21512-16-3|5-Formylthiophene-2-carbonitrile| Ambeed

Structure of 21512-16-3

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Quality Control of [ 21512-16-3 ] Purity: 98% SDS Specification

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Product Details of [ 21512-16-3 ]

CAS No. :	21512-16-3
Formula :	C₆H₃NOS
M.W :	137.16
SMILES Code :	N#CC1=CC=C(C=O)S1
MDL No. :	MFCD09037804
InChI Key :	PZIFYWVUYHMYOA-UHFFFAOYSA-N
Pubchem ID :	12280004

Safety of [ 21512-16-3 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H319
Precautionary Statements:	P305+P351+P338

Computational Chemistry of [ 21512-16-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	9
Num. arom. heavy atoms	5
Fraction Csp3	0.0
Num. rotatable bonds	1
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	34.42
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	69.1 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.32
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	1.45
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.43
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.	-0.27
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	2.62
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.31

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.95
Solubility	1.54 mg/ml ; 0.0112 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.	-2.51
Solubility	0.427 mg/ml ; 0.00311 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	-1.67
Solubility	2.93 mg/ml ; 0.0213 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.	-6.11 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.	0.55

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	1.0 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)	2.25

Application In Synthesis of [ 21512-16-3 ]

* 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 [ 21512-16-3 ]

[ 21512-16-3 ] Synthesis Path-Downstream 1~42

1
[ 21512-16-3 ]
[ 75-52-5 ]
[ 98555-96-5 ]

References: [1]Journal of Organic Chemistry,1957,vol. 22,p. 1636,1640.

2
[ 21512-16-3 ]
[ 75-07-0 ]
[ 89898-73-7 ]

References: [1]Journal of Organic Chemistry,1957,vol. 22,p. 1636,1640.

3
[ 90924-79-1 ]
[ 21512-16-3 ]

References: [1]Journal of Organic Chemistry,1957,vol. 22,p. 1636,1640.

4
[ 120-75-2 ]
[ 21512-16-3 ]
5-(2-benzothiazol-2-yl-vinyl)-thiophene-2-carbonitrile [ No CAS ]

References: [1]Journal of Organic Chemistry USSR (English Translation),1973,vol. 9,p. 2596 - 2600.
Zhurnal Organicheskoi Khimii,1973,vol. 9,p. 2577 - 2582.

5
[ 21512-16-3 ]
[ 34165-09-8 ]
[ 62195-17-9 ]

References: [1]Arzneimittel-Forschung/Drug Research,1977,vol. 27,p. 82 - 89.

7
[ 21512-16-3 ]
[ 51412-95-4 ]

References: [1]Journal of Organic Chemistry USSR (English Translation),1973,vol. 9,p. 2596 - 2600.
Zhurnal Organicheskoi Khimii,1973,vol. 9,p. 2577 - 2582.

8
[ 16494-36-3 ]
[ 21512-16-3 ]

References: [1]Journal of Organic Chemistry,1957,vol. 22,p. 1636,1640.

9
[ 72835-25-7 ]
[ 21512-16-3 ]

Yield	Reaction Conditions	Operation in experiment
60%		The starting 5-cyanothiophene-2-carboxaldehyde was obtained by oxidation of 5-cyano-2-methylthiophene with chromium trioxide (Org. Synthesis, Collected Volume II, 441, 1943) as a colourless solid (60percent yield), m.p. 91°-93° C.; IR: 2210 (CN) and 1670 (CHO) cm-1; m/e 137 (M+).

References: [1]Patent: US5053415,1991,A .
[2]Journal of Organic Chemistry,1957,vol. 22,p. 1636,1640.

10
[ 21512-16-3 ]
[ 98278-95-6 ]

References: [1]Journal of Organic Chemistry,1957,vol. 22,p. 1636,1640.

11
[ 21512-16-3 ]
[ 106595-12-4 ]

References: [1]Journal of Organic Chemistry,1957,vol. 22,p. 1636,1640.

12
[ 21512-16-3 ]
[ 89891-71-4 ]

References: [1]Journal of Organic Chemistry,1957,vol. 22,p. 1636,1640.

13
[ 21512-16-3 ]
2-Aminomethyl-5-carbobenzyloxyamidinothiophene dihydrogen chloride salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		2-Cyano-5-formylthiophene (EX-55A) (15.8 g, 0.229 moles) was stirred in ethanol (375 ml), and sodium borohydride (4.36 g, 0.115 moles) added in small portions. After 15 min., the solvent was removed in vacuo, and residue taken up in ethyl acetate. After the ethyl acetate was washed with 1 N potassium hydrogen sulfate and brine, the organic layer was dried over magnesium sulfate, filtered, and solvent removed in vacuo. The residue was dried on vacuum pump to yield 9.57 g (59percent) of the alcohol EX-55B as a brown-orange oil: 1H NMR (300 MHz, CDCl3) d 7.53 (m, 1H), 7.00 (m, 1H), 4.88 (s, 2H), 2.84 (br s, 1H). To a stirring solution of EX-55B (9.57 g, 0.069 moles) in tetrahydrofuran (80 ml) was added triphenylphosphine (19.86 g, 0.075 moles) and carbon tetrabromide (25.11 g, 0.075 moles). After 18 h. the reaction was concentrated in vacuo, and the crude material chromatographed to yield EX-55C as a brown oil: 1H NMR (300 MHz, CDCl3) d 7.52 (m, 1H), 7.14 (m, 1H), 4.69 (s,2H). 2-Aminomethyl-5-carbobenzyloxyamidinothiophene dihydrogen chloride salt (EX-55D) was prepared by the method outlined in Synthetic Communications, 28(23), 4419-4429 (1998) by substituting 5-bromomethyl-2-cyanothiophene (EX-55C) for 4-cyanobenzyl bromide to give after trituration with acetonitrile EX-55D: 1H NMR (300 MHz, DMSO) d 9.98 (br s, 1H), 8.83 (br s, 2H), 8.10 (s, 1H), 7.40-7.48 (m, 7H), 5.26 (s, 2H), 4.31 (s, 2H); HRMS calcd for C14H16N3O2S 290.0963, found 290.0949.

References: [1]Patent: US6664255,2003,B1 .Location in patent: Page column 117.

14
[ 1003-31-2 ]
[ 21512-16-3 ]

Yield	Reaction Conditions	Operation in experiment
6.9 g (84%)	With n-butyllithium; diisopropylamine; citric acid; In tetrahydrofuran; N-methyl-acetamide; water; ethyl acetate;	EXAMPLE 65 STR100 A) Preparation of 2-cyano-5-formylthiophene To a flame-dried 3 neck 1 L round bottom flask was added diisopropylamine (9 mL, 66 mmol) and THF (150 mL) under a nitrogen atmosphere. The flask was cooled to an internal temperature of -78° C. (dry ice/acetone). To this stirring solution was added n-butyllithium (1.6 M in hexanes, 41.3 mL, 66.1 mmol) via syringe and the mixture was allowed to stir for 5 min. To this solution was added a solution of 2-thiophenecarbonitrile (6.55 g, 60 mmol) in THF (30 mL) over 10 min. The resulting bright red solution was allowed to stir at -78° C. for 45 min, at which time dimethylformamide (23.3 mL, 300 mmol) was added via syringe. This mixture was allowed to stir for 2 h at -78° C. and then solid citric acid (about 10 g) was added followed by water (60 mL). Volatile solvents were removed in vacuo and the residue was partitioned between diethyl ether and brine (200 mL each). Layers were separated and the aqueous phase was washed once with diethyl ether. The combined organic phase was washed once with brine, dried (MgSO4), filtered and concentrated in vacuo to give a yellow solid which was purified by silica gel chromatography using an ethyl acetate/hexanes gradient (hexanes to 50percent ethyl acetate/hexanes). Fractions containing pure product were pooled and concentrated in vacuo to give 6.9 g (84percent) of 2-cyano-5-formyl-thiophene.
6.9 g (84%)	With n-butyllithium; diisopropylamine; citric acid; In tetrahydrofuran; N-methyl-acetamide; water; ethyl acetate;	EXAMPLE 65 STR95 A) Preparation of 2-cyano-5-formylthiophene To a flame-dried 3 neck 1L round bottom flask was added diisopropylamine (9 mL, 66 mmol) and THF (150 mL) under a nitrogen atmosphere. The flask was cooled to an internal temperature of -78° C. (dry ice/acetone). To this stirring solution was added n-butyllithium (1.6M in hexanes, 41.3 mL, 66.1 mmol) via syringe and the mixture was allowed to stir for 5 min. To this solution was added a solution of 2-thiophenecarbonitrile (6.55 g, 60 mmol) in THF (30 mL) over 10 min. The resulting bright red solution was allowed to stir at -78° C. for 45 min, at which time dimethylformamide (23.3 mL, 300 mmol) was added via syringe. This mixture was allowed to stir for 2 h at -78° C. and then solid citric acid (about 10 g) was added followed by water (60 mL). Volatile solvents were removed in vacuo and the residue was partitioned between diethyl ether and brine (200 mL each). Layers were separated and the aqueous phase was washed once with diethyl ether. The combined organic phase was washed once with brine, dried (MgSO4), filtered and concentrated in vacuo to give a yellow solid which was purified by silica gel chromatography using an ethyl acetate/hexanes gradient (hexanes to 50percent ethyl acetate/hexanes). Fractions containing pure product were pooled and concentrated in vacuo to give 6.9 g (84percent) of 2-cyano-5-formyl-thiophene.
6.9 g (84%)	With n-butyllithium; diisopropylamine; citric acid; In tetrahydrofuran; N-methyl-acetamide; water; ethyl acetate;	A) Preparation of 2-cyano-5-formylthiophene To a flame-dried 3 neck 1L round bottom flask was added diisopropylamine (9 mL, 66 mmol) and THF (150 mL) under a nitrogen atmosphere. The flask was cooled to an internal temperature of -78° C. (dry ice/acetone). To this stirring solution was added n-butyllithium (1.6M in hexanes, 41.3 mL, 66.1 mmol) via syringe and the mixture was allowed to stir for 5 min. To this solution was added a solution of 2-thiophenecarbonitrile (6.55 g, 60 mmol) in THF (30 mL) over 10 min. The resulting bright red solution was allowed to stir at -78° C. for 45 min, at which time dimethylformamide (23.3 mL, 300 mmol) was added via syringe. This mixture was allowed to stir for 2 h at -78° C. and then solid citric acid (about 10 g) was added followed by water (60 mL). Volatile solvents were removed in vacuo and the residue was partitioned between diethyl ether and brine (200 mL each). Layers were separated and the aqueous phase was washed once with diethyl ether. The combined organic phase was washed once with brine, dried (MgSO4), filtered and concentrated in vacuo to give a yellow solid which was purified by silica gel chromatography using an ethyl acetate/hexanes gradient (hexanes to 50percent ethyl acetate/hexanes). Fractions containing pure product were pooled and concentrated in vacuo to give 6.9 g (84percent) of 2-cyano-5-formyl-thiophene.

6.9 g (84%)	With n-butyllithium; diisopropylamine; citric acid; In tetrahydrofuran; N-methyl-acetamide; water; ethyl acetate;	EXAMPLE 65 STR106 A) Preparation of 2-cyano-5-formylthiophene To a flame-dried 3 neck 1 L round bottom flask was added diisopropylamine (9 mL, 66 mmol) and THF (150 mL) under a nitrogen atmosphere. The flask was cooled to an internal temperature of -78° C. (dry ice/acetone). To this stirring solution was added n-butyllithium (1.6M in hexanes, 41.3 mL, 66.1 mmol) via syringe and the mixture was allowed to stir for 5 min. To this solution was added a solution of 2-thiophenecarbonitrile (6.55 g, 60 mmol) in THF (30 mL) over 10 min. The resulting bright red solution was allowed to stir at -78° C. for 45 min, at which time dimethylformamide (23.3 mL, 300 mmol) was added via syringe. This mixture was allowed to stir for 2 h at -78° C. and then solid citric acid (about 10 g) was added followed by water (60 mL). Volatile solvents were removed in vacuo and the residue was partitioned between diethyl ether and brine (200 mL each). Layers were separated and the aqueous phase was washed once with diethyl ether. The combined organic phase was washed once with brine, dried (MgSO4), filtered and concentrated in vacuo to give a yellow solid which was purified by silica gel chromatography using an ethyl acetate/hexanes gradient (hexanes to 50percent ethyl acetate/hexanes). Fractions containing pure product were pooled and concentrated in vacuo to give 6.9 g (84percent) of 2-cyano-5-formyl-thiophene.
50%Chromat.		A solution of diisopropylamine (35.3 ml, 0.251 moles) in tetrahydrofuran (500 ml) was cooled to -78 C. under a nitrogen blanket. To this was added 1.6M n-butyllithium in hexanes (157 ml, 0.251 moles) and allowed to stir for 5 min. Then slowly added thiopene-2-carbonitrile (21.33 ml, 0.229 moles) in tetrahydrofuran (115 ml) and allowed to stir. After 45 min. was added NN-dimethylformamide (88.66 ml, 1.145 moles) at -78 C. Citric acid (40 g) was added after 2 h. followed by water (240 ml) and stirred for 18 h. The reaction was concentrated in vacuo, transferred to a separatory funnel, diluted with brine, and extracted twice with ether. The combined ether layers were washed with brine, dried over magnesium sulfate, filtered, and the solvent removed in vacuo. Chromatography yielded 15.8 g (50percent) of 2-cyano-5-formylthiophene (EX-55A) as a brown solid: 1H NMR (300 MHZ, CDCl3) d 10.02 (s, 1H), 7.79 (m, 1H), 7.30 (m, 1H).

References: [1]Patent: US5914319,1999,A .
[2]Patent: US5707966,1998,A .
[3]Patent: US5710130,1998,A .
[4]Patent: US5726159,1998,A .
[5]Patent: US6664255,2003,B1 .Location in patent: Page column 117.

15
[ 21512-16-3 ]
[ 172349-09-6 ]

Yield	Reaction Conditions	Operation in experiment
6.1 g (88%)	With sodium borohydrid; In ethanol;	B) Preparation of 2-cyano-5-(hydroxymethyl)thiophene To a solution of 2-cyano-5-formyl-thiophene (6.9 g, 50 mmol) in EtOH (100 mL) was added sodium borohydride (1.9 g, 50 mmol) in portions. After 5 min of stirring, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and brine. The layers were separated and the organic phase was washed once with 1M citric acid and once with brine, then dried (MgSO4), filtered and concentrated in vacuo to give 6.1 g (88percent) of 2-cyano-5-(hydroxymethyl)thiophene. 1 H NMR FD-MS, m/e 140 (M+) Analysis for C6 H5 NOS:Calc: C, 51.78; H, 3.62; N, 10.06;Found: C, 51.54; H, 3.62; N, 9.86.
6.1 g (88%)	With sodium borohydrid; In ethanol;	B) Preparation of 2-cyano-5-(hydroxymethyl)thiophene To a solution of 2-cyano-5-formyl-thiophene (6.9 g, 50 mmol) in EtOH (100 mL) was added sodium borohydride (1.9 g, 50 mmol) in portions. After 5 min of stirring, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and brine. The layers were separated and the organic phase was washed once with 1M citric acid and once with brine, then dried (MgSO4), filtered and concentrated in vacuo to give 6.1 g (88percent) of 2-cyano-5-(hydroxymethyl)thiophene. 1 H NMR FD-MS, m/e 140 (M+) Analysis for C6 H5 NOS: Calc: C, 51.78; H, 3.62; N, 10.06; Found: C, 51.54; H, 3.62; N, 9.86.
6.1 g (88%)	With sodium borohydrid; In ethanol;	B) Preparation of 2-cyano-5-(hydroxymethyl)thiophene To a solution of 2-cyano-5-formyl-thiophene (6.9 g, 50 mmol) in EtOH (100 mL) was added sodium borohydride (1.9 g, 50 mmol) in portions. After 5 min of stirring, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and brine. The layers were separated and the organic phase was washed once with 1M citric acid and once with brine, then dried (MgSO4), filtered and concentrated in vacuo to give 6.1 g (88percent) of 2-cyano-5-(hydroxymethyl)thiophene. 1 H NMR FD-MS, m/e 140 (M+) Analysis for C6 H5 NOS: Calc: C, 51.78; H, 3.62; N, 10.06; Found: C, 51.54; H, 3.62; N, 9.86.

6.1 g (88%)	With sodium borohydrid; In ethanol;	B) Preparation of 2-cyano-5-(hydroxymethyl)thiophene To a solution of 2-cyano-5-formyl-thiophene (6.9 g, 50 mmol) in EtOH (100 mL) was added sodium borohydride (1.9 g, 50 mmol) in portions. After 5 min of stirring, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and brine. The layers were separated and the organic phase was washed once with 1M citric acid and once with brine, then dried (MgSO4), filtered and concentrated in vacuo to give 6.1 g (88percent) of 2-cyano-5-(hydroxymethyl)thiophene. 1 H NMR FD-MS, m/e 140 (M+) Analysis for C6 H5 NOS: Calc: C, 51.78; H, 3.62; N, 10.06; Found: C, 51.54; H, 3.62; N, 9.86.
		(1) 5-Hydroxymethylthiophene-2-carbonitrile 5-Formylthiophene-2-carbonitrile obtained in Example 155-(1) (274 mg) was dissolved in tetrahydrofuran (3 mL). Sodium borohydride (151 mg) was added at room temperature and the mixture was stirred for 1.5 hours. 1 M hydrochloric acid and water were sequentially added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried over magnesium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate) to obtain the title compound (277 mg). 1H-NMR (400 MHz, CDCl3) delta (ppm): 1.20 (t, J=5.6 Hz, 1H) , 4.88 (d, J=5.6 Hz, 2H), 6.98 (d, J=3.6 Hz, 1H), 7.50 (d, J=3.6 Hz, 1H).

References: [1]Patent: US5914319,1999,A .
[2]Patent: US5707966,1998,A .
[3]Patent: US5710130,1998,A .
[4]Patent: US5726159,1998,A .
[5]Patent: EP2017275,2009,A1 .Location in patent: Page/Page column 83.

16
[ 72835-25-7 ]
[ 134135-41-4 ]
[ 21512-16-3 ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide; hexamethylenetetramine; dibenzoyl peroxide; In tetrachloromethane; chloroform; water; acetic acid;	8 g of 5-bromomethylthiophene-2-carbonitrile (prepared by brominating 5.7 g of 5-methylthiophene-2-carbonitrile and 8.42 g of N-bromosuccinimide in 68 ml of carbon tetrachloride under exposure to light and with the addition of 185 mg of benzoyl peroxide) is refluxed for 30 minutes in 35 ml of chloroform with 5.6 g of hexamethylenetetramine. The precipitated salt is suctioned off and refluxed in 30 ml of acetic acid and 30 ml of water for 2 hours. After extraction with ether, washing of the ether phase with water, drying, and evaporation, 2.43 g of 5-cyanothiophene-2-aldehyde is obtained.

References: [1]Patent: US5135937,1992,A .

17
[ 21512-16-3 ]
[ 7333-51-9 ]
[ 134135-41-4 ]
(5-cyano-thien-2-yl)methylphosphonic acid diethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; triethyl phosphite; In hexane;	The corresponding phosphorane is produced from 3 g of cyclohexyltriphenylphosphonium bromide in 80 ml of ether by dropwise addition of 4.5 ml of a 1.5-molar solution of butyllithium in hexane at room temperature. To this product is added dropwise 1 g of 5-cyanothiophene-2-aldehyde in 45 ml of ether. After 16 hours of agitation at room temperature, a precipitate is suctioned off, and the filtrate is concentrated by evaporation. The residue is recrystallized from isopropanol, thus obtaining 610 mg of the title compound (b) (1), mp 98-100°. In a second process, 20 g of 5-bromomethyl-thiophene-2-carbonitrile is heated with 200 ml of triethyl phosphite for 4 hours to 150°. Then triethyl phosphite is removed at 40°-60°/0.06 mbar, and the residue is distilled on a bulb tube at 130°-150°/0.004 mbar, resulting in 24 g of (5-cyano-2-thienyl)methylphosphonic acid diethyl ester.

References: [1]Patent: US5135937,1992,A .

18
[ 110-89-4 ]
[ 21512-16-3 ]
3-(5-Cyano-2-thiophenyl)-propenoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With malonic acid; In pyridine;	(a) 3-(5-Cyano-2-thiophenyl)-propenoic acid A stirred solution of <strong>[21512-16-3]5-cyano-2-thiophene carboxaldehyde</strong> (3.3 g) and malonic acid (2.5 g) in pyridine (35 ml) and piperidine (0.7 ml) was heated under reflux for 2 hours adding further malonic acid (1.3 g) after 1 hour. The solution was evaporated and the residue was stirred with M hydrochloric acid solution (100 ml) to give a pale solid which was washed with water and dried, m.p. ca 260° C. (subliming).
	With malonic acid; In pyridine;	a) 3-(5-Cyano-2-thiophenyl)-propenoic acid A stirred solution of <strong>[21512-16-3]5-cyano-2-thiophene carboxaldehyde</strong> (3.3 g) and malonic acid (2.5 g) in pyridine (35 ml) and piperidine (0.7 ml) was heated under reflux for 2 hours adding further malonic acid (1.3 g) after 1 hour. The solution was evaporated and the residue was stirred with M hydrochloric acid solution (100 ml) to give a pale solid which was washed with water and dried, m.p. ca 260°C (subliming).

References: [1]Patent: US4886885,1989,A .
[2]Patent: EP314464,1991,B1 .

19
[ 21512-16-3 ]
ethyl 3-amino-4-(2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethoxy)-but-2-enoate [ No CAS ]
[ 95399-93-2 ]
3-ethyl 5-methyl 4-(5-cyanothietan-2-yl) (((1,3-dihydro-1,3-2H-isoindol-2-yl)ethoxy)methyl)-6-(fluoromethyl)-6-hydroxy-1,4,5,6,-tetrahydro-3,5-pyridinedicarboxylate [ No CAS ]
3-Ethyl 5-methyl 4-(5-cyanothien-2-yl)-2-((2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethoxy)methyl)-6-(fluoromethyl)-1,4-dihydro-3,5-pyridinedicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In tert-butyl alcohol;	3-Ethyl 5-methyl 4-(5-cyanothien-2-yl)-2-((2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethoxy)methyl)-6-(fluoromethyl)-1,4-dihydro-3,5-pyridinedicarboxylate 5-Formylthiophene-2-carbonitrile (1.0g, 7.3mmoles), methyl 4-fluoro-3-oxobutanoate (0.98g, 7.3mmoles) and ethyl 3-amino-4-(2-(1,3-dihydro-1,3-dioxo-2H-isoindol 2-yl)ethoxy)-but-2-enoate (2.32g, 7.3mmoles) in dry t-butanol (10ml) were stirred at 40° for 6 days. Evaporation of the solvent and trituration of the residue with petroleum ether afforded 3-ethyl 5-methyl 4-(5-cyanothietan-2-yl) (((1,3-dihydro-1,3-2H-isoindol-2-yl)ethoxy)methyl)-6-(fluoromethyl)-6-hydroxy-1,4,5,6,-tetrahydro-3,5-pyridinedicarboxylate (1.2g) as pale buff crystals, mp 141-3°.

References: [1]Patent: EP225175,1988,A3 .

20
[ 1003-31-2 ]
[ 68-12-2 ]
[ 21512-16-3 ]

Yield	Reaction Conditions	Operation in experiment
76%		Method C5- Formylthiophene-2-carbonitrile (Intermediate compound)Under inert atmosphere BuLi (1 1 .7 ml, 29.3 mmol, 2.5 M) was added to a mixture of diisopropylamine (4.1 ml, 29.3 mmol) and THF (150 ml) at below - 70°C. When addition was finished, the mixture was allowed to reach room- temperature. The mixture was cooled back to -70°C again, where 2- thiophenecarbonitrile (3.0 g, 26.7 mmol), solved in THF (15 ml) was added drop- wise and stirred an additional hour. At -78°C. DMF (8.2 ml, 106.6 mmol) was added below -70°C. The mixture was stirred for 1 .5 h at -78°C. Citric acid (10 g) was added to the reaction-mixture. The reaction-mixture was poured out on water. The aqueous phase was extracted with diethylether. The product was dried and evaporated. The reaction mixture was purified by silica gel column chromatography using 10-50percent heptane/EtOAc as solvent. The product was isolated as a solid. Yield 2.8 g (76percent).
		5-formylthiophene-2-carbonitrile A tetrahydrofuran solution (250 mL) of lithium diisopropyl amide (1.09N hexane solution, 92.8 mL, manufactured by Kanto Chemical Co., Inc) was cooled down at -78° C., and a tetrahydrofuran solution (50 mL) of 2-cyanothiophene (8.55 mL, manufactured by Aldrich) was dropped thereto. After that, the resultant mixture was stirred for 45 minutes at the same temperature, N,N-dimethyl formamide (30 mL, manufactured by Kanto Chemical Co., Inc) was added to the mixture, and the resultant blend was stirred for 1 hour. After the stirring was ended, citric acid (20 g, manufactured by Wako Pure Chemical Industries, Ltd.) was added to the reaction solution and the resultant was poured into water. After tetrahydrofuran was distilled away, extraction was performed by using diethyl ether. An organic layer was washed with a saturated saline solution, and dried by using magnesium sulfate. After concentrating at a reduced pressure, chromatography (as an elution solution, 4:1 (v/v) of hexane/ethyl acetate was used) using Biotage 40M cartridge was performed, so that the titled compound (7.45 g) was obtained. 1H-NMR (CDCl3): 10.0 (1H, s), 7.77 (1H, d, J=3.3), 7.74 (1H, d, J-3.3)

References: [1]Patent: WO2011/73298,2011,A1 .Location in patent: Page/Page column 18.
[2]Patent: US2008/200535,2008,A1 .Location in patent: Page/Page column 169.

21
[ 21512-16-3 ]
tert-butyl 3-aminopropanoate hydrochloride [ No CAS ]
[ 1008770-07-7 ]

Yield	Reaction Conditions	Operation in experiment
		Process 2; 3-((5-cyanothiophene-2-yl)methylamino)propanoic acid t-butyl ester; To a dichloromethane solution (150 mL) of 5-formylthiophen-2-carbonitrile (2.16 g) obtained in Process 1, beta alanine-t-butyl ester hydrochloride (3.15 g, manufactured by Kokusan Kagaku Company) and sodium triacetoxyborohydride (6.7 g, manufactured by Aldrich) by using the same method as that of Reference Example 16 were added. The resultant mixture was stirred for 3 hours at room temperature. After the stirring was ended, the reaction solution was poured into a saturated sodium bicarbonate aqueous solution, and extraction was performed by using dichloromethane. An organic layer was washed with a saturated saline solution, dried by using magnesium sulfate, and further concentrated under a reduced pressure. For the residue, chromatography (as an elution solution, 4:1 (v/v) of hexane/ethyl acetate was used) using Biotage 40M cartridge was performed, so that the titled compound (2.94 g) was obtained.

References: [1]Patent: US2008/200535,2008,A1 .Location in patent: Page/Page column 169.

22
[ 21512-16-3 ]
[ 1576-35-8 ]
[ 1312367-95-5 ]

Yield	Reaction Conditions	Operation in experiment
85%	hydrogenchloride; In ethanol; water; at 20 - 80℃; for 16h;	Method BN-[(5-Cyano-2-thienyl)methyleneamino1-4-methyl-benzenesulfonamide(Intermediate compound)P-toluenesulfonhydrazide (1 .40 g, 7.29 mmol) was dissolved in ethanol (6 ml, 99percent). Aqueous hydrochloric acid (0.2 ml, 1 M) was added followed by addition of <strong>[21512-16-3]5-formylthiophene-2-carbonitrile</strong> (1 .00 g, 7.29 mmol). The reaction mixture was stirred for 1 h at 80°C, followed by stirring at room-temperature for 15 h. The reaction-mixture was evaporated. Water was added and the suspension formed was stirred for one hour. The crystalline product was filtered and washed with water. Yield 1 .88 g (85percent).

References: [1]Patent: WO2011/73298,2011,A1 .Location in patent: Page/Page column 18.

23
[ 21512-16-3 ]
5-[2-(3-pyridyl)tetrazol-5-yl]thiophene-2-carbonitrile hydrochloride [ No CAS ]

References: [1]Patent: WO2011/73298,2011,A1 .

24
[ 21512-16-3 ]
C₂₁H₂₄ClN₇O₂S*2ClH [ No CAS ]

References: [1]Patent: US6664255,2003,B1 .

25
[ 3731-52-0 ]
[ 21512-16-3 ]
[ 1437787-03-5 ]