• K Ganapathi

      Articles written in Proceedings – Section A

    • Chemotherapy of bacterial infections - Part II. Synthesis of some sulphanilamide derivatives and the relation of chemical constitution to chemotherapeutic action

      K Ganapathi

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      The synthesis and the chemotherapeutic effects in experimentalstreptococcal andpneumococcal infections in mice of new sulphanilamide derivatives are described. 2-N1 sulphanilamidothiazol appears to possess a very striking effect in these infections.

      The realtionship of chemical constitution to chemotherapeutic action in this group of compounds has been outlined basing on a study of the therapeutic properties of about 500 compounds till now reported. While the substitution at the amino radical of sulphanilamide does not produce compounds of increased activity but only suppress the polyvalent action of the original compound, the substitution at the amide part of the molecule, especially by a heterocyclic ring, produces compounds of increased activity, particularly in infections in which sulphanilamide is very little effective. The highly active diaminodiphenylsulphone derivatives have to be properly modified to be used in practical therapy. There does appear to be a sort of specificity of the compounds towards different types of infections so that the new compounds produced should be tested in different types of infections also.

    • Chemotherapy of Bacterial Infections - Part III. Synthesis of (N4)-amino-substituted heterocyclic derivatives of sulphanilamide

      K Ganapathi

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      The synthesis of thirteen (N4) amino-substituted sulphanilamide compounds of thiozal and related derivatives is described. None of them showed any activity in experimentalstreptococcal andpneumococcal infections in mice. Five sulphanilamide derivatives of acridine of the above group have also been described. Though some of them possessed considerable activity in thestreptococcal infections, they were inactive inpneumococcal infections. It is apparent that for pronounced antibacterial action the heterocyclic ring should be substituted in the sulphonamide radical leaving a free amino group, which appears to play some significant, but as yet not perfectly understood, rôle in the mechanism of therapeutic action.

    • Chemotherapy of bacterial infections - Part IV. Synthesis of (N1)-sulphonamide substituted heterocyclic derivatives of sulphanilamide

      K Ganapathi

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      In an attempt to assess the antibacterial effect of sulphanilamides with various heterocyclic rings introduced into the (N1)-sulphonamide radical, typical derivatives, of guanidine, thiodiazole, uracil, barbituric and pyrimidine have been synthesised and are reported here.

    • Errata

      Bhola Nath Singh T S Raghavan A R Srinivasan K Ganapathi R Sanjiva Rao

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    • Chemotherapy of bacterial infections - Part V. Synthesis of 2-N1-sulphanilamido-5-alkyl- and 2-N1-sulphanilamido-4-methyl-5-alkyl-thiazoles

      K Ganapathi M V Shirsat C V Deliwala

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      In the course of the attempts to study the effects of the different types of substituents in the molecule of 2-N1-sulphanilamidothiazole, the synthesis of a series of 2-N1-sulphanilamido-5-alkyl- and 2-N1-sulphanilamido-4-methyl-5-alkyl- thiazoles, wherein the alkyl group varies from ethyl to hexyl, have been effected and these compounds are described.

    • Chemotherapy of bacterial infections - Part VI. Synthesis of N1-substituted sulphanilamides: Poly- and hetero-cyclic derivatives

      S Rajagopalan K Ganapathi

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      With the object of studying the antibacterial effect of sulphanilamide derivatives with cyclic substituents at the sulphonamide radical, typical N1-sulphanilamido derivatives of diphenylether, phenanthrene, chrysene, dibenzofuran, carbazole, coumarin, acridine, tetrahydroquinoline and phenanthridine have been synthesised and are reported. Aminosulphonamide derivatives of naphthalene and diphenyl are also described.

    • Chemotherapy of bacterial infections - Part VII. Synthesis of sulphanilamide derivatives of the pyrimidine group

      K Ganapathi C V Deliwala M V Shirsat

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      Sulphanilylguanidine condensed with ethyl acetoacetate and its α-alkyl derivatives to yield 2-sulphanilamido-4-methylpyrimidone and 2-sulphanilamido-4-methyl-5-alkylpyrimidones respectively. Experiments have been recorded which support these structures and a number of intermediate compounds are described. Ethyl formylacetate condensed with sulphanilyl-guanidine to furnish 2-sulphanilamidopyrimidone. Hydroxymethyleneacetone and hydroxymethylene ethylbutylketone failed to condense with sulphanilylguanidine to yield the corresponding pyrimidines in appreciable yields. Mesityl oxide, on the other hand, has yielded two products which are represented provisionally as the two possible pyrimidine derivatives (XIV) and (XV).

    • Chemotherapy of bacterial infections - Part VIII. Synthesis of carboxylic acid derivatives of 2-sulphanilamidothiazole

      K Ganapathi C V Deliwala M V Shirsat

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      A number of carboxylic acid derivatives of 2-sulphanilamidothiazole with the acid grouping attached directly or through alkyl radicals to the thiazole ring at the positions 4 or 5, are described.

    • Chemotherapy of bacterial infections - IX. Synthesis of some sulphathiazole derivatives

      K Ganapathi

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      The synthesis of various derivatives of sulphathiazole with alkyl and substituted alkyl substituents at the ring nitrogen of the thiazole nucleus has been described. Of these compounds only the methyl derivative showed good therapeutic activity in experimental streptococcal, pneumococal and plague infections in mice.

    • Chemotherapy of bacterial infections - X. 2-Acetsulphanilimido-3-acetsulphanilylthiazolone and 2-Diacetsulphanilylamidothiazole. A new route to sulphathiazole

      C V Deliwala K Ganapathi M V Shirsat

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      2-Aminothiazole condensed with acetsulphanilylchloride in aqueous solution or suspension in the presence of sodium bicarbonate, calcium carbonate or barium carbonate to yield 2-diacetsulphanilylamidothiazole m.p. 128–29°; the same product is also obtained by condensing 2-aminothiazole with two molecular equivalents of acetsulphanilylchloride in pyridine or by condensing 2-acetsulphanilamidothiazole with acetsulphanilylchloride in alkaline solution. This compound on boiling with alcohol isomerises into 2-acetsulphanilimido-3-sulphanilylthiazolone. These two products are hydrolysed by acid or alkali to sulphathiazole in good yield. A process of preparation of sulphathiazole is described.

    • Chemotherapy of bacterial infections - Part XI. Synthesis of some derivatives of diphenylsulphone

      K Ganapathi Alamela Venkataraman

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      Starting from 4-nitro-4′-aminodiphenylsulphone, by diazotisation and further transformation, the corresponding 4′-chloro, bromo, iodo and hydroxy compounds were obtained. For the preparation of the chloro and bromo compounds it was found to be advantageous to treat the diazonium salt with an aqueous solution of copper sulphate and sodium halide. Treatment of the diazo product with cuprous oxide or copper bronze in alcohol yielded 4-nitrodiphenylsulphone. The 4′-cyano-compound could not be prepared smoothly by the Sandmeyer’s reaction but only by fusing the 4′-halo derivative with cuprous cyanide. All the nitro-compounds were smoothly reduced to the amino derivatives by means of iron dust in acidified alcohol or-sodium hydrosulphite. Compounds of formula (III) to (VIII) have been prepared by treating 4-nitro-4′-aminodiphenylsulphone and 4-nitro-4′-aminodiphenylsulphide each with α-picoline, 2∶4-dimethylthiazole and 2-hydroxy-4-methylthiazole respectively in the presence of paraformaldehyde.

    • Chemistry of the thiazoles - Part I. Synthesis of 5-aminothiazole derivatives

      K Ganapathi Alamela Venkataraman

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    • Chemistry of the thiazoles - Part II. Synthesis of 4-aminothiazole derivatives

      K Ganapathi Alamela Venkataraman

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      That chloracetonitrile condenses with thiourea to yield 2∶4-diaminothiazole hydrochloride has been confirmed. The diacetamino compound prepared from this by acetylation has been found to be identical with that prepared from ethyl 2-aminothiazole-4-carboxylate by the Curtius method. Chloracetonitrile reacted with other thioamide compounds but the products are found to be not 4-aminothiazole derivatives.

      Ethyl 2-methylthiazole-4-carboxylate could not be converted into 2-methyl-acetaminothiazole.

    • Chemistry of the thiazoles - Part III. Synthesis of thiazole derivatives unsubstituted in position 2: An evaluation of various possible methods

      K Ganapathi Alamela Venkataraman

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      Three methods of synthesising thiazole derivatives unsubstituted in position 2 of the thiazole ring have been investigated to ascertain their scope. The reactions involving the condensation of thioformamide with α-halogenoketones are best effected by treating the halogenoketones with a mixture of formamide and phosphorous pentasulphide; syntheses of 4-methylthiazole, 4∶5-dimethylthiazole, 4-methyl-5-acetylthiazole and ethyl 4-methylthiazole-5-carboxylate are described as examples. By this method thiazole and ethyl thiazole-4-carboxylate could not be prepared.

      2-Aminothiazole, the 5-methyl and 5-ethyl derivatives have been converted into the corresponding 2-chloro and 2-bromo derivatives in good yields by diazotising the aminothiazoles in a mixture of phosphoric acid and nitric acid or about 45 per cent. sulphuric acid and treating the diazonium products with an aqueous solution of copper sulphate and sodium halide. Treatment of the diazonium solutions with cuprous oxide in alcohol or calcium hypophosphite yielded the deaminated products, the latter giving better yields than the former reagent. These reactions are not of universal applicability and their scope has been ascertained by studying them in a number of cases. 2-Chloro-5-nitrothiazole and 2-bromo-5-nitrothiazole have been prepared by diazotising 2-amino-5-nitrothiazole in dilute sulphuric acid containing copper-sulphate and the sodium halide.

      The preparation of 2-hydroxythiazole derivatives by condensing α-halogenoketone with either the thiocyanates or ammonium thiocarbamate has been studied using chloracetone, dichloracetone, α-chloromethyl-ethylketone, chloracetylacetone and ethyl α-chloroacetoacetate. In the case of the chloroderivatives of β-ketonic ester and β-diketone, ammonium thiocarbamate yields the expected 2-hydroxy thiazole derivative while the product obtained using the thiocyanates is of doubtful constitution. The 2-hydroxythiazol compounds could be converted into the 2-chlorothiazole in good yields by treating with phosphorous oxychloride. Saturation of α-thiocyanomethylethylketone with hydrogen chloride furnished 2-chloro-4∶5-dimethylthiazole.

    • Chemotherapy of bacterial infections - XII. Synthesis of some sulphanilamide and sulphone derivatives of thiazole

      K Ganapathi Alamela Venkataraman

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      Condensation of 2-bromo-5-nitrothiazole with sulphanilamide yielded (i) in the presence of potassium carbonate and copper powder, 2-sulphaniamido-5-nitrothiazole and (ii) in alcoholic solution the isomeric N4-(5-nitro-2-thiazolyl)-sulphanilamide. 2-Hydroxy-4-methyl-5-aminothiazole and 2∶4-dimethyl-5-aminothiazole condensed with acetsulphanilylchloride to yield respectively 2-hydroxy-4-methyl-5-acetsulphanilamidothiazole and 2∶4-dimethyl-5-acetsulphanilamidothiazole. The latter, on hydrolysis, furnished 2∶4-dimethyl-5-sulphanilamidothiazole, which was about as active as sulphathiazole in experimental pneumococcal andP. pestis infections in mice but much more toxic. By condensing 2-methylthiazole, 2∶4-dimethylthiazole and 2-hydroxy-4-methylthiazole with formalin and sulphanilamide, were obtained respectively 2-β-(p-aminobenzenesulphonamido) ethylthiazole, 4-methyl-2-β-(p-aminobenzenesulphonamido) ethylthiazole and 2-hydroxy-4-methyl-5-(p-aminobenzenesulphonamido) methylthiazole, none of which showed any therapeutic activity in experimental pneumococcal infections in mice. Condensation of potassium acetaminobenzenesulphinate with 2-chloro-4∶5-dimethylthiazole, 2-chloro-5-ethylthiazole and 2-bromo-5-nitro-thiazole, the corresponding 2-p-acetaminobenzene sulphonylthiazoles were obtained which were deacetylated to the corresponding amino compounds; these compounds also did not show any striking therapeutic activity.

    • Chemotherapy of malaria - Part I. A study of the methods of synthesis of diguanides

      L Fernandes K Ganapathi

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      In the course of attempts to prepare quinoline derivatives with substituted diguanide side chains, the methods of syntheses of N1-p-chlorophenyl-N5-isopropyldiguanide (I) as a model compound have been investigated. The diguanide (I) was obtained by the condensation ofisopropylguanidine with (1)p-chlorophenylcynamide, (2) S-methyl-p-chlorophenylisothiourea and (3)p-chlorophenylthiourea in the presence of lead acetate. Attempts to prepare the compound (III) by the condensation ofp-chlorophenylisothiocyanate withisopropyl guanidine were unsuccessful.p-Chlorophenyl-isothiocyanate condensed with S-methylisothiourea to yield S-methyl-N1-(p-chloroanilino)-thioformylisothiourea (VI but the methylmercapto group of this compound could not be replaced by either imino orisopropylimino groups.p-Chloraniline condensed withisopersulphocyanic acid to yieldp-chlorophenyldithiobiuret which on boiling with ammonia andisopropylamine in the presence of mercuric oxide furnished respectivelyp-chlorophenyldicyandiamide and N-p-chlorphenyl-N′-isopropyl-N″-cyanoguanidine (X).p-Chlorophenyldithiobiuret on oxidation with iodine yieldedp-chlorophenylthiuret which on treatment with ammonia andisopropylamine in the presence of mercuric oxide furnished respectivelyp-chlorophenyldicyandiamide and N-p-chlorophenyl-N′-isopropyl-N″-cyanguanidine. On treatment withisopropylamine,p-chlorophenylthiuret yielded only N-(p-chlorophenyl)-N′-isopropyl-N″-aminothioformylguanidine (XII), which easily undergoes desulphurisation to yield the compound (X); however, in the presence of alcoholic ammonia and mercuric oxide,p-chlorophenyldicyanamide was obtained.

    • Chemotherapy of Tuberculosis - Part I. Synthesis of possible lipophilic chemotherapeuticals of the sulphonamide and sulphone series derived from fatty acids, including those of the chaulmoogra group

      C V Deliwala K Ganapathi S Rajagopalan

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      Twenty-three compounds have been synthesised as possible lipophilic chemotherapeuticals of the sulphonamide and sulphone series. Among such compounds are the hydnocarpic acid derivatives of N4-n-fatty acyl sulphanilamides, N4, N1-dihydnocarpylsulphanilamide, normal fatty-acyl derivatives of 4-nitro-4′-amino- and 4∶4′-diamino-diphenylsulphones, 4∶4′-bis-adipylamido- and 4∶4′-bis-sebacylamido-diphenylsulphones, and the N4-n-caproyl derivatives of 2-sulphanilamidopyrimidine, 2-sulphanilamido-4-methyl-and 2-sulphanilamido-4∶6-dimethyl pyrimidines.

    • Chemotherapy of malaria - II. Synthesis of some thiazole derivatives

      L Fernandes K Ganapathi

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      To trace the antimalarial activity in the thiazole compounds, twenty-one thiazole derivatives of general formula I have been synthesised by the standard method of reacting the corresponding thiourea derivatives with chloracetal, chloracetone and ethyla-chloracetoacetate respectively. The guaridino compound of formula II could not be prepared by the action ofp-chlorophenylcyanamide on thiourea or by the action of desulphurising agents on a mixture ofp-chlorophenylthiourea and 2-aminothiazole.p-Chlorophenylguanidinothioformamide (IV) could not be prepared by the action of hydrogen sulphide onp-chlorophenyldicyandiamide.p-Chlorophenylisothiocyanate reacted with 2-aminothiazole to furnish 2-(p-chlorophenylthiocarbamido) thiazole (V) which on treatment with mercuric oxide in alcoholic ammonia solution furnished the guanidinothiazole derivative (II).

    • Chemotherapy of bacterial infections - XIII. Synthesis of unsymmetrical diphenylsulphones

      R A Bellare K Ganapathi

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      Nineteen diarylsulphones of general formulæ (I) and (II) listed in the table have been synthesised by the Hinsberg reaction, with a view to study them for their action against gram positive anaerobes.

    • Chemotherapy of malaria - III. Attempted synthesis of biguanide and guanidino derivatives of quinoline

      K Ganapathi M H Shah

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      Of the methods available for the synthesis of the 4-aminoquinoline derivatives, the best one was found to consist of passing ammonia into a mixture of 4-chloroquinolines and phenol maintained at 130 60. Accordingly 4-amino-7-chloroquinoline, 4-amino-6-methoxyquinaldine, 4-amino-8-methoxy quinaldine, and 4-amino-6-chloroquinaldine were prepared in good yields. Attempts to prepare the guanidine and biguanide derivatives of formula (I) and (II) failed. The amino group in position 4 of the quinolines showed properties of neither the aliphatic nor the aromatic amino group.

      4-Chloroquinolines do not react with guanidine salts to yield the 4-guanidinoquinolines. Similarly 4-methoxyquinolines also do not react with guanidine salts.

    • Chemotherapy of malaria - IV. Synthesis of 4-(Guanidylphenylamino)quinolines

      K Ganapathi M H Shah

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      Attempts made to evolve a general method for the synthesis of 4-(guanidylphenylamino) quinoline derivatives of formula (II) are described. By reacting 4-chloro-6-methoxyquinaldine, 4-chloro-8-methoxyquinaldine, 4:6-dichloroquinaldine and 4:7-dichloroquinoline individually withp-acetphenylediamine were obtained respectively 4-(p-acetaminoanilino)-6-methoxyquinaldine, 4-(p-acetaminoanilino)-8-methoxyquinaldine, 4-(acetaminoanilino)-6-chloroquinaldine and 4-(p-acetaminoanilino)-7-chloroquinoline. On hydrolysis, these furnished the corresponding amino derivatives.p-Nitraniline condensed with 4:7-dichloroquinoline to furnish 4-(p-nitroanilino)-7-chloroquinoline which on reduction with iron and acetic acid yielded the corresponding amino compound identical with that reported above.p-Bromoaniline also easily condensed with 4:7-dichloroquinoline. In contrast to the reactivity of the 4-chloroquinolines, the 2-chloro analogues were very sluggish and condensed with aromatic amines only under drastic conditions.

      The reaction of 4-(p-aminoanilino)-7-chloroquinoline with isopropylisothiocyanate as well as the condensation of 4:7-dichloroquinoline withp-aminophenylisopropylthiourea (V) furnished the thiourea derivative (IV) which on desulphurisation with mercuric oxide in alcoholic ammonia did not furnish the corresponding guanidine compound. This was obtained however by the action of N1-isopropyl-N3-p-aminophenylguanidine on 4:7-dichloroquinoline. The latter also reacted withp-aminophenylguanidine to furnish the corresponding guanidine of formula (II). This method appears to be of general applicability for the preparation of quinilinoamino-phenylguanidine derivatives of formula (II).

    • Chemotherapy of malaria - V. Synthesis of 4-(thiazolylamino)-quinolines and 4-phenoxyquinolines

      K Ganapathi M H Shah

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      Ten thiazolylaminoquinolines of formula (I) have been prepared by heating the 4-chloroquinolines with 2-aminothiazoles in phenol medium, at about 150–60°. In some cases, instead of the compounds of formula (I), only the 4-phenoxyquinolines could be isolated. The 2-chlorolepidines do not undergo this condensation at all. 4:7-Dichloroquinoline condensed with 2-amino-4-methylpyrimidine to yield the compound (II); but 2-aminopyrimidine and 2-amino-4-methyl-6-chloropyrimidine did not react with the chloroquinoline. Evidence has been presented to show that in the condensation of the chloroquinolines with amines in phenol medium, the phenoxyquinoline is not the intermediate as was supposed by some authors. A different mechanism seems to operate.

    • Chemotherapy of malaria - VI. Quinolylsulphones

      R A Bellare K Ganapathi

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      Twenty-one aryquinolylsulphones described in the table have been prepared by reacting the chloroquinolines with substituted arylsulphinic acids. The 4-chloroquinolines furnish the sulphones very readily and these sulphones are easily hydrolysed to the corresponding 4-hydroxyquinolines.

      These compounds do not show any activity when tested for their prophylactic activity in mosquitoes againstPlasmodium gallinaceum infection.

    • Chemotherapy of malaria - Part VII. Phenylene-diguanidine derivatives

      K Ganapathi B S Kulkarni

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      Phenylenediguanidine derivatives of formula (I) have been synthesised to assess their antimalarial activity. The method consists in condensing phenylthiourea derivatives of formula (VI) with a series of isothiocyanates, to obtain the dithiourea derivatives (VII), the di-S-methyl derivatives of which reacted with ammonia to furnish the diguanidine derivatives (I). The other methods tried to prepare diguanidine derivatives are also described. Eleven

    • Chemotherapy of malaria - Part VIII. Synthesis of uracils, thiouracils, pteridines and thiopteridines

      K Ganapathi B N Palande

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      Twenty-two pteridines of formula (I) and twenty-one thiopteridines of formula (II) have been synthesisedvia 4-aminouracils and 4∶5-diaminouracils for assessing their antimalarial and antibacterial properties.

    • Chemistry of the thiazoles - IV. Bromination and nitration of some monosubstituted thiazoles

      K Ganapathi K D Kulkarni

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      In connection with the study of the orienting influences in the thiazole nucleus, 2-methylthiazole, 4-methylthiazole, 5-methylthiazole, 2-hydroxythiazole, 2-methoxythiazole, 5-acetamidothiazole and 5-acetamidothiazole-2-carboxylic acid have been nitrated and brominated and the results obtained have been presented. The significance of the results is discussed in the next part.

    • Chemistry of the thiazoles - Part V. Fine structure and orientation

      K Ganapathi K D Kulkarni

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    • Chemistry of the thiazoles - Part VI. Chrysean and some of its derivatives

      K Ganapathi K D Kulkarni

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      Chrysean has been isolated in two forms; whether they are stereosoimers or only dimorphic forms is discussed. A mechanism of formation of chrysean is suggested. With methyl iodide it gives readily the S-methyl derivative which reacts easily with aniline,p-chloraniline andm-aminophenol to furnish the amidino derivatives of formula (IX). Chrysean on being refluxed with ethyl acetoacetate in alcohol gave the acrylidene derivative (X) which cyclises on heating to the pyridinothiazole derivative (XI). Ethyl acetoacetate and chrysean at higher temperature condensed to yield the acetoacetyl derivative (XIII) which however did not cyclise to furnish (XIV).

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