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There are provided novel compounds of formula (I) STR1 wherein X, R1, R2, R3, R4 and R5 are as defined in the specification and optical isomers and racemates thereof and pharmaceutically acceptable salts thereof; together with processes for their preparation, compositions containing them and their use in therapy.

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An additive-free Pd-catalyzed alpha-allylation of different imino-group-ontaining heterocycles is reported. The activation of alpha-CH pronucleophiles (pKa (DMSO) > 25) occurs without the addition of strong bases or Lewis acids using only the Pd/Xantphos catalyst system. The reaction scope has been studied for various 5- and 6-membered nitrogen-containing heterocycles (yields up to 96%). Mechanistic investigations suggest an initial allylation of the imine-N followed by a Pd-catalyzed formal aza-Claisen rearrangement.

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The importance and structural diversity of chiral amines is well-demonstrated by the myriad nonenzymatic methods for their chemical production. In nature, the production of amines is performed by transamination rather than by reduction of an imine precursor derived from the corresponding ketone. Imine reductases, however, show great potential in the reduction of cyclic imines that are stable towards hydrolysis in aqueous reaction media. Here, we report the catalytic activity of two S-selective imine reductases towards 3,4-dihydroisoquinolines and 3,4-dihydro-beta-carbolines and their activity in the direct reductive amination of ketone substrates. The crystal structures of the enzyme from Streptomyces sp. GF3546 in complex with the cofactor NADPH and from Streptomyces aurantiacus in native form have been solved and refined to a resolution of 1.9 A.

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Reactions of alkyl-substituted 3,4-dihydroisoquinolines with 2-acetylcyclopentane-1,3-dione were used to prepare 3,4-dihydroisoquinolinium 2-acetylcyclopentane-1,3-dionates, which could not be converted into ABCD-tetracyclic derivatives of the 8-azagonane series (benzo[a]cyclopentano[f]quinolizines). The salts obtained were studied and characterized by physicochemical methods. It was shown by combining the NMR and H/D-isotope exchange methods that for 1-alkyl-3,4-dihydroisoquinolines and their salts in solutions, an imine-enamine (iminium-enaminium), and for the 2-acetylcyclopentane-1,3-dione anion, a keto-enol tautomeric equilibrium takes place. 1998 Plenum Publishing Corporation.

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A new imine reductase from Stackebrandtia nassauensis (SnIR) was identified, which displayed over 25- to 1400-fold greater catalytic efficiency for 1-methyl-3,4-dihydroisoquinoline (1-Me DHIQ) compared to other imine reductases reported. Subsequently, an efficient SnIR-catalyzed process was developed by simply optimizing the amount of cosolvent, and up to 15 g L-1 1-Me DHIQ was converted completely without a feeding strategy. Furthermore, the reaction proceeded well for a panel of dihydroisoquinolines, affording the corresponding tetrahydroisoquinolines (mostly in S-configuration) in good yields (up to 81%) and with moderate to excellent enantioselectivities (up to 99% ee).

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A new approach to the construction of polycyclic skeletons of fused azines with nitrogen at the bridgehead based on a novel reaction of cyclic Schiff’s bases (1-alkyl-substituted-3,4-dihydroisoquinolines) with alpha-aminomethylenecarbonyl) compounds (2-aminomethylenecyclohexane-1,3-diones or aminomethylenemalonic ester) was developed. – Keywords: cyclic Schiff’s bases; azomethines; 1-alkyl-3,4-dihydroisoquinolines; enamines; aminoenones; beta-aminoacrylates; 2-aminomethylenecyclohexane-1,3-diones; aminomethylene malonates; benzoquinolizines; dibenbzoquinolizinium chlorides; 8-aza-D-homogonanium chlorides; 8-azasteroids; <3+3>cyclocondensation; annelation.

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THE SYNTHESIS OF FUSED RING NITROGEN HETEROCYCLES VIA REGIOSPECIFIC INTRAMOLECULAR HECK REACTIONS

A series of palladium (and in some cases rhodium) catalysed regiospecific 5-exo-, 6-endo- and 6-exo-trig cyclisations of aryl iodides and vinyl bromides onto proximate alkenes or heteroaromatic rings (indole, pyrrole) lead to a wide variety of fused ring systems.In appropriate cases the methodology provides a facile approach to the creation of tetrasubstituted carbon centres.Double bond isomerisation in the product is only observed in a few cases.

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When associated with a noncoordinating bulky counteranion, a cationic Cp*Rh(III)-diamine catalyst displayed excellent enantioselectivities in asymmetric hydrogenation of cyclic imines, affording bioactive tetrahydroisoquinolines and tetrahydro-beta-carbolines frequently with 99% ee-s. Copyright

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A new approach (AB + D -> ABCD) to the construction of tetracyclic 8-azagonane (cyclopenta[5,6]pyrido[2,1-a]isoquinoline or benzo[a]cyclopenta[f]quinolizine) structures was developed and exemplified by cyclocondensation of 1-alkyl-3,4-dihydroisoquinolines with ethyl 2-oxocyclopentanecarboxylate.

A new approach (AB + D -> ABCD) to the construction of tetracyclic 8-azagonane (cyclopenta[5,6]pyrido[2,1-a]isoquinoline or benzo[a]cyclopenta[f]quinolizine) structures was developed and exemplified by cyclocondensation of 1-alkyl-3,4-dihydroisoquinolines with ethyl 2-oxocyclopentanecarboxylate.

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Reactions of a series of 4-cyano- and 4-acylsubstituted triafulvenes 1-5 wiith cyclic imines 8-13 give rise to polyheterocyclic derivatives of 2-methylenetetrahydropyridine (14, 18, 20, 31, 33), 4-methylene tetrahydroazocines (37) and 4(2)-methylene-2(3)-pyrrolines (41-43).The spectroscopic and chemical properties of the products obtained, as well as their independent syntheses in some cases, are reported.

Reactions of a series of 4-cyano- and 4-acylsubstituted triafulvenes 1-5 wiith cyclic imines 8-13 give rise to polyheterocyclic derivatives of 2-methylenetetrahydropyridine (14, 18, 20, 31, 33), 4-methylene tetrahydroazocines (37) and 4(2)-methylene-2(3)-pyrrolines (41-43).The spectroscopic and chemical properties of the products obtained, as well as their independent syntheses in some cases, are reported.

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