327056-73-5|3-Chloro-5-fluorobenzonitrile| Ambeed

Structure of 327056-73-5

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Quality Control of [ 327056-73-5 ] Purity: 95% SDS Specification

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Product Details of [ 327056-73-5 ]

CAS No. :	327056-73-5
Formula :	C₇H₃ClFN
M.W :	155.56
SMILES Code :	C1=C(Cl)C=C(F)C=C1C#N
MDL No. :	MFCD03407967
InChI Key :	GIKLRWNRBOLRDV-UHFFFAOYSA-N
Pubchem ID :	2734841

Safety of [ 327056-73-5 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H319
Precautionary Statements:	P305+P351+P338

Computational Chemistry of [ 327056-73-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	36.12
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.	1.82
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	2.37
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.77
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.	2.48
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	2.86
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.46

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.74
Solubility	0.282 mg/ml ; 0.00181 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.	-2.51
Solubility	0.481 mg/ml ; 0.00309 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	-3.36
Solubility	0.0673 mg/ml ; 0.000433 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.	-5.57 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)	1.74

Application In Synthesis of [ 327056-73-5 ]

* 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.

Downstream synthetic route of [ 327056-73-5 ]

[ 327056-73-5 ] Synthesis Path-Downstream 1~35

1
[ 327056-73-5 ]
[ 304853-90-5 ]
[ 304853-30-3 ]

References: [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 4379 - 4382.

2
[ 327056-73-5 ]
[ 765302-48-5 ]
[ 867366-61-8 ]

Yield	Reaction Conditions	Operation in experiment
48%	With potassium carbonate; In N-methylpyrrolidone (NMP); at 0 - 120℃; for 6h;	A solution of <strong>[327056-73-5]3-chloro-5-fluorobenzonitrile</strong> (59a, 9.2 g, 59.14 mmol), 6 (10.44 g, 53.76 mmol), K2CO3 (22.29 g, 161.3 mmol) and NMP (100 mL) was stirred and heated to 120 C. for 6 h. The reaction mixture was cooled to 0 C. and diluted with saturated NaHSO3 (100 mL) and twice extracted with EtOAc. The combined organic extracts were washed sequentially with water (6 times) and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 column chromatography eluting with a EtOAc/hexane gradient (0 to 10% EtOAc) to afford 9.28 g (48% theory) of 112a.

References: [1]Patent: US2005/239881,2005,A1 .Location in patent: Page/Page column 30.

3
[ 327056-73-5 ]
[ 367259-04-9 ]
[ 1056986-94-7 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of methyl 3-hydroxy-5-methoxy-phenyl acetate (32b, 0.500 g, 2.55 mmol), <strong>[327056-73-5]3-chloro-5-fluorobenzonitrile</strong> (0.3964 g, 2.55 mmol), K2CO3 (1.057 g, 7.65 mmol) and NMP (5 mL) were stirred and heated at 120 C. for 12 h. The reaction mixture was cooled to RT and diluted with H2O (35 mL), adjusted to pH 11 with 1N NaOH and twice extracted with EtOAc. The combined organic extracts were washed sequentially with water (6 times) and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 column chromatography eluting with a EtOAc/hexane gradient (0 to 25% EtOAc) to afford 34.

References: [1]Patent: US2005/239881,2005,A1 .Location in patent: Page/Page column 52.

4
[ 327056-73-5 ]
[ 857261-39-3 ]
C₁₇H₁₄ClNO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A solution of 28a (0.500 g, 2.77 mmol), <strong>[327056-73-5]3-chloro-5-fluoro-benzonitrile</strong> (0.4316 g, 2.77 mmol), K2CO3 (1.150 g, 8.32 mmol) and NMP (5 mL) was stirred and heated for 8 h at 120 C. The reaction mixture was cooled to RT and diluted with H2O (150 mL), acidified with 10% aqueous HCl and twice extracted with EtOAc. The combined organic extracts were washed sequentially with water (6 times) and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 column chromatography eluting with EtOAc/hexane gradient (0 to 25% EtOAc) to afford 30a.

References: [1]Patent: US2005/239881,2005,A1 .Location in patent: Page/Page column 53.

5
[ 33863-76-2 ]
[ 557-21-1 ]
[ 327056-73-5 ]

Yield	Reaction Conditions	Operation in experiment
66%		A mixture of 1-bromo-3-chloro-5-fluorobenzene (8Og, 480mmol), zinc cyanide (33.65g, 290mmol) and zinc dust (0.94g, 14.46mmol) in DMF (34OmL) was stirred at rt for 5 min. Dichloro[1 ,1 '- EPO <DP n="34"/>bis(diphenylphosphino)ferrocene] palladium(ll) (4.99g, 16mmol) was then added and the mixture was heated under reflux for 50 min. The reaction mixture was cooled to rt and filtered through Arbocel, washing through with diethyl etherpentane (50:50, 7 x 10OmL). The phases were separated and the organic phase was diluted with water (10OmL) and extracted with further diethyl ethe?pentane (50:50, 3 x 10OmL). The combined organic solutions were then washed with water, dried over magnesium sulfate and concentrated in vacuo. Distillation of the residue under reduced pressure afforded the title compound as a colourless solid in 66% yield, 48.5g. LRMS: m/z APCI 155 [MH+]

References: [1]Patent: WO2006/67587,2006,A2 .Location in patent: Page/Page column 32; 33.

6
[ 109-01-3 ]
[ 327056-73-5 ]
[ 896466-67-4 ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium carbonate; In dimethyl sulfoxide; at 80℃; for 20h;	5-Fluoro-3-chloro-benzonitrile (Ig, 6.4 mmol) was dissolved in DMSO (20 ml) followed by addition Of K2CO3 (1.3g, 9.6 mmol) and 1 -methyl piperazine (1.4 ml, 12.8 mmol). The reaction mixture was heated at 80 0C for 20 hours. Diethyl ether was added to the crude material (10 ml) then acidified with IN HCl. A precipitate was filtered off from the crude reaction mixture to give 3-chloro-5-(4-methyl- rhoirhoerazin-l-yl)-benzonitrile (1.4g, 93% yield) as a white solid (LC/MS: Rt 1.83 [M + H]+ 236, acidic method).
93%	With potassium carbonate; In dimethyl sulfoxide; at 80℃; for 20h;	18A. Synthesis of 3-Cmoro-5-(4-methyl^iperazm-l-ylVbeiizomtrile; 5-Fluoro-3-chloro-benzonitrile (Ig, 6.4 mmol) was dissolved in DMSO (20 ml) followed by addition OfK2CO3 (1.3g, 9.6 mmol) and 1-methyl piperazine (1.4 ml, 12.8 mmol). The reaction <n="215"/>mixture was heated at 80 0C for 20 hours. Diethyl ether was added to the crude material (10 ml) then acidified with IN HCl. A precipitate was filtered off from the crude reaction mixture to give 3-chloro-5-(4-methyl-piperazin-l-yl)-benzonitrile (1.4g, 93% yield) as a white solid (LC/MS: Rt 1.83 [M + H]+ 236, acidic method).
61%	With potassium carbonate; In dimethyl sulfoxide; at 100℃;	STEP A A mixture of <strong>[327056-73-5]3-chloro-5-fluoro-benzonitrile</strong> (1.1 g, 7.07 mmol), 1-methyl-piperazine (1.18 ml, 10.6 mmol), and K2CO3 (2.92 g, 21.21 mmol) in DMSO (25 ml) was heated to 100C overnight and then partitioned between water and Et2O. The aqueous phase was extracted with Et2O and the collected organic phases were dried over Na2SO4 and evaporated under vacuum. The residue was dissolved in Et2O and extracted with 0.5 M HCl. The aqueous phase was basified with NH4OH and extracted with DCM. The organic phase was dried over Na2SO4 and evaporated to give 1.01 g of 3-chloro-5-(4-methyl-piperazin-1-yl)-benzonitrile. Y=61%

	With potassium carbonate; In N,N-dimethyl-formamide; at 140℃; for 0.666667h;microwave irradiation;	Preparation 4: 1 -[3-ChIoro-5-(4-methyI-piperazin-1 -yl)-phenyl]-ethanone; STEP A; A mixture of <strong>[327056-73-5]3-chloro-5-fluoro-benzonitrile</strong> (1 g, 6.45 mmol), 1-methyl-piperazine (0.715 ml, 6.45 mmol), and K2CO3 (2.64 g, 19.3 mmol) in DMF (5 ml) was heated to 1400C for 40 min in a microwave apparatus. The resulting slurry was filtered and the solvent was removed in vacuo to give 1 g of 3-chloro-5-(4-methyl- piperazin-1-yl)-benzonitrile. The crude reaction mixture was used in the next step without any further purification.
	With potassium carbonate; In dimethyl sulfoxide; at 20 - 80℃;	3-Chloro-5-fluorobenzonitrile (0.50 g, 3.21 mmol) in dimethyl sulfoxide (10 ml.) was stirred at room temperature under an atmosphere of argon (following a similar method to that of WO200670195). Potassium carbonate (0.67 g, 4.82 mmol) and then 1-methylpiperidine (0.71 ml_, 6.42 mmol) were added. The reaction mixture was heated at 80 0C overnight. The reaction mixture was cooled to room temperature and diethyl ether (5 ml.) was added. A white precipitate formed which was filtered off. The filtrate was acidified using 1 M hydrochloric acid to pH 5. The white precipitate was filtered. Further product precipitated out in the filtrate and was collected. This was repeated twice to give the title compound. LC/MS (ES+ve): [M+H]+ at m/z 236, 238 (Ci2H14CIN3 requires [M+H]+ at m/z 236, 238).

References: [1]Patent: WO2006/70195,2006,A1 .Location in patent: Page/Page column 155.
[2]Patent: WO2007/77435,2007,A1 .Location in patent: Page/Page column 213-214.
[3]Patent: EP2033956,2009,A1 .Location in patent: Page/Page column 14-15.
[4]Patent: WO2007/113249,2007,A2 .Location in patent: Page/Page column 52.
[5]Patent: WO2009/819,2008,A1 .Location in patent: Page/Page column 37-38.

7
[ 327056-73-5 ]
[ 895572-18-6 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of the appropriate phenol (1 eq.) in DMF (0.8 to 1.85mLmmor1) was added cesium carbonate (1-2 eq.) at rt and the solution was stirred for 10 min. The compound from preparation 37 (1.3 eq.) was then added and the reaction mixture was heated at 85 C for up to 48h (reactions monitored by tic). The solvent was removed in vacuo and the residue was partitioned between EtOAc (5OmL) and brine (5OmL). The phases were separated and the aqueous layer extracted with EtOAc (1 OmL). The organic extracts were combined, dried over magnesium sulfate and the solvent was removed in vacuo to give the crude residue. Purification by column chromatography on silica gel using pentane:ethyl acetate as eluent afforded the desired product.

References: [1]Patent: WO2006/67587,2006,A2 .Location in patent: Page/Page column 23.

8
[ 327056-73-5 ]
[ 895572-23-3 ]

Yield	Reaction Conditions	Operation in experiment
81%		Preparation 23: 3-Chloro-5-[2-methoxy-5-(trifluoromethoxy)phenoxylbenzonitrile To a solution of the compound of preparation 22 (270mg, 1.30mmol) in DMF (5mL) was added cesium carbonate (551 mg, 1.69mmol) at rt. The reaction mixture was stirred for 5 min and the compound from preparation 37 (1.69mmol, 263mg) was added. The mixture was then heated at 85 0C for 3h and cooled to rt. Brine was added followed by water and the aqueous phase was extracted with EtOAc. The organic extract was dried over magnesium sulfate and the solvent was concentrated in vacuo to afford the crude residue. Purification by column chromatography on silica gel using pentane:ethyl acetate (88:12) as eluent afforded the desired product, 360mg (81%). LRMS (APCI) 343 [MH"]; Preparations 2-7 To a solution of the appropriate phenol (1 eq.) in DMF (0.8 to 1.85mLmmor1) was added cesium carbonate (1-2 eq.) at rt and the solution was stirred for 10 min. The compound from preparation 37 (1.3 eq.) was then added and the reaction mixture was heated at 85 C for up to 48h (reactions monitored by tic). The solvent was removed in vacuo and the residue was partitioned between EtOAc (5OmL) and brine (5OmL). The phases were separated and the aqueous layer extracted with EtOAc (1 OmL). The organic extracts were combined, dried over magnesium sulfate and the solvent was removed in vacuo to give the crude residue. Purification by column chromatography on silica gel using pentane:ethyl acetate as eluent afforded the desired product. EPO <DP n="25"/>A = 4-hydroxy-3-methoxybenzonitrile prepared as described in Synthesis 1989(6); 451-2. The product was isolated after trituration with methanol.B = potassium carbonate was used in place of cesium carbonate.

References: [1]Patent: WO2006/67587,2006,A2 .Location in patent: Page/Page column 23; 28.

Yield	Reaction Conditions	Operation in experiment
		The reaction was repeated and the two batches of pot material are distilled through a 430*20 mm column filled with glass helices at 70-80 and 8 mm to give 3-chloro-5-fluorobenzonitrile as a volatile white solid.

10
[ 327056-73-5 ]
3-chloro-5-fluorobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; In water;	EXAMPLE 43 A mixture of sulfuric acid (500 ml) and water (100 ml) is heated to 95 and <strong>[327056-73-5]3-chloro-5-fluorobenzonitrile</strong> (94.8 gms) added. After 4 hours the mixture is cooled and poured over ice and water added to make 3.6 L. In 1.2 L portions the mixture is filtered, the solid rinsed with hexane and the aqueous rinsed with hexane (4120 ml) then extracted with ethyl acetate (2100 ml). The solid and the ethyl acetate extracts were combined, dried over magnesium sulfate and stripped to give 3-chloro-5-fluorobenzamide as a white solid.

References: [1]Patent: US5098466,1992,A .

11
[ 327056-73-5 ]
[ 65262-96-6 ]
[ 1034890-86-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 120℃; for 6h;	3-chloro-5-(3-chloro-5-methoxyphenoxy)benzonitrile(B-3); A mixture of 1.00 g (6.31 mmol) of 3-chloro-5-methoxyphenol (B-1), of 1.28 g (8.20 mmol) <strong>[327056-73-5]3-fluoro-5-chlorobenzonitrile</strong> (B-2), and 2.62 g (18.93 mmol) of potassium carbonate in 10 mL of N-methylpyrrolidinone was heated at 120 C. in a nitrogen atmosphere with vigorous stirring. After 6 hours, LC/MS analysis indicated that the reaction was complete. The reaction was cooled to room temperature and filtered, and the solid washed with EtOAc. The filtrate was diluted further with EtOAc, and was washed with 20 mL of 1N HCl, 20 mL of 1 N NaOH, 20 mL of water, and 20 mL of brine. The organic layer was dried (anhydrous MgSO4), filtered, and the filtrate concentrated in vacuo to an orange oil. The oil was purified by flash column chromatography over silica gel with 3:1 cloroform/hexanes to give the desired product B-3 as a clear oil. MS: M+1=295. 1H NMR(CDCl3): 3.81 delta(s, 3H), 6.44 m, 1H), 6.62 (m,1H), 6.78 (m,1H), 7.14 (m,1H), 7.22(m,1H), 7.37(m,1H).

References: [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2959 - 2966.
[2]Patent: US2007/21442,2007,A1 .Location in patent: Page/Page column 33.

12
[ 327056-73-5 ]
[ 193357-36-7 ]
C₁₇H₁₃Cl₂NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 110℃; for 6h;	A solution of 19 (1.07 g, 5 mmol), 16 (1.3 g, 7.56 mmol), K2CO3 (2.07 g, 15.0 mmol) and NMP (10 mL) was stirred and heated to 110 C. for 6 h. The reaction mixture was cooled to RT and diluted with H2O (50 mL) and twice extracted with EtOAc. The combined organic extracts were washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with EtOAc/hexane (10:90) to afford 0.328 g of 31.

References: [1]Patent: US2007/88053,2007,A1 .Location in patent: Page/Page column 19.

13
[ 327056-73-5 ]
[ 34918-57-5 ]
[ 1207544-06-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 110 - 120℃; for 1.41667h;Microwave;	To a solution of (3-bromo-4-hydroxy-phenyl)-acetic acid ethyl ester (32, 1.6 g, 6.20 mmol) in NMP (12 mL) was added K2CO3 (2.56 g, 18.6 mmol) and 16 (0.96 g, 6.20 mmol). The reaction was heated in a laboratory microwave at 110 C. for 5 min and at 120 C. for 80 min. The reaction mixture was cooled to RT and HCl (10%) was added. The mixture was thrice extracted with EtOAc. The combined extracts were washed with H2O and brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude product was purified via SiO2 chromatography eluding with hexane/EtOAc to afford 33. Steps 2-4 were carried out as described for steps 2-4 of example 1 which afforded I-46: mp=205.3-207.4 C., ms, [M-H]=518.

References: [1]Patent: US2007/88053,2007,A1 .Location in patent: Page/Page column 19-20.

14
[ 327056-73-5 ]
[ 29121-25-3 ]
[ 1207542-34-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 110 - 120℃; for 1.41667h;Microwave;	To a solution of 15 (1.6 g, 6.20 mmol) in NMP (12 mL) was added K2CO3 (2.56 g, 18.6 mmol) and <strong>[327056-73-5]3-chloro-5-fluorobenzonitrile</strong> (16, 0.96 g, 6.20 mmol). The reaction was heated in a laboratory microwave at 110 C. for 5 min and at 120 C. for 80 min. The reaction mixture was cooled to RT and diluted with 10% aqueous HCl. The mixture was extracted 3 times with EtOAc. The combined organics were washed with H2O and brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude product was purified via SiO2 chromatography eluting with MeOH/hexane to afford 17a

References: [1]Patent: US2007/88053,2007,A1 .Location in patent: Page/Page column 15.

15
[ 327056-73-5 ]
[ 60563-13-5 ]
[ 1207544-60-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 100℃; for 5h;	To a solution of (4-hydroxy-3-methoxy-phenyl)-acetic acid ethyl ester (34, 2.0 g, 9.51 mmol) in NMP (10 mL) was added K2CO3 (3.94 g, 28.5 mmol) and 16 (1.48 g, 9.51 mmol). The reaction was heated at 100 C. for 5 h. The reaction mixture was cooled to RT and HCl (10%) was added. The mixture was extracted 3 times with EtOAc. The combined organics were washed with H2O and brine, dried over Na2SO4, filtered and evaporated in vacuo. The crude product was purified by SiO2 chromatography eluding with hexane/EtOAc to afford 35. Steps 2-4 were run as described for steps 2-4 of example 1, except in step 4, 4-amino-3-methyl-benzenesulfonamide was used in place of 4-amino-benzenesulfonamide which afforded I-51.

References: [1]Patent: US2007/88053,2007,A1 .Location in patent: Page/Page column 20.

16
[ 327056-73-5 ]
[ 886498-60-8 ]
[ 895572-46-0 ]

References: [1]Organic and Biomolecular Chemistry,2007,vol. 5,p. 3431 - 3433.

17
[ 327056-73-5 ]
[ 72955-97-6 ]
[ 895572-22-2 ]

References: [1]Organic and Biomolecular Chemistry,2007,vol. 5,p. 3431 - 3433.

18
[ 327056-73-5 ]
[ 90-05-1 ]
[ 960078-23-3 ]

References: [1]Organic and Biomolecular Chemistry,2007,vol. 5,p. 3431 - 3433.

19
[ 327056-73-5 ]
[ 152434-94-1 ]
[ 960078-26-6 ]

References: [1]Organic and Biomolecular Chemistry,2007,vol. 5,p. 3431 - 3433.

20
[ 327056-73-5 ]
[ 1034474-37-7 ]
[ 1034474-38-8 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 140℃; for 72h;	Step 3: 3-Chloro-5-[5-chloro-l-(4-methoxybenzyl)-lH-l,2,3-benzotriazol-4- yl]oxy}benzonitrile; A stirred suspension of 5 -chloro-l-(4-methoxybenzy I)- IH- 1,2, 3 -benzotriazol-4-ol (0.050 g, 0.173 mmol), <strong>[327056-73-5]3-fluoro-5-chloro-benzonitrile</strong> (0.081 g, 0.518 mmol) and cesium <n="39"/>carbonate (0.068 g, 0.207 mmol) in NMP (1.5 mL) was heated at 1400C for 72 hours. The reaction mixture was then quenched with aqueous ammonium chloride (25 mL) and extracted with dichloromethane (2 x 100 mL). The combined extracts were concentrated under reduced pressure. The resulting residue was subjected to reverse phase chromatography (5-95% MeCN/H2theta, 0.1% TFA). The product fractions were combined and extracted with dichloromethane (2 x 100 mL). The combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure to yield the title product. lH NMR (DMSO dbeta) delta 7.90- 7.88(m, IH), 7.80(s, IH), 7.79-7.75(m, IH), 7.60-7.55(m, 2H), 7.40-7.35(d, J-6.9Hz, 2H), 6.95- 6.88 (m, 2H), 5.80(s, 2H), 3.71(s, 3H).

References: [1]Patent: WO2008/76223,2008,A1 .Location in patent: Page/Page column 37-38.

21
[ 327056-73-5 ]
[ 18113-04-7 ]
[ 1034890-85-1 ]

References: [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 6503 - 6511.
[2]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2959 - 2966.

22
[ 327056-73-5 ]
[ 261762-91-8 ]
[ 1089178-82-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; caesium carbonate; In ISOPROPYLAMIDE; at 120℃; for 5.5h;	To a solution of <strong>[327056-73-5]3-chloro-5-fluorobenzonitrile</strong> (E-1, 10 g, 64.28 mmol) and 6-chloro-2-fluoro-3-methyl-phenol (E-2, 9.38 g, 58.44 mmol) in DMA (100 mL) was added Cs2CO3 (1.9 g, 5.84 mmol) followed by K2CO3 (8.9 g, 64.28 mmol). The mixture was heated to 120 C. (oil bath) under argon for 5.5 h. The reaction was cooled to RT and water (150 mL) was added. The mixture was extracted with EtOAc (150 mL) and the aqueous phase back extracted with EtOAc (2×100 mL). The combined EtOAc extracts were dried (MgSO4), filtered and concentrated in vacuo afford 11.1 g (75% purity) of E-3a as a white crystalline solid.
	With potassium carbonate; caesium carbonate; In ISOPROPYLAMIDE; at 120℃; for 5.5h;	To a solution of <strong>[327056-73-5]3-chloro-5-fluorobenzonitrile</strong> (10 g, 64.28 mmol) and 6- chloro-2-fluoro-3-methyl-phenol (9.38 g, 58.44 mmol) in DMA (100 mL) was added Cs2CO3 (1.9 g, 5.84 mmol) followed by K2CO3 (8.9 g, 64.28 mmol). The mixture was heated to 120 C (oil bath) under argon for 5.5 h . The reaction was cooled to RT and water (150 mL) was added. The mixture was extracted with EtOAc (150 mL) and the aqueous phase back extracted with EtOAc (2 x 100 mL). The EtOAc phase was dried (MgSO4), filtered and concentrated in vacuo afford 11.1 g (75% purity) of B-3a as a white crystalline solid.

References: [1]Patent: US2009/12034,2009,A1 .Location in patent: Page/Page column 16.
[2]Patent: WO2008/145562,2008,A1 .Location in patent: Page/Page column 22; 34.

23
[ 110-91-8 ]
[ 327056-73-5 ]
[ 1095274-30-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dimethyl sulfoxide; at 20 - 80℃;	A solution of <strong>[327056-73-5]3-chloro-5-fluorobenzonitrile</strong> (1.0 g, 6.4 mmol) in dimethyl sulfoxide (20 ml.) was stirred at room temperature under an atmosphere of argon. Potassium carbonate (1.33 g, 9.6 mmol) and then morpholine (1.12 ml_, 12.8 mmol) were added. The reaction mixture was heated at 800C under an atmosphere of argon overnight. The reaction mixture was cooled to room temperature, filtered to remove the solid potassium carbonate and then acidified to pH 5 using 1 M hydrochloric acid. No precipitate formed and so the product was applied to 2 x 10 g SCX cartridges (pre-wetted with methanol). The product did not stick to the cartridges and was washed through with the methanol. The product containing fractions were combined and concentrated under reduced pressure. The product (in dimethyl sulfoxide) was partitioned between diethyl ether and water, and a white precipitate formed. More <n="39"/>water was added to encourage precipitation. The title compound, a white solid, was collected by filtration and air dried under low vacuum.LC/MS (ES+ve): [M+H]+ at m/z 223, 225 (CH H11 CIN2O requires [M+H]+ at m/z 223, 225).

References: [1]Patent: WO2009/819,2008,A1 .Location in patent: Page/Page column 37-38.

24
[ 327056-73-5 ]
[ 506-59-2 ]
[ 1095274-75-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 2h;Microwave irradiation;	3-Chloro-5-fluorobenzonitrile (600 mg, 3.86 mmol), dimethylamine hydrochloride (629 mg, 7.71 mmol) and potassium carbonate (1.866 g, 13.50 mmol) were added together in dimethyl sulfoxide (12 ml.) and the resulting mixture heated in the microwave at 100 0C for 2 hours at high absorption. The reaction mixture was filtered and the filtrate diluted with water and extracted with diethyl ether (x 3). The diethyl ether layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by Biotage column chromatography eluting with 1 :9 ethyl acetate/iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a white solid. LC/MS (ES+ve): [M+H]+ at m/z 181 , 183 (C9H9CIN2 requires [M+H]+ at m/z 181 , 183).D49 was taken forward by standard methods described herein to afford E29.

References: [1]Patent: WO2009/819,2008,A1 .Location in patent: Page/Page column 61.

25
[ 327056-73-5 ]
[ 3749-51-7 ]
[ 1155846-97-1 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 4-hydroxy-6-methyl-2-oxo-l,2-dihydropyridine (3-2; 20.1 g; 161 mmol) in NMP (1.6 L) was added <strong>[327056-73-5]3-chloro-5-fluorobenzonitrile</strong> (3-1; 25 g; 161 mmol) and potassium carbonate (44.4 g; 321 mmol). The resulting solution stirred at 12O0C overnight. The reaction mixture was cooled to ambient temperature and diluted with 4 L of ice- water. The aqueous layer was acidified to pH 5 to precipitate out the product. The precipitate was collected via filtration, washed with water, and air dried. The crude solid product was triturated in 5% methanol/dichloromethane and filtered to give a solid. The solid was triturated with 1 : 1 ethyl acetate :hexane, stirred, and filtered to afford the title product as a tan solid. MS M+l = 261.0. lH NMR (CD3OD): 2.30 (s, 3H), 5.62 (s, IH), 6.05 (s, IH), 7.55 (s, IH), 7.0 (s, IH), 7.76 (s, IH).

References: [1]Patent: WO2009/67166,2009,A2 .Location in patent: Page/Page column 81.

26
[ 327056-73-5 ]
[ 920036-39-1 ]
[ 920036-41-5 ]

Yield	Reaction Conditions	Operation in experiment
88%		Step 3: 3-chloro-5-(2-chloro-3-fluoro-5-methoxyphenoxy)benzonitrile (50-4); Under a nitrogen atmosphere, 2-chloro-3-fluoro-5-methoxyphenol (50-2) (6.7 g, 37.9 mmol) was diluted in NMP (40 mL, 0.95 M). To this solution Cs2CO3 (24.73 g, 76 mmol) was added and the reaction was allowed to stir at room temperature for 5 minutes. Then, <strong>[327056-73-5]3-chloro-5-fluorobenzonitrile</strong> (11.81 g, 76 mmol) was added to the reaction and it was then heated to 120 C. After 2 hours the reaction was cooled to room temperature and then diluted with EtOAc (40 mL). It was partitioned with water (20 mL) and then extracted with EtOAc (3×30 mL). The organic extracts were then washed with water (3×20 mL) and brine (1×20 mL), dried over sodium sulfate and concentrated. Silica gel chromatography (1%-15% EtOAc/Hexanes) gave 3-chloro-5-(2-chloro-3-fluoro-5-methoxyphenoxy)-benzonitrile (50-4) (10.4 g, 88%).

References: [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 7163 - 7169.
[2]Patent: US2007/21442,2007,A1 .Location in patent: Page/Page column 58.

27
[ 327056-73-5 ]
[ 1232143-68-8 ]
[ 1242061-95-5 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 2 ^_(4-{(lJR)-14(R)-(3-CHLORO-5-CYANOPHENOXY)(4- CHLOROPHENYL)METHYL]BUTYL}BENZOYL)~beta-ALANINETo a solution of INTERMEDIATE 1 (100 mg, 0.239 mmol) and 3-chloro-5- fluorobenzonitrile (40.9 mg, 0.263 mmol) in DMF (2 mL) was added potassium tert-butoxide (107 nig, 0.957 mmol), then the resulting mixture was allowed to stir at 120 0C for 16 hours. After being allowed to cool to RT, the mixture was diluted with 2 N HCl (aq) then extracted with EtOAc. The organic layer was washed twice with water then concentrated. The resulting yellow residue was purified by preparative reverse phase HPLC eluting with 30-100% CHaCN/water + 0.1% TFA. Following lyophilization, this afforded the title compound as a white solid. 1H NMR (500 MHz, CD3OD): 6 7.70 (d, J - 8.5 Hz, 2 H); 7.34 (d, J = 8.5 Hz, 2 H); 7.30 (d, J = 8.0 Hz, 2 H); 7.25 (d, J - 8.5 Hz, 2 H); 7.20 (s, 1 H); 7.09 (s, 1 H); 7.06 (s, 1 H); 5.55 (d, J = 6.5 Hz, 1 H); 3.61 (t, J = 7.0 Hz, 2 H); 3.16 (m, 1 H); 2.62 (t, J = 7.0 Hz, 2 H); 1.80 (m, 1 H); 1.54 (m, 1 H); 1.11-1.07 (m, 2 H); 0.78 (t, J = 7.2 Hz, 3 H); LC3 3.93 min. (M+H)+ 523.

References: [1]Patent: WO2010/98948,2010,A1 .Location in patent: Page/Page column 43-44.

28
[ 327056-73-5 ]
[ 1242063-19-9 ]
[ 1242063-04-2 ]

Yield	Reaction Conditions	Operation in experiment
		Step A. JV-(4- {(Iff): 1 :[(R)-[3-(Aminocarbonyl)-5-chlorophenoxy](4-chlorophenyl)methyl]" 4,414-trifluorobutyUbenzoyl)-beta-alanineSodium tert-butoxide (92 mg, 0.96 mmol) was added to a solution of 3-chloro-5- fluorobenzomtrile (67.9 mg, 0.359 mmol) and N-(4-{(1R)-l-[(R)~(4- chlorophenyl)(hydroxy)methyl]-4s4,4-trifluorobulyl}benzoyl)-beta-alanine (prepared using the procedures from INTERMEDIATE 1 and the saponification step of EXAMPLE I, 100 mg, 0.239 mmol) in DMF (3 mL), then the resulting brown mixture was stirred at 80 0C for 16 hours. The mixture was diluted with EtOAc, then washed with 2 N HCl (aq), then washed twice with water. The organic layer was then concentrated, and the resulting yellow residue was purified by reverse phase HPLC eluting with 30-100% MeCN/water + 0.1% TFA. Following lyophilization, this afforded the title compound. LC3 3.35 min. (M+H)+ 577.

References: [1]Patent: WO2010/98948,2010,A1 .Location in patent: Page/Page column 65-66.

29
[ 327056-73-5 ]
[ 308795-93-9 ]
[ 1257239-71-6 ]

References: [1]Journal of Organic Chemistry,2010,vol. 75,p. 8330 - 8332.

30
[ 327056-73-5 ]
[ 895572-24-4 ]