γ-Bromoacetoacetanilide reacts with the Michael adducts obtained from the reaction of cyanothioacetamide with aromatic aldehydes and Meldrum’s acid to form (E)-2-{2-[2-aryl-1-cyanovinyl]thiazol-4-yl}-N-phenylacetamides. These compounds were also synthesized via a convergent synthesis from aldehydes, cyanothioacetamide, and γ-bromoacetoacetanilide. Additionally, new 2-(thiazol-4-yl)acetanilides were synthesized by the Hantzsch reaction of γ-bromoacetoacetanilide with cyanothioacetamide or with 3-(arylamino)-2-cyanothioacrylamides. For all new compounds, in silico predictive analysis and molecular docking were performed to determine bioavailability parameters and identify potential protein targets.

The aim of this work was to synthesize previously unknown thieno[2,3-b]pyridines bearing a β-ketoamide moiety, to study their structure, and to evaluate their agrochemical potential as 2,4-D herbicide safeners. A series of 3-(3-aminothieno[2,3-b]pyridine-2-yl)-3-oxo-N-phenylpropanamides were prepared via S-alkylation of readily available 2-thioxonicotinonitriles or 3-cyanopyridine-2-thiolates with γ-bromoacetoacetanilide, followed by base-promoted Thorpe–Ziegler cyclization. The structure of 4-[(3-cyano-4,6-dimethylpyridin-2-yl)thio]-3-oxo-N-phenylbutanamide was unambiguously established by single-crystal X-ray diffraction. Quantum chemical calculations (B3LYP-D3BJ/6-311+G(2d,p)) revealed that the ketone form is significantly more stable than the enol tautomer with a calculated equilibrium constant in DMSO of 1.52 × 10⁻⁵, which is consistent with the absence of enol form signals in the NMR spectra. The calculated IR frequencies, after scaling, showed excellent agreement with experimental data. Additionally, we found that 4-[(3-cyano-4,6-dimethylpyridin-2-yl)thio]-3-oxo-N-phenylbutanamide undergoes intramolecular cyclization upon heating in AcOH or DMF, to give 4-hydroxy-7,9-dimethylthieno [2,3-b:4,5-b′]dipyridin-2(1H)-one via aniline elimination, thus providing an alternative route to tricyclic thieno [2,3-b;4,5-b]dipyridine ensembles. Agrochemical screening demonstrated that some compounds exhibit pronounced antidote activity against the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) in sunflower seedlings, with root and hypocotyl protection reaching 119–156% in laboratory tests. Field trials for the three most active compounds confirmed their efficacy, providing crop yield increases of 46–57% relative to the herbicide-only control. These results indicate that the newly synthesized thienopyridine β-ketoamides represent a promising class of 2,4-D herbicide safeners.

The reaction of γ-bromoacetoacetanilide with 2-thioxo-1,2-dihydropyridine-3-carbonitriles afforded novel β-ketoamides bearing a heterocyclic fragment, namely 4-{(3-cyanopyridin-2-yl)thio}-3-oxo-N-phenylbutanamides and 3-(3-aminothieno[2,3-b]pyridin-2-yl)-3-oxo-N-phenylpropanamides. The structure of the reaction products was found to be critically dependent on the reaction conditions: under mild conditions, the S-alkylation products are formed, whereas upon heating in the presence of bases, these intermediates undergo Thorpe–Ziegler isomerization to give the corresponding thienopyridine β-ketoamides. Prolonged heating of the latter leads to further cascade cyclization, affording 4-hydroxythieno[2,3-b:4,5-b']dipyridin-2(1H)-ones. All synthesized compounds were subjected to in silico bioavailability assessment and molecular docking to identify potential protein targets.

The structure of various tautomeric forms of 3-oxo-4-thiocyanato-N-phenylbutanamide (γ-thiocyanatoacetoacetanilide) has been studied in detail and their stability has been assessed using NMR spectroscopy, X-ray analysis, and quantum-chemical calculations. The reactions of this compound with some C- and N-nucleophiles have been investigated, and the structure and tautomerism of the products are discussed. Contrary to literature data, the azo coupling reaction of γ-thiocyanatoacetoacetanilide with aryldiazonium salts leads to (Z)-2-[2-arylhydrazinylidene]-3-oxo-4-thiocyanato-N-phenylbutanamides, whose structure has been confirmed by single crystal X-ray analysis. The synthesized compounds were tested for antimicrobial activity, and one of the products exhibited moderate activity against S. enterica and S. aureus.