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trans-2-Amino-4-aryl-5-benzoyl-4,5-dihydrothiophene-3-carbonitriles were prepared either by the reaction of 3-aryl-2-cyanothioacrylamides with α-thiocyanatoacetophenone or by the Michael-type addition of cyanothioacetamide to α-bromochalcones followed by intramolecular cyclization. The mechanism of the first reaction was studied using high-level quantum chemical calculations. Density functional theory (DFT) studies were carried out to determine the mechanism of the first reaction. A new approach toward the construction of the thieno[2,3-d]pyrimidine core system was demonstrated by the reaction of the prepared dihydrothiophenes with HCHO and RNH2 under noncatalyzed Mannich conditions.

Hydroxymethylation of (E)-3-aryl-2-cyanoprop-2-enethioamides with an aqueous alcoholic solution of formaldehyde has afforded (E)-3-aryl-N-(hydroxymethyl)-2-cyanoprop-2-enethioamides. The predictive analysis of the biological activity of the obtained compounds in silico has been carried out.

The reaction of cyanothioacetamide with ethoxymethylenemalonate and triethylamine in ethanol upon heating is non-selective and leads to the formation of a mixture of triethylammonium 1,5-diamino-2,4-dicyano-5-thioxopenta-1,3-diene-1-thiolate and triethylammonium 6-oxo-3-cyano-5-ethoxycarbonyl-1H-pyridin-2-thiolate with a predominance of the latter. When treating with primary amines and 37% formalin in boiling aqueous alcohol, the reaction product gives only 4-(1,3,5-thiadiazinan-2-ylidene)-2-(3,4-dihydro-2H-1,3,5-thiadiazin-6-yl)pent-2-enedinitrile instead of the expected pyrido[2,1-b][1,3,5]thiadiazine derivatives. Triethylammonium 6-oxo-3-cyano-5-ethoxycarbonyl-1H-pyridin-2-thiolate does not react under these conditions.

This microreview summarizes new data (2014–2019) on the use of 1-cyanoacetyl-3,5-dimethylpyrazole in organic synthesis.

3-Aminothieno[2,3-b]pyridine-2-carboxylic acid esters readily reacted with 3,5-dimethyl-1-(cyanoacetyl)-1H-pyrazole to give previously unknown N-(thieno[2,3-b]pyridin-3-yl)cyanoacetamides. Reactions of the latter with 2-(arylmethylidene)malononitriles were nonselective, and mixtures of different heterocyclization products were generally formed. The cyclization of ethyl 4,6-dimethyl-3-[(cyanoacetyl)amino]thieno[2,3-b]-pyridine-2-carboxylate afforded 2,4-dihydroxy-7,9-dimethylthieno[2,3-b : 4,5-b′]dipyridine-3-carbonitrile whose tautomeric equilibrium was studied by DFT quantum chemical calculations. In silico analysis of biological activity of the synthesized compounds was performed.

The review summarizes the results obtained by our research group over the past 15 years in chemistry of N-, S,N-, and Se,N-heterocycles resulted from aminomethlation of a wide range of acyclic and heterocyclic substrates derived from active methylene amides, thioamides, and selenoamides. A series of 1,3,5-thia(selena)diazines, 3,7-diazabicyclo[3.3.1] nonanes, 3,5,7,11-tetraazatricyclo[7.3.1.02,7]tridec-2-enes, 1,3,5,7-tetrazocines, and pyrido[1,2-a][1,3,5]triazines were synthesized. The general regularities of the Mannich reaction in the series of N-, S,N-, and Se,N-containing pyridine substrates were discussed. Biological activities of some synthesized compounds were studied to reveal compounds with antiviral, analeptic, anti-inflammatory, and antipyretic activities.

The reaction of 5-amino-3-(cyanomethyl)-1H-pyrazole-4-carbonitrile with 3-aryl-5-hydroxy-5- methyl-2,4-di(ethoxycarbonyl)cyclohexanones in acetic acid furnished previously unknown 4,5,6,7,8,9-hexahydropyrazolo[1,5-a]quinazoline derivatives.

D-Pantoic acid amide obtained by treatment of D-(–)-pantolactone with ammonia reacted with acetic anhydride in the presence of perchloric acid to give 5-[2-(acetoxy)-1,1-dimethylethyl]-2-methyl-4-oxo- 4,5-dihydro-1,3-oxazolium perchlorate. Reaction of the latter with aromatic aldehydes afforded 2-(2- arylethenyl)-4-oxo-4,5-dihydro-1,3-oxazolium perchlorates which showed no appreciable growth-regulating activity but clearly exhibited antidotal activity against 2,4-dichlorophenoxyacetic acid (2,4-D herbicide).

Three series of new cyclic sulfones have been prepared by a one-pot multi-component reaction (MCR) starting from the readily available dihydro-2H-thiopyran-3(4H)-one-1,1-dioxide. The in silico screening of the synthesized compounds revealed their high anti-inflammatory, antiarthritic, antiasthmatic and antiallergic potential coupled with the strong probability levels of cystinyl aminopeptidase inhibition. The key structures were confirmed by 2D NMR techniques.

The reaction of aromatic aldehydes with Meldrum's acid and malononitrile dimer in the presence of triethylamine led to the formation of (4-aryl-3-cyano-6-oxo-1,4,5,6-tetrahydropyridin-2-yl)malononitrile triethylammonium salts, which were converted upon acidification to (4-aryl-3-cyano-6-oxopiperidin-2-ylidene)malononitriles. The reaction of these compounds with thioglycolic acid anilide was observed to produce derivatives of 1,6-naphthyridine or thieno[2,3-h][1,6]naphthyridine, depending on the conditions. Structures of (3-cyano-6-oxo-4-phenylpiperidin-2-ylidene)malononitrile and its triethylammonium salt were studied by X-ray structural analysis.

The current paper describes optimization of the formulations of asphalt concrete roadway protective impregnation compositions based on BND 60/90 bitumen modified with petroleum resin. Physicochemical, technological and operating parameters of the prepared samples of the compositions are investigated.

To examine the cytotoxic activity of congeners of 3-amino-isoquinoline, we performed the phenotypic screening using panel of 60 cell lines and found that (N-(6,7-dimethoxy-1-methyl-isoquinolin-3-yl)-4-{[(1-ethyl-4-methyl-1H-pyrazol-3-yl)methyl]amino}benzamide (4d)) exhibited the significant effect against different tumor cell lines while showing the high activity toward human colorectal cancer HCT-116 cells (IC50 = 18 μm) and human breast cancer T-47D cells (GI50 = 1.9 μm). Virtual screening indicated that these compounds target protein kinases and phosphodiesterases (PDE). However, wet screening among panel of protein kinases did not show any significant activity. By contrast, 50 μm of 4c and 4d inhibited the growth of HKe3-mtKRAS spheroids in the 3D floating (3DF) culture suggesting that 4c and 4d target PDE4B which is selectively upregulated by mtKRAS in 3DF culture.

Derivatives of a novel heterocyclic system, 8,9,10,11-tetrahydro-7-thia-1,4,6,8-tetraazabenzo[de]anthracene, were obtained by interaction of 5Н-pyrido[2′,3′:2,3]thiopyrano[4,5-b]pyridines, formed by treating N-methylmorpholinium 4-aryl-3-cyano-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates with malononitrile dimer, Ас2О or carboxylic acid chlorides.

The reaction of cyanothioacetamide with diethyl ethoxymethylenemalonate in the presence of triethylamine in hot EtOH proceeds non-selectively and leads to the formation of a mixture of triethylammonium 1,5-diamino-2,4-dicyano-5-thioxopenta-1,3-diene-1-thiolate (minor) and triethylammonium 3-cyano-5-ethoxycarbonyl-6-oxo-1Н-pyridine-2-thiolate (major). Upon treatment with primary amines and 37% aqueous HCHO in boiling aqueous ethanol, the reaction product affords only 4-(1,3,5-thiadiazinan-2-ylidene)-2-(3,4-dihydro-2H-1,3,5-thiadiazin- 6-yl)pent-2-enedinitrile derivatives, instead of the expected pyrido[2,1-b][1,3,5]thiadiazines. Triethylammonium 3-cyano-5-ethoxycarbonyl-6-oxo-1Н-pyridine-2-thiolate does not react under these conditions. The structure of the resulted products was confirmed by means of NMR, IR spectroscopy, and LCMS. The mechanism of the formation of the products is discussed.

The reaction of 5-amino-3-(cyanomethyl)-1H-pyrazole-4-carbonitrile with 3-aryl-2,4-di (ethoxycarbonyl)-5-hydroxy-5-methylcyclohexanones in boiling acetic acid leads to the formation of new 4,5,6,7,8,9-hexahydropyrazolo[1,5-a]quinazolines. The mechanism is discussed. The structure of the products was confirmed by means of 1Н и 13С (DEPTQ) NMR, as well as 2D NMR (NOESY, 1Н–13С HSQC, HMBC).

New polyheterocyclic ensembles of 8,9,10,11-tetrahydro-7-thia-1,4,6,8-tetraazabenzo[de]anthracenes were prepared by reaction of easily available 5Н-pyrido[2’,3’:2,3]thiopyrano[4,5-b]pyridines with Ас2О or acyl chlorides. The starting 5Н-pyrido[2’,3’:2,3]thiopyrano[4,5-b]pyridines were prepared by reaction of N-methylmorpholinium 4-aryl-3-cyano-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates with malononitrile dimer.

6-Amino-4-aryl-7-phenyl-3-(phenylamino)-4,7-dihydro-3Н-[1,2]dithiolo[3,4-b]pyridine-5-carbonitriles were synthesized via the reaction of arylmethylidenemalononitriles with dithiomalonic acid dianilide in the presence of an excess of morpholine. The structure of 6-amino-4-(3,4-dimethoxyphenyl)-7-phenyl-3-(phenylamino)-4,7-dihydro-3Н-[1,2]dithiolo[3,4-b]pyridine-5-carbonitrile was studied by X-ray structural analysis.

Currently, to strengthen and extend the durability of the bituminous macadam pavement surface compositions are used-impregnating composition (emulsions, solutions). These compositions are effective, but they have several disadvantages: instability to temperature changes; high water saturation; low water loss when applied, because of which the service life of the surface layer and of the pavement are reduced, and resource consumption is quite high; long drying time and others. This paper presents a brief overview of the main components included in the protective impregnating compositions for road pavements in Russian Federation, as well as the optimal in its purpose, and its components, the composition of the impregnating composition to protect the pavement from the negative effects of natural and manmade factors.

Triethylammonium salts of (4-aryl-3-cyano-6-oxo-1,4,5,6-tetrahydropyridin-2-yl)malononitriles were prepared by reaction of aldehydes with Meldrum's acid and 2-amino-1,1,3-tricyanopropene (malononitrile dimer) in the presence of triethylamine. Upon treatment with alpha-mercaptocarbonyl compounds in the presence of alkali, new thieno[2,3-h][1,6]naphthyridines were prepared in good yields.

The reaction of D-(–)-pantolactone with ammonia leads to the formation of D-pantoamide, which reacts with Ас2О and HClO4 to give 5-[2-(acetoxy)-1,1-dimethylethyl]-2-methyl-4-oxo-4,5-dihydro-1,3-oxazolium perchlorate. The obtained 2-methyl-1,3-oxazolium perchlorate readily reacts with aromatic aldehydes to afford 2-(2-arylvinyl)-1,3-oxazolium perchlorates. The plant protecting properties of the obtained compounds were studied. We found that 2-(2-arylvinyl)-4-oxo-4,5-dihydro-1,3-oxazolium perchlorates are effective as antidotes towards herbicide 2,4-D but have no plant growth activity.

The Mannich-type reaction of N-methylmorpholinium 4-aryl-3-cyano-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates with 2-R-propanals (ocean propanal, isobutyraldehyde) and primary aromatic amines afforded 7-aryl-2-R-2-methyl-3-arylamino-5-oxo-2,3,6,7-tetrahydro-5Н-thiazolo[3,2-a]pyridine-8-carbonitriles in modest yields; the structure of a key compound was confirmed by X-ray crystal structure analysis. The mechanism of the reaction is discussed.

The Alzheimer's disease (AD) is acknowledged as the most common type of dementia in aging adults. It is characterized by the formation of intracellular neurofibrillary tangles and extracellular amyloid plaques. The latter insoluble deposits mainly consist of β-amyloid peptides (Aβ), which are the derivatives of the amyloid precursor protein (APP). The formation of neurotoxic Aβ-peptides involves the cleavage of APP with beta-secretase enzyme (beta-site APP cleaving enzyme 1, BACE1) so the potential of BACE1 inhibitors as therapeutic agents for AD is now drawing much attention. The patent application WO2016023927 reports the preparation of new 1,2,4-thiadiazine inhibitors of BACE1 activity and their use as therapeutically active substances. Some of the new compounds are claimed to be good inhibitors with the IC50 values in the 0.000292-0.134165 μM range. Several pharmaceutical preparations based on these compounds are proposed for possible treatment and prevention of AD. Expert opinion: In light of the novelty from the chemical point of view and improved biological activity, the reported 2,2,2-trifluoroethylthiadiazines could be considered as promising BACE1 inhibitors. However, the available data are insufficient to make a recommendation if these compounds can be considered as drug candidates. Further studies with a larger number of compounds are required. The compounds described in the patent have to be characterized more thoroughly from the chemical viewpoint (e.g., by means of IR, 1H and 13C NMR spectroscopy, X-ray crystallography), especially as regards stereochemical details.

A novel one-pot procedure for accessing the comparatively little studied title compounds (III) is reported.

2,6-Dioxopiperidine-3,5-dicarbonitriles (also known as Guareschi imides) and their salts are readily prepared by condensation of ketones, cyanoacetic ester, and ammonia [1-3] and have proved over more than a century to be convenient reagents for synthesizing derivatives of glutarimide, 3,3-disubstituted glutaric acids [46], azaspiranes [7], etc. A single method has been reported in the literature for the cyclization of Guareschi imides to bispidines (3,7-diazabicyclo[3.3.1]nonane derivatives) under conditions of acid hydrolysis of the nitrile groups [4, 8-11]. The compounds obtained are of interest as intermediate products in the preparation of substances with anti-ischemic activity [12] and of sparteine alkaloids [13]. We have previously reported a convenient method for the synthesis of 4-monosubstituted Guareschi imide salts by the reaction of 3-aryl-2-cyanoacrylamides with cyanoacetylpyrazole [14, 15]. These compounds, and other known 2,6-dioxopiperidine-3,5-dicarbonitriles are of general interest (as C-3/C-5 dinucleophilic reagents) for the preparation of substituted bispidines via a double aminomethylation reaction. The Mannich reaction of 3,5-dinucleophilic pyridine derivatives is one of the most generally applicable methods of preparing 3,7-diazabicyclo[3.3.1]nonanes [16, 17]. However, to this time there was no published evidence for the aminomethylation of Guareschi imides. We have found that the reaction of the glutarimide salt 1a with benzylamine and an excess of formaldehyde occurred under mild conditions to give the 2,4-dioxo-3,7-diazabicyclo[3.3.1]nonane salt ("bispidinate") 2. Reaction of salt 1a with -phenethylamine and salt 1b with benzylamine proceeded similarly. Acidification gave the expected bispidines 3a,b. These reactions serve as a first example of the synthesis of 3,7-diazabicyclo[3.3.1]nonane derivatives using Guareschi imides. The structure of compounds 2 and 3a,b was confirmed by IR and H NMR spectroscopy data, HPLC-MS, and elemental analysis. Optimization of the conditions, limits, and potential uses of the reaction will be the subject of future investigations.

Derivatives of 2,6-dioxopiperidine-3,5-dicarbonitrile (Guareschi imides) are of practical interest as anticonvulsants, sedatives, and analgesics [1] as well as promising building blocks for the preparation of bispidine (3,7-diazabicyclo[3.3.1]nonane) derivatives [2, 3] and biologically active compounds [4–6]. The most convenient method for the preparation of these compounds is the Guareschi reaction, namely, the reaction of ethyl cyanoacetate with ketones and ammonia [7–11] or, in an alternative variant, the reaction of 2-cyanoacrylates with cyanoacetamide [4, 6, 12, 13]. The classical Guareschi reaction has its disadvantages. The yields and reaction times vary. Also, there are limitations related to the need to use only ketones as the carbonyl components. Guareschi imides are known to undergo facile oxidation by atmospheric oxygen [14]. When aldehydes are used in this reaction instead of ketones, the final products are only the oxidation products, namely, 4-alkylor 4-aryl-6-hydroxy-2-oxo-1,2-dihydropyridine-3,5-dicarbonitriles or their salts [15–19]. Only a few examples of the preparation of 4-aryl-2,6-dioxopiperidine-3,5-dicarbonitriles or their salts have been reported [1, 20, 21]. As a rule, either the products are obtained in low yield or the methods require the use of exotic reagents such as Li3N as the source of NH3. We have found that the salt of the Guareschi imide, triethylammonium 4-(2-chlorophenyl)-3,5-dicyano6-oxo-1,4,5,6-tetrahydropyridine-2-olate (1), may be synthesized under mild conditions by the Michael reaction of readily available 1-cyanoacetyl-3,5-dimethylpyrazole 2 [22, 23] with 3-(2-chlorophenyl)-2-cyanoacrylamide 3. Pyridinolate 1 is formed in 76% yield as a mixture of cis and trans diastereomers and, according to the H NMR spectrum, does not contain oxidation product impurities. This method is the first efficient procedure for preparing 4-aryl-ubstituted Guareschi imides and one of the first examples of the use of azolide 2 as an active methylene compound serving as an alternative to ethyl cyanoacetate. Work on the optimization of the method and clarification of its scope is currently underway.

The Et3N-promoted reaction of (E)-3-aryl-2-cyanoacrylamides (arylmethylenecyanoacetamides) with 1-cyanoacetyl-3,5-dimethylpyrazole was thoroughly studied. It was found that either triethylammonium 4-aryl-3,5-dicyano-6-oxo-1,4,5,6-tetrahydropyridine-2-olates 1 (salts of Guareschi imides) or their oxidation products – triethylammonium 4-aryl-3,5-dicyano-6-oxo-1,6-dihydropyridine-2-olates 2 were formed, depending on the nature of substituents in the 3-aryl fragment of starting acrylamides. Thus, when Ar = ortho-, meta-substituted phenyl or hetaryl such as 2-furyl, 3-thienyl etc., only Guareschi imides salts 1 were obtained in good to excellent yields. In the case of para-substituted or unsubstituted phenyl, pyridine-2-olates 2 were isolated as major products due to fast oxidation of Guareschi intermediates. The influence of reaction conditions and the nature of the base on the structure of final products is discussed.

The reaction of 1-cyanoacetyl-3,5-dimethylpyrazole with 2-cyanoacrylamides in the presence of triethylamine leads to triethylammonium 3,5-dicyano-6-oxo-1,4,5,6-tetrahydropyridine-2-olates (salts of Guareshi imides). The latter reacted with primary amines RNH2 and excessive HCHO to give triethylammonium salts of 7-R-2,4-dioxo-3,7-diazabicyclo[3.3.1]nonane-1,5-dicarbonitriles. When treated with HCl or alkyl halides, the salts afforded corresponding 3-R- or 3,7-disubstituted bispidines.

The method is efficient procedure for the synthesis of 4-aryl substituted Guareschi imides.