There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.

Type	HazMat fee for 500 gram (Estimated)
Excepted Quantity	USD 0.00
Limited Quantity	USD 15-60
Inaccessible (Haz class 6.1), Domestic	USD 80+
Inaccessible (Haz class 6.1), International	USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic	USD 100+
Accessible (Haz class 3, 4, 5 or 8), International	USD 200+

*Storage: {[sel_prStorage]}

*Shipping: {[sel_prShipping]}

{[proInfo.proName]}

CAS No.: 145689-34-5

4.5 *For Research Use Only !

{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]} Purity: {[proInfo.pro_purity]}

Change View

Size	Price	VIP Price	US Stock	Global Stock	In Stock
{[ item.pr_size ]}		Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]}

US Stock: ship in 0-1 business day
Global Stock: ship in 2 weeks

{[ item.pr_size ]}

In Stock

- +

Please Login or Create an Account to: See VIP prices and availability

US Stock: ship in 0-1 business day
Global Stock: ship in 2 weeks

Quality Control of [ 145689-34-5 ] Purity: 98% SDS Specification

COA

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

NMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

CNMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

HPLC

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

LC-MS

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

1-2 Day Shipping
High Quality
Technical Support Online Technical Q&A

Product Details of [ 145689-34-5 ]

CAS No. :	145689-34-5
Formula :	C₈H₅F₂N
M.W :	153.13
SMILES Code :	N#CCC1=CC=CC(F)=C1F
MDL No. :	MFCD00061277
InChI Key :	IYRCHGRRMKOSHW-UHFFFAOYSA-N
Pubchem ID :	518968

Safety of [ 145689-34-5 ]

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H301-H311-H331
Precautionary Statements:	P261-P280-P301+P310-P311
Class:	6.1
UN#:	3276
Packing Group:	Ⅲ

Calculated chemistry of [ 145689-34-5 ] 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	3.0
Num. H-bond donors	0.0
Molar Refractivity	35.88
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	23.79 ?2

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.66
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	1.78
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.87
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.	2.63
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	2.96
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.38

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.25
Solubility	0.864 mg/ml ; 0.00564 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.	-1.9
Solubility	1.94 mg/ml ; 0.0127 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very 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	-3.43
Solubility	0.0569 mg/ml ; 0.000372 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.	-5.97 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)	1.49

Application In Synthesis of [ 145689-34-5 ]

* 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 [ 145689-34-5 ]

[ 145689-34-5 ] Synthesis Path-Downstream 1~27

1
[ 145689-34-5 ]
[ 292638-85-8 ]
C₁₆H₁₇NO₄F₂ [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 3006 - 3009.

2
[ 145689-34-5 ]
[ 866130-46-3 ]
3-[4-(5-difluoromethoxy-3-trifluoro-methyl-pyrazol-1-yl)-phenyl]-2-(2,3-di-fluoro-phenyl)-acrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With potassium hydroxide; In ethanol; water; for 1h;	Step 5: A stirred solution of 4-(5-difluoromethoxy-3-trifluoromethyl-pyrazol-1-yl)-benzaldehyde (40.5 mg, 0.13 mmol) and 2,3-difluorobenzylacetonitrile (20.3 mg, 0.13 mmol) in Ethanol (1 mL) was treated with 40% aqueous KOH (0.1 mL) at room temperature. The mixture was stirred for 1 hour. The resultant white precipitate was collected by filtration and washed with water to provide 5-difluoromethoxy-1-{4-[2-(2,3-difluoro-phenyl)-2-isocyano-vinyl]-phenyl}-3-trifluoromethyl-1H-pyrazole (30 mg, 51% yield) as a white solid: 1H-NMR (CDCl3) delta 6.39 (s, 1H), 6.62 (t, 1H, J=70.8 Hz), 7.14-7.28 (m, 2H), 7.36-7.42 (m, 1H), 7.65 (s, 1H), 7.80 (d, 2H, J=8.7), 8.02 (d,2H,J=8.7) ppm. ESMS calculated for C20H10F7N3O: 441.1; Found: 442.0 (M+H)+.

References: [1]Patent: US2005/272699,2005,A1 .Location in patent: Page/Page column 15-16.

3
[ 145689-34-5 ]
[ 374813-99-7 ]
3-[4-(3,5-bis-trifluoromethyl-pyrazol-1-yl)-phenyl]-2-(2,3-difluoro-phenyl)-acrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With potassium hydroxide; In ethanol; water; for 1h;	A stirred solution of 4-(3,5-bis-trifluoromethyl-pyrazol-1-yl)-benzaldehyde (0.31 g, 1 mmol) and 2,3-difluorobenzylacetonitrile (0.15 g, 1 mmol) in ethanol (0.85 mL) was treated with 40% aqueous KOH (0.23 mL) in Ethanol (0.46 mL) and stirred for 1 hour. The precipitate was collected by filtration and washed with water to give 3-[4-(3,5-bis-trifluoromethyl-pyrazol-1-yl)-phenyl]-2-(2,3-difluoro-phenyl)-acrylonitrile (0.24 g, 52% yield) as a white solid: 1H-NMR (CDCl3) delta 7.13 (s, 1H), 7.18-7.25 (m, 2H), 7.38-7.44 (m, 1H), 7.66 (d, 2H, J=8.7), 7.68 (s, 1H), 8.05 (d, 2H, J=8.7) ppm. ESMS calculated for C20H9F8O3: 443.0; Found: 444.0 (M+H)+.

References: [1]Patent: US2005/272699,2005,A1 .Location in patent: Page/Page column 16-17.

4
[ 145689-34-5 ]
[ 2969-81-5 ]
[ 885032-26-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 3.5h;	INTERMEDIATE 33 3 - Mlgamma-6-(23 -difluorophenyl)azepan-2-oneStep A: Ethyl 5-cvano-5-(2,3-difluorophenyl)pentanoate; Sodium hydride (60% dispersion in mineral oil; 2.9 g, 71.8 mmol) was slowly added to a solution of <strong>[145689-34-5](2,3-difluorophenyl)acetonitrile</strong> (10.0 g, 65.3 mmol) and ethyl 4- bromobutanoate (12.7 g, 65.3 mmol) in LambdazetaN-dimethylformamide (100 mL) at 0 0C. After 30 min, the reaction mixture was warmed to ambient temperature. After 3 h, water was added and the mixture was extracted with ethyl acetate (2x). The organic extracts were washed with saturated aqueous ammonium chloride, saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound. MS 267.1 (M+l).

References: [1]Patent: WO2006/44504,2006,A1 .Location in patent: Page/Page column 105.

5
[ 145689-34-5 ]
[ 880177-56-0 ]
2-(2,3-difluoro-phenyl)-3-[4-(2-trifluoromethyl-benzoimidazol-1-yl)-phenyl]-acrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; In ethanol; water; at 20℃; for 1h;	To a solution of the above 4~(2-Trifluoromethyl-benzoimidazol-1-yl)- benzaldehyde (0.155g, 0.53 mmol) and (2,3-Difluoro-phenyl)-acetonitrile (83 mg, 0.54 mmol) in EtOH (5 mL) was added a solution of KOH (0.2g) in H2O (0.5 mL). The mixture was then stirred at rt for 1 h, partitioned betweenEtOAc/H2O. The organic layer was dried and concentrated followed by silica gel chromatography (20% Hexane/EtOAc) to afford the product Compound 47 as a colorless oil.
	With potassium hydroxide; In ethanol; water; at 20℃; for 1h;	A stirred mixture of 2-Trifluoromethyl-1 H-benzoimidazole (4.92g, 26.4 mmol), 4-fluorobenaldehyde (3.1 mL, 29.1 mmol), and K2CO3 (4.37g, 31.7 mmol) in DMF (50 mL) was heated to 150 0C for 16 h. After being cooled to room temperature, the reaction mixture was partitioned between H2O and EtOAC. After usual workup, the crude product was purified by silica gel chromatography (20% Hexane/EtOAc to 30% Hexane/EtOAc) to afford a yellow oil which was subjected to a second silica gel chromatography (DMC) to provide the aldehyde intermediate 4-(2-Trifluoromethyl-benzoimidazol-1-yl)- <n="140"/>benzaldehyde as a white solid (4.0 g).To a solution of the above 4-(2-Trifluoromethyl-benzoimidazol-1-yl)- benzaldehyde (0.155g, 0.53 mmol) and (2,3-Difluoro-phenyl)-acetonttrile (83 mg, 0.54 mmol) in EtOH (5 mL) was added a solution of KOH (0.2g) in H2O (0.5 mL). The mixture was then stirred at rt for 1h, partitioned between EtOAc/H2theta. The organic layer was dried and concentrated followed by silica gel chromatography (20% Hexane/EtOAc) to afford the product Compound 47 as a colorless oil.To a stirred solution of 4-(2-Trifluoromethyl-benzoimidazol-1-yl)-benzaldehyde (0.58 g, 2 mmol) in acetone (25 mL) was added Jone's reagent (1.0 mL, 2.0 M) at O0C. After stirring at room temperature for 2h, the mixture was partitioned between EtOAc and saturated NaHCO3 solution. After usual workup, the crude material was separated by silica gel chromatography (50% Hexane/EtOAc to EtOAc) to afford the intermediate acid 4-(2-Trifluoromethyl- benzoimidazol-1-yl)-benzoic acid as a while solid (490 mg).To a stirred solution of 4-(2-Trifluoromethyl-benzoirnidazol-1-yl)-benzoic acid (102 mg, 0.33 mmol) in dry CHCI3 (15 mL) was added oxalyl chloride (0.09 mL) followed by one drop of DMF at room temperature. After 1h, the reaction pot was concentrated and vacuum dried. Dry chloroform (15 mL) and pyridine (0.1 mL) was then added followed by the addition of 2,3-difluoroaniHine (36 mg, 0.28 mmol). The reaction was monitored by TLC, after completion, the mixture was partitioned between 1 N HCI and DCM. Organic layer was separated and dried (Na2SO4). Removal of solvents followed silica gel chromatography (20% hexane/EtOAc) afforded the product Compound 46 as a white solid.

References: [1]Patent: WO2006/34402,2006,A2 .Location in patent: Page/Page column 123.
[2]Patent: WO2007/112093,2007,A2 .Location in patent: Page/Page column 138-139.

6
[ 145689-34-5 ]
[ 1019107-54-0 ]
[ 1019107-55-1 ]

References: [1]Journal of Organic Chemistry,2008,vol. 73,p. 3212 - 3217.

7
[ 145689-34-5 ]
[ 1019107-54-0 ]
(2S,4E)-2-tert-butoxycarbonylamino-5-cyano-5-(2,3-difluorophenyl)pent-4-enoic acid ethyl ester [ No CAS ]
[ 1019107-61-9 ]

References: [1]Journal of Organic Chemistry,2008,vol. 73,p. 3212 - 3217.

8
[ 145689-34-5 ]
[ 1019107-54-0 ]
[ 74-88-4 ]
(2S,4E)-2-tert-butoxycarbonylamino-5-cyano-5-(2,3-difluorophenyl)pent-4-enoic acid methyl ester [ No CAS ]
[ 1019107-56-2 ]

References: [1]Journal of Organic Chemistry,2008,vol. 73,p. 3212 - 3217.

9
[ 145689-34-5 ]
[ 74-88-4 ]
[ 913719-86-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In 1-methyl-pyrrolidin-2-one; diethyl ether; at 20℃; for 15h;	Step A: Preparation of 2-(2,3-Difiuorophenyl)-2- methylpropanenitrile; [0389] A mixture of NaH (5.7 g, 144 mmol) in 100 mL NMP stirred atO0C, was treated dropwise with a mixture of MeI (9.0 mL, 144 mmol) and 2- <strong>[145689-34-5](2,3-difluorophenyl)acetonitrile</strong> (10 g, 65 mmol) in 50 mL ether. The mixture was stirred at room temperature for 15 hours. The mixture was then carefully quenched with 20 mL H2O and extracted with ether (3 x 100 mL). The combined organic layers were washed with H2O (2 x 50 mL) and brine (20 mL), dried over anhydrous Na2SO4, concentrated in vacuo, and purified by column chromatography eluting with 10-20 % EtOAc/hexane to give 1 1.4 g of the title compound as a pale yellow oil.

References: [1]Patent: WO2008/76427,2008,A2 .Location in patent: Page/Page column 98.

10
[ 145689-34-5 ]
[ 74-88-4 ]
[ 945542-22-3 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 65; 2-[1-(2,3-Difluoro-phenyl)-ethyl]-4,5-dihydro-1H-imidazole; a) rac-2-(2,3-Difluoro-phenyl)-propionitrile; A solution of 1.586 g (16 mmol) diisopropylamine in 25 ml tetrahydrofuran was cooled with sodium chloride/ice to -10 C. A solution of 9 ml (14 mmol) 1.6 M butyl lithium in hexanes was added drop-wise. After stirring for 10 min the resulting LDA solution was cooled to -78 C. and a solution of 2.00 g (13 mmol) <strong>[145689-34-5]2,3-difluorophenyl-acetonitrile</strong> in 5 ml tetrahydrofuran slowly added. The reaction mixture was stirred at -78 C. for 40 min, then 2.22 g (16 mmol) methyl iodide were added and the cooling bath was removed after 5 min. The mixture was stirred for 2.5 h at room temperature, and then aqueous ammonium chloride solution was added. The mixture was extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and evaporated. The residue was purified using column chromatography (SiO2, heptanes/ethyl acetate 9:1) to yield 1.12 g of rac-2-(2,3-difluoro-phenyl)-propionitrile as a light yellow liquid; MS (EI): 167.1 (M+·), 152.1 (((M-CH3)+·), 100%).

References: [1]Patent: US2007/197621,2007,A1 .Location in patent: Page/Page column 34.

11
[ 145689-34-5 ]
[ 140-88-5 ]
[ 1375470-96-4 ]

Yield	Reaction Conditions	Operation in experiment
	With hydroquinone; potassium hydroxide; In methanol; at 160℃; for 16h;	Intermediate 13 (3S,5S)-3-Amino-5-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride; Step A: Ethyl 4-cyano-4-(2,3-difluorophenyl)butanoate; To a mixture of <strong>[145689-34-5](2,3-difluorophenyl)acetonitrile</strong> (40.5 g, 265 mmol), ethyl acrylate (24 mL, 220 mmol), and hydroquinone (50 mg, 0.45 mmol) was added KOH (2 M in MeOH, 2.0 mL, 4.0 mmol) and the resulting mixture was heated at 160 C. for 16 h and then allowed to cool to ambient temperature. The crude mixture was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc-100:0 to 50:50, to give the title compound. MS: m/z=207.9 (M-OEt).
	With hydroquinone; potassium hydroxide; In methanol; at 160℃; for 16h;	(35',5^-3-Amino-5-(23-difluorophenyl)-l-(2,2,2-trifluoroethyl piperidin-2-one hydrochloride; Step A: Ethyl 4-cvano-4-f2,3-difluorophenyl)butanoate; To a mixture of <strong>[145689-34-5](2,3-difluorophenyl)acetonitrile</strong> (40.5 g, 265 mmol), ethyl acrylate (24 mL, 221 mmol), and hydroquinone (50 mg, 0.45 mmol) was added OH (2 M in MeOH, 2.0 mL, 4.0 mmol) and the resulting mixture was heated at 160 C for 16 h and then allowed to cool to ambient temperature. The crude mixture was purified by silica gel chromatography, eluting with a gradient of hexanes: EtOAc - 100:0 to 50:50, to give the title compound. MS: miz = 207.9 (M - OEt).
	With hydroquinone; potassium hydroxide; In methanol; at 160℃; for 16h;	To a mixture of <strong>[145689-34-5](2,3-difluorophenyl)acetonitrile</strong> (40.5 g, 265 mmol), ethyl acrylate (24 mL, 221 mmol), and hydroquinone (50 mg, 0.45 mmol) was added KOH (2 M in MeOH, 2.0 mL, 4.0 mmol) and the resulting mixture was heated at 160 C for 16 h and then allowed to cool to ambient temperature. The crude mixture was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc - 100:0 to 50:50, to give the title compound. MS: mlz = 207.9 (M - OEt).

With hydroquinone; potassium hydroxide; In methanol; at 160℃; for 16h;

Step A: Ethyl 4-cyano-4-(2,3-difluorophenyl)butanoate (0256) To a mixture of <strong>[145689-34-5](2,3-difluorophenyl)acetonitrile</strong> (40.5 g, 265 mmol), ethyl acrylate (24 mL, 221 mmol), and hydroquinone (50 mg, 0.45 mmol) was added KOH (2 M in MeOH, 2.0 mL, 4.0 mmol) and the resulting mixture was heated at 160 C. for 16 h and then allowed to cool to ambient temperature. The crude mixture was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc-100:0 to 50:50, to give the title compound. MS: m/z=207.9 (M-OEt).

References: [1]Patent: US2012/122899,2012,A1 .Location in patent: Page/Page column 26.
[2]Patent: WO2012/129013,2012,A1 .Location in patent: Page/Page column 34-35.
[3]Patent: WO2012/129014,2012,A1 .Location in patent: Page/Page column 36.
[4]Patent: US9499541,2016,B2 .Location in patent: Page/Page column 48.

12
[ 145689-34-5 ]
N-t-butoxycarbonyl-3-iodo-D-alanine methyl ester [ No CAS ]
methyl 2-[(tert-butoxycarbonyl)amino]-4-cyano-4-(2,3-difluorophenyl)butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 11 tert-Butyl [(3S,5S)-5-(2,3-difluorophenyl)-2-oxopiperidin-3-yl]carbamate; Step A: Methyl 2-[(tert-butoxycarbonyl)amino]-4-cyano-4-(2,3-difluorophenyl)butanoate; To a solution of <strong>[145689-34-5](2,3-difluorophenyl)acetonitrile</strong> (18.6 g, 122 mmol) in N,N-dimethylformamide (243 mL) at 0 C. was added sodium hydride (60% dispersion in mineral oil) (4.37 g, 109 mmol). After 20 min, methyl N-(tert-butoxycarbonyl)-3-iodo-D-alaninate (20.0 g, 60.8 mmol) was added, and the resulting mixture stirred 50 min. Saturated aqueous sodium bicarbonate was added, and the mixture was warmed to ambient temperature. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes?20% hexanes/ethyl acetate) gave the title compound. MS: m/z=377.3 (M+Na).
12 g		Example 1.2 (6S .V (6￡8.S)-6-(2,3-Difluo^ <3]pyridin-8-yl]-2l-oxo 25j etrahy ft]pyr idine] -3 -carb xamide Step A: Methyl 2-[(feA-f-butoxycarbonyl)aminol-4-cyano-4-(2,3-difluorophenyl)butanoate To a solution of <strong>[145689-34-5](2,3-difluorophenyl)acetonitrile</strong> (18.6 g, 122 mmol) ?eta Nu,Nu- dimethylformamide (243 mL) at 0 C was added sodium hydride (60% dispersion in mineral oil) (4.37 g, 109 mmol). After 20 min, methyl N~(tert~butoxycarbonyl)~3~iodo-Z)-alaninate (20.0 g, 60.8 mmol) was added, and the resulting mixture stirred 50 min. Saturated aqueous sodium bicarbonate was added, and the mixture was warmed to ambient temperature. Water was added and the mixture was extracted with ethyl acetate (3 ). The combined organic extracts were washed with water (3x), brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes? 20% hexanes/ ethyl acetate) gave the title compound (12.0 g). MS 377.3 (M+Na),

References: [1]Patent: US2012/122899,2012,A1 .Location in patent: Page/Page column 25.
[2]Patent: WO2013/66360,2013,A1 .Location in patent: Page/Page column 34-35.

13
[ 145689-34-5 ]
tert-butyl [(3R,5R)-5-(2,3-difluorophenyl)-2-oxopiperidin-3-yl]carbamate [ No CAS ]
[ 1375541-88-0 ]

References: [1]Patent: US2012/122899,2012,A1 .

14
[ 145689-34-5 ]
[ 1375541-90-4 ]

References: [1]Patent: US2012/122899,2012,A1 .

15
[ 145689-34-5 ]
[ 1375541-92-6 ]

References: [1]Patent: US2012/122899,2012,A1 .

16
[ 145689-34-5 ]
[ 1375470-97-5 ]

References: [1]Patent: US2012/122899,2012,A1 .
[2]Patent: US9499541,2016,B2 .

17
[ 145689-34-5 ]
[ 1375470-98-6 ]

References: [1]Patent: US2012/122899,2012,A1 .
[2]Patent: WO2012/129013,2012,A1 .
[3]Patent: US9499541,2016,B2 .

18
[ 145689-34-5 ]
(3RS,5RS)-3-azido-5-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)piperidin-2-one [ No CAS ]

References: [1]Patent: US2012/122899,2012,A1 .
[2]Patent: WO2012/129013,2012,A1 .
[3]Patent: WO2012/129014,2012,A1 .

19
[ 145689-34-5 ]
[ 1375471-00-3 ]
[ 1375471-01-4 ]

References: [1]Patent: US2012/122899,2012,A1 .
[2]Patent: WO2012/129013,2012,A1 .
[3]Patent: WO2012/129014,2012,A1 .

20
[ 145689-34-5 ]
[ 1375470-95-3 ]

References: [1]Patent: US2012/122899,2012,A1 .
[2]Patent: WO2012/129013,2012,A1 .
[3]Patent: WO2012/129014,2012,A1 .
[4]Patent: US9499541,2016,B2 .

21
[ 145689-34-5 ]
[ 1375541-88-0 ]