5147-80-8|2-(Bis(methylthio)methylene)malononitrile| Ambeed

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Structure of 5147-80-8

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Quality Control of [ 5147-80-8 ] Purity: 97% SDS Specification

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Product Details of [ 5147-80-8 ]

CAS No. :	5147-80-8
Formula :	C₆H₆N₂S₂
M.W :	170.26
SMILES Code :	N#CC(C#N)=C(SC)SC
MDL No. :	MFCD00052730
InChI Key :	FICQFRCPSFCFBY-UHFFFAOYSA-N
Pubchem ID :	99229

Safety of [ 5147-80-8 ]

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H301+H311+H331-H315-H319
Precautionary Statements:	P501-P261-P270-P271-P264-P280-P337+P313-P305+P351+P338-P361+P364-P332+P313-P301+P310+P330-P302+P352+P312-P304+P340+P311-P403+P233-P405
Class:	6.1
UN#:	3439
Packing Group:	Ⅲ

Computational Chemistry of [ 5147-80-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	0
Fraction Csp3	0.33
Num. rotatable bonds	2
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	45.16
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	98.18 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.7
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	1.38
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.97
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.	0.26
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	0.96
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.25

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.63
Solubility	3.96 mg/ml ; 0.0233 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.	-3.05
Solubility	0.153 mg/ml ; 0.000902 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	-1.13
Solubility	12.6 mg/ml ; 0.0738 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	No
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.	-6.36 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.	1.0 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)	2.92

Application In Synthesis of [ 5147-80-8 ]

* 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 [ 5147-80-8 ]

[ 5147-80-8 ] Synthesis Path-Downstream 1~54

1
[ 5147-80-8 ]
[ 62-53-3 ]
[ 17823-65-3 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; for 1.5h;	2-(Bis-methylsulfanyl-methylene)-malononitrile (3.40 g, 20 mmol) and aniline (1.82 ml, 20 mmol) were refluxed in ethanol (50 ml) for 1.5 h until reaction completion (LCMS). The mixture was allowed to cool down, the precipitate formed was filtered, washed with ethanol (3 x 7 ml), and dried on air to afford 2-(methylsulfanyl-phenylamino-methylene)-malononitrile (2.97 g, 13.8 mmol) as an off-white solid.
	In ethanol; for 8h;Reflux;	General procedure: Method A (three components)Equimolar amounts (3 mmol) of bis(methylthio)methylenemalononitrile (1) and primary amine 2 namely: aniline,4-chloro-, 2-methy-, 3-methy-, 4-methy-aniline, 2-aminopropaneor b-phenylethylamine in 40 cm3 ethanol werestirred with reflux for about 8 h,
4.85 g	In methanol; at 65℃;	Add aniline (3.00 g, 32.24 mmol), 2-(bis(methylthio)methylene)malononitrile (5.48 g, 32.24 mmol) and 50 ml methanol to a 100 ml reaction flask, and react at 65C. After the reaction was monitored by TLC, most of the methanol was evaporated under reduced pressure, cooled and filtered to obtain 4.85 g of white solid.

References: [1]Chemical and Pharmaceutical Bulletin,2007,vol. 55,p. 881 - 889.
[2]Journal of the Chemical Society. Perkin transactions I,1986,p. 1187 - 1196.
[3]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 775 - 783.
[4]Arzneimittel-Forschung/Drug Research,2002,vol. 52,p. 482 - 488.
[5]Chemische Berichte,1962,vol. 95,p. 2871 - 2880.
[6]Tetrahedron Letters,1981,vol. 22,p. 2285 - 2288.
[7]Chemistry Letters,1982,p. 1933 - 1936.
[8]Journal of Medicinal Chemistry,1997,vol. 40,p. 3601 - 3616.
[9]Patent: WO2009/62118,2009,A2 .Location in patent: Page/Page column 205.
[10]Heterocycles,2009,vol. 78,p. 899 - 903.
[11]Tetrahedron Letters,2015,vol. 56,p. 521 - 524.
[12]Monatshefte fur Chemie,2017,vol. 148,p. 2129 - 2134.
[13]Patent: CN111480649,2020,A .Location in patent: Paragraph 0296.
[14]Bioorganic Chemistry,2021,vol. 116.

2
[ 75-15-0 ]
[ 77-78-1 ]
[ 109-77-3 ]
[ 5147-80-8 ]

Yield	Reaction Conditions	Operation in experiment
85%		The reaction mixture of potassium hydroxide (0.2 mol, 27.0 g) in water (8 ml), DMF 25 ml was cooled at 0C. To this mixture, malononitrile (0.1 mol, 6.60 g) was added and the resultant solution stirred at the room temperature for 2 h. Carbon disulfide (0.22 mol, 15.20 ml) was then added dropwise through dropping funnel for 0.5 h. The reaction mixture was raised and kept for 1 h at room temperature. DMS (0.2 mol, 24.4 ml) was added dropwise at 0-5C and the reaction mixture stirred for 4 h at room temperature (TLC check, n-hexane:ethyl acetate, 8:2). The reaction mass was quenched by adding crushed ice with stirring, the solid was filtered and washed with water, dried and recrystallized from ethanol to give a faint yellow solid. Yield 85%; 14 g, m.p. 80C; m.p. Lit [2,21,22] 80-81C. The structure of compound 1 was determined on the basis of spectral and analytical data and compared to literature values.[2,21,22]

References: [1]Synthetic Communications,2003,vol. 33,p. 3989 - 3995.
[2]Journal of Sulfur Chemistry,2016,vol. 37,p. 426 - 437.
[3]Chemische Berichte,1962,vol. 95,p. 2861 - 2870.
[4]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 5453 - 5458.

3
[ 75-15-0 ]
[ 109-77-3 ]
[ 74-88-4 ]
[ 5147-80-8 ]

Yield	Reaction Conditions	Operation in experiment
93.9%		At room temperature, 7.5 g (113.7 mmol) of malononitrile and 17.3 g (125.0 mmol) of potassium carbonate were added to 75 mL of DMSO, cooled to 0 C and 7.5 mL (125 mmol) of carbon disulfide was gradually added dropwise. After dripping, stir at 20 C for 2h. Cool the reaction to 0 C. 14.1 mL (227.3 mmol) of methyl iodide was gradually added dropwise, and the reaction was completed at 20 C for 12 h. After the reaction is completed, the reaction solution is poured into 75 mL of ice water, and a yellow solid is precipitated. It was washed with water and dried to obtain 18.2 g of a yellow solid with a yield of 93.9%.
		General procedure: To a solution of malononitrile (100 g, 1.51 mol) in DMF (1 L) wasadded solid potassium carbonate (209 g, 1.51 mol). The mixture wasallowed to stir at 25 C for 15 min, then carbon disulfide (115 g,1.51 mol) was added dropwise. After being allowed to stir for 15 min,tetrabutylammonium iodide (55.9 g, 151 mmol) was added to thereaction mixture. The reaction mixture was allowed to cool in an icewaterbath and ethyl iodide (354 g, 2.27 mol) was added dropwise overone hour. Upon completion of addition, the reaction mixture waswarmed to 50 C for 16 h. Following the heating interval, the reactionmixture was cooled to rt, poured into a separatory funnel, diluted withwater (1 L) and extracted with ethyl acetate (3 × 500 mL). The combinedextracts were twice washed with brine, dried over sodium sulfate,filtered and concentrated under reduced pressure. The resulting crudeproduct was purified by silica gel chromatography (hexanes to 30/70ethyl acetate/hexanes) to afford 46 (120 g, 40%)

References: [1]Gazzetta Chimica Italiana,1995,vol. 125,p. 115 - 118.
[2]Organic process research and development,2011,vol. 15,p. 556 - 564.
[3]Patent: CN110759900,2020,A .Location in patent: Paragraph 0105; 0106.
[4]Tetrahedron,2009,vol. 65,p. 10453 - 10458.
[5]Journal of Medicinal Chemistry,2003,vol. 46,p. 1229 - 1241.
[6]Journal of Chemical Research - Part S,1999,p. 492 - 493.
[7]Tetrahedron,1976,vol. 32,p. 1779 - 1787.
[8]Chemische Berichte,1990,vol. 123,p. 541 - 547.
[9]Synthetic Communications,2002,vol. 32,p. 3509 - 3517.
[10]Synthetic Communications,2005,vol. 35,p. 693 - 699.
[11]Synthetic Communications,2006,vol. 36,p. 2963 - 2973.
[12]Synthesis,2009,p. 1271 - 1278.
[13]Egyptian Journal of Chemistry,2012,vol. 55,p. 529 - 547.
[14]Patent: WO2003/101455,2003,A2 .Location in patent: Page 35-36.
[15]Bioorganic and medicinal chemistry,2020,vol. 28.

4
[ 123-75-1 ]
[ 5147-80-8 ]
[ 85106-63-4 ]

Yield	Reaction Conditions	Operation in experiment
	In pentanonitrile; at 50℃; for 1h;	General procedure: to a solution of 5 (1.0 mmol) in n-BuCN (1.0 ml), R1R2NH (1.0 equiv) was added, and then the resulting solution was stirred at 50 C for 1 h. K2CO3 (2.0 equiv) and R3-BnNH2 (1.2 equiv) were added to the solution, and the mixture was stirred for 5 h at 130 C. After cooling to room temperature, K2CO3 (2.0 equiv), NMP (1.0 ml), ethyl bromoacetate (1.5 equiv), and H2O (10 μl) were added. The resulting mixture was stirred for 4 h at 110 C. The slurry was filtered through Celite, then filtrate was concentrated, and the residue was purified by SiO2 in a column chromatgraphy (hexane/EtOAc = 8:1-3:1).

References: [1]Chemistry Letters,1982,p. 1933 - 1936.
[2]European Journal of Medicinal Chemistry,2003,vol. 38,p. 245 - 252.
[3]Tetrahedron,2009,vol. 65,p. 10453 - 10458.
[4]Tetrahedron Letters,2011,vol. 52,p. 2767 - 2770.
[5]European Journal of Medicinal Chemistry,2013,vol. 64,p. 464 - 476.
[6]Journal of Chemical Research,2015,vol. 39,p. 220 - 222.
[7]Tetrahedron Letters,2015,vol. 56,p. 7016 - 7019.

5
[ 110-89-4 ]
[ 5147-80-8 ]
[ 3012-89-3 ]

Yield	Reaction Conditions	Operation in experiment
	In pentanonitrile; at 50℃; for 1h;	General procedure: to a solution of 5 (1.0 mmol) in n-BuCN (1.0 ml), R1R2NH (1.0 equiv) was added, and then the resulting solution was stirred at 50 C for 1 h. K2CO3 (2.0 equiv) and R3-BnNH2 (1.2 equiv) were added to the solution, and the mixture was stirred for 5 h at 130 C. After cooling to room temperature, K2CO3 (2.0 equiv), NMP (1.0 ml), ethyl bromoacetate (1.5 equiv), and H2O (10 μl) were added. The resulting mixture was stirred for 4 h at 110 C. The slurry was filtered through Celite, then filtrate was concentrated, and the residue was purified by SiO2 in a column chromatgraphy (hexane/EtOAc = 8:1-3:1).

6
[ 5147-80-8 ]
[ 72760-85-1 ]

Yield	Reaction Conditions	Operation in experiment
85%	With hydrazine hydrate; In ethanol;Cooling with ice; Reflux;	[Bis(methylsulfanyl)methylene]malononitrile (10 g) was added to a solution of hydrazine monohydrate (4.5 g) in ethanol (10 ml) under ice-cooling. After stirred at room temperature for 30 minutes and refluxed at 80C for one hour, water was added dropwise to the reaction solution under ice-cooling. The precipitated solid was separated by filtration and dried to obtain 5-amino-3-(methylsulfanyl)-1H-pyrazole-4-carbonitrile (colorless solid) (7.6 g, 85%). MS(ESI):155(M+H)+,153(M-H)- 1H NMR(600MHz,DMSO-D6)δppm 2.44(s,3H),6.47(bs,2H), 12.00(bs,1H)
	With hydrazine hydrate; In methanol; at 50℃; for 5h;	General procedure: 2-(Bis(ethylthio)methylene)malononitrile (46, 120 g, 0.605 mol)was dissolved in methanol (1 L). The solution was allowed to stir at rt.To the stirred solution was added hydrazine hydrate (35.3 mL,726 mmol) dropwise over 1 h. Upon completion of addition, the reactionmixture was allowed to stir at 50 C for 4 h before cooling to rt, atwhich time the reaction was complete. Solvent was removed underreduced pressure to afford the product 47 (100 g, quant.)

References: [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 775 - 783.
[2]Patent: EP2123654,2009,A1 .Location in patent: Page/Page column 17-18.
[3]Journal of the Iranian Chemical Society,2018,vol. 15,p. 2803 - 2809.
[4]Monatshefte fur Chemie,1999,vol. 130,p. 1167 - 1173.
[5]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2006,vol. 45,p. 483 - 488.
[6]Bioorganic and medicinal chemistry,2020,vol. 28.

7
[ 134-32-7 ]
[ 5147-80-8 ]
[ 85106-73-6 ]

Yield	Reaction Conditions	Operation in experiment
3 g	With sodium hydride; In tetrahydrofuran; at 65℃;	Weigh out 1-naphthylamine (2.00 g, 13.97 mmol), 2-(bis(methylthio)methylene)malononitrile (0.84 g, 14.71 mmol), and sodium hydride (0.84 g, 21.00 mmol) Put 30 ml of tetrahydrofuran and 30 ml of tetrahydrofuran in a 50 ml single-necked flask and react under reflux at 65C. After the reaction is monitored by TLC, most of the tetrahydrofuran is evaporated under reduced pressure, cooled and filtered to obtain 3.00 g of white solid.

References: [1]Chemistry Letters,1982,p. 1933 - 1936.
[2]Patent: CN111480649,2020,A .Location in patent: Paragraph 0298.

8
[ 5147-80-8 ]
[ 3656-03-9 ]
[ 155375-45-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	In N,N-dimethyl-formamide; at 154℃; for 0.166667h;Microwave irradiation;	General procedure: A solution of compounds 1 (10 mmol) and 2-(bis(methylthio)methylene) malononitrile8 (10 mmol) dissolved in DMF (20 mL) and boiled at 154C undermicrowave 600Wfor 10 minutes. The reaction was monitored by TLC (petroleumether-EtOAc 3;1) until the reactants disappeared. The solvent was then evaporatedand the remaining residue was trituratedwithMeOHto afford compounds 10 whichwas separated by column chromatography and recrystallized from the appropriatesolvent. Yield (86%).

References: [1]Nucleosides, nucleotides and nucleic acids,2016,vol. 35,p. 459 - 478.
[2]Bulletin of the Chemical Society of Japan,1994,vol. 67,p. 738 - 741.

9
[ 5147-80-8 ]
[ 3656-04-0 ]
[ 155375-42-1 ]

Yield	Reaction Conditions	Operation in experiment
90%	In N,N-dimethyl-formamide; at 154℃; for 0.166667h;Microwave irradiation;	General procedure: A solution of compounds 1 (10 mmol) and 2-(bis(methylthio)methylene) malononitrile8 (10 mmol) dissolved in DMF (20 mL) and boiled at 154C undermicrowave 600Wfor 10 minutes. The reaction was monitored by TLC (petroleumether-EtOAc 3;1) until the reactants disappeared. The solvent was then evaporatedand the remaining residue was trituratedwithMeOHto afford compounds 10 whichwas separated by column chromatography and recrystallized from the appropriatesolvent. Yield (86%).

References: [1]Nucleosides, nucleotides and nucleic acids,2016,vol. 35,p. 459 - 478.
[2]Bulletin of the Chemical Society of Japan,1994,vol. 67,p. 738 - 741.

10
[ 5147-80-8 ]
[ 62679-03-2 ]
2,5-diamino-3-((4-bromophenyl)diazenyl)-7-(methylthio)pyrazolo[1,5-a]pyrimidine-6-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	In N,N-dimethyl-formamide; at 154℃; for 0.166667h;Microwave irradiation;	General procedure: A solution of compounds 1 (10 mmol) and 2-(bis(methylthio)methylene) malononitrile8 (10 mmol) dissolved in DMF (20 mL) and boiled at 154C undermicrowave 600Wfor 10 minutes. The reaction was monitored by TLC (petroleumether-EtOAc 3;1) until the reactants disappeared. The solvent was then evaporatedand the remaining residue was trituratedwithMeOHto afford compounds 10 whichwas separated by column chromatography and recrystallized from the appropriatesolvent. Yield (86%).

References: [1]Nucleosides, nucleotides and nucleic acids,2016,vol. 35,p. 459 - 478.
[2]Bulletin of the Chemical Society of Japan,1994,vol. 67,p. 738 - 741.

11
[ 5147-80-8 ]
[ 6975-75-3 ]
[ 155375-48-7 ]

Yield	Reaction Conditions	Operation in experiment
95%	In N,N-dimethyl-formamide; at 154℃; for 0.166667h;Microwave irradiation;	General procedure: A solution of compounds 1 (10 mmol) and 2-(bis(methylthio)methylene) malononitrile8 (10 mmol) dissolved in DMF (20 mL) and boiled at 154C undermicrowave 600Wfor 10 minutes. The reaction was monitored by TLC (petroleumether-EtOAc 3;1) until the reactants disappeared. The solvent was then evaporatedand the remaining residue was trituratedwithMeOHto afford compounds 10 whichwas separated by column chromatography and recrystallized from the appropriatesolvent. Yield (86%).

References: [1]Nucleosides, nucleotides and nucleic acids,2016,vol. 35,p. 459 - 478.
[2]Bulletin of the Chemical Society of Japan,1994,vol. 67,p. 738 - 741.

12
[ 5147-80-8 ]
[ 3656-02-8 ]
[ 155375-38-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	In N,N-dimethyl-formamide; at 154℃; for 0.166667h;Microwave irradiation;	General procedure: A solution of compounds 1 (10 mmol) and 2-(bis(methylthio)methylene) malononitrile8 (10 mmol) dissolved in DMF (20 mL) and boiled at 154C undermicrowave 600Wfor 10 minutes. The reaction was monitored by TLC (petroleumether-EtOAc 3;1) until the reactants disappeared. The solvent was then evaporatedand the remaining residue was trituratedwithMeOHto afford compounds 10 whichwas separated by column chromatography and recrystallized from the appropriatesolvent. Yield (86%).

References: [1]Nucleosides, nucleotides and nucleic acids,2016,vol. 35,p. 459 - 478.
[2]Bulletin of the Chemical Society of Japan,1994,vol. 67,p. 738 - 741.

13
[ 5147-80-8 ]
[ 2365-48-2 ]
[ 129332-45-2 ]

Yield	Reaction Conditions	Operation in experiment
99%	With triethylamine; In methanol; for 2h;Reflux;	Example 5: Synthesis of 3-(4-chlorophenyl)-4-cyano-N-methyI-5-morpholin-4- yIthiophene-2-carboxamide (69) ;<n="51"/>69[00150] Step 1: methyl 3-amino-4-cyano-5-(methylsulfanyl)thiophene-2-carboxylate[00151] ; A mixture of [bis(methylsulfanyl)methylene]malononitrile (40 g, 230 mmol), methylthioglycolate (21 mL, 230 mmol) and TEA (24 mL, 173 mmol) in MeOH (600 mL) was allowed to stir at reflux for 2 h. The reaction mixture was allowed to cool overnight and the precipitate was filtered off, washed with cold MeOH (x3) to give methyl 3-amino-4-cyano-5-(methylsulfanyl)thiophene-2- carboxylate (52.4 g, 99 %). LCMS: (AA) ES+ 229.2. 1H NMR (400 MHz, J6-DMSO) δ: 3.74s, 3H) and2.70 (s, 3H).

References: [1]Patent: WO2009/94224,2009,A1 .Location in patent: Page/Page column 49-50.
[2]Journal of Heterocyclic Chemistry,1994,vol. 31,p. 771 - 774.
[3]ACS Medicinal Chemistry Letters,2012,vol. 3,p. 789 - 792,4.
[4]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 915 - 918.

14
[ 5147-80-8 ]
[ 95-54-5 ]
[ 4933-40-8 ]

Yield	Reaction Conditions	Operation in experiment
84%		General procedure: Equimolar amounts (3 mmol) of bis(methylthio)methylenemalononitrile (1) and bidentate amine namely: 2-aminopropan-1-ol, 1-aminopropan-2-ol or o-phenylenediamine in 40 cm3 ethanol were stirred with reflux for about 8 h, then3 mmol of cyanoguanidine (3) in freshly prepared sodiumethoxide solution (4 mmol of sodium in 20 cm3 absoluteethanol) was added and the reaction mixture was refluxedfor about 5 h. After completion of reaction (monitored withTLC), the reaction mixture was cooled to RT and poured inice-cold water and neutralized to pH *7.0 with dilutedHCl. The formed precipitate was collected by filtration,washed several times with distilled water, dried, andrecrystallized from dioxane.
77.6%	In ethanol; at 70℃; for 4h;	(Step 1) <strong>[5147-80-8][Bis(methylthio)methylene]malononitrile</strong> (6.00 g, 35.2 mmol) was dissolved in ethanol (50 mL) and a solution of phenylenediamine (3.80 g, 35.6 mmol) in ethanol (20 mL) was added dropwise, followed by stirring at 70C for 4 hours. The mixture was cooled and the precipitated white solid was collected by filtration to obtain (benzimidazolidin-2-ylidene)malononitrile (4.97 g, 77.6 %). 1H NMR (DMSO-d6, δppm): 7.19 (dd, J = 3.1, 6.1 Hz, 2H), 7.30 (dd, J = 3.1, 6.1 Hz, 2H), 12.82 (br s, 2H).

References: [1]Gazzetta Chimica Italiana,1995,vol. 125,p. 115 - 118.
[2]Monatshefte fur Chemie,2017,vol. 148,p. 2129 - 2134.
[3]Patent: EP1847530,2007,A1 .Location in patent: Page/Page column 122.
[4]Il Farmaco,2001,vol. 56,p. 277 - 283.

15
[ 5147-80-8 ]
[ 111-41-1 ]
[ 149138-82-9 ]

Yield	Reaction Conditions	Operation in experiment
95.2%	In tetrahydrofuran; at 0 - 20℃; for 3h;	(Step 1) <strong>[5147-80-8][Bis(methylthio)methylene]malononitrile</strong> (10.0 g, 58.7 mmol) was dissolved in THF (67 mL) and under ice-cooling, a solution of N-(2-hydroxyethyl)ethylenediamine (6.24 g, 59.9 mmol) was dissolved in THF (15 mL). After stirring at room temperature for 3 hours, the mixture was added with diisopropylether (100 mL), followed by stirring for 2 hours under ice-cooling. The precipitated white solid was collected by filtration to obtain [1-(2-hydroxyethyl)imidazolidin-2-ylidene]malononitrile (9.96 g, 95.2%). 1H NMR (DMSO-d6, δppm): 3.39-3.64 (m, 6H), 3.72-3.82 (m,2H).

References: [1]Patent: EP1847530,2007,A1 .Location in patent: Page/Page column 89-90.
[2]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2288 - 2291.
[3]Synthetic Communications,1996,vol. 26,p. 459 - 473.

16
[ 5147-80-8 ]
[ 623-51-8 ]
[ 116170-90-2 ]

Yield	Reaction Conditions	Operation in experiment
99%	With triethylamine; In methanol; for 2h;Reflux;	00461] Step 1: Ethyl 3-amino-4-cyano-5-(methylsulfanyl)thiophene-2-carboxylate MPI09-013Pl RNWOM PCT FILING[00462] A mixture of [bis(methylsulfanyl)methylene]malononitrile (40 g, 230 mmol), ethylthioglycolate (29 g , 230 mmol) and TEA (24 mL, 173 mmol) in MeOH (600 niL) was allowed to stir at reflux for 2 h. The reaction mixture was allowed to cool overnight and the precipitate was filtered off, washed with cold MeOH (3x50 mL) to give ethyl 3-amino-4-cyano-5-(methylsulfanyl)thiophene-2- carboxylate (52.4 g, 99 %). LCMS: (FA) ES+ 275.
99%	With triethylamine; In methanol; for 2h;Reflux;	Example 2: 4-(2,4-dichlorophenyl)-2-(2-(fluoromethyl)morphoIino)-5-(4H-l£,4-triazoI- 3-yl)thiophene-3-carbonitrile (Compound 1-11); <n="46"/> [00122] Step 1: Ethyl 3-amino-4-cyano-5-(methylsulfanyl)thiophene-2-carboxylate; [00123] A mixture of [bis(methylsulfanyl)methylene]malononitrile (40 g, 230 mmol), ethylthioglycolate (29 g , 230 mmol) and TEA (24 mL, 173 mmol) in MeOH (600 mL) was allowed to stir at reflux for 2 h. The reaction mixture was allowed to cool overnight and the precipitate was filtered off, washed with cold MeOH (3x50 mL) to give ethyl 3-amino-4-cyano-5-(methyIsulfanyl)thiophene-2- carboxylate (52.4 g, 99 %). LCMS: (FA) ES+ 275.
72.6%	With triethylamine; In ethanol; at 0 - 20℃; for 12h;	At room temperature, 15.0 g (88.2 mmol) of intermediate 1a and 9.8 mL (88.2 mmol) of ethyl mercaptoacetate were added to 75 mL of ethanol, cooled to 0 C, and 12.2 mL (88.2 mmol) of triethylamine was gradually added dropwise. Reaction at 20 C for 12h. After the reaction was completed, suction filtration was performed, the filter cake was washed with a little ethanol, and dried to obtain 15.5 g of an off-white solid with a yield of 72.6%.

72.6%

With triethylamine; In ethanol; at 0 - 20℃; for 12h;

At 0 C, 2-(Bis(Methylthio)methylene)malononitrile 1 (15.0 g,88.2 mmol) was added to a solution of ethyl 2-mercaptoacetate(9.8 mL, 88.2 mmol) in EtOH (75 mL), then Et3N (12.2 mL,88.2 mmol) was added dropwise to the solution and stirred for12 h at 20 C. The reaction mixture was filtered, washed with EtOH(20 mL) and dried under reduced pressure to afford product 2 as awhite solid (15.5 g, 72.6%). 1H NMR (400 MHz, CDCl3) δ 5.79 (s, 2H).4.28 (q, J 7.2 Hz, 2H) 2.64 (s, 3H) 1.34 (t, J 7.1 Hz, 3H). HRMS (ESI)calculated for C9H11N2O2S2 [M H] m/z 243.0264, found243.0266.

References: [1]Patent: WO2010/90716,2010,A1 .Location in patent: Page/Page column 217-218.
[2]Patent: WO2009/154741,2009,A1 .Location in patent: Page/Page column 44-45.
[3]Patent: CN110759900,2020,A .Location in patent: Paragraph 0107; 0108.
[4]European Journal of Medicinal Chemistry,2020,vol. 197.
[5]Organic process research and development,2011,vol. 15,p. 556 - 564.
[6]Bioorganic and Medicinal Chemistry Letters,1997,vol. 7,p. 3101 - 3106.
[7]Chinese Chemical Letters,2012,vol. 23,p. 411 - 414.

17
[ 5147-80-8 ]
[ 100-46-9 ]
[ 152588-23-3 ]

Yield	Reaction Conditions	Operation in experiment
	In ethyl acetate;	Step 1.1 43.6 ml (400 mmol) of benzylamine are added to a suspension of 68.4 g (400 mmol) of 3,3-bis(methylsulfanyl)-2-cyano-acrylonitrile (Maybridge) in 400 ml of ethyl acetate. The clear solution is slowly heated to 70 C. (→evolution of MeSH!), stirred at that temperature for 1.5 hours, cooled to RT and concentrated by evaporation, yielding crystalline 3-benzylamino-3-methylsulfanyl-2-cyano-acrylonitrile; 1H-NMR: (CD3OD) 7.36 (m, 5H), 4.77 (s, 2H), 2.59 (s, 3H).
2.14 g	In methanol; at 65℃;	Add benzylamine (1.00 g, 9.34 mmol), 2-(bis(methylthio)methylene)malononitrile (1.59 g, 9.35 mmol) and 50 ml methanol to a 100 ml reaction flask, and react at 65C under reflux After the reaction was monitored by TLC, most of the methanol was evaporated under reduced pressure, cooled, filtered, and 2.14 g of white solid was obtained

References: [1]Heterocycles,2009,vol. 78,p. 899 - 903.
[2]Journal of Medicinal Chemistry,1997,vol. 40,p. 3601 - 3616.
[3]Patent: US6251911,2001,B1 .
[4]Tetrahedron Letters,2015,vol. 56,p. 7016 - 7019.
[5]Patent: CN111480649,2020,A .Location in patent: Paragraph 0283.
[6]Chemistry - An Asian Journal,2021,vol. 16,p. 2272 - 2275.

18
[ 5147-80-8 ]
[ 1668-54-8 ]
2-[(4-Methoxy-6-methyl-[1,3,5]triazin-2-ylamino)-methylsulfanyl-methylene]-malononitrile [ No CAS ]

References: [1]Synthetic Communications,1998,vol. 28,p. 3965 - 3971.

19
[ 5397-03-5 ]
[ 5147-80-8 ]
[ 106508-06-9 ]

Yield	Reaction Conditions	Operation in experiment
88%	In 1,4-dioxane; for 2h;Reflux;	General procedure: A mixture of bis(methylthio)methylene malononitrile 8 (0.34 g, 2 mmol) and alkyl hydrazinecarbodithioate 1a,b (2 mmol) was refluxed in dioxane for 2 hr (monitored by TLC). After cooling the formed precipitate was collected by filtration, dried and recrystallized from dioxane to afford 9a,b.
	With triethylamine; In ethanol; at 20℃;	The solid MAMPC sample was prepared by the reaction of a ketene with a hydrazine derivative. A mixture of 0.01 mol2-bis(methylthio)methylene malononitrile, (SCH3)2C=C(CN)2 and 0.012 mol of either methyl hydrazinecarbodithioate or benzyl hydrazinecarbodithioate in 30 mL absolute ethanol was stirred at room temperature in the presence of a few drops of triethylamine until the thiol evolution ceased. A white brown powder was collected and re-crystallized several times from ethanol [32]. The purity of MAMPC (m.p. 215 +/- 1 C) was confirmed by thin layer chromatography (TLC) and mass spectral measurements.

References: [1]Synthetic Communications,2021,vol. 51,p. 570 - 584.
[2]Phosphorus, Sulfur and Silicon and the Related Elements,2001,vol. 175,p. 109 - 127.
[3]Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy,2011,vol. 79,p. 1722 - 1730.

20
[ 13331-31-2 ]
[ 5147-80-8 ]
benzyl 5-amino-4-cyano-3-(methylthio)-1H-pyrazole-1-carbodithioate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	In 1,4-dioxane; for 2h;Reflux;	General procedure: A mixture of bis(methylthio)methylene malononitrile 8 (0.34 g, 2 mmol) and alkyl hydrazinecarbodithioate 1a,b (2 mmol) was refluxed in dioxane for 2 hr (monitored by TLC). After cooling the formed precipitate was collected by filtration, dried and recrystallized from dioxane to afford 9a,b.

References: [1]Synthetic Communications,2021,vol. 51,p. 570 - 584.
[2]Phosphorus, Sulfur and Silicon and the Related Elements,2001,vol. 175,p. 109 - 127.

21
[ 538-28-3 ]
[ 5147-80-8 ]
4-amino-2-benzylthio-5-cyano-6-methylthiopyrimidine [ No CAS ]

References: [1]Synthetic Communications,2003,vol. 33,p. 3989 - 3995.

22
[ 27578-60-5 ]
[ 5147-80-8 ]
[(2-piperidinoethylamino)(3-piperidinopropylamino)methylene]malononitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%		Example 1 [(2-Piperidinoethylamino)(3-piperidinopropylamino) methylene]malononitrile (Compound 1) <strong>[5147-80-8][Bis(methylthio)methylene]malononitrile</strong> (300 mg, 1.76 mmol) was dissolved in THF (4 mL), and a solution obtained by dissolving 3-piperidinopropylamine (251 mg, 1.76 mmol) in THF (1 mL) was added thereto. After stirring the mixture at room temperature for 1.5 hours, a solution obtained by dissolving 1-(2-aminoethyl) piperidine (226 mg, 1.76 mmol) in THF (1 mL) was added thereto, followed by stirring at room temperature for 1.5 hours, and further stirring at 30C for 5 hours. After cooling, the resulting mixture was added with water, and the pH of the mixture was adjusted to 4 with 2 mol/L hydrochloric acid. Then, the pH of the mixture was adjusted to 9 with a saturated aqueous sodium hydrogen carbonate solution, and the precipitated solid was obtained by filtration. The obtained solid was washed with water, triturated with diisopropyl ether and recrystallized from n-hexane/ethyl acetate, to obtain the titled compound (273 mg, 45%) as a white solid.

References: [1]Patent: EP1847530,2007,A1 .Location in patent: Page/Page column 87.

23
[ 3529-08-6 ]
[ 5147-80-8 ]
[Bis(3-piperidinopropylamino)methylene]malononitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42.0%		Example 2 [Bis(3-piperidinopropylamino)methylene]malononitrile (Compound 2) <strong>[5147-80-8][Bis(methylthio)methylene]malononitrile</strong> (300 mg, 1.76 mmol) was dissolved in THF (4 mL) and a solution of 3-piperidinopropylamine (251 mg, 1.76 mmol) in THF (1 mL) was added thereto. After stirring the mixture at room temperature for 2 hours, the mixture was added with a solution of 3-piperidinopropylamine (251 mg, 1.76 mmol) in THF (1 mL) and stirred at room temperature for 16 hours. Then, a solution of 3-piperidinopropylamine (75.2 mg, 0.529 mmol) in THF (0.5mL) was added thereto, followed by stirring at room temperature for 1.5 hours, and further stirring at 30C for 5 hours. After cooling, the mixture was added with water and the pH of the mixture was adjusted to 5 with 2 mol/L hydrochloric acid. Then, the pH of the mixture was adjusted to 9 with saturated aqueous sodium hydrogencarbonate solution and the precipitated solid was collected by filtration. The obtained solid was washed with water and triturated with diisopropylether, followed by recrystallizing from n-hexane/ethyl acetate to obtain the titled compound (266 mg, 42.0%) as a white solid. 1H NMR (CDCl3, δppm): 1.44-1.50 (m, 4H), 1.57-1.64 (m, 8H), 1.71-1.80 (m, 4H), 2.39-2.45 (m, 12H), 3.43 (dd, J = 5.7, 11.0 Hz, 4H), 7.41 (brs, 2H). Melting point: 110-112C.

References: [1]Patent: EP1847530,2007,A1 .Location in patent: Page/Page column 88.

24
[ 5147-80-8 ]
[ 107-15-3 ]
[ 5624-24-8 ]

Yield	Reaction Conditions	Operation in experiment
85.5%	In tetrahydrofuran; at 20℃; for 1.5h;	Example 4 {1,3-Bis[2-(1-methylpyrrolidin-2-yl)ethyl] imidazolidin-2-ylidene}malononitrile (Compound 4) (Step 1) <strong>[5147-80-8][Bis(methylthio)methylene]malononitrile</strong> (3.00 g, 17.6 mmol) was dissolved in THF (20 mL) and the solution was added with ethylenediamine (1.20 mL, 18.0 mmol), followed by stirring at room temperature for 1.5 hours. Then, the mixture was added with diisopropylether (35 mL), stirred under ice-cooilng for 2.5 hours and the precipitated white solid was collected by filtration to obtain (imidazolidin-2-ylidene)malononitrile (2.02 g, 85.5%). 1H NMR (DMSO-d6, δppm): 3.55 (s, 4H), 8.16 (br s, 2H).

References: [1]Patent: EP1847530,2007,A1 .Location in patent: Page/Page column 88.
[2]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2288 - 2291.
[3]Bulletin of the Korean Chemical Society,2010,vol. 31,p. 859 - 862.

25
[ 40226-15-1 ]
[ 5147-80-8 ]
[ 904676-82-0 ]

Yield	Reaction Conditions	Operation in experiment
73%	In tetrahydrofuran; at 20℃; for 2h;	(Step 3) <strong>[5147-80-8][Bis(methylthio)methylene]malononitrile</strong> (4.02 g, 23.6 mmol) was dissolved in THF (25 mL) and the solution was added with a solution of 3-(3-aminopropylamino)-1-propanol (3.18 g, 24.1 mmol) obtained in the Step 2 in THF (7 mL). After stirring at room temperature for 2 hours, the mixture was added with diisopropylether (64 mL) and ice-cooled. The precipitated solid was collected by filtration to obtain [1-(3-hydroxypropyl) hexahydropyrimidin-2-ylidene]malononitrile (3.54 g, 73 %). 1H NMR (CD3OD, δppm): 1.91-2.00 (m, 4H), 3.24-3.41 (m, 4H), 3.60-3.66 (m, 4H).

References: [1]Patent: EP1847530,2007,A1 .Location in patent: Page/Page column 121.

26
[ 5147-80-8 ]
[ 141-43-5 ]
[ 904676-97-7 ]

Yield	Reaction Conditions	Operation in experiment
57.7%		(Step 1) <strong>[5147-80-8][Bis(methylthio)methylene]malononitrile</strong> (3.00 g, 17.6 mmol) was dissolved in THF (30 mL) and the solution was added with 4-amino-1-benzylpiperidine (3.59 mL, 17.6 mmol), followed by stirring at room temperature for 19 hours. Next, the mixture was added with 2-aminoethanol (1.06 mL, 17.6 mmol) and heated under reflux for 5 hours. The mixture was further added with 2-aminoethanol (0.30 mL, 5.0 mmol), heated under reflux for 3 hours and further added with 2-aminoethanol (0.40 mL, 6.6 mmol), followed by heating under reflux for 2 hours. After cooling the mixure to room temperathre, the solvent was evaporated under reduced' pressure. The obtained brown solid was washed with ethyl acetate/diisopropylether (1:1) to obtain [(1-benzylpiperidin-4-ylamino)(2-hydroxyethylamino) methylene]malononitrile (3.18 g, 57.7 %) as a brown solid. 1H NMR (CD3OD, δppm): 1.52-1.68 (m, 2H), 1.92-2.04 (m, 2H), 2.10-2.22 (m, 2H), 2.82-2.93 (m, 2H), 3.31 (t, J = 4.5 Hz, 2H), 3.52 (s, 2H), 3.62-3.80 (m, 3H), 7.20-7.35 (m, 5H).

References: [1]Patent: EP1847530,2007,A1 .Location in patent: Page/Page column 124.

27
[ 27578-60-5 ]
[ 5147-80-8 ]
[(2-piperidinoethylamino)(4-piperidinopiperidino)methylene]malononitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%		Example 143 [(2-Piperidinoethylamino)(4-piperidinopiperidino) methylene]malononitrile (Compound 143) <strong>[5147-80-8][Bis(methylthio)methylene]malononitrile</strong> (242 mg, 1.42 mmol) was dissolved in ethanol (2 mL) and the solution was added with a solution of 4-piperidinopiperidine (251 mg, 1.49 mmol) in ethanol (3 mL), followed by stirring at room temperature for 0.5 hour. The mixture was added with 1-(2-aminoethyl)piperidine (0.319 mL, 2.24 mmol) and stirred at 70C for 6 hours. Further, the mixture was added with 1-(2-aminoethyl) piperidine (0.213 mL, 1.49 mmol) and stirred at 70C for 2 hours. After cooling, the reaction mixture was added with saturated brine and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-hexane/ethyl acetate (1:1)) to obtain the titled compound (465 mg, 88%) as a yellow oily substance. 1H NMR (CDCl3, δppm): 1.38-1.69 (m, 13H), 1.94 (d, J=11.2Hz, 2H), 2.34-2.57 (m, 12H), 3.08 (t, J = 12.9 Hz, 2H), 3.31-3.38 (m, 2H), 3.88 (d, J = 12.9 Hz, 2H), 5.97 (br s, 1H). APCIMS m/z: [M+H]+371. Melting point: 198-200C.

References: [1]Patent: EP1847530,2007,A1 .Location in patent: Page/Page column 134.

28
4-(N-methyl-N-phenylamino)piperidine dihydrochloride [ No CAS ]
[ 5147-80-8 ]
[ 904677-47-0 ]

Yield	Reaction Conditions	Operation in experiment
97%	With sodium hydroxide; In tetrahydrofuran; water; at 20℃; for 0.25h;	(Step 1) <strong>[5147-80-8][Bis(methylthio)methylene]malononitrile</strong> (177 mg, 1.04 mmol) was dissolved in THF (3 mL) and the solution was added with a solution of 4-(N-methyl-N-phenylamino)piperidine dihydrochloride (300 mg, 1.14 mmol) obtained in Reference Example 1 in a mixed solvent of THF (2 mL) and 2 mol/L aqueous sodium hydroxide solution (1.71 mL, 3.42 mmol) under ice bath, followed by stirring at room temperature for 0.25 hour. The reaction mixture was added with saturated brine and extracted with ethyl acetate. After washing with saturated brine, the organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography (n-hexane/ethyl acetate (2:1)) to obtain [4-(N-methyl-N-phenylamino)piperidino](methylthio) methylene}malononitrile (315 mg, 97 %) as a red crystal. 1H NMR (CDCI3, δppm): 1.75-2.02 (m, 4H), 2.60 (s, 3H), 2.77 (s, 3H), 3.38 (td, J = 2.8, 13.0 Hz, 2H), 3.89 (m, 1H), 4.38 (dt, J =2.0Hz, 13.0 Hz, 2H), 6.75-6.87 (m, 3H), 7.21-7.30 (m, 2H).

References: [1]Patent: EP1847530,2007,A1 .Location in patent: Page/Page column 134-135.

29
4-piperidinomethylpiperidine dihydrochloride [ No CAS ]
[ 5147-80-8 ]
[ 904677-50-5 ]

Yield	Reaction Conditions	Operation in experiment
64%	With sodium hydroxide; In tetrahydrofuran; water; at 0 - 20℃; for 0.25h;	(Step 1) <strong>[5147-80-8][Bis(methylthio)methylene]malononitrile</strong> (266 mg, 1.33 mmol) was dissolved in THF (4 mL) and the solution was added with a solution of 4-piperidinomethylpiperidine dihydrochloride (416 mg, 1.63 mmol) obtained in Reference Example 2 in a mixed solvent of THF (4 mL) and 2 mol/L aqueous sodium hydroxide solution (2.10 mL, 4.20 mmol) under ice bath, followed by stirring at room temperature for 0.25 hour. The reaction mixture was added with saturated brine and extracted with ethyl acetate. After washing with saturated brine, the organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-hexane/ethyl acetate (1:1)) to obtain [(methylthio)(4-piperidinomethylpiperidino)methylene]malononitrile (268 mg, 64 %) as a yellow oily substance. 1H NMR (CDCl3, δppm): 1.20-1.36 (m, 2H), 1.36-1.48 (m, 2H); 1.48-1.64 (m, 4H), 1.79-1.91 (m, 1H), 1.91-2.03 (m, 2H), 2.16 (d, J =7.6Hz, 2H), 2.26-2.40 (m, 4H), 2.57 (s, 3H), 3.30 (td, J = 2.4, 12.9 Hz, 2H), 4.26 (d,J = 12.9 Hz, 2H).

References: [1]Patent: EP1847530,2007,A1 .Location in patent: Page/Page column 135.

30
4-(2-methylpyrrolidin-1-ylmethyl)piperidine dihydrochloride [ No CAS ]
[ 5147-80-8 ]
[ 904677-53-8 ]

Yield	Reaction Conditions	Operation in experiment
98%	With sodium hydroxide; In tetrahydrofuran; water; at 0 - 20℃; for 0.25h;	(Step 1) <strong>[5147-80-8][Bis(methylthio)methylene]malononitrile</strong> (582 mg, 3.42 mmol) was dissolved in THF (6 mL) and the solution was added with a solution of 4-(2-methylpyrrolidin-1-ylmethyl)piperidine dihydrochloride (873 mg, 3.42 mmol) obtained in Reference Example 3 in a mixed solvent of THF (4 mL) and 2 mol/L aqueous sodium hydroxide solution (5.20 mL, 10.4 mmol) under ice bath, followed by stirring at room temperature for 0.25 hour. The reaction mixture was added with saturated brine and extracted with ethyl acetate. After washing with saturated brine, the obtained organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-hexane/ethyl acetate (1:1)) and [4-(2-methylpyrrolidin-1-ylmethyl)piperidino] (methylthio) methylene}malononitrile (1.02 g, 98 %) was obtained as a yellow oily substance. 1H NMR (CDCl3, δppm): 1.03 (d, J = 5.9 Hz, 3H), 1.17-1.45 (m, 3H), 1.63-1.97 (m, 5H), 2.00-2.20 (m, 3H), 2.20-2.33 (m, 1H), 2.48-2.57 (m, 1H), 2.58 (s, 3H), 3.05-3.12 (m, 1H), 3.24-3.38 (m, 2H), 4.22-4.31 (m, 2H).

References: [1]Patent: EP1847530,2007,A1 .Location in patent: Page/Page column 136.

31
[ 4897-50-1 ]
[ 5147-80-8 ]
[ 904677-87-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	In tetrahydrofuran; at 0 - 20℃; for 0.25h;	(Step 1) <strong>[5147-80-8][Bis(methylthio)methylene]malononitrile</strong> (1.94 g, 11.3 mmol) was dissolved in THF (10 mL) and the solution was added with a solution of 4-piperidinopiperidine (2.30 g, 13.7 mmol) in THF (10 mL) under ice bath. After stirring at room temperature for 0.25 hour, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol (9:1)) to obtain [(methylthio)(4-piperidinopiperidino)methylene]malononitrile (3.31 g, 100 %) as a yellow crystal. 1H NMR (CDCl3, δppm): 1.39-1.50 (m, 2H), 1.52-1.74 (m, 6H), 1.94-2.05 (m, 2H), 2.44-2.56 (m, 5H), 2.58 (s, 3H), 3.32 (td, J =2.6, 12.7 Hz, 2H), 4.29 (d, J = 12.7 Hz, 2H).

References: [1]Patent: EP1847530,2007,A1 .Location in patent: Page/Page column 143.

32
[ 5147-80-8 ]
[ 141-43-5 ]
[ 904678-56-4 ]

Yield	Reaction Conditions	Operation in experiment
84.8%		(Step 1) <strong>[5147-80-8][Bis(methylthio)methylene]malononitrile</strong> (5.74 g, 33.7 mmol) was dissolved in THF (60 mL) and the solution was added with 4-aminopiperidine-1-carboxylic acid tert-butylester (6.75 g, 33.7 mmol) dissolved in THF (12 mL), followed by stirring at room temperature for 1.5 hours. Next, 2-aminoethanol (2.10 mL, 35.4 mmol) was added to the mixture and refluxed for 5 hours. The mixture was further added with 2-aminoethanol (0.30 mL, 5.0 mmol), refluxed for 24 hours and further added with 2-aminoethanol (0.40 mL, 6.6 mmol) and refluxed for 7 hours. After the mixture was cooled to room temperature, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform to chloroform/methanol (10:1)) to obtain ([1-(1-tert-butyloxycarbonyl)piperidin-4-ylamino]-3-(2-hydroxyethylamino)methylene}malononitrile (9.59 g, 84.8 %) as a white solid. 1H NMR (CDCl3, δppm): 1.35-1.45 (m, 2H), 1.46 (s, 9H), 1.99-2.08 (m, 2H), 2.92-3.00 (m, 3H), 3.40 (td, J = 5.4, 4.4 Hz, 2H), 3.78-3.85 (m, 2H), 3.93-4.08 (m, 3H), 5.67-5.76 (m, 1H), 7.05-7.11 (m, 1H).

References: [1]Patent: EP1847530,2007,A1 .Location in patent: Page/Page column 161.

33
[ 5147-80-8 ]
[ 156-87-6 ]
[ 904678-69-9 ]

Yield	Reaction Conditions	Operation in experiment
99.5%		(Step 1) <strong>[5147-80-8][Bis(methylthio)methylene]malononitrile</strong> (2.01 g, 11.8 8 mmol) was dissolved in THF (60 mL) and the solution was added with 4-amino-1-benzylpiperidine (2.41ml,11.8 mmol) dissolved in THF (2 mL), followed by stirring at room temperature for 2.5 hours. Then the mixture was added with 3-aminopropanol (0.96 mL, 12.4 mmol) and stirred at 60C for 8 hours. Further, the mixture was added with 3-aminopropanol (0.45 mL, 5.9 mmol) and stirred at 60C for 8 hours. After the mixture was cooled to room temperature, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol (100:1)) to obtain [1-(1-benzylpiperidin-4-ylamino)-2-(3-hydroxypropylamino) methylene]malononitrile (3.98 g, 99.5 %). 1H NMR (CDCl3, δppm): 1.50-1.65 (m, 2H), 1.72-1.87 (m, 2H), 1.96-2.02 (m, 2H), 2.10-2.17 (m, 2H), 2.81-2.86 (m, 2H), 3.46-3.53 (m, 4H), 3.62-3.74 (m, 1H), 3.83 (t, J = 5.5 Hz, 2H), 5.69 (brd, J = 11.1 Hz, 1H), 5.98 (s, 1H), 7.27-7.35 (m, 5H).

References: [1]Patent: EP1847530,2007,A1 .Location in patent: Page/Page column 165.

34
[ 102877-78-1 ]
[ 5147-80-8 ]
C₁₆H₁₂N₄OS [ No CAS ]

References: [1]Patent: WO2005/54246,2005,A2 .Location in patent: Page/Page column 88.

35
[ 56344-32-2 ]
[ 5147-80-8 ]
[ 471929-88-1 ]

Yield	Reaction Conditions	Operation in experiment
82.4%	In tetrahydrofuran; at 20℃; for 2h;	(Step 1) <strong>[5147-80-8][Bis(methylthio)methylene]malononitrile</strong> (10.2 g, 59.9 mmol) was dissolved in THF (68 mL) and under ice-cooling, a solution of N-(3-hydroxypropyl)ethylenediamine (7.24 g, 61.3 mmol) in THF (10 mL) was added thereto. After stirring at room temperature for 2 hours, the mixture was added with ethyl acetate/diisopropylether (1:1) (70 mL) and under ice-cooling, the mixture was stirred for 1 hour. The precipitated white solid was collected by filtration to obtain [1-(3-hydroxypropyl) imidazolidin-2-ylidene]malononitrile (9.48 g, 82.4%). 1H NMR (DMSO-d6, δppm): 1.65-1.79 (m, 2H), 3.38-3.55 (m,6H), 3.63-3.75 (m, 2H), 4.54 (t, J = 4.6 Hz, 1H), 7. 87 (br s, 1H).
15.0 g (87%)	In dichloromethane; di-isopropyl ether;	Step 1 1-(3-Hydroxypropyl)-2-imidazolidinylidenepropanedinitrile (Compound (VIa)): In 10 ml of methylene chloride was dissolved 10.4 g of N-(2-aminoethyl)propanolamine, and the solution was added to 15.0 g of [bis(methylthio)methylene]propanedinitrile. The mixture was allowed to stand at room temperature for 1 hour under reduced pressure. Diisopropyl ether was added to the mixture, and the solid was collected by filtration. The crystals were purified by silica gel column chromatography (chloroform:methanol=5:1) to give 15.0 g (87%) of Compound (VIa) as pale yellow crystals.

References: [1]Patent: EP1847530,2007,A1 .Location in patent: Page/Page column 90.
[2]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2288 - 2291.
[3]Chemical and Pharmaceutical Bulletin,2009,vol. 57,p. 288 - 293.
[4]Patent: US6469002,2002,B1 .

36
[ 5147-80-8 ]
[ 59334-11-1 ]

Yield	Reaction Conditions	Operation in experiment
91%	With phenylhydrazine; In ethanol;	(1) Synthesis of 5-amino-3-methylthio-1-phenylpyrazole-4-carbonitrile: A mixture comprised of 17.0 g (100 mmol) of bis(methylthio)methylenepropanedinitrile, 10.8g (100mmol) of phenylhydrazine and 80 ml of ethanol was heated under reflux for 2 hours. The solvent was removed through distillation, and 20 ml of ethanol was added to the residue, which was thus crystallized. The resulting crystals were taken out by means of filtration under suction to give 20.9 g (9.1 mmol) of the entitled product as colorless, needle-like crystals having a melting point of from 136 to 137C. The yield was 91 %.

References: [1]Patent: EP745684,1996,A1 .

37
[ 5147-80-8 ]
[ 116170-90-2 ]

Yield	Reaction Conditions	Operation in experiment
95%	With triethylamine;	Ethyl 3-amino-4-cyano-5-methylsulfanylthiophene-2-carboxylate Ethyl 3-amino-4-cyano-5-methylsulfanylthiophene-2-carboxylate may be prepared by adaptation of the method described in Synthesis 2003, 735, starting with 89.5 g of 2-[bis(methylsulfanyl)methylene]malononitrile and replacing the potassium carbonate with triethylamine. 120.5 g (95%) of crude ethyl 3-amino-4-cyano-5-methylsulfanylthiophene-2-carboxylate are obtained after drying, in the form of a pink powder melting at 149 C.

References: [1]Patent: US2008/146542,2008,A1 .Location in patent: Page/Page column 18.
[2]Journal of Sulfur Chemistry,2016,vol. 37,p. 426 - 437.
[3]Tetrahedron,2016,vol. 72,p. 1342 - 1350.

38
[ 4244-84-2 ]
[ 5147-80-8 ]
[ 141-43-5 ]
[(2-ethoxycarbonylethylamino)(2-hydroxyethylamino)methylidene]propanedinittile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%		A mixture of β-alanine ethyl ester hydrochloride (30 g), triethylamine (38 mL), [bis(methylthio)methylidene]propanedinitrile (32 g) and ethanol (310 mL) was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and 2-aminoethanol (20 mL) was added thereto, followed by stirring at 70 C. for 2 hours. After cooling, the reaction mixture was purified by silica gel column chromatography (chloroform:methanol=30:1 to 20:1) to give Compound Aa (28 g, 60%) as a pale yellow oily substance. [0449] 1H NMR (270 MHz, CDCl3) δ7.00-6.78 (1H, m), 6.30-6.12 (1H, m), 4.19 (2H, q), 3.91-3.60 (4H, m), 3.57-3.30 (2H, m), 2.80-2.55 (3H, m), 1.29 (3H, t).

References: [1]Patent: US2003/225288,2003,A1 .Location in patent: Page 23.

39
[ 7357-70-2 ]
[ 5147-80-8 ]
2-amino-6-mercapto-4-(methylthio)pyridine-3,5-dicarbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With triethylamine; In N,N-dimethyl-formamide; at 20℃;	10 g (58.74 mmol) of [bis(methylthio)methylene]malononitrile and 6.5 g (64.61 mmol) of cyanothioacetamide are initially charged in 20 ml of DMF, and 16.4 ml (117.5 mmol) of triethylamine are added dropwise at room temperature. The mixture is stirred at room temperature for 8 h and allowed to stand for a further two days. The mixture is then added to 250 ml of 3 N hydrochloric acid. The resulting precipitate is filtered off with suction, washed with water and acetone and dried. This gives a yellow powder.Yield: 12.9 g (99% of theory)1H-NMR (400 MHz, CDCl3): δ=3.98 (s, 1H), 2.72 (s, 3H).LC-MS (Method 3): Rt=1.43 min; MS (ESIpos): m/z=222 [M+H]+.
93%	With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 18h;	2-(Bis(methylthio)methylene)malononitrile (10 g, 58.7 mmol) and cyanothioacetamide (7.06 g, 70.5 mmol) were added to a round-bottom flask and dissolved in N,N-dimethylformamide (21 mL). Triethylamine (16.37 mL, 117 mmol) was added dropwise at room temperature and the mixture was stirred for 18 hours. The reaction mixture was added to 300 mL of 3 N hydrochloric acid. The resulting precipitate was filtered off, washed with water and dried with suction to afford 2-amino-6-mercapto-4-(methylthio)pyridine-3,5-dicarbonitrile (13.5 g, 54.7 mmol, 93% yield). LCMS m/z = 222.9 [M+H]+.
89%	With triethylamine; In N,N-dimethyl-formamide; at 20℃;	10 g (58.74 mmol) of 2-(di(methylthio))methylidenemalononitrile and 7.1 g (70.48 mmol) of cyanothioacetamide were initially charged in 21 ml of DMF, and 16.4 ml (117.47 mmol) of triethylamine were added dropwise at room temperature. The mixture was stirred at room temperature for 8 h. The reaction mixture was added to 300 ml of 3N hydrochloric acid. The resulting precipitate was filtered off with suction, washed with water and dried. This gave the product as a powder.Yield: 12.2 g (89% of theory, 96% pure)1H-NMR (400 MHz, CDCl3): δ=3.98 (s, 1H), 2.72 (s, 3H).LC-MS (Method 7): Rt=1.56 min; MS (ESIpos): m/z=223 [M+H]+.

References: [1]Patent: US2010/69363,2010,A1 .Location in patent: Page/Page column 7; 14.
[2]Patent: WO2017/216726,2017,A1 .Location in patent: Page/Page column 641; 777.
[3]Patent: US2011/3845,2011,A1 .Location in patent: Page/Page column 35-36.

40
sodium selenide [ No CAS ]
[ 5147-80-8 ]
[ 105-39-5 ]
[ 1380809-92-6 ]

Yield	Reaction Conditions	Operation in experiment
21%		Example 32Synthesis of ethyl 4-["(3-chloro-4-fluorophenyl)amino1-5-methylthioselenophenof3,4- dlpyrimidine-7-carboxylate (compd. No. 32)Step a: Ethyl 3-amino-4-cvano-5-methylthioselenophene-2-carboxylate: To a suspension of sodium selenide (4.6 g, 37.5 mmol) in DMF (37 mL) was added a solution of 2- [bis(methylsulfanyl)methylene]malononitrile (6.37 g, 37.5 mmol; Baraldi, P. G.; Fruttarolo, F.; Tabrizi, M. A.; Preti, D.; Romagnoli, R.; El-Kashef, H.; Moorman, A.; Varani, K.; Gessi, S.; Merighi, S.; Borea, P. A. J. Med. Chem., 2003, 46, 1229-1241 ; Thomae, D.; Perspicace, E.; Henryon, D.; Xu, Z.; Schneider, S.; Hesse, S.; Kirsch, G.; Seek, P. Tetrahedron, 2009, 65, 10453-10458) in DMF ( 8 mL) at rt for 5 min and stirred the mixture at 70-80C for 2 h. Then ethyl chloroacetate (6.38 mL, 75 mmol) was added dropwise to the reaction mixture and again stirred at 70-80C for 2 h. Then, a suspension of sodium methoxide (2.0 g, 37.5 mmol) in methanol (37 mL) was added and stirring was continued for 1.5 h at the same temperature. The mixture was allowed to rt and poured into cold water and stirred for 15 min. The solution was extracted with chloroform (3 χ 100 mL). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-ethyl acetate (90: 10) as eluents to give the product as a brown color solid (2.2 g, 21 %), mp 128-130C. NMR (400 MHz, CDC13): δ 5.86 (2H, br s), 4.27 (2H, q, J=7.06 Hz), 2.67 (3H, s), 1.32 (3H, t, J=7.0 Hz); LC-MS (positive ion mode): m/z 289, 291 (M+H)+.

References: [1]Patent: WO2012/77135,2012,A2 .Location in patent: Page/Page column 53; 101.

41
[ 320578-21-0 ]
[ 5147-80-8 ]
[ 1439402-94-4 ]

Yield	Reaction Conditions	Operation in experiment
71%	With acetic acid; In ethanol; for 24h;Reflux;	General procedure: Compound 1 or 2 (0.02 mol) was refluxed with -cyanohydrazines 3 (0.02 mol) and a few drops of acetic acidas catalytic amount in absolute ethanol (30 mL). The procedureis general, except the reaction time, which was 24 hoursfor pyrazolopyrimidines 4 and 48 hours for triazolopyrimidines5. Finally, the solvent was concentrated and the separatedsolid product was filtered, dried and recrystallized frommethanol.

References: [1]Letters in Organic Chemistry,2013,vol. 10,p. 118 - 120.

42
[ 320578-36-7 ]
[ 5147-80-8 ]
[ 1439402-95-5 ]

Yield	Reaction Conditions	Operation in experiment
72%	With acetic acid; In ethanol; for 24h;Reflux;	General procedure: Compound 1 or 2 (0.02 mol) was refluxed with -cyanohydrazines 3 (0.02 mol) and a few drops of acetic acidas catalytic amount in absolute ethanol (30 mL). The procedureis general, except the reaction time, which was 24 hoursfor pyrazolopyrimidines 4 and 48 hours for triazolopyrimidines5. Finally, the solvent was concentrated and the separatedsolid product was filtered, dried and recrystallized frommethanol.

References: [1]Letters in Organic Chemistry,2013,vol. 10,p. 118 - 120.

43
[ 320578-35-6 ]
[ 5147-80-8 ]
[ 1439402-96-6 ]

Yield	Reaction Conditions	Operation in experiment
74%	With acetic acid; In ethanol; for 24h;Reflux;	General procedure: Compound 1 or 2 (0.02 mol) was refluxed with -cyanohydrazines 3 (0.02 mol) and a few drops of acetic acidas catalytic amount in absolute ethanol (30 mL). The procedureis general, except the reaction time, which was 24 hoursfor pyrazolopyrimidines 4 and 48 hours for triazolopyrimidines5. Finally, the solvent was concentrated and the separatedsolid product was filtered, dried and recrystallized frommethanol.

References: [1]Letters in Organic Chemistry,2013,vol. 10,p. 118 - 120.

44
[ 320718-41-0 ]
[ 5147-80-8 ]
[ 1439402-97-7 ]

Yield	Reaction Conditions	Operation in experiment
72%	With acetic acid; In ethanol; for 24h;Reflux;	General procedure: Compound 1 or 2 (0.02 mol) was refluxed with -cyanohydrazines 3 (0.02 mol) and a few drops of acetic acidas catalytic amount in absolute ethanol (30 mL). The procedureis general, except the reaction time, which was 24 hoursfor pyrazolopyrimidines 4 and 48 hours for triazolopyrimidines5. Finally, the solvent was concentrated and the separatedsolid product was filtered, dried and recrystallized frommethanol.

References: [1]Letters in Organic Chemistry,2013,vol. 10,p. 118 - 120.

45
[ 5147-80-8 ]
[ 650628-55-0 ]
5-amino-3-methylsulfanyl-1-(1-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1H-pyrazole-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	In ethanol; for 3h;Heating;	General procedure: To a solution of compound 3 (1.20 g, 0.005 mol) in ethanol (30 mL), ethoxymethylenemalononitrile, or bis(methylthio)methylenemalononitrile (0.005 mol), was added, respectively. The reaction mixture was heated for 2-3 h. The formed precipitate was filtered off and recrystallized from an appropriate solvent to give compounds 4 and 5, respectively.

References: [1]Molecules,2014,vol. 19,p. 5459 - 5469.

46
[ 50-01-1 ]
[ 5147-80-8 ]
2,6-dihydro-2,6-diimino-4,8-bis(methylthio)-1H-pyrimido[1,2-a]pyrimidine-3,7-dicarbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With potassium carbonate; In N,N-dimethyl-formamide; for 12h;Reflux;	General procedure: A mixture of guanidine hydrochloride (1) (0.01 mol) and bis(methylthio)methylenemalononitrile (2) (0.02 mol) in 20 ml of N,N-dimethylformamide (DMF) and anhydrous potassiumcarbonate (10 mg) was refluxed for 12 hours. After completion of reaction, the reaction mixture was cooled to room temperature and poured in to ice cold water. The seperated solid product was filtered, washed with water and recrystalized from N,N-dimethyl formamide-ethanol mixture to give pure(3). Yellow powder, Yield 62%, M.P. 190-192C. IR (KBr/cm-1) 3416 cm-1(=NH) , 3380 cm-1(-NH),2205 cm-1(CN), 1680 cm-1(C=N-): 1HNMR (400MHz,DMSO-d6): δ= 2.1 (s, 1H, -NH), 2.7 ( s, 6H,SCH3), 8.1 (s, 2H,=NH): EI-MS(m/z: RA% ): 303 (M+). Anal. Calcd for C11H9N7S2:C:43.56, H:2.97, N:32.34, found: C:43.31, H:2.84, N:32.21.

References: [1]Oriental Journal of Chemistry,2014,vol. 30,p. 1877 - 1882.

47
[ 3111-61-3 ]
[ 5147-80-8 ]
2,7-diamino-5-(4-methylphenyl)pyrazolo[1,5-α]pyridine-3,6-dicarbonitrile [ No CAS ]