760-58-7|2-Cyano-4-methylpent-2-enoic acid| Ambeed

Structure of 760-58-7

*Storage: {[sel_prStorage]}

*Shipping: {[sel_prShipping]}

4.5 *For Research Use Only !

{[proInfo.pro_purity]}

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

Change View

Size

Price

VIP Price

DE Stock

US Stock

Asia 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) ]}

{[ item.pr_size ]}

In Stock

- +

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

Quality Control of [ 760-58-7 ] Purity: 97% 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

Product Details of [ 760-58-7 ]

CAS No. :	760-58-7
Formula :	C₇H₉NO₂
M.W :	139.15
SMILES Code :	CC(C)/C=C(C#N)/C(O)=O
MDL No. :	MFCD22377852
InChI Key :	JYFREZOLRUHBAQ-ZZXKWVIFSA-N
Pubchem ID :	5956093

Safety of [ 760-58-7 ]

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

Computational Chemistry of [ 760-58-7 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	0
Fraction Csp3	0.43
Num. rotatable bonds	2
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	36.81
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	61.09 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.26
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	1.3
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.18
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.	0.54
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	0.46
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.95

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.39
Solubility	5.67 mg/ml ; 0.0408 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.18
Solubility	0.913 mg/ml ; 0.00656 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	-0.23
Solubility	82.9 mg/ml ; 0.596 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	No
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.	-6.23 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	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.56

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	2.0 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)	2.33

Application In Synthesis of [ 760-58-7 ]

* 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 [ 760-58-7 ]

[ 760-58-7 ] Synthesis Path-Downstream 1~54

1
[ 372-09-8 ]
[ 78-84-2 ]
[ 760-58-7 ]

Yield	Reaction Conditions	Operation in experiment
89%	With pyrrolidine; pyridine; at 20℃;	Into a 100-mL round-bottom flask, was placed 2-cyanoacetic acid (2 g, 23.51 mmol, 1.00 eq.), pyridine (10 mL), 2-methylpropanal (1.85 g, 25.66 mmol, 1.09 eq.), pyrrolidine (400 mg, 5.62 mmol, 0.24 eq.). The resulting solution was stirred for 1.5 h at rt. The reaction was then quenched by the addition of hydrogen chloride:H20 (12:20 mL). The resulting solution was extracted with ethyl acetate (2 x 20 mL). The organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 2.9 g (89%) of 2-cyano-4-methylpent-2-enoic acid as a light yellow solid.
83%	With ammonium acetate; In toluene;Reflux;	Step 1 - 2-Cyano-4-methyl-2-pentenoic acidA stirred suspension of cyanoacetic acid (42.5g, 0.5 mol), ammonium acetate(1 .56g, 0.02 mol, 4 mol%) and isobutyraldehyde (55ml, 39.66g, 0.55 mol, 1 .1 eq) in toluene (130ml) was heated to reflux with Dean-Stark removal of water. When generation of water ceased, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a yellow solid (79.5g). Hexane (150ml) was added and the suspension was stirred at 400rpm for 1 hour. The solid was filtered, washed with hexane (2 x 50ml) and dried to provide the title compound as a yellow crystalline solid (58.5g, 83% yield).
11.2 g		To a solution of 2-cyanoacetic acid (8.7g, 102 mmol) in methanol (200mL) was added 2-methylpropanal (18.6 mL, 204 mmol) and the solution was stirred with a slight exotherm noted. After 30 minutes, added piperidine (1 1.1 mL, 1 12 mmol) and continued stirring for 1 h before removing solvent in vacuo with gentle heating. The thick material was diluted with ether and washed with 125mL of 1.0M HC1 and then washed with brine. The organic phase was dried over sodium sulfate and concentrated to afford a colorless oil weighing 11.2 g of 2- cyano-4-methylpent-2-enoic acid which precipitated on standing.

References: [1]Organic Process Research and Development,2014,vol. 18,p. 109 - 121.
[2]Patent: WO2019/99582,2019,A1 .Location in patent: Paragraph 0336; 0339; 0347; 0350.
[3]Patent: WO2012/25861,2012,A1 .Location in patent: Page/Page column 22.
[4]Journal of the Chemical Society,1932,p. 445,453.
Journal of the Chemical Society,1933,p. 613.
[5]Patent: WO2014/39899,2014,A1 .Location in patent: Page/Page column 52.
[6]Journal of Molecular Catalysis B: Enzymatic,2014,vol. 101,p. 67 - 72.

3
[ 760-58-7 ]
[ 148553-50-8 ]

References: [1]Patent: WO2012/25861,2012,A1 .
[2]Patent: WO2012/25861,2012,A1 .
[3]Patent: WO2012/25861,2012,A1 .
[4]Advanced Synthesis and Catalysis,2014,vol. 356,p. 1878 - 1882.
[5]Advanced Synthesis and Catalysis,2014,vol. 356,p. 1878 - 1882.

4
[ 760-58-7 ]
[ 181289-39-4 ]

References: [1]Patent: WO2012/25861,2012,A1 .
[2]Patent: WO2012/25861,2012,A1 .
[3]Organic Process Research and Development,2014,vol. 18,p. 109 - 121.

5
[ 760-58-7 ]
5-methyl-3-cyanohexanoic acid ethyl ester [ No CAS ]
[ 181289-39-4 ]

References: [1]Patent: WO2012/25861,2012,A1 .

6
[ 760-58-7 ]
potassium (S)-3-cyano-5-methylhexanoate [ No CAS ]

References: [1]Patent: WO2012/25861,2012,A1 .
[2]Patent: WO2012/25861,2012,A1 .
[3]Patent: WO2012/25861,2012,A1 .

7
[ 760-58-7 ]
[ 914254-26-5 ]

References: [1]Patent: WO2012/25861,2012,A1 .
[2]Patent: WO2012/25861,2012,A1 .
[3]Patent: WO2012/25861,2012,A1 .

8
[ 760-58-7 ]
[ 1335223-63-6 ]

References: [1]Patent: WO2012/25861,2012,A1 .
[2]Organic Process Research and Development,2014,vol. 18,p. 109 - 121.

9
[ 760-58-7 ]
[ 1334950-50-3 ]

References: [1]Patent: WO2012/25861,2012,A1 .

10
[ 760-58-7 ]
[ 18283-41-5 ]

Yield	Reaction Conditions	Operation in experiment
100%		Step 3 - 2-Cyano-4-methylpentanoic acid (by sodium borohydride reduciton) A suspension of 4-methyl-2-cyano-2-butenoic acid (10g, 71 .9mmol) in water (60ml_) was cooled to 0C with an ice bath, then NaHCO3 (7.25g, 1 .2 eq.) was added slowly to the mixture. The mixture is stirred for 15 mins to provide a clear solution, then NaBH4 (5.44g, 2 eq.) was added slowly at 0C and the reaction was stirred at room temperature for 5h. The mixture was cooled down to 0C and a solution of HCI 20% (44ml_, 4 eq.) was slowly added to the mixture (pH= 2-3). The product was extracted with EtOAc (3x 30ml_) and the combined organic phases were washed with water (3x 20 ml_), dried over MgSO , filtered and evaporated under reduced pressure to give material identical to that obtained by the hydrogenation route (10.2g, 100%).

References: [1]Patent: WO2012/25861,2012,A1 .Location in patent: Page/Page column 23.
[2]Journal of Molecular Catalysis B: Enzymatic,2014,vol. 101,p. 67 - 72.

11
[ 760-58-7 ]
[ 1335223-70-5 ]

References: [1]Patent: WO2012/25861,2012,A1 .

12
[ 760-58-7 ]
[ 1248544-41-3 ]

References: [1]Patent: WO2012/25861,2012,A1 .
[2]Journal of Molecular Catalysis B: Enzymatic,2014,vol. 101,p. 67 - 72.

13
[ 760-58-7 ]
[ 1335223-71-6 ]

References: [1]Patent: WO2012/25861,2012,A1 .

14
[ 760-58-7 ]
[ 1239326-95-4 ]

References: [1]Patent: WO2012/25861,2012,A1 .

15
[ 760-58-7 ]
[ 1413943-94-8 ]
[ 1413943-91-5 ]

Yield	Reaction Conditions	Operation in experiment
	With bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; at 0℃;Inert atmosphere;	Step 4To a 25 mL round bottom flask, (R)-4-(4-phenoxyphenyl)-6-(piperidin-3-yl)-lH- pyrazolo[4,3-c]pyridin-3-amine (O.lg, 0.00025 mole) and <strong>[760-58-7]2-cyano-4-methylpent-2-enoic acid</strong> (0.046g, O.00033mole) were taken in dry DCM (lmL) and the solution was cooled to 0C under argon atmosphere. To above, PyBrOP (0.133g, 0.000285mole) was added slowly followed by triethylamine (0.1 mL, 0.000778 mole) at 0 C. The completion of the reaction was monitored on TLC using MeOH: DCM (1 :9) as a mobile phase. After completion of the reaction the reaction, the crude material was directly loaded onto a column packed with 100- 200 mesh sized silica eluting with neat ethyl acetate to afford 38 mg of the title compound. MS (pos. ion) m/z: 507 (M+l).

References: [1]Patent: WO2012/158810,2012,A1 .Location in patent: Page/Page column 119.

16
[ 760-58-7 ]
[ 1414357-70-2 ]
[ 1414355-34-2 ]

Yield	Reaction Conditions	Operation in experiment
40%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 4h;Inert atmosphere;	Step 5. To a mixture of (R)-3-(4-(2,3difluorophenoxy)-2-fluorophenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.23 mmol, 1.0 eq), <strong>[760-58-7]2-cyano-4-methyl-pent-2-enoic acid</strong> (38 mg, 0.27 mmol, 1.2 eq) and DIEA (88 mg, 0.68 mmol, 3.0 eq) in 10 ml DCM was added HATU (130 mg, 0.34 mmol, 1.5 eq). The reaction mixture was stirred for 4 h at RT under N2. The mixture was purified by Pre-HPLC to give the title compound (25 mg, 40% yield). LCMS: m/z (562.2) (M+H)+.
40%	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 4h;Inert atmosphere;	Step 5 To a mixture of (R)-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.23 mmol, 1.0 eq), <strong>[760-58-7]2-cyano-4-methyl-pent-2-enoic acid</strong> (38 mg, 0.27 mmol, 1.2 eq) and DIEA (88 mg, 0.68 mmol, 3.0 eq) in 10 ml DCM was added HATU (130 mg, 0.34 mmol, 1.5 eq). The reaction mixture was stirred for 4 h at RT under N2. The mixture was purified by Pre-HPLC to give the title compound (25 mg40% yield). LCMS: m/Z+ (562.2) (M+H)+1HNMR (400 MHz, CDCl3): delta 0.784?1.186 (m, 7H), 1.765?2.254 (m, 5H), 2.861?4.937 (m, 4H), 6.218 (m, 0.4H), 6.857?7.600 (m, 6H), 8.255 (s, 1H) and 9.888 (m, 1H).

References: [1]Patent: WO2014/22569,2014,A1 .Location in patent: Page/Page column 100.
[2]Patent: US8673925,2014,B1 .Location in patent: Page/Page column 245.

17
[ 760-58-7 ]
[ 1575819-64-5 ]
[ 1575819-65-6 ]

Yield	Reaction Conditions	Operation in experiment
0.2 g	With triethylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; at 0℃; for 0.25h;Inert atmosphere;	To a 25 mL one necked round bottom flask, benzyl (2-(4-chlorobenzamido)-l- (pyrrolidin-2-ylmethyl)-lH-benzo[d]imidazol-5-yl)methyl((S)-3,3-dimethylbutan-2-yl)carbamate TFA salt (0.55 g, 0.00091 mole), <strong>[760-58-7]2-cyano-4-methylpent-2-enoic acid</strong> (0.380 g, 0.00274 mole) were added in CH2C12 (3 mL), followed by addition of PyBrOP (0.466 g, 0.001 mole) and TEA (0.63 mL,0.0045 mole) at 0 C under nitrogen atmosphere and the reaction mixture was stirred for 15 min at same temperature. After the completion of the reaction, the reaction mixture was purified using column purification by eluting compound with 25% ethyl acetate in hexanes to yield 0.2g of benzyl (2-(4-chloro-benzamido)-l-((l-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2- yl)methyl)-lH-benzo[d]imidazol-5-yl)methyl((S)-3,3-dimethylbutan-2-yl)carbamate.

References: [1]Patent: WO2014/36016,2014,A1 .Location in patent: Page/Page column 119; 120.

18
[ 760-58-7 ]
[ 1575819-92-9 ]
[ 1575819-94-1 ]

Yield	Reaction Conditions	Operation in experiment
0.27 g	With triethylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; at 0℃; for 0.5h;Sealed tube;	To a 25 mL sealed tube under nitrogen atmosphere, benzyl (2-(4-(difluoromethyl)- benzamido)-l-(pyrrolidin-2-ylmethyl)-lH-benzo[d]imidazol-5-yl)methyl((S)-3,3-dimethylbutan- 2-yl)carbamate as TFA salt (0.5 g, 0.000683 mole), <strong>[760-58-7]2-cyano-4-methylpent-2-enoic acid</strong> (0.284 g, 0.002049 mole) and PyBrOP (0.350 g, 0.000751 mole) were taken in CH2C12 (5 mL) and cooled to 0 C. TEA (0.47 mL, 0.003415 mole) was added drop wise to a reaction mixture and to stir at 0 C for 30 min. After completion of the reaction, water was added to reaction mixture and product was extracted with EtOAc. The combined organic layer was dried over a2S04 and evaporated to get crude. The crude compound was purified by column purification using 60-120 mesh size neutral silica by eluting with 20% EtOAc in hexanes to yield 0.27g of benzyl (l-((l-(2- cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-2-(4-(difluoromethyl)benzamido)-lH- benzo[d]imidazol-5-yl)methyl((S)-3,3-dimethylbutan-2-yl)carbamate.

References: [1]Patent: WO2014/36016,2014,A1 .Location in patent: Page/Page column 133.

19
[ 760-58-7 ]
[ 1575820-50-6 ]
[ 1575818-10-8 ]

Yield	Reaction Conditions	Operation in experiment
10 mg	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1.66667h;	To a solution of (R)-5-(difluoromethyl)-N-(5-(hydroxymethyl)-l-(pyrrolidin-2- ylmethyl)-lH-benzo[d]imidazol-2-yl)thiophene-2-carboxamide (27 mg, 0.07 mmol), 2-cyano-4- methyl-pent-2-enoic acid (13.87 mg, 0.10 mmol), HATU (25.24 mg, 0.07 mmol), DIPEA (0.01 mL, 0.07 mmol) in DMF (10 mL) was stirred at rt for 100 minutes. The reaction mixture was evaporated to afford an oil which was worked up with DCM and water. The organic layers were dried (MgS04) and concentrated and the oil was purified by chromatography to obtain 10 mg of (R)-N-( 1 -((1 -(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-(hydroxymethyl)- 1 H- benzo[d]-imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamideas white solid. MS (pos. ion) m/z: 528 (M+l).

References: [1]Patent: WO2014/36016,2014,A1 .Location in patent: Page/Page column 180.

20
[ 760-58-7 ]
[ 1575820-59-5 ]
N-(1-(((R)-1-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-5-((2,6-dimethylmorpholino)methyl)-1H-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 4h;	To the solution of 5-(difluoromethyl)-N-(5-((2,6-dimethylmorpholino)methyl)-l-((R)- pyrrolidin-2-ylmethyl)-lH-benzo[d]imidazol-2-yl)thiophene-2-carboxamide (65 mg, 0.13 mmol), DIPEA (0.07 mL, 0.39 mmol), <strong>[760-58-7]2-cyano-4-methyl-pent-2-enoic acid</strong> (53.88 mg, 0.39 mmol) and DMF (4 mL) was stirred for 10 minutes and then added HATU (98.09 mg, 0.26 mmol). The reaction mixture was stirred at room temperature. After 4 h, the crude mixture was concentrated and purified by chromatography to obtain 55 mg (68%) of N-(l-(((R)-l-(2-cyano-4-methylpent- 2-enoyl)pyrrolidin-2-yl)methyl)-5-((2,6-dimethylmorpholino)methyl)-lH-benzo[d]imidazol-2- yl)-5-(difluoromethyl)thiophene-2-carboxamide as off white solid. MS (pos. ion) m/z: 625 (M+l).

References: [1]Patent: WO2014/36016,2014,A1 .Location in patent: Page/Page column 167.

21
[ 760-58-7 ]
[ 1575821-14-5 ]
[ 1575818-24-4 ]

Yield	Reaction Conditions	Operation in experiment
47.4 mg	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	(R)-3-Methyl-N-( 1 -(pyrrolidin-2-ylmethyl)- 1 H-benzo[d]imidazol-2-yl)benzamide (prepared as in Example 50 but substituting 3-methylbenzoic acid for 5- (difluoromethyl)thiophene-2-carboxylic acid) was dissolved in N,N-dimethylformamide (10 mL). DIEA (231.9 mg, 1.79 mmol, 4.00 equiv), HATU (255.8 mg, 0.67 mmol, 1.50 equiv), and <strong>[760-58-7]2-cyano-4-methylpent-2-enoic acid</strong> (93.6 mg, 0.67 mmol, 1.50 equiv) were added to the reaction mixtureand the resulting solution was stirred overnight at rt. The reaction was quenched with water and the resulting solution was extracted with dichloromethane, and the combined organic layers were concentrated under vacuum. The crude product (100 mg) was purified by Prep HPLC to afford 47.4 mg of (R)-N-(l-((l-(2-cyano-4-methylpent-2-enoyl)pyrrolidin-2-yl)methyl)-lH- benzo[d]imidazol-2-yl)-3-methylbenzamide as a white solid. LC-MS (m/z): 456.3 [M+l].

References: [1]Patent: WO2014/36016,2014,A1 .Location in patent: Page/Page column 189; 190.

22
[ 760-58-7 ]
[ 1575821-18-9 ]
[ 1575818-29-9 ]

Yield	Reaction Conditions	Operation in experiment
173 mg	With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	(R)-5-(Difluoromethyl)-N-(l-(pyrrolidin-3-yl)-lH-benzo[d]imidazol-2-yl)thiophene-2- carboxamide (prepared as in Example 50 but substituting (R)-tert-butyl 3-aminopyrrolidine-l- carboxylate for (R)-tert-butyl 2-(aminomethyl)pyrrolidine-l -carboxylate) was dissolved in 20 mL of DMF. TEA (335.1 mg, 3.31 mmol), <strong>[760-58-7]2-cyano-4-methylpent-2-enoic acid</strong> (153.6 mg, 1.10 mmol, and HATU (629.5 mg, 1.66 mmol) were added to the reaction mixture. The resulting solution was stirred overnight at rt and then concentrated under vacuum. The crude product was purified by Prep-HPLC to afford 173 mg of (R)-N-(l-(l-(2-cyano-4-methylpent-2- enoyl)pyrrolidin-3-yl)-lH-benzo[d]imidazol-2-yl)-5-(difluoromethyl)thiophene-2-carboxamide LC-MS m/z: 484.2 [M+l].

References: [1]Patent: WO2014/36016,2014,A1 .Location in patent: Page/Page column 193.

23
[ 760-58-7 ]
[ 1575819-51-0 ]
[ 1575819-52-1 ]

Yield	Reaction Conditions	Operation in experiment
0.19 g	With triethylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; at 0℃; for 0.25h;Inert atmosphere;	To a 50 mL one necked round bottom flask were added benzyl (2-(4-chlorobenzamido)-l- (piperidin-3-yl)-lH-benzo[d]imidazol-5-yl)methyl-((S)-3,3-dimethylbutan-2-yl)carbamate TFA salt (0.5 g,0.7150 mmole), <strong>[760-58-7]2-cyano-4-methylpent-2-enoic acid</strong> (0.298 g, 2.1450 mmole) and CH2CI2 (10 mL); followed by addition of PyBrOP (0.366 g, 0.7860 mmole) and TEA (0.3 mL) at 0 C under nitrogen atmosphere and stirred for 15 min at the same temperature. After completion of the reaction, the reaction mixture was purified using column purification by eluting compound with 20% ethyl acetate in hexanes to yield 0.19 g of benzyl (2-(4- chlorobenzamido)-l-(l-(2-cyano-4-methylpent-2-enoyl)piperidin-3-yl)-lH-benzo[d]imidazol-5 yl)methyl((S)-3,3-dimethylbutan-2-yl)carbamate.

References: [1]Patent: WO2014/36016,2014,A1 .Location in patent: Page/Page column 112; 113.

24
[ 760-58-7 ]
[ 1575590-64-5 ]
[ 1575590-56-5 ]

Yield	Reaction Conditions	Operation in experiment
34 mg	With triethylamine; ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V); In dichloromethane; at 20℃;	The mixture of l-(azetidin-3-yl)-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin-4-amine (80 mg, 0.210 mmol, <strong>[760-58-7]2-cyano-4-methyl-pent-2-enoic acid</strong> (44.4 mg, 0.320 mmol), PyAOP (121.9 mg, 0.230 mmol) and TEA (0.09 mL, 0.640 mmol) in DCM (3 mL), were stirred overnight at room temperature. The solvent was removed and the residue was purified on a silica gel plate using 6:94 MeOH:CH2Ci2 to get 2-[3-[4-amino-3-(2-fluoro- 4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]azetidine-l-carbonyl]-4-methyl-pent-2- enenitrile (34 mg) as white powder. LC-MS (ES, m/z): 498 [M+H].

References: [1]Patent: WO2014/39899,2014,A1 .Location in patent: Page/Page column 76-77.

25
[ 760-58-7 ]
[ 1575590-17-8 ]
[ 1575590-07-6 ]

Yield	Reaction Conditions	Operation in experiment
39.8%	With triethylamine; ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V); In dichloromethane; at 20℃; for 1h;	To a solution of <strong>[760-58-7]2-cyano-4-methyl-pent-2-enoic acid</strong> (30.7 mg, 0.220 mmol), 1- (azetidin-2-ylmethyl)-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-amine (57.5 mg, 0.150 mmol in DCM (2 mL) was added PyAOP (86.2 mg, 0.160 mmol) and TEA (0.06 mL, 0.440 mmol) and the resulting yellow solution stirred at rt for lh. LCMS showed that the reaction was complete and the crude mixture was directly loaded onto a silica gel cartridge for purification (3 to 5% MeOH: CH2C12). Removal of solvent from cleanest fractions afforded 30mg of the desired compound 2-[2-[[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-l -yl]methyl]azetidine-l-carbonyl]-4-methyl-pent-2- enenitrile (30mg,0.0586mmol, 39.8% yield) as judged by LCMS. (M+l = 512).

References: [1]Patent: WO2014/39899,2014,A1 .Location in patent: Page/Page column 70.

26
[ 760-58-7 ]
[ 1575590-37-2 ]
[ 1575590-29-2 ]

Yield	Reaction Conditions	Operation in experiment
12 mg	With triethylamine; ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V); In dichloromethane; at 20℃; for 1h;	To a solution of <strong>[760-58-7]2-cyano-4-methyl-pent-2-enoic acid</strong> (48.12 mg, 0.350 mmol) ,1- (azetidin-3-ylmethyl)-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-amine (90 mg, 0.230 mmol) in DCM (2 mL) was added PyAOP (134.9 mg, 0.250 mmol) and TEA (0.1 mL, 0.690 mmol) and the resulting yellow solution stirred at rt for lh. LCMS showed that the reaction was completed and the crude mixture was directly loaded onto a silica gel cartridge for purification (0.2 to 3% MeOH: CH2C12). Removal of solvent from cleanest fractions afforded afforded 2-[3-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l- yl]methyl]azetidine-l-carbonyl]-4-methyl-pent-2-enenitrile (12 mg LCMS. (M+l = 512).

References: [1]Patent: WO2014/39899,2014,A1 .Location in patent: Page/Page column 73.

27
[ 760-58-7 ]
C₉H₁₅NO₂ [ No CAS ]
C₉H₁₅NO₂ [ No CAS ]

References: [1]Journal of Molecular Catalysis B: Enzymatic,2014,vol. 101,p. 67 - 72.

28
[ 760-58-7 ]
methyl (S)-3-cyano-5-methyl-hexanoate [ No CAS ]
methyl (R)-3-cyano-5-methyl-hexanoate [ No CAS ]

References: [1]Journal of Molecular Catalysis B: Enzymatic,2014,vol. 101,p. 67 - 72.

29
[ 760-58-7 ]
3-cyano-5-methylhexanoic acid methyl ester [ No CAS ]

References: [1]Journal of Molecular Catalysis B: Enzymatic,2014,vol. 101,p. 67 - 72.

30
[ 760-58-7 ]
[ 1415320-55-6 ]

References: [1]Journal of Molecular Catalysis B: Enzymatic,2014,vol. 101,p. 67 - 72.

31
[ 760-58-7 ]
(S)-methyl 3-cyano-5-methylhexanoate [ No CAS ]
C₉H₁₄⁽²⁾HNO₂ [ No CAS ]

References: [1]Journal of Molecular Catalysis B: Enzymatic,2014,vol. 101,p. 67 - 72.

32
[ 760-58-7 ]
C₉H₁₄⁽²⁾HNO₂ [ No CAS ]

References: [1]Journal of Molecular Catalysis B: Enzymatic,2014,vol. 101,p. 67 - 72.

33
[ 760-58-7 ]
C₁₁H₁₈⁽²⁾HNO₂ [ No CAS ]

References: [1]Journal of Molecular Catalysis B: Enzymatic,2014,vol. 101,p. 67 - 72.

34
[ 760-58-7 ]
[ 925-61-1 ]
[ 1421868-97-4 ]

References: [1]Journal of Molecular Catalysis B: Enzymatic,2014,vol. 101,p. 67 - 72.

35
[ 372-09-8 ]
[ 590-86-3 ]
[ 760-58-7 ]