- A medicine intermediate 5 - aza indole synthesis method (by machine translation)
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The present invention discloses a pharmaceutical intermediate 5 - aza indole synthesis method, comprises the following steps: the 3 - methyl - 4 - aminopyridine with acetone after mixing, heating to 40 - 60 °C, adding catalyst after adding the oxalate, under stirring conditions, refluxing reaction 1 - 2 h, filtering, the filtrate by reduced pressure distillation, recrystallization, prepared 4 - aminopyridine - 3 - pyruvate ester; in its entry into the DMA, adding salicylic acid then adding the FeO, heated to 60 - 70 °C, stirring reflux reaction for 2 - 3 h, filter, the filtrate is distilled under reduced pressure, to obtain 5 - aza indole - 2 - carboxylic acid; and after mixing with the carbon tetrachloride, heating to 70 - 90 °C, adding ZnO mixing, stirring reflux reaction for 2 - 3 h after, filtering, the filtrate is distilled under reduced pressure, to obtain 5 - azaindole. The application of the synthesis method is simple in operation, mild condition, less by-products, the product has high purity, product yield is relatively high. (by machine translation)
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Paragraph 0019-0063
(2019/03/28)
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- Synthesis method of 5-azaindole
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The invention discloses a synthesis method of 5-azaindole. The synthesis method of the 5-azaindole comprises the following steps of after mixing 3-chloro-4-aminopyridine and tetrahydrofuran, adding into a reaction kettle, heating to 100 to 130 DEG C, adding diethyl ether and Ni(COD)2, adding a catalyst, adding acetylene under a stirring condition, carrying out microwave radiation for 20 to 30min,then continuously carrying out reflux reaction for 4 to 6h, filtering after finishing reaction, removing the tetrahydrofuran from a filter liquor, extracting by using ethyl acetate, recrystallizing byusing water, carrying out suction filtration, drying, and obtaining 5-azaindole. The synthesis method provided by the invention is simple to operate, mild in conditions, less in byproducts, high in product purity, and higher in product yield.
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Paragraph 0020-0031; 0032-0037; 0038-0043; 0044-0049
(2018/05/01)
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- Preparation method of5-diazaindene
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The invention discloses apreparation method of 5-diazaindene. 3-methyl-4-aminopyridine is evenly stirred and mixed with acetic anhydride and a catalyst for reaction, the obtained product is evenly mixed with pyrrolidine and DMF-DMA, reaction is performed at the temperature of 80-90 DEG Cunder the condition of the catalyst for 2-3 hours to obtain the final product 5-diazaindene. The method produces fewer by-products and is high in productpurity.In addition, the added novel catalyst makes reaction temperaturemore moderate, and reaction time is shortened greatly. In a word, the steps of the whole production process are simple, operation is easy, the cost of large-scale industrial production is low, and implementation is easy.
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Paragraph 0016; 0017; 0018; 0019; 0020; 0021-0039
(2017/04/26)
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- HETEROCYCLIC COMPOUNDS AS PROTEIN KINASE INHIBITORS
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The present invention provides a heterocyclic compound of formula (I), a pharmaceutically acceptable salt thereof, a prodrug thereof or a hydrate thereof, wherein A, A′ B, D, R1, R2 and R3 are as defined herein, a pharmaceutical composition comprising a compound of formula (I) as an active ingredient, methods of production, and methods of use thereof. Particularly, the present invention provides a compound of formula (I) useful for treating or preventing a disease, condition or disorder associated with protein kinases, preferably Janus Kinase family.
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Paragraph 0435
(2014/06/23)
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- Design, synthesis and antiproliferative activity evaluation of new 5-azaisoindigo derivatives
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New 5-azaisoindigo derivatives were synthesized with two key intermediates 5-azaoxindole (7) and substituted indole-2,3-dione (10) in this paper. Intermediate 7 was prepared from 3-methylpyridine (1) through 6 steps containing oxidation reaction and so on. Intermediate 10 was obtained by a convenient Sandmeyer's method. The target compounds 5-azaisoindigo derivatives 11a-f were obtained by condensation of these two intermediates 7 and 10 in acidic condition. All target compounds were evaluated for their antiproliferative activity against seven cell lines by SRB assay. Compounds 11e and 11f showed significant antiproliferative activity against K562 cells (IC50: 8.9 μM and 13.6 μM, respectively).
- Zhao, Ping,Yan, Yun,Li, Yanzhong,Zhang, Aiying,Zhan, Xiaoping,Liu, Zenglu,Mao, Zhenmin,Chen, Shaoxiong,Wang, Liqun
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p. 1923 - 1932
(2014/08/18)
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- HETEROCYCLIC COMPOUNDS AS PROTEIN KINASE INHIBITORS
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The present invention provides a heterocyclic compound of formula (I), a pharmaceutically acceptable salt thereof, a prodrug thereof or a hydrate thereof, wherein A, A' B, D, R1, R2 and R3 are as defined herein, a pharmaceutical composition comprising a compound of formula (I) as an active ingredient, methods of production, and methods of use thereof. Particularly, the present invention provides a compound of formula (I) useful for treating or preventing a disease, condition or disorder associated with protein kinases, preferably Janus Kinase family.
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Page/Page column 72
(2012/12/13)
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- Novel 3-azaindolyl-4-arylmaleimides exhibiting potent antiangiogenic efficacy, protein kinase inhibition, and antiproliferative activity
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Tumor growth and metastasis are highly associated with the overexpression of protein kinases (PKs) regulating cell growth, apoptosis resistance, and prolonged cell survival. This study describes novel azaindolyl-maleimides with significant inhibition of PKs, such as VEGFR, FLT-3, and GSK-3β which are related to carcinogenesis. Furthermore, these compounds exhibit high kinase selectivity and potent inhibition of angiogenesis and cell proliferation, offering versatile options in cancer treatment strategies.
- Ganser, Christopher,Lauermann, Eva,Maderer, Annett,Stauder, Torsten,Kramb, Jan-Peter,Plutizki, Stanislav,Kindler, Thomas,Moehler, Markus,Dannhardt, Gerd
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p. 9531 - 9540
(2013/01/16)
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- Molecular recognition at the active site of catechol-O-methyltransferase (COMT): Adenine replacements in bisubstrate inhibitors
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L-Dopa, the standard therapeutic for Parkinson's disease, is inactivated by the enzyme catechol-O-methyltransferase (COMT). COMT catalyzes the transfer of an activated methyl group from S-adenosylmethionine (SAM) to its catechol substrates, such as L-dopa, in the presence of magnesium ions. The molecular recognition properties of the SAM-binding site of COMT have been investigated only sparsely. Here, we explore this site by structural alterations of the adenine moiety of bisubstrate inhibitors. The molecular recognition of adenine is of special interest due to the great abundance and importance of this nucleobase in biological systems. Novel bisubstrate inhibitors with adenine replacements were developed by structure-based design and synthesized using a nucleosidation protocol introduced by Vorbrueggen and co-workers. Key interactions of the adenine moiety with COMT were measured with a radiochemical assay. Several bisubstrate inhibitors, most notably the adenine replacements thiopyridine, purine, N-methyladenine, and 6-methylpurine, displayed nanomolar IC50 values (median inhibitory concentration) for COMT down to 6 nM. A series of six cocrystal structures of the bisubstrate inhibitors in ternary complexes with COMT and Mg2+ confirm our predicted binding mode of the adenine replacements. The cocrystal structure of an inhibitor bearing no nucleobase can be regarded as an intermediate along the reaction coordinate of bisubstrate inhibitor binding to COMT. Our studies show that solvation varies with the type of adenine replacement, whereas among the adenine derivatives, the nitrogen atom at position 1 is essential for high affinity, while the exocyclic amino group is most efficiently substituted by a methyl group. Copyright
- Ellermann, Manuel,Paulini, Ralph,Jakob-Roetne, Roland,Lerner, Christian,Borroni, Edilio,Roth, Doris,Ehler, Andreas,Schweizer, W. Bernd,Schlatter, Daniel,Rudolph, Markus G.,Diederich, Francois
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supporting information; experimental part
p. 6369 - 6381
(2011/08/06)
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- NOVEL COMPOUNDS
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The present invention relates to new CGRP-antagonists of general formula I wherein U, V, X, Y, R1, R2, R3 and R4 are defined as in the description, the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates, the mixtures thereof and the salts thereof and the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, medicaments containing these compounds, their use and processes for preparing them.
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Page/Page column 47-48
(2011/02/18)
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- Novel indole and azaindole (pyrrolopyridine) cannabinoid (CB) receptor agonists: Design, synthesis, structure-activity relationships, physicochemical properties and biological activity
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The discovery, synthesis and structure-activity relationship (SAR) of a novel series of cannabinoid 1 (CB1) and cannabinoid 2 (CB 2) receptor ligands are reported. Based on the aminoalkylindole class of cannabinoid receptor agonists, a biphenyl moiety was introduced as novel lipophilic indole 3-acyl substituent in 11-16. Furthermore, the 3-carbonyl tether was replaced with a carboxamide linker in 17-20 and the azaindole (pyrrolopyridine) nucleus was designed as indole bioisostere with improved physicochemical properties in 21-25. Through these SAR efforts, several high affinity CB1/CB2 dual cannabinoid receptor ligands were identified. Indole-3-carboxamide 17 displayed single-digit nanomolar affinity and ~80 fold selectivity for CB1 over the CB2 receptor. The azaindoles displayed substantially improved physicochemical properties (lipophilicity; aqueous solubility). Azaindole 21 elicited potent cannabinoid activity. Cannabinoid receptor agonists 17 and 21 potently modulated excitatory synaptic transmission in an acute rat brain slice model of cannabinoid receptor-modulated neurotransmission.
- Blaazer, Antoni R.,Lange, Jos H.M.,Van Der Neut, Martina A.W.,Mulder, Arie,Den Boon, Femke S.,Werkman, Taco R.,Kruse, Chris G.,Wadman, Wytse J.
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p. 5086 - 5098
(2011/11/29)
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- Microwave-assisted synthesis of indole- and azaindole-derivatives in water via cycloisomerization of 2-alkynylanilines and alkynylpyridinamines promoted by amines or catalytic amounts of neutral or basic salts
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An efficient methodology is described and exploited for the preparation of differently substituted indoles and azaindoles via microwave-assisted cycloisomerization in water of 2-alkynylanilines and alkynylpyridinamines, which is promoted by catalytic amounts of neutral or basic salts or by stoichiometric weak organic bases. Good to high yields in the cyclization can be achieved for a variety of 2-amino(hetero)aryl alkynes. Reactions are run without any added metal catalyst. A comparison with the cycloisomerization conducted under conventional heating is also described. An efficient methodology is described for the preparation of differently substituted 1H-indoles and 1H-azaindoles via microwave-assisted cycloisomerization in water of 2-alkynylanilines and alkynylpyridinamines, promoted by catalytic amounts of neutral or basic salts or by weak organic bases.
- Carpita, Adriano,Ribecai, Arianna,Stabile, Paolo
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experimental part
p. 7169 - 7178
(2010/10/01)
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- Site-selective azaindole arylation at the azine and azole rings via N-oxide activation
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Subjection of N-methyl 6-and 7-azaindole N-oxides to a Pd(OAc) 2/DavePhos catalyst system enables regioselective direct arylation of the azine ring. Following deoxygenation, 7-azaindole substrates undergo an additional regioselective azole direct arylation event in good yield.
- Huestis, Malcolm P.,Fagnou, Keith
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supporting information; scheme or table
p. 1357 - 1360
(2009/09/05)
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- Synthesis and evaluation of CCR5 antagonists containing modified 4-piperidinyl-2-phenyl-1-(phenylsulfonylamino)-butane
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Synthesis of analogs containing more rigid bicyclic piperidine replacements for the 4-benzyloxycarbonyl-(ethyl)amino-piperidine moiety of the CCR5 antagonist structure, 1, is described. Although similar binding affinity to the lead was achieved with some analogs they were overall less potent anti-HIV agents suggesting that other features besides CCR5 binding are required for good anti-viral activity.
- Shah, Shrenik K.,Chen, Natalie,Guthikonda, Ravindra N.,Mills, Sander G.,Malkowitz, Lorraine,Springer, Martin S.,Gould, Sandra L.,DeMartino, Julie A.,Carella, Anthony,Carver, Gwen,Holmes, Karen,Schleif, William A.,Danzeisen, Renee,Hazuda, Daria,Kessler, Joseph,Lineberger, Janet,Miller, Michael,Emini, Emilio A.,MacCoss, Malcolm
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p. 977 - 982
(2007/10/03)
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- Substituted pyrroline kinase inhibitors
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The present invention is directed to novel substituted pyrroline compounds useful as kinase or dual-kinase inhibitors and methods for treating or ameliorating a kinase or dual-kinase mediated disorder.
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- 1,4-Disubstituted benzo-fused urea compounds
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Disclosed are compounds of the formulas (I) and (II) shown below which are active as anti-inflammatory agents. Also disclosed are methods of using and making such compounds. wherein G, X, A and Q are described herein.
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- Azaindolylalkylamine derivatives as 5-hydroxytryptamine-6 ligands
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The present invention provides a compound of formula I and the use thereof for the therapeutic treatment of disorders relating to or affected by the 5-HT6 receptor.
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- Sulfonic acid sulfonylamino n-(heteroaralkyl)-azaheterocyclylamide compounds
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The compounds of formula I herein exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. More specifically, they are inhibitors of the activity of Factor Xa. The present invention is directed to compounds of formula I, compositions containing compounds of formula I, and their use, for treating a patient suffering from, or subject to, a physiological condition which can be ameliorated by the administration of an inhibitor of the activity of Factor Xa.
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- Chemical synthesis of azaindoles
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The present invention relates to a process for the preparation of azaindole derivatives of the formula STR1 wherein Q is hydrogen, C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy, aryl or arylC1-4 alkyl; one of X, Y and Z is --N= and the others are --CH=; R1 is hydrogen, C1-6 alkyl, C2-6 alkenyl or C1-6 alkyl substituted by a group selected from aryl or --NR2 R3 where R2 and R3 each independently represent C1-4 alkyl, or R2 and R3, together with the nitrogen atom to which they are attached, form a 4-7 membered saturated heterocyclic ring, optionally containing in the ring an oxygen or sulphur atom or a group NR4 where R4 is C1-4 alkyl, aryl or arylC1-4 alkyl; and R5 is a hydrogen atom or a group selected from C1-6 alkyl or aryl.
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- A convenient method for the preparation of 5-, 6- and 7-azaindoles and their derivatives
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The directed ortho lithiation of 2-tert-butoxycarbonylamino-3-methylpyridine (6a) has provided a convenient method for the preparation of 1H-pyrrolo[2,3-b]pyridine (4a, 7-azaindole). This procedure has been used to prepare a range of 3-substituted 2-tert-butoxycarbonylaminopyridines 6, 2- and 3-substituted and 2,3-disubstituted 1H-pyrrolo[2,3-b]pyridines 4 and shown to be of value in the preparation of 1H-pyrrolo[3,2-c]pyridine (15, 5-azaindole) and 1H-pyrrolo[2,3-c]pyridine (18, 6-azaindole) and derivatives.
- Hands, David,Bishop, Brian,Cameron, Mark,Edwards, John S.,Cottrell, Ian F.,Wright, Stanley H. B.
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p. 877 - 882
(2007/10/03)
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Total synthesis of modified ellipticines 1c and 1f is described from 2-chloronicotinic acid and respectively 5-methoxy -indole and 5-azaindole in 11 to 13 steps with overall yields of 11% and 18%. A new route to 5-azaindole has also been developed. The synthetic strategy calls for frequent use of homo- and hetero aromatic metallation reactions necessiting resolution of problems associated with the presence of the pyridine ring. With respect to the numerous synthesis described in the litterature, the originality of this approach resides above all in the formation of ring C in basic medium.1 such conditions being dictated by the presence of the pyridine A ring in the case of 1f. Both synthesis have been extrapolated to produce several kilogrammes of final product. That first part deals with the preparation of the precursors.
- Dormoy, Jean-Robert,Heymes, Alain
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p. 2885 - 2914
(2007/10/02)
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- Synthesis of Pyrrolopyridines (Azaindoles)
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Improved, convenient, and reliable routes for synthesis of 4-,5-,6-, and 7-azaindole, 7-methyl-4-azaindole, 7-methyl-6-azaindole, and the hithero unreported 7-amino-4-azaindole are described.The syntheses have been accomplished either by significant modifications to established procedures or by new methods with afford the compounds in improved yields.
- Mahadevan,Indumathy,Rasmussen, Malcolm
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p. 359 - 367
(2007/10/02)
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- CONDENSED HETEROAROMATIC RING SYSTEMS. XXII. SIMPLE AND GENERAL SYNTHESIS OF 1H-PYRROLOPYRIDINES
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Four kinds of 1H-pyrrolopyridines having no substituent were simply and easily synthesized by the palladium-catalyzed reaction of easily available nitropyridine derivatives with (Z)-1-ethoxy-2-tributylstannylethene as a key reaction.
- Sakamoto, Takao,Satoh, Chisato,Kondo, Yoshinori,Yamanaka, Hiroshi
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p. 2379 - 2384
(2007/10/02)
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- Condensed Heteroaromatic Ring Systems. XII. Synthesis of Indole Derivatives from Ethyl 2-Bromocarbanilates
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The palladium-catalyzed reaction of ethyl 2-bromocarbanilate with trimethylsilylacetylene yielded ethyl 2-(trimethylsilylethynyl)carbanilate, which was treated with sodium ethoxide to give indole.The carbanilates having a methyl or a bromo substituent were similarly transformed to corresponding indole derivatives.Furthermore, pyrrolo- and Pyrrolopyridines were synthesized by this method.Keywords---palladium-catalyzed reaction; trimethylsilylacetylene; ethyl 2-halocarbanilate; ethyl 2-halopyridinecarbamate; ethyl 2-(trimethylsilylethynyl)carbanylate; ethyl o-(trimethylsilylethynyl)pyridinecarbamate;indole;pyrrolopyridine
- Sakamoto, Takao,Kondo, Yoshinori,Iwashita, Shigeki,Yamanaka, Hiroshi
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p. 1823 - 1828
(2007/10/02)
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- Process for preparing 5-aza-indole and intermediates used in this process
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A process for preparing 1H-pyrrolo-[3,2-c]-pyridine or 5-aza-indole in high yield, comprising condensing 3-methyl-4-nitropyridine-1-oxide with a compound having a formula STR1 wherein R represents a di-loweralkylamino, morpholino, piperidino or pyrrolidino group and R1 and R2, which are the same or different, each represent a loweralkoxy group or a group R as defined; to form an enamine having a formula: STR2 wherein R is as define and subjecting the enamine IV to reduction cyclization; the enamines IV are new compounds.
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