solid was filtered off and washed with water. The solid was transferred to a round bottom flask, suspended in toluene and evaporated to dryness twice to provide the title compound as an off white solid. Yield=4.4 g, 63percent. Analytical LCMS method 2, retention time 4.28 min, M+H=281. 1H NMR: (CDCl3) delta: 11.0 (br, s, 1H), 8.57 (d, 1H), 8.04 (d, 1H), 7.61 (dd, 1H), 6.95 (d, 1H), 6.37 (d, 1H), 4.04 (s, 3H).

References: [1]Patent: US2009/247519,2009,A1 .Location in patent: Page/Page column 144.

11
[ 21702-84-1 ]
[ 55305-43-6 ]
[ 144649-99-0 ]

References: [1]Chemistry - A European Journal,2011,vol. 17,p. 4217 - 4222.

12
[ 144649-99-0 ]
[ 73183-34-3 ]
[ 1220219-22-6 ]

Yield	Reaction Conditions	Operation in experiment
92%	With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 80℃; for 18h;	2-Methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile: To a solution of <strong>[144649-99-0]2-methoxy-5-bromobenzonitrile</strong> (5.0 g, 23.6 mmol) in /?-dioxane (125 mL), bis(pinacolato)diborane (9.0 g, 35.4 mmol), KOAc ( 7.0 g, 71.3 mmol), and Pd(dppf)Cl2 ( 0.863 g, 1.17 mmol) were added. The resulting mixture was stirred for 18 h at 80 °C. The cooled reaction crude was diluted with 1200 mL EtOAc, washed with H20 and brine, dried (Na2S04), filtered, and concentrated in vacuo. The residue was purified by column chromatography on Si02 (Hexanes/EtOAc) to afford the title compound (5.6 g, 92percent).
92%	With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 80℃; for 18h;	Preparation of Intermediate 1-2; 5-(2-Chloropyrimidin-4-yl)-2-methoxybenzonitrileReagents: (a) Pd(dppf)Cl2, KOAc, /?-dioxane: (b) 2,4-dichloropyrimidine, K2C03,Pd(PPh3)4, CH3CN, H20, reflux, 5 h;[0209] Step 1. 2-Methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile: To a solution of <strong>[144649-99-0]2-methoxy-5-bromobenzonitrile</strong> (5.0 g, 23.6 mmol) in /?-dioxane (125 mL), bis(pinacolato)diborane (9.0 g, 35.4 mmol), KOAc (7.0 g, 71.3 mmol), and Pd(dppf)Cl2 (0.863 g, 1.17 mmol) were added. The resulting mixture was stirred for 18 h at 80 °C. The cooled reaction crude was diluted with 120 mL EtOAc, washed with H20 and brine, dried (Na2S04), filtered, and concentrated in vacuo. The residue was purified by column chromatography on Si02 (Hexanes/EtOAc) to afford the title compound (5.6 g, 92percent). GC/MS (EI, M+) 245

References: [1]Patent: WO2011/46970,2011,A1 .Location in patent: Page/Page column 92; 93.
[2]Patent: WO2012/142329,2012,A1 .Location in patent: Page/Page column 60.
[3]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 834 - 838.

13
[ 144649-99-0 ]
[ 1292317-51-1 ]

References: [1]Patent: WO2011/46970,2011,A1 .

14
[ 144649-99-0 ]
[ 1292317-73-7 ]

References: [1]Patent: WO2011/46970,2011,A1 .

15
[ 955135-14-5 ]
[ 144649-99-0 ]
[ 1338327-52-8 ]

Yield	Reaction Conditions	Operation in experiment
47.6%	With caesium carbonate;palladium diacetate; XPhos; In toluene; at 120℃; for 50h;Inert atmosphere;	Intermediate 52f: (i?)-5-(2-(tert-Butyldimethylsilyloxy)propylamino)-2- methoxybenzonitrile Pd(OAc)2 (0.529 g, 2.36 mmol) and dicyclohexyl(2',4',6'-triisopropylbiphenyl-2- yl)phosphine (1.124 g, 2.36 mmol) were added in one portion to a degassed solution of 5- bromo-2-methoxybenzonitrile (5 g, 23.58 mmol), (R)-2-(tert- butyldimethylsilyloxy)propan-l -amine (Intermediate 48g; 5.36 g, 28.30 mmol) and cesium carbonate (11.52 g, 35.37 mmol) in toluene (100 mL) at 20°C under nitrogen. The resulting suspension was stirred at 120 °C for 50 hours. The reaction mixture was diluted with EtOAc (150 mL) and water (150 mL) and the biphasic mixture was filtered through celite. The organic layer was separated and washed sequentially with water (150 mL) and saturated brine (150 mL). The organic layer was evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20percent> EtOAc in isohexane. Pure fractions were evaporated to dryness to afford the title compound (3.60 g, 47.6 percent) as a pale yellow oil. 1H NMR (400 MHz, CDC13) 0.05 (3H, s), 0.07 (3H, s), 0.90 (9H, s), 1.21 (3H, d), 2.87 - 2.97 (1H, m), 3.09 (1H, d), 3.85 (3H, s), 3.99 - 4.07 (1H, m), 6.69 - 6.91 (3H, m), 7.63 - 7.69 (1H, m). m/z (ES+) (M+H)+ = 321.38

References: [1]Patent: WO2011/121350,2011,A1 .Location in patent: Page/Page column 139.

16
[ 1195-14-8 ]
[ 144649-99-0 ]
[ 1372135-15-3 ]

References: [1]Organic Letters,2012,vol. 14,p. 1951 - 1953.

17
[ 491-38-3 ]
[ 144649-99-0 ]
[ 1393533-80-6 ]

References: [1]Journal of the American Chemical Society,2012,vol. 134,p. 13584 - 13587.

18
[ 144649-99-0 ]
[ 1419746-20-5 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 834 - 838.

19
[ 144649-99-0 ]
[ 40530-18-5 ]