- A concise synthesis of 2-chloro-3-amino-4-methylpyridine
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An improved and commercially valuable process is developed for the scalable synthesis of 2-chloro-3-amino-4-methylpyridine (CAPIC), a key intermediate of Nevirapine. The synthesis was accomplished in four steps, featuring condensation starting from 4,4-dimethoxyl-2-butanone and cyanoacetamide with ammonium acetate and acetic acid as catalysts. The total yield of the process is 62.1%. The pure CAPIC sample was confirmed with FTIR, 1H NMR, and 13C NMR spectra.
- Ge, Xin,Chen, Han-Geng,Cao, Chang-Hui,Liu, Jin-Qiang,Qian, Chao,Chen, Xin-Zhi
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- Synthesis of 2-cyanoacrylates containing pyridinyl moiety under ultrasound irradiation
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Reaction of ethyl cyanoacetate with carbon disulfide and dimethyl sulfate in the presence of sodium methoxide in anhydrous methanol yields ethyl 2-cyano-3,3-dimethyl-thioacrylate, followed by the nucleophilic substitution with 2-amino-3-chloro-4- methylpy
- Zhang, Huiping,Song, Baoan,Zhong, Huimin,Yang, Song,Jin, Linhong,Hu, Deyu,He, Wei
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- Synthesis, docking study and kinase inhibitory activity of a number of new substituted pyrazolo[3,4-c]pyridines
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A series of new pyrazolo[3,4-c]pyridines bearing various 1, 3, 5 or 1, 3, 7 pattern substitutions, were designed and synthesized. Some of them showed interesting inhibitory activity mainly against glycogen synthase kinase 3 (GSK3)α/β as well as against cdc2-like kinases 1 (CLK1) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), with good selectivity and remarkable structure-activity relationships (SARs), without being cytotoxic. Molecular simulations in correlation with biological data revealed the importance of the existence of N1-H as well as the absence of a bulky 7-substituent.
- Sklepari, Meropi,Lougiakis, Nikolaos,Papastathopoulos, Athanasios,Pouli, Nicole,Marakos, Panagiotis,Myrianthopoulos, Vassilios,Robert, Thomas,Bach, Stéphane,Mikros, Emmanuel,Ruchaud, Sandrine
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- Improved synthesis of 2-chloro-3-amino-4-methylpyridine
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2-Chloro-3-amino-4-methylpyridine (), a key intermediate in the synthesis of nervirapine, was prepared from 2-cyanoacetamide and 4,4-dimethoxyl-2-butanone via condensation, cyclization, one-pot reaction of chlorination and hydrolysis, and Hofmann reaction. Utilization of the quadratic orthogonal test resulted in a high yield (62.1%) of the whole process.
- Zhao, Qian,Chen, Han-Geng,Qian, Chao,Chen, Xin-Zhi
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- DIARYLTHIOHYDANTOIN COMPOUND AS ANDROGEN RECEPTOR ANTAGONIST
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The present application belongs to the field of medicine. In particular, the present application relates to a diarylthiohydantoin compound as an androgen receptor antagonist or a pharmaceutically acceptable salt thereof, a preparation method of the same, a pharmaceutical composition comprising the compound, and a use thereof in treating a cell proliferative disease mediated by androgen. The compound of the present application has good antagonistic effect on androgen receptor and exhibits excellent antitumor effect.
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Paragraph 0205-0207
(2020/07/07)
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- 4-methylpiperidine-3-ketone and simple preparation method of 4-methylpiperidine-3-ketone derivative
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The invention relates to 4-methylpiperidine-3-ketone and a simple preparation method of a 4-methylpiperidine-3-ketone derivative. According to the 4-methylpiperidine-3-ketone and the simple preparation method of the 4-methylpiperidine-3-ketone derivative, 1-nitro-3-methyl-5-hydroxy n-amyl-2-ketone is prepared by using a reaction of alpha-methyl-gamma-butyrolactone and nitromethane, then 1-nitro-3-methyl-5-protection oxy-n-pentyl-2-ketone is obtained through sulfonyl chloride reagent protection hydroxide radical, then nitro is reduced to amino through hydrogenation, and meanwhile 4-methylpiperidine-3-ketone is obtained through cyclization. The invention further provides a method for preparing 2-chlorin-3-amino-4-methylpyridine and N-benzyl-4-methylpiperidine-3-ketone from 4-methylpiperidine-3-ketone. Raw materials used in the simple preparation method and the method are cheap and readily available, the condition is mild, operation is simple and convenient and safe, reaction selectivityis high, the product yield and purity are high, the cost is low, the amount of "three wastes" is low, and environmental protection is realized.
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- Synthesis and Antiproliferative Activity of New pyrazolo[3,4-c]pyridines
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Background: Several pyrazolopyridines possess promising pharmacological activities, mainly attributed to their antagonistic nature towards the natural purines in many biological processes. Cytotoxicity and anticancer potential of this class of compounds a
- Gavriil, Efthymios-Spyridon,Lougiakis, Nikolaos,Pouli, Nicole,Marakos, Panagiotis,Skaltsounis, Alexios-Leandros,Nam, Sangkil,Jove, Richard,Horne, David,Gioti, Katerina,Pratsinis, Harris,Kletsas, Dimitris,Tenta, Roxane
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p. 365 - 374
(2017/06/21)
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- Increasing global access to the high-volume HIV drug nevirapine through process intensification
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Access to affordable medications continues to be one of the most pressing issues for the treatment of disease in developing countries. For many drugs, synthesis of the active pharmaceutical ingredient (API) represents the most financially important and technically demanding element of pharmaceutical operations. Furthermore, the environmental impact of API processing has been well documented and is an area of continuing interest in green chemical operations. To improve drug access and affordability, we have developed a series of core principles that can be applied to a specific API, yielding dramatic improvements in chemical efficiency. We applied these principles to nevirapine, the first non-nucleoside reverse transcriptase inhibitor used in the treatment of HIV. The resulting ultra-efficient (91% isolated yield) and highly-consolidated (4 unit operations) route has been successfully developed and implemented through partnerships with philanthropic entities, increasing access to this essential medication. We anticipate an even broader global health impact when applying this model to other active ingredients.
- Verghese, Jenson,Kong, Caleb J.,Rivalti, Daniel,Yu, Eric C.,Krack, Rudy,Alcázar, Jesus,Manley, Julie B.,McQuade, D. Tyler,Ahmad, Saeed,Belecki, Katherine,Gupton, B. Frank
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p. 2986 - 2991
(2017/07/24)
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- Preparation method for nevirapine intermediate
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The invention relates to a preparation method for an intermediate, i.e., 2-chloro-3-amino-4-methylpyridine, of an anti-AIDs drug nevirapine. The intermediate has a chemical structural formula I as described in the specification. The preparation method is characterized in that 4-methylpyridine is subjected to halogenation, ammonia substitution and chlorination so as to prepare 2-chloro-3-amino-4-methylpyridine. The preparation reactions are as shown in the specifications, wherein X is bromine or chlorine; a halogenation condition is Br2/AlCl3/95-105 DEG C, Br2/AlCl3/MBr/110 to 130 DEG C (wherein M is Li, Na or K), Br2/Fe/135-145 DEG C, Cl2/AlCl3, Br2/FeCl3 or Br2/SnCl4; an ammonia substitution condition is NH3(g)/CuSO4/CH3OH/170-190 DEG C, NH3(aq)/CuSO4/170-190 DEG C, or NaNH2; and a chlorination reaction condition is Cl2/AlCl3 or HCl/H2O2/30-50 DEG C.
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- LOWCOST, HIGH YIELD SYNTHESIS OF NEVIRAPINE
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Improved methods of producing the HIV drug substance, nevirapine are provided. The methods employ a cost effective and high yield synthetic methods for preparing the nevirapine building block 2-chloro-3-amino-4-picoline (CAPIC) and 2-cyclopropyl amino nicotinate (Me-CAN), and improvements in other steps of nevirapine synthesis.
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- Experimental study on seawater applications in organic reactions
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Background: Total water resources account for only 2.5% of freshwater on earth, and only 1% of total water resources can be exploited by humans. The development of practical methods of seawater desalination and comprehensive utilization technology can help address the shortage of freshwater resources in the world, and achieve sustainable use of water resources to ensure sustainable development in a society. Direct seawater utilization currently involves industrial cooling water, water for agricultural irrigation, and flushing water. Applications in aqueous phase organic reactions, particularly the direct use of seawater in industrial organic synthesis reactions, are seldom reported. Methods: we used seawater instead of freshwater in selected basic organic chemical reactions. The application of seawater in aqueous phase organic reactions was systematically investigated. Six types of reactions were studied using freshwater and seawater, namely, preparation of acetanilide, synthesis of mandelic acid, Cannizzaro reaction, Hofmann degradation reaction, preparation of quinazolin-4-one, and preparation of adipic acid. Results: Seven organic compounds were produced. Results show that some organic reactions could directly use seawater or treated seawater as an alternative to freshwater. The yields of the reactions using seawater could be compared with literature values, or were even better than literature values. Conclusion: This research provides new opportunities for the comprehensive utilization of seawater. Some organic reactions could directly use seawater or treated seawater instead of freshwater. The use of seawater instead of freshwater for organic reactions in industrial production may greatly conserve freshwater resources and protect the environment.
- Liu, Gang,Qiu, Mingxiang,Sun, Lin,Wen, Quanwu,Xu, Shengguang,Wang, Xuyuan,Wang, Peng
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- Method for preparing 2-chloro-4-methylpyridine-3-carbonitrile
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The invention discloses a method for preparing 2-chloro-4-methylpyridine-3-carbonitrile. The method comprises the following steps: at -20 DEG C to 50 DEG C, a hydrogen chloride solution is used for treating raw materials containing 4,4-dicyano-3-methyl-3-butenal dimethyl acetal. 2-chloro-4-methylpyridine-3-carbonitrile whose HPLC purity reaches 99% or above can be conveniently obtained, which has important meanings for subsequent preparation of high purity 2-chloro-4-methylpyridine-3-carbonitrile and nevirapine; the method has the advantages of short process route, simple operation, high yield, low cost, etc., a highly toxic product phosphorous oxychloride is avoided, discharge of waste water is reduced, and the method is very suitable for industrial production.
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Paragraph 0056; 0058; 0059
(2016/11/14)
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- FUSED HETEROCYCLIC COMPOUNDS
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The present invention provides a compound which has the effect of PDE inhibition, and which is useful as an agent for preventing or treating schizophrenia. The compound is represented by the formula (I): wherein the symbols are defined in the specification.
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Page/Page column 70
(2012/01/13)
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- PREPARATION AND UTILITY OF NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
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Disclosed herein are non-nucleoside reverse transcriptase inhibitors having structural Formula ( I ), processes of preparation thereof, pharmaceutical compositions thereof, and the methods of their use thereof. Formula ( I )
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Page/Page column 72-73
(2008/12/08)
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- AN IMPROVED PROCESS FOR INDUSTRIAL MANUFACTURE OF NEVIRAPINE
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An improved cost-effective, environmental friendly, industrial method for manufacture of Nevirapine.Formula (I):
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(2008/06/13)
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- SYNTHESIS OF 3-AMINO-2-CHLORO-4-METHYLPYRIDINE FROM ACETONE AND ETHYL CYANOACETATE
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A method for making 3-amino-2-chloro-4-methylpyridine from acetone and ethyl cyanoacetate, as depicted in the following reaction scheme.
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(2010/02/14)
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- SYNTHESIS OF 3-AMINO-2-CHLORO-4-METHYLPYRIDINE FROM MALONONITRILE AND ACETONE
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A method for making 3-amino-2-chloro-4-methylpyridine from malononitrile, as depicted in the following reaction scheme.
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- Process for making 3-amino-2-chloro-4-methylpyridine
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A method for making 3-amino-2-chloro-4-methylpyridine, as shown in Scheme 12, below.
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- Preparation of 4-substituted 3-amino-2-chloropyridines, synthesis of a nevirapine analogue
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A new method for preparing 3-amino-2-chloropyridines with a substituent (methyl, phenyl, carboxamide, methoxycarbonyl, acetyl, benzoyl and cyano) at the 4-position has been developed. An isoquinoline analogue of the reverse transcriptase inhibitor Nevirapine has been synthesized from the 4-amino-3-chloroisoquinoline.
- Bakke,Riha
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- Synthesis of 3-amino-2-chloro-4-methylpyridine from acetone and ethyl cyanoacetate
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A method for making 3-amino-2-chloro-4-methylpyridine from acetone and ethyl cyanoacetate, as depicted in the following reaction scheme.
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- Method for the preparation of 3-amino-2-chloro-4-alkylpyridines
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A process for the preparation of a 3-amino-2-chloro-4-alkylpyridine of the formula: STR1 wherein R1 is a linear, branched or cyclic hydrocarbon of from one to eight carbon atoms, optionally substituted with one or more electron stabilizing groups, an inte
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- Method for preparing 3-amino-2-chloro-4-alkylpyridine or-4-arylpyridine
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The present invention relates to a new process for preparing 3-amino-2-chloro-4-alkyl- or -4-aryl-pyridines on an industrial scale.
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- Method for the preparation of 3-amino-2-chloro-4-methylpyridines
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A process for the preparation of a 3-amino-2-chloro-4-alkylpyridine of the formula: STR1 wherein R is alkyl of from one to three carbon atoms, an intermediate in the preparation of certain 5,11-dihydro-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepine compounds useful in the prevention and treatment of HIV infection.
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- Processes for producing 2-Halo-nicotinic acid derivatives and precursors thereto
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Disclosed are preferred processes for the preparation of 2-halo-nicotinic acid derivatives of formula (IV): STR1 by cyclocondensation of a 4-halo-4-cyanocarbonyl compound of formula (III): STR2 wherein X is Cl or Br; Y is a carbonyl group and R1, R2 and R3 are each, independently, H, Cl, Br or an organic radical. Further preferred aspects include the preparation of the above-noted 4-halo-4-cyanocarbonyl compound via Michael addition of a 2-halonitrile with an α,β-unsaturated aldehyde or ketone, and the preparation of the 2-halonitrile by redistribution of halogen between a 2,2-dihalonitrile and a parent nitrile.
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- Regioselective synthesis of 2-chloro 3-pyridinecarboxylates
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2-Chlorocyanoacetate was found to undergo base-catalyzed Michael addition to α,β-unsaturated ketones or aldehydes to afford 5-oxopentenenitrile derivatives. In the presence of anhydrous HCl, these compounds cyclize to yield 2-chloro-3-pyridinecarboxylates. The process is highly regiospecific and useful in the synthesis of 2,3-disubstituted pyridines.
- Zhang,Stout,Keay,Scriven,Toomey,Goe
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p. 13177 - 13184
(2007/10/03)
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- Synthesis of nevirapine and its major metabolite
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Several synthetic methods were developed during the process optimization for the large scale synthesis of nevirapine (1), a non-nucleoside inhibitor of HIV-1 Reverse Transcriptase. The synthesis of its putative major metabolite 11-cyclopropyl-5,11-dihydro-4-hydroxymethyl-6H-[3,2-b:2',3'-e][1,4]dia zepin-6-one (2) and the oxidation of 2 to the corresponding aldehyde 3, are described.
- Grozinger,Fuchs,Hargrave,Mauldin,Vitous,Campbell,Adams
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p. 259 - 263
(2007/10/02)
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- 5,11-dihydro-6H-dipyrido(3,2-B:2',3'-E)(1,4)diazepines and their use in the prevention or treatment of HIV infection
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Disclosed are novel 5,11-dihydro-6H-dipyrido[3,2-b; 2',3'-e][1,4]diazepines. These are useful in the prevention or treatment of HIV infection.
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- Method for preparing 3-amino-2-chloro-4-alkylpyridines
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A process for the preparation of a 3-amino-2-chloro-4-alkylpyridine of the formula: STR1 wherein R is alkyl of from one to three carbon atoms, an intermediate in the preparation of certain 5,11-dihydro-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepine compounds useful in the prevention and treatment of HIV infection.
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- Novel Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase. 1. Tricyclic Pyridobenzo- and Dipyridodiazepinones
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Novel pyridobenzodiazepinones (I), pyridobenzodiazepinones (II), and dipyridodiazepinones (III) were found to inhibit human immunodeficiency virus type 1 (HIV-1) reverse transcriptase in vitro at concentrations as low as 35 nM.In all three series, small substituents (e.g., methyl, ethyl, acetyl) are preferred at the lactam nitrogen, whereas slightly larger alkyl moieties (e.g., ethyl, cyclopropyl) are favored at the other (N-11) diazepinone nitrogen.In general, lipophilic substituents are preferred on the A ring, whereassubstitution on the C ring generally reduces potency relative to the corresponding compounds with no substituents on the aromatic rings.Maximum potency is achieved with methyl substitution at the position ortho to the lactam nitrogen atom; however, in this case an unsubstituted lactam nitrogen is preferred.Additional substituents on the A ring can be readily tolerated.The dipyridodiazepinone derivative 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyridodiazepin-6-one (96, nevirapine) is a potent (IC50 = 84 nM) and selective non-nucleoside inhibitor of HIV-1 reverse transcriptase, and has been chosen for clinical evaluation.
- Hargrave, Karl D.,Proudfoot, John R.,Grozinger, Karl G.,Cullen, Ernest,Kapadia, Suresh R.,et al.
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p. 2231 - 2241
(2007/10/02)
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- Pyrazolopyridines. Part 5. Preparation and Reactions of Pyrazolopyridines
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A series of pyrazolopyridines has been prepared by nitrosation of 3-acetamido-4-methylpyridines and subsequent rearrangement and cyclisation of the N-acetyl-N-nitroso-compounds produced.The reactions of the pyrazolopyridines have been investigated. 1- and 2-Acetyl and 1- and 2-benzyl compounds were obtained and their structures elucidated spectroscopically.The ring system readily undergoes electrophilic substitution in the 3-position. 7-Chloropyrazolopyridine has been shown to be more susceptible to nucleophilic substitution than the isomeric 5-chloro-compound.
- Chapman, David,Hurst, Jim
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p. 2398 - 2404
(2007/10/02)
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