Compounds for complexation of rare earth elements and / or s-, p-, d- block metals, their coordination compounds, peptide conjugates, method of their preparation and use thereof

Abstract

The present invention relates to compounds of general formula (I) for use as complexing agents. The invention further relates to the coordination compounds thereof, peptide conjugates, method of their preparation and use thereof.

Description

Compounds for complexation of rare earth elements and / or s-, p-, d- block metals, their coordination compounds, peptide conjugates, method of their preparation and use thereof State of Art The present invention relates to new macrocyclic compounds suitable as cross-bridged chelators for complexation of rare earth elements and / or s-, p-, d- block metals, forming extremely stable coordination compounds. These coordination compounds are suitable for use as labels for quantitative detection of peptide conjugates, and / or as contrast agents for magnetic resonance imaging. The invention further relates to a method of preparation of the chelators and to a method of tracing peptide / protein containing medicaments. Background Art Metal elements find biomedical applications such as imaging contrast agents, radiotherapeutic agents or bioanalytical labels. For most of these applications, it is necessary to bind the metal in a stable chelate that can be covalently linked to other molecules, such as targeting vectors based on peptides or antibodies. The most universal example of a chelator applicable to majority of metal elements is DOTA (1,4,7,10- tetraazacyclododecane-1,4,7,10-tetraacetic acid) and its derivatives. A broad range of other chelators have been developed specifically for particular metal elements. [Price E. W., Orvig C. (2014), Chem. Soc. Rev. 43(1), 260 <semantics>−290<annotation encoding="application / x-tex">-290< / annotation>< / semantics>]. Rare earth elements (scandium - Sc, yttrium - Y, lanthanum - La, cerium - Ce, praseodymium - Pr, neodymium - Nd, promethium - Pm, samarium - Sm, europium - Eu, gadolinium - Gd, terbium - Tb, dysprosium - Dy, holmium - Ho, erbium - Er, thulium - Tm, ytterbium - Yb and lutetium - Lu) are a group of metals that offer a broad range of medical applications. Radiopharmaceuticals based on 90Y, 153Sm and 177Lu are approved by FDA, clinical trials are ongoing with 166Ho, and others show advantageous properties for Positron Emission Tomography (PET), Single-Photon Emission Computed Tomography (SPECT) or therapy (44Sc, 47Sc, 86Y, 149Pm, 159Gd, 149Tb, 161Tb, 165Dy, 161Ho, 169Er and 175Yb). Stable, non-radioactive Gd chelates are in clinical use as contrast agents for Magnetic Resonance Imaging (MRI). Stable isotopes of rare earth elements also serve as labels for analytical purposes. Compounds of interest labeled in this way can be visualized, traced and quantified based on unique luminescence or isotope mass of the elements that have zero background in biological systems. The unique isotope mass is especially useful, as it allows many compounds to be quantified simultaneously in a single analysis (multiplexing), typically with the use of inductively-coupled plasma mass spectrometry (ICP-MS) [Bodenmiller B. et al. (2012), Nat. Biotechnol. 30(9), 858-867]. Other metal elements 2 from s-, p- and d-block of the periodic system, such as 89Sr, 223Ra, 117mSn, 212Pb, 213Bi, 64Cu, 225Ac, find use in radiopharmaceutical compounds for imaging or therapy. For practical use, metal chelates must be very stable, so that the metal ion cannot easily escape from the chelator and detach from the carrier molecule. In this respect, thermodynamic stability constant provides insufficient information, because most applications proceed under conditions far from thermodynamic equilibrium (e.g. in- vivo). Instead, kinetic inertness that characterizes the rate at which the metal ion escapes from the chelate under given conditions must be considered. Kinetic inertness strongly correlates with rigidity of the chelator. Acyclic chelators of the type DTPA (diethylenetriaminepentaacetic acid) have more flexible structure and provide lower kinetic inertness than macrocyclic chelators of the type DOTA, which are more rigid. Chelates with high kinetic inertness are desirable particularly for in-vivo applications, where the metal chelate is challenged with excess of competing biogenic chelators and metal ions. For this reason, the rigid and kinetically inert macrocyclic chelators are preferred to the flexible acyclic ones. For example, practically all radiopharmaceuticals based on the radionuclide 177Lu (half-life 6.7 days) that are approved or in development make use of the macrocyclic chelator DOTA, as the metal must remain bound to the targeting molecule in-vivo for weeks in order to have the desired curative effect. Similarly, in MRI contrast agents, macrocyclic chelates of gadolinium(III) are preferred to the acyclic DTPA type. It has been recently found that significant amount of free gadolinium is released in-vivo from the acyclic agents and deposited in human brain for long time. [Fur M. L., Caravan P. (2019), Metallomics 11(2), 240-254 In response to this finding and to prevent potential harm to patients, the use of the acyclic MRI contrast agents has been severely restricted around the globe by drug-regulating agencies. It is therefore likely that the importance of kinetic inertness of metal chelates will grow in medical and other applications, and chelators providing higher inertness will be needed. Methods to further increase kinetic inertness rely on reinforcement and rigidification of the macrocyclic chelators with additional rings. For example, a cross-bridged macrocyclic chelator cb-TE2A (4,11- bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane) provides much more inert chelates with copper(II) ion than the non-cross-bridged analogues [Boswell C. A. et al. (2004), J. Med. Chem. 47(6), 1465- 1474]. Another similar chelator cb-TEDPA (6,6'-((1,4,8,11-Tetraazabicyclo[6.6.2]hexadecane-4,11- diyl)bis(methylene))dipicolinic acid) was shown to provide exceptionally inert lanthanide(III) chelates [Rodríguez-Rodríguez A. et al. (2016), Inorg. Chem. 55(5), 2227-2239]. Another cyclen-based cross-bridged chelator provided extremely inert copper(II) chelates [Esteves, C. V. et al. (2013), Inorg. Chem. 52(9), 5138- 5153]. A common feature of these chelators is that the bridge is independent from the coordinating pendant arms and is oriented on the opposite side from the pendant arms in the chelate. Chelators where the bridge connected the pendant arms themselves have also been made, but the effect on stability of the chelates was strongly negative [Vipond, J. et al. (2007), Inorg. Chem. 46(7), 2584-2595]. There are also practical limitations when too high kinetic inertness becomes counterproductive. This is because the energy barrier that the metal ion must overcome on the way out of the chelate is similar to the barrier that it has to overcome on the way in during chelate formation. Generally, the more inert a chelate is, the more difficult it is to make. The formation kinetics can be accelerated with high temperature and long reaction times. However, such reaction conditions are often incompatible with sensitive targeting vectors (e.g. antibodies) and / or half-life of metal radionuclides in preparation of radiopharmaceuticals. There remains a strong need for new types of chelators, which would form highly kinetically inert metal complexes quickly and under mild synthetic conditions. Disclosure of Invention We have circumvented problems of the background art with a new type of chelators, which form a bridge after complexation of the metal ion that rigidifies the structure and increases kinetic inertness. The bridge is formed between two coordinating pendant arms based on cycloaddition reaction between alkyne and azide substituents on the opposite pendant arms. This reaction does not require catalyzation by Cu(I) ions as is usually the case, and occurs spontaneously after formation of a non-bridged chelate. The chelator therefore acts as a one-way trap for the metal ion. Initial formation of the non-bridged chelate is relatively fast. Then, a bridge is formed that traps the metal inside the chelator. For rare earth elements, the resulting bridged chelates show extremely high kinetic inertness that is up to 6 orders of magnitude higher than for the analogous chelates with DOTA. Such unusually high inertness allows new uses of the chelates as analytical labels that can withstand harsh hydrolytic conditions in concentrated acids and can be quantified in the lysate as intact chelates with liquid chromatography – mass spectrometry (LC-MS). The use of LC-MS is advantageous, as it is much more common instrument than ICP-MS. The extremely high inertness is also advantageous for potential in-vivo use of the chelates, such as MRI contrast agents or radiopharmaceuticals, as no free metal is released in-vivo from the coordination compounds, therefore no metal deposit occurs in human or animal body. The compounds according to the present invention are capable of acting as extremely efficient molecular traps, which can coordinate metal ions in an extremely stable, rigid and well defined manner. The ligands can be prepared in relatively a few number of steps of organic synthesis. After coordination of the metal ion, the click reaction is performed between the azide group and a triple bond present in opposite pendant arms of the macrocycle, forming a triazole bridge, and enclosing the metal ion within the cage (forming the so-called click- zipped complex). The formation of triazole is irreversible and is depicted in Scheme 1 below. Scheme 1. Schematic representation of the click-zip principle illustrated on the example of ligand TD647. [Image disponible dans le document PDF, Image available in the PDF document] In first aspect, the subject of the present invention relates to compounds of general formula (I) [Image disponible dans le document PDF, Image available in the PDF document] wherein Y is selected from a group consisting of nitrogen (N); N-oxide (N+-O-); <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is selected from the group consisting of H; halogen; <semantics>−OH<annotation encoding="application / x-tex">-OH< / annotation>< / semantics>; <semantics>−N3<annotation encoding="application / x-tex">-N_3< / annotation>< / semantics>; <semantics>−(CH2)nN3<annotation encoding="application / x-tex">-(CH_2)_nN_3< / annotation>< / semantics>, wherein n is an integer in the range of from 1 to 3; –NR2, wherein R is independently selected from H or C1 to C6 alkyl, which may be branched or linear; <semantics>−(CH2)nNR2<annotation encoding="application / x-tex">-(CH_2)_nNR_2< / annotation>< / semantics>, wherein n and R are as defined above; <semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics> to <semantics>C10<annotation encoding="application / x-tex">C_{10}< / annotation>< / semantics> aryl, which can optionally be substituted with -NH2, -NO2, -N3, \( \frac{\xi}{2} \) = CH, -COOH, -CH2Cl and / or -CH2COOH; C7 to C10 arylalkyl, which can optionally be substituted with -NH2, -NO2, -N3, \( \frac{\bigset}{=} \equiv CH, \quad -COOH, -CH2Cl and / or - CH2COOH; <semantics>−CF3<annotation encoding="application / x-tex">-CF_3< / annotation>< / semantics>; <semantics>−COOR<annotation encoding="application / x-tex">-COOR< / annotation>< / semantics>, wherein R is as defined above; <semantics>−(CH2)nCOOR<annotation encoding="application / x-tex">-(CH_2)_nCOOR< / annotation>< / semantics>, wherein n and R are as defined above; <semantics>=−Si−iPr<annotation encoding="application / x-tex">= -Si - iPr< / annotation>< / semantics> <semantics>iPr;−CH2CH(OMe)2;<annotation encoding="application / x-tex">iPr ; -CH_2CH(OMe)_2;< / annotation>< / semantics> <semantics>=−CH2CH(OMe)2;<annotation encoding="application / x-tex">= -CH_2CH(OMe)_2;< / annotation>< / semantics> <semantics>=−CH2CH(OMe)2;<annotation encoding="application / x-tex">= -CH_2CH(OMe)_2;< / annotation>< / semantics> <semantics>=−CH2CH(OMe)2;<annotation encoding="application / x-tex">= -CH_2CH(OMe)_2;< / annotation>< / semantics> <semantics>=−CH2CH(OMe)2;<annotation encoding="application / x-tex">= -CH_2CH(OMe)_2;< / annotation>< / semantics> <semantics>=−CH2CH(OMe)2;<annotation encoding="application / x-tex">= -CH_2CH(OMe)_2;< / annotation>< / semantics> <semantics>=−CH2CH(OMe)2;<annotation encoding="application / x-tex">= -CH_2CH(OMe)_2;< / annotation>< / semantics> <semantics>=−CH2CH(OMe)2;<annotation encoding="application / x-tex">= -CH_2CH(OMe)_2;< / annotation>< / semantics> <semantics>=−CH2CH(OMe)2;<annotation encoding="application / x-tex">= -CH_2CH(OMe)_2;< / annotation>< / semantics> <semantics>=−CH2CH(OM<annotation encoding="application / x-tex">= -CH_2CH(OM< / annotation>< / semantics> <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is <semantics>N3<annotation encoding="application / x-tex">N_3< / annotation>< / semantics>; or <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is <semantics>N3<annotation encoding="application / x-tex">N_3< / annotation>< / semantics>; or <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is <semantics>N3<annotation encoding="application / x-tex">N_3< / annotation>< / semantics>, wherein <semantics>n<annotation encoding="application / x-tex">n< / annotation>< / semantics> is an integer in the range of from 1 to 3; preferably, <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is <semantics>N3<annotation encoding="application / x-tex">N_3< / annotation>< / semantics> or <semantics>E−CH2−N3<annotation encoding="application / x-tex">E-CH_2-N_3< / annotation>< / semantics>; more preferably <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is <semantics>N3<annotation encoding="application / x-tex">N_3< / annotation>< / semantics>; A are independently selected from the group consisting of H; <semantics>−(CH2)nCOOH<annotation encoding="application / x-tex">-(CH_2)_nCOOH< / annotation>< / semantics>, wherein n is an integer from 1 to 3; -CH(CH3)COOH; -CH((CH2)nCH3)COOH, wherein n is as defined above; -CH2P(=O)(OR)2, wherein R is as defined above; <semantics>−CH((CH2)nCOOH)COOH<annotation encoding="application / x-tex">-CH((CH_2)_nCOOH)COOH< / annotation>< / semantics>, wherein n is an integer from 1 to 3; <semantics>−CH((CH2)nNH2)COOH<annotation encoding="application / x-tex">-CH((CH_2)_nNH_2)COOH< / annotation>< / semantics>, wherein n is an integer from 1 to 3; <semantics>−CH2C(=O)(NH2)<annotation encoding="application / x-tex">-CH_2C(=O)(NH_2)< / annotation>< / semantics>; <semantics>−CH2C(=O)(NH)−CH2COOH<annotation encoding="application / x-tex">-CH_2C(=O)(NH)-CH_2COOH< / annotation>< / semantics>; <semantics>−CH2P(=O)(OH)(Ar)<annotation encoding="application / x-tex">-CH_2P(=O)(OH)(Ar)< / annotation>< / semantics>, wherein Ar is phenyl, which can optionally be substituted with <semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics> to <semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics> alkyl; Z is selected from a group consisting of [Image disponible dans le document PDF, Image available in the PDF document] wherein [Image disponible dans le document PDF, Image available in the PDF document] R4 is selected from the group consisting of H; halogen; piperidinyl; trimethylsilyl; triisopropylsilyl; phenyl; C1 to <semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics> alkyl, which may be branched or linear; <semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics> to <semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics> cycloalkyl; <semantics>−CF3<annotation encoding="application / x-tex">-CF_3< / annotation>< / semantics>; <semantics>−(CH2)nNHR6<annotation encoding="application / x-tex">-(CH_2)_nNHR^6< / annotation>< / semantics>, wherein <semantics>n<annotation encoding="application / x-tex">n< / annotation>< / semantics> is an integer in the range of from 1 to 3 and R6 is selected from H, fluorenylmethyloxycarbonyl, tert-butyloxycarbonyl and benzyloxycarbonyl; <semantics>−C(CH3)2(NHR6)<annotation encoding="application / x-tex">-C(CH_3)_2(NHR^6)< / annotation>< / semantics>, wherein <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics> is as defined above; adamantyl; <semantics>ξ<annotation encoding="application / x-tex">\frac{\xi}{}< / annotation>< / semantics> <semantics>=<annotation encoding="application / x-tex">=< / annotation>< / semantics> <semantics>CH<annotation encoding="application / x-tex">CH< / annotation>< / semantics>: <semantics>−(CH2)nCOOH<annotation encoding="application / x-tex">-(CH_2)_nCOOH< / annotation>< / semantics>, wherein <semantics>n<annotation encoding="application / x-tex">n< / annotation>< / semantics> is as defined above; <semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics> to <semantics>C10<annotation encoding="application / x-tex">C_{10}< / annotation>< / semantics> aryl, which can optionally be substituted with <semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>, <semantics>−NO2,−N3,<annotation encoding="application / x-tex">-NO_2, -N_3,< / annotation>< / semantics> COOH, <semantics>−CH2Cl<annotation encoding="application / x-tex">-CH_2Cl< / annotation>< / semantics> and / or <semantics>−CH2COOH<annotation encoding="application / x-tex">-CH_2COOH< / annotation>< / semantics>; <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics> is <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> or <semantics>=<annotation encoding="application / x-tex">=< / annotation>< / semantics> <semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>, wherein <semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics> is as defined above; preferably <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics> is H; <semantics>−CF3<annotation encoding="application / x-tex">-CF_3< / annotation>< / semantics>; halogen; <semantics>−OH<annotation encoding="application / x-tex">-OH< / annotation>< / semantics>; <semantics>C7<annotation encoding="application / x-tex">C_7< / annotation>< / semantics> to C10 arylalkyl, which can optionally be substituted with –NH2, –NO2, –COOH, –CH2Cl and / or <semantics>−CH2COOH<annotation encoding="application / x-tex">-CH_2COOH< / annotation>< / semantics>; or <semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>. [Image disponible dans le document PDF, Image available in the PDF document] and / or R2 and R3 together form a 1,2,3-triazole group of formula R4 is defined above; with the proviso that at most one A is H. When the compounds of this invention contain a chiral centre, then all enantiomers, mixtures of enantiomers and racemates fall within the framework of the present invention. The present invention further includes the compounds of general formula (I) in the form of salts with alkali metals, ammonium or amines, as well as in the form of addition salts with acids. The term ,,halogen" means any iozotop of F, Cl, Br, and I; in particular, this term includes non-radioactive izotopes, such as 19F, 35Cl, 37Cl, 79Br, 81Br, 127I; and radioizotopes, such as 18F, 36Cl, 77Br, 83Br, 123I, 124I, 125I, <semantics>131<annotation encoding="application / x-tex">^{131}< / annotation>< / semantics>I. In one embodiment, A are independently selected from the group consisting of H; <semantics>−(CH2)nCOOH<annotation encoding="application / x-tex">-(CH_2)_nCOOH< / annotation>< / semantics>, wherein n is an integer from 1 to 3; <semantics>−CH(CH3)COOH<annotation encoding="application / x-tex">-CH(CH_3)COOH< / annotation>< / semantics>; <semantics>−CH((CH2)nCH3)COOH<annotation encoding="application / x-tex">-CH((CH_2)_nCH_3)COOH< / annotation>< / semantics>, wherein n is an integer from 1 to 3; <semantics>−CH2P(=O)(OR)2<annotation encoding="application / x-tex">-CH_2P(=O)(OR)_2< / annotation>< / semantics>, wherein R is as defined above; <semantics>−CH2C(=O)(NH2)<annotation encoding="application / x-tex">-CH_2C(=O)(NH_2)< / annotation>< / semantics>; <semantics>−CH2C(=O)(NH)−CH2COOH<annotation encoding="application / x-tex">-CH_2C(=O)(NH)-CH_2COOH< / annotation>< / semantics>; <semantics>−CH2P(=O)(OH)(Ar)<annotation encoding="application / x-tex">-CH_2P(=O)(OH)(Ar)< / annotation>< / semantics>, wherein Ar is phenyl, which can optionally be substituted with <semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics> to <semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics> alkyl. In one embodiment, R1 is selected from the group consisting of H; halogen; -OH; -N3; -CH2N3; -NR2, wherein R is independently selected from H or C1 to C6 alkyl, which may be branched or linear; –CH2NR2, wherein R are as defined above; C6 to C10 aryl, which can optionally be substituted with –NH2, –NO2, –COOH and / or -CH2COOH; C7 to C10 arylalkyl, which can optionally be substituted with -NH2, -NO2, -COOH, -CH2Cl and / or <semantics>−CH2COOH<annotation encoding="application / x-tex">-CH_2COOH< / annotation>< / semantics>; <semantics>−CF3<annotation encoding="application / x-tex">-CF_3< / annotation>< / semantics>; <semantics>−COOR<annotation encoding="application / x-tex">-COOR< / annotation>< / semantics>, wherein R is as defined above; <semantics>−(CH2)nCOOR<annotation encoding="application / x-tex">-(CH_2)_nCOOR< / annotation>< / semantics>, wherein n and R are as [Image disponible dans le document PDF, Image available in the PDF document] defined above; wherein Ar is phenyl; NO2; preferably <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is selected from H; halogen; <semantics>−OH<annotation encoding="application / x-tex">-OH< / annotation>< / semantics>; <semantics>−N3<annotation encoding="application / x-tex">-N_3< / annotation>< / semantics>; <semantics>−CH2N3<annotation encoding="application / x-tex">-CH_2N_3< / annotation>< / semantics>; <semantics>−N(CH3)2<annotation encoding="application / x-tex">-N(CH_3)_2< / annotation>< / semantics>; phenyl; carboxyphenyl; <semantics>−CF3<annotation encoding="application / x-tex">-CF_3< / annotation>< / semantics>; [Image disponible dans le document PDF, Image available in the PDF document] -COOR, wherein R is as defined above; and In one embodiment, R4 is selected from the group consisting of H; halogen; piperidinyl; trimethylsilyl; triisopropylsilyl; phenyl; C1 to C6 alkyl, which may be branched or linear; C3 to C6 cycloalkyl; –CF3; – CH2NHR6, wherein R6 is selected from H, fluorenylmethyloxycarbonyl, tert-butyloxycarbonyl and benzyloxycarbonyl; –C(CH3)2(NHR6), wherein R6 is as defined above; adamantyl; <semantics>ξ<annotation encoding="application / x-tex">\xi< / annotation>< / semantics> preferably R4 is selected from the group consisting of H; trifluoromethyl; 4-piperidinyl; -CH2-NH2; phenyl; cyclopropyl; adamantyl; terc-butyl; trimethylsilyl (TMS); triisopropylsilyl (TIPS); halogen (F, Cl, Br, I); <semantics>−C(CH3)2NH2<annotation encoding="application / x-tex">-C(CH_3)_2NH_2< / annotation>< / semantics>; and <semantics>−C(CH3)2NHBoc<annotation encoding="application / x-tex">-C(CH_3)_2NHBoc< / annotation>< / semantics>. More preferably, <semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics> is hydrogen. In one embodiment of the present invention, the compounds of general formula (I) comprises the following substituents: Y is nitrogen (N); <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is selected from the group consisting of H; halogen; <semantics>−OH<annotation encoding="application / x-tex">-OH< / annotation>< / semantics>; <semantics>−N3<annotation encoding="application / x-tex">-N_3< / annotation>< / semantics>; <semantics>−CH2N3<annotation encoding="application / x-tex">-CH_2N_3< / annotation>< / semantics>; <semantics>−NR2<annotation encoding="application / x-tex">-NR_2< / annotation>< / semantics>, wherein R is independently selected from H or C1 to C6 alkyl, which may be branched or linear; C6 to C10 aryl, which can optionally be substituted with -NH2, -NO2, -COOH and / or -CH2COOH; C7 to C10 arylalkyl, which can optionally be substituted with -NH2, -NO2, -COOH, -CH2Cl and / or -CH2COOH; [Image disponible dans le document PDF, Image available in the PDF document] -CF3; -COOR, wherein R is as defined above; [Image disponible dans le document PDF, Image available in the PDF document] A are independently selected from the group consisting of H; <semantics>−(CH2)nCOOH<annotation encoding="application / x-tex">-(CH_2)_nCOOH< / annotation>< / semantics>, wherein n is an integer from 1 to 3; <semantics>−CH(CH3)COOH<annotation encoding="application / x-tex">-CH(CH_3)COOH< / annotation>< / semantics>; <semantics>−CH((CH2)nCH3)COOH<annotation encoding="application / x-tex">-CH((CH_2)_nCH_3)COOH< / annotation>< / semantics>, wherein n is as defined above; <semantics>−CH2P(=O)(OR)2<annotation encoding="application / x-tex">-CH_2P(=O)(OR)_2< / annotation>< / semantics>, wherein R is as defined above; <semantics>−CH2C(=O)(NH2)<annotation encoding="application / x-tex">-CH_2C(=O)(NH_2)< / annotation>< / semantics>; <semantics>−CH2C(=O)(NH)−CH2COOH<annotation encoding="application / x-tex">-CH_2C(=O)(NH)-CH_2COOH< / annotation>< / semantics>; <semantics>−CH2P(=O)(OH)(Ar)<annotation encoding="application / x-tex">-CH_2P(=O)(OH)(Ar)< / annotation>< / semantics>, wherein Ar is phenyl, which can optionally be substituted with <semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics> to <semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics> alkyl; Z is selected from a group consisting of [Image disponible dans le document PDF, Image available in the PDF document] wherein [Image disponible dans le document PDF, Image available in the PDF document] R4 is selected from the group consisting of H; halogen; piperidinyl; trimethylsilyl; triisopropylsilyl; phenyl; C1 to C6 alkyl, which may be branched or linear; C3 to C6 cycloalkyl; -CF3; -CH2NHR6, wherein R6 is selected from H, fluorenylmethyloxykarbonyl and benzyloxycarbonyl; <semantics>−C(CH3)2(NHR6)<annotation encoding="application / x-tex">-C(CH_3)_2(NHR^6)< / annotation>< / semantics>, wherein <semantics>R6<annotation encoding="application / x-tex">R^6< / annotation>< / semantics> is as defined above; adamantyl; \( \frac{1}{2} \) CH; <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics> is H; <semantics>−CF3<annotation encoding="application / x-tex">-CF_3< / annotation>< / semantics>; halogen; <semantics>−OH<annotation encoding="application / x-tex">-OH< / annotation>< / semantics>; <semantics>C7<annotation encoding="application / x-tex">C_7< / annotation>< / semantics> to <semantics>C10<annotation encoding="application / x-tex">C_{10}< / annotation>< / semantics> arylalkyl, which can optionally be substituted with <semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>, <semantics>−NO2<annotation encoding="application / x-tex">-NO_2< / annotation>< / semantics>, -COOH, -CH2Cl and / or -CH2COOH; or <semantics>=<annotation encoding="application / x-tex">=< / annotation>< / semantics> R4, wherein R4 is as defined above; [Image disponible dans le document PDF, Image available in the PDF document] and / or R2 and R3 together form a 1,2,3-triazole group of formula R4 is defined above; with the proviso that at most one A is H. In one preferred embodiment, Y is nitrogen, thus forming a pendant arm comprising a pyridyl moiety, substituted with <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>. In one embodiment, <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is in meta-position from Y, and para-position from <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>-CH2-. In one embodiment, <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is in meta-position from Y, and orto-position from <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>-CH2-. In another embodiment, <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is in para-position from Y. In one preferred embodiment, <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is <semantics>ξ−N3<annotation encoding="application / x-tex">{}^{\xi}-N_3< / annotation>< / semantics>. Preferably, <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is <semantics>ξ<annotation encoding="application / x-tex">{}^{\xi}< / annotation>< / semantics>-<semantics>N3<annotation encoding="application / x-tex">N_3< / annotation>< / semantics> and <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is selected from the group comprising H, phenyl, carboxyphenyl, halogen (preferably Cl), trifluoromethyl, carboxyl, carboxylic ester or amine, more preferably R1 is H or carboxyphenyl. [Image disponible dans le document PDF, Image available in the PDF document] In one embodiment, Z is . [Image disponible dans le document PDF, Image available in the PDF document] In one preferred embodiment, Z is and R3 and R5 are as defined above. Preferably, Z is [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] even more preferably, Z is In the compound of general formula (I), A can be the same or different. Preferably, A are the same. [Image disponible dans le document PDF, Image available in the PDF document] In one embodiment, Z is ٠ [Image disponible dans le document PDF, Image available in the PDF document] In one embodiment, Z is • In one embodiment, A is selected from the group comprising <semantics>−(CH2)COOH<annotation encoding="application / x-tex">-(CH_2)COOH< / annotation>< / semantics>; <semantics>−(CH2)2COOH<annotation encoding="application / x-tex">-(CH_2)_2COOH< / annotation>< / semantics>; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Preferably, A is selected from the group comprising <semantics>−(CH2)COOH<annotation encoding="application / x-tex">-(CH_2)COOH< / annotation>< / semantics>; <semantics>−CH2P(=O)(OEt)2<annotation encoding="application / x-tex">-CH_2P(=O)(OEt)_2< / annotation>< / semantics>; <semantics>−CH2P(=O)(OH)2<annotation encoding="application / x-tex">-CH_2P(=O)(OH)_2< / annotation>< / semantics>; <semantics>−CH2P(=O)(OH)(OEt)<annotation encoding="application / x-tex">-CH_2P(=O)(OH)(OEt)< / annotation>< / semantics>; and <semantics>−CH2P(=O)(Ph)(OH)<annotation encoding="application / x-tex">-CH_2P(=O)(Ph)(OH)< / annotation>< / semantics>. Most preferably, A is <semantics>−(CH2)COOH<annotation encoding="application / x-tex">-(CH_2)COOH< / annotation>< / semantics>. In one embodiment, Y is nitrogen; R1 is selected from the group consisting of H; Cl; –N(CH3)2; phenyl, which can optionally be substituted with –COOH or –CH2COOH; benzyl, which can optionally be substituted with -COOH or -CH2COOH; -CF3; -COOCH3; -COOCH(CH3)2; [Image disponible dans le document PDF, Image available in the PDF document] -COOtBu SH; A are independently selected from the group consisting of H; <semantics>−(CH2)nCOOH<annotation encoding="application / x-tex">-(CH_2)_nCOOH< / annotation>< / semantics>, wherein n is 1 or 2; <semantics>−CH2P(=O)(OH)2<annotation encoding="application / x-tex">-CH_2P(=O)(OH)_2< / annotation>< / semantics>; <semantics>−CH2P(=O)(OH)(OEt)<annotation encoding="application / x-tex">-CH_2P(=O)(OH)(OEt)< / annotation>< / semantics>; <semantics>−CH2P(=O)(OEt)2<annotation encoding="application / x-tex">-CH_2P(=O)(OEt)_2< / annotation>< / semantics>; <semantics>−CH2C(=O)(NH2)<annotation encoding="application / x-tex">-CH_2C(=O)(NH_2)< / annotation>< / semantics>; <semantics>−CH2C(=O)(NH)2<annotation encoding="application / x-tex">-CH_2C(=O)(NH)_2< / annotation>< / semantics> <semantics>CH2COOH<annotation encoding="application / x-tex">CH_2COOH< / annotation>< / semantics>; <semantics>−CH2P(=O)(OH)(Ph)<annotation encoding="application / x-tex">-CH_2P(=O)(OH)(Ph)< / annotation>< / semantics>; Z is selected from a group consisting of [Image disponible dans le document PDF, Image available in the PDF document] wherein [Image disponible dans le document PDF, Image available in the PDF document] R4 is selected from the group consisting of H; halogen; piperidinyl; trimethylsilyl; triisopropylsilyl; phenyl; cyclopropyl, terc-butyl; <semantics>−CF3<annotation encoding="application / x-tex">-CF_3< / annotation>< / semantics>; <semantics>−CH2NH2<annotation encoding="application / x-tex">-CH_2NH_2< / annotation>< / semantics>; <semantics>−CH2N(H)(Fmoc)<annotation encoding="application / x-tex">-CH_2N(H)(Fmoc)< / annotation>< / semantics>; <semantics>−C(CH3)2(NH2)<annotation encoding="application / x-tex">-C(CH_3)_2(NH_2)< / annotation>< / semantics>; <semantics>−C(CH3)2(NHBoc)<annotation encoding="application / x-tex">-C(CH_3)_2(NHBoc)< / annotation>< / semantics>; adamantyl; <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics> is H or <semantics>=<annotation encoding="application / x-tex">=< / annotation>< / semantics> <semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>, wherein <semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics> is as defined above; with the proviso that at most one A is H. [Image disponible dans le document PDF, Image available in the PDF document] In one preferred embodiment, Z is ; R4 and R5 are as defined above, preferably R4 and R5 are H. [Image disponible dans le document PDF, Image available in the PDF document] In another embodiment, R2 and R3 together form a 1,2,3-triazole group of formula or [Image disponible dans le document PDF, Image available in the PDF document] wherein R4 is as defined above, preferably R4 is hydrogen. In such embodiment, a bridge is formed between two opposite nitrogen atoms of the cyclen moiety, and the compound of general formula (I) thus forms a cage-like structure. The bridge is an entity of general formula (IIa) or (IIb) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (IIa) (IIb); wherein L is a linker selected from the group consisting of [Image disponible dans le document PDF, Image available in the PDF document] and R1, R4 and R5 are as defined above. The linker L is derived from the group Z defined above. [Image disponible dans le document PDF, Image available in the PDF document] Preferably, L is • In one preferred embodiment, the compound of general formula (I) is selected from the group comprising compounds with the following combinations of substituents: 5 Y is <semantics>N+−O−<annotation encoding="application / x-tex">N^+-O^-< / annotation>< / semantics>; <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>, <semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics> and <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics> is H: [Image disponible dans le document PDF, Image available in the PDF document] Y is N; <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>, <semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics> and <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics> is H: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Y is N; and R2 and R3 together form a 1,2,3-triazole group of formula , [Image disponible dans le document PDF, Image available in the PDF document] ala N=N: Y is N; and R2 and R3 together form a 1,2,3-triazole group of formula [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Y is N; <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is phenyl; and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is <semantics>N3:A∩R3<annotation encoding="application / x-tex">N_3 : A \cap R^3< / annotation>< / semantics> is <semantics>CH<annotation encoding="application / x-tex">CH< / annotation>< / semantics>: [Image disponible dans le document PDF, Image available in the PDF document] Y is N; A is –(CH2)COOH; <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is H; and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is <semantics>ξ<annotation encoding="application / x-tex">^{\xi}< / annotation>< / semantics>–<semantics>N3<annotation encoding="application / x-tex">N_3< / annotation>< / semantics>: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Y is N; A is <semantics>−CH(CH3)COOH<annotation encoding="application / x-tex">-CH(CH_3)COOH< / annotation>< / semantics>; <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is <semantics>ξ−N3<annotation encoding="application / x-tex">^{\xi}-N_3< / annotation>< / semantics>: and Z is : 5 [Image disponible dans le document PDF, Image available in the PDF document] In the most preferred embodiment, the compound of general formula (I) is selected from the group [Image disponible dans le document PDF, Image available in the PDF document] comprising compounds, wherein Y is nitrogen, Z is and the remaining substituents are present in the following combinations: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] In another aspect, the subject of the present invention is a method of synthesis of the compounds of general formula (I), comprising the following steps: i) providing an alkyne intermediate of general formula Z-Cl, wherein Z is as defined above; ii) providing an azide intermediate of general formula (III) [Image disponible dans le document PDF, Image available in the PDF document] (III); wherein Y, <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> are as defined above; iii) providing a cyclen derivative of general formula (IV) [Image disponible dans le document PDF, Image available in the PDF document] (IV), wherein pA is selected from the group comprising <semantics>−(CH2)nCOOtBu<annotation encoding="application / x-tex">-(CH_2)_nCOO^tBu< / annotation>< / semantics>, wherein n is an integer from 1 to 3; benzyloxycarbonyl; –CH(CH3)COOtBu; –CH(CH3)COOR, wherein R is tert-butyl, methyl or ethyl; -CH((CH2)nCOOR, wherein n and R are as defined above; -CH((CH2)nCOOR)COOR, wherein n is as defined above and R are independently selected from tert-butyl, methyl or ethyl;—<semantics>CH2P(=O)(OR)2<annotation encoding="application / x-tex">CH_2P(=O)(OR)_2< / annotation>< / semantics>, wherein R is C1 to C6 alkyl, which may be branched or linear; -CH2C(=O)(NH2); -CH2C(=O)(NH)-CH2COOH; - <semantics>CH2P(=O)(OH)(Ar)<annotation encoding="application / x-tex">CH_2P(=O)(OH)(Ar)< / annotation>< / semantics>, wherein Ar is phenyl, which can optionally be substituted with <semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics> to <semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics> alkyl; preferably pA is selected from the group comprising –CH2COOtBu; -CH2P(O)(OEt)2; -(CH2)2COOtBu; iv-A) reacting the cyclen derivative of general formula (IV) with alkyne intermediate Z-Cl to obtain an intermediate of general formula (V) [Image disponible dans le document PDF, Image available in the PDF document] <semantics>(V)<annotation encoding="application / x-tex">(V)< / annotation>< / semantics>, wherein Z and pA are as defined above; or iv-B) reacting the cyclen derivative of general formula (IV) with the azide intermediate of general formula (III) to obtain an intermediate of general formula (VI) [Image disponible dans le document PDF, Image available in the PDF document] (VI), wherein Y, <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>, <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> and pA are as defined above; v-A) reacting the intermediate of general formula (V) with the azide intermediate of general formula (III) to obtain an intermediate of general formula (VII) [Image disponible dans le document PDF, Image available in the PDF document] (VII) wherein Y, <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>, <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>, pA and Z are as defined above; or v-B) reacting the intermediate of general formula (VI) with the alkyne intermediate Z-Cl to obtain the intermediate of general formula (VII); vi) optionally, hydrolysis of protecting groups, resulting in the compound of general formula (I). In general, compounds of general formula Z-Cl can be obtained commercially or can be synthesised using Pd(0) catalyzed Sonogashira cross-coupling reaction from corresponding 2-halopyridines (preferably Br, I) and terminal alkynes or silyl-protected acetylenes. Compounds of general formula (III) can be obtained from 2,6-bis(halomethyl)pyridines (preferably Cl) by desymetrization using sodium azide as a source of azide moiety. Cyclene derivatives of general formula (IV) are commercially available or may be prepared by reaction of cyclen or trans-N-bis-protected cyclen (preferably carbamate protected) with alkyl haloacetates (alkylation), alkyl acrylates (Michael addition) or trialkylphosphites in the presence of (para)formaldehyde (Kabachnik- Fields reaction). Steps iv-A), iv-B), v-A) and v-B) take place in a solvent selected from the group comprising MeCN (preferably), DMSO or DMF. The reaction takes place at room temperature for usually several hours up to several days. Step vi) of deprotecting pA groups is optional, for example if pA is -CH2P(O)(OEt)2, then if no deprotection takes place, the resulting A in general formula (I) equals pA. Specific conditions for deprotection of the protecting group depend on the chemical nature of the protecting group, and are known to the person skilled in the art. Typically, terc-butyl ester protecting groups and Boc protecting group are hydrolyzed under acidic conditions (TFA) or thermally, methyl or isopropyl protecting groups are hydrolyzed under alkaline conditions, ethyl phosphonate ester are converted to corresponding phosphonic acids by transesterification using trimethylsilylbromide in presence of pyridine base. Another subject of the present invention is a coordination compound of the compound of the general formula (I) as defined above with a metal cation, selected from the group consisting of lanthanide(III) cations, Na+, <semantics>Ba2+<annotation encoding="application / x-tex">Ba^{2+}< / annotation>< / semantics>, <semantics>Pb2+<annotation encoding="application / x-tex">Pb^{2+}< / annotation>< / semantics>, <semantics>Sr2+<annotation encoding="application / x-tex">Sr^{2+}< / annotation>< / semantics>, <semantics>Ca2+<annotation encoding="application / x-tex">Ca^{2+}< / annotation>< / semantics>, <semantics>Cd2+<annotation encoding="application / x-tex">Cd^{2+}< / annotation>< / semantics>, <semantics>Zn2+<annotation encoding="application / x-tex">Zn^{2+}< / annotation>< / semantics>, <semantics>Mn2+<annotation encoding="application / x-tex">Mn^{2+}< / annotation>< / semantics>, <semantics>Pt2+<annotation encoding="application / x-tex">Pt^{2+}< / annotation>< / semantics>, <semantics>Cu2+<annotation encoding="application / x-tex">Cu^{2+}< / annotation>< / semantics>, <semantics>Ni2+<annotation encoding="application / x-tex">Ni^{2+}< / annotation>< / semantics>, <semantics>Sc3+<annotation encoding="application / x-tex">Sc^{3+}< / annotation>< / semantics>, <semantics>Y3+<annotation encoding="application / x-tex">Y^{3+}< / annotation>< / semantics>, <semantics>Bi3+<annotation encoding="application / x-tex">Bi^{3+}< / annotation>< / semantics>, <semantics>In3+<annotation encoding="application / x-tex">In^{3+}< / annotation>< / semantics>, <semantics>Ru3+<annotation encoding="application / x-tex">Ru^{3+}< / annotation>< / semantics>, <semantics>Ir3+<annotation encoding="application / x-tex">Ir^{3+}< / annotation>< / semantics>, <semantics>Ga3+<annotation encoding="application / x-tex">Ga^{3+}< / annotation>< / semantics>, <semantics>Tl3+<annotation encoding="application / x-tex">Tl^{3+}< / annotation>< / semantics>, <semantics>Pd2+<annotation encoding="application / x-tex">Pd^{2+}< / annotation>< / semantics>; preferably the metal cation is selected from the group consisting of La3+, Ce3+, Pr3+, Nd3+, Sm3+, Eu3+, Gd3+, Tb3+, Dy3+, Ho3+, Er3+, Tm3+, Yb3+, Lu3+, Y3+, Sc3+, Bi3+, In3+, Tl3+, Pb2+, Ca2+, Cd2+, Zn2+, Cu2+, Ni2+, Mn2+, Pd2+, Na+. The metal ions shall be undestood as comprising any izotope of the particular metal, including stable isotopes such as 40Ca, 42Ca, 43Ca, 44Ca, 46Ca, 48Ca, 45Sc, 89Y, 138La, 139La, 136Ce, 138Ce, 140Ce, 142Ce, 141Pr, 142Nd, 143Nd, 144Nd, 145Nd, 146Nd, 148Nd, 150Nd, 144Sm, 147Sm, 148Sm, 149Sm, 150Sm, 152Sm, 154Sm, 151Eu, 153Eu, 152Gd, 154Gd, 155Gd, 156Gd, 157Gd, 158Gd, 160Gd, 159Tb, 156Dy, 158Dy, 160Dy, 161Dy, 162Dy, 163Dy, 164Dy, 165Ho, 162Er, 164Er, 166Er, 167Er, 168Er, 170Er, 169Tm, 168Yb, 170Yb, 171Yb, 172Yb, 173Yb, 174Yb, 176Yb, 175Lu, 176Lu, and radioisotopes such as 44Sc, 47Sc, 64Cu, 67Cu, 86Y, 90Y, 140Nd, 149Pm, 151Pm, 153Sm, 159Gd, 149Tb, 161Tb, 165Dy, 161Ho, 166Ho, 169Er, 167Tm, 175Yb, 177Lu. Lanthanides (Ln) are defined as chemical elements comprising 15 metallic chemical elements with atomic numbers in the range of from 57 to 71 (from lanthanum through lutetium). Preferably, the coordination compound has a general formula (VIII) [Image disponible dans le document PDF, Image available in the PDF document] (VIII); wherein M is the metal cation, <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>, <semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>, <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics> and A are as defined above, and n is selected from 1, 2, 3 and 4; more preferably, the coordination compound has a general formula (VIIIa) [Image disponible dans le document PDF, Image available in the PDF document] (VIIIa). The coordination compounds according to the present invention comprise also solvates and salts of pharmaceutically acceptable acids. The positive charge of the metal cation is counterbalanced by two negative charges arising from A pendant arms (e.g. acetates). Therefore, the overall charge of the coordination compound is -1 (for monovalent metal ions), 0 (for divalent metal ions) or +1 (trivalent metal ions). The counterion, compensating for the overall charge of the coordination compound, is selected from the group, comprising anions derived from the following pharmaceutically acceptable acids: 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4- acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; hydrobromic acid; hydrochloric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (- L); malonic acid; mandelic acid (DL); methanesulfonic acid; naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; nitric acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (- L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid (p); undecylenic acid; trifluoroacetic acid. The coordination compound as defined herein can be prepared according to a method comprising the following steps: i) synthesis of the compound of the general formula (I) according to the method defined herein; ii) providing a salt of an inorganic acid and a metal cation, selected from the group consisting of lanthanide(III) cations, Na+, Ba2+, Pb2+, Sr2+, Ca2+, Cd2+, Zn2+, Mn2+, Pt2+, Cu2+, Ni2+, Sc3+, Y3+, Bi3+, In3+, Ru3+, Ir3+, Ga3+, Tl3+, 24 Pd2+; preferably, the salt is selected from a group comprising chloride, nitrate, acetate, formate, trifluoroacetate, trifluoromethylsulfonate; iii) mixing the compound of the general formula (I) from step i) with the metal salt from step ii) in aqueous solution, preferably for at least 1 hour at temperature in the range of from 25 to 100 °C, resulting in chelation of the metal cation by the compound of general formula (I) and formation of the coordination compound as defined herein; iv) optionally, transformation of the coordination compound from step iii), wherein the transformation is selected from at least one of the following reactions: - substitution reaction of halogen group present in R1 and / or R4 and / or R5, with a phenylboronic acid, thus transforming the halogen substituent into –COOH; - substitution reaction of halogen group present in R1 and / or R4 and / or R5, with -N3 group by reaction with <semantics>NaN3<annotation encoding="application / x-tex">NaN_3< / annotation>< / semantics>; - hydrolysis of TIPS protecting group present in R1 and / or R4 and / or R5 substituent, wherein R1 and / or R3 and / or [Image disponible dans le document PDF, Image available in the PDF document] , resulting in <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and / or <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> and / or <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics> being <semantics>E−<annotation encoding="application / x-tex">E^{-}< / annotation>< / semantics> - addition reaction of methanol to R1 and / or R4 and / or R5, wherein R1 and / or R3 and / or R5 is [Image disponible dans le document PDF, Image available in the PDF document] thus transforming the triple bond to dimethyl acetal; - deuteration of CH2 groups of the pendant arms in D2O in presence of DBU, transforming them into CD2 groups; [Image disponible dans le document PDF, Image available in the PDF document] - selective reduction of pyridyl cycle of Z substituent, wherein Z is and R3 and R5 are as defined herein, using NaBH4 or NaBD4 as the reducing agent, thus transforming the Z group into [Image disponible dans le document PDF, Image available in the PDF document] - reaction of NH2 group of R1 and / or R4 and / or R5 and / or A, wherein R1 and / or R4 and / or R5 and / or A contains -NH₂ or -(CH₂)nNH₂, with FmocCl, resulting in transformation of -NH₂ group into -NHFmoc group; - reaction of –COOH group present in R1 and / or R4 and / or R5 and / or A, with an amino group of an aminoacid or peptide, thus forming a peptide bond; - S-alkylation reaction of a halogen, preferably Cl, of R1, R4 and / or R5 substituent with a thiol, resulting in trasforming the halogen into sulfide; - reaction of <Formule mathématique disponible dans le document PDF, Math available in the PDF document>$\S$——CH group of <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>, <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> and / or <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>, wherein <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>, <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> and / or <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics> contains <Formule mathématique disponible dans le document PDF, Math available in the PDF document>$\S$——CH, with an azide, preferably with alkyl- or arylazide, thereby forming a triazole bridge connecting the alkyl- or aryl- to R1, R3 and / or R5 group; - reaction of <semantics>−N3<annotation encoding="application / x-tex">-N_3< / annotation>< / semantics> group of <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and / or <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>, wherein <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and / or <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics> contains <semantics>−N3<annotation encoding="application / x-tex">-N_3< / annotation>< / semantics> group, with a substituent comprising a carbon-carbon triple bond, thereby forming a triazole bridge connecting the substituent with the coordination compound; - reaction of -SH group of R1 and / or R5, with a substituent comprising maleimide, thereby forming thiosuccinimide linkage connecting the substituent with the coordination compound; - reaction of –SH group of R1 and / or R5, with a substituent comprising another –SH group, thereby forming a disulfide bridge connecting the substituent with the coordination compound; - reaction of –SH group of R1 and / or R5, with alkyl- or arylhalogenide, thereby forming a thioether linkage connecting the alkyl- or aryl- to the coordination compound; - reaction of –NO2 group of R1 and / or R5, with a substituent comprising –SH group, thereby forming a thioether linkage connecting the substituent with the coordination compound. The coordination compounds can be prepared according to Scheme 1 above from the free ligand of general formula (I) (preferably the non-caged, therefore preferably without the trazole bridge) and a metal salt (typically water soluble metal salt, preferably selected from a group comprising chloride, nitrate, acetate, formate, trifluoroacetate, trifluoromethylsulfonate, more preferably chloride or nitrate salt). By stirring of these reactants in an aqueous environment (pH 5-7) at temperature in the range of from 25 °C to 100 °C, the metal cation coordinates into the compound of general formula (I) and the R2 and R3 substituents then "click-zip" the metal cation inside the cage by forming the triazole bridge (reaction temperatures and times are strongly dependent on the choice of ligand and metal cation). However, the suitable ligands are not limited to the non-caged compounds of general formula (I), eventhough they are preferred because wider range of metal cations (such as lanthanides) may form the caged coordination compounds. The bridged (caged) compounds of general formula (I) with 1,5-triazole bridge are capable of forming coordination compounds with metal cations, typically selected from the group comprising Tl3+, Pb2+, Bi3+, In3+, Cd2+, Ca2+, Cu2+, Ni2+, Mn2+, Pd2+, Na+. The bridged (caged) compounds of general formula (I) with 1,4-triazole bridge are capable of forming coordination compounds with metal cations, typically selected from the group comprising La3+, Ce3+, Pr3+, Nd3+, Sm3+, Eu3+, Gd3+, Tb3+, Dy3+, Ho3+, Er3+, Tm3+, Yb3+, Lu3+, Y3+, Tl3+, Pb2+, Bi3+, In3+, Cd2+, Ca2+, Cu2+, Ni2+, Mn2+, Pd2+, Na+. The resulting coordination compounds are very inert and stable, therefore suitable for various applications, such as MRI contract agents, radiodiagnostics or radiotherapy, peptide or protein containing drug tracing. The coordination of the compound of general formula (I) to a metal cation takes place via the macrocyclic nitrogen atoms of the cyclene moiety, oxygen atoms present in groups A (pendant arms) and Y group (when Y is N-oxide), and via nitrogen atoms of Y group (when Y is nitrogen) and nitrogen atom present in Z group. In one embodiment, the coordination compounds according to the present invention may undergo a post- clickzip transformation. It means that after the metal cation is coordinated within the cage of the compound of general formula (I) by either following the Scheme 1 or coordinating with the caged compound of general formula (I), some functional groups, if present, may undergo a further reaction. Typically, such functional group is a halogen, preferably Cl, NO2 or SH, present within substituent R1 or R5 of the coordination compound, however, post-clickzip transformations may include reactions of R1, R4, R5 and / or A groups (such as amidic coupling reactions of non-coordinated carboxylic or amino groups). For example, when <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is halogen, preferably Cl; or <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is <semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics> to <semantics>C10<annotation encoding="application / x-tex">C_{10}< / annotation>< / semantics> aryl, substituted with <semantics>−CH2Cl<annotation encoding="application / x-tex">-CH_2Cl< / annotation>< / semantics>, then the coordination compound of general formula (VIII) may undergo post-click transformation using Pd(0) catalyzed Suzuki cross-coupling reaction with phenylboronic acids (3-borono-5-nitrobenzoic acid or 2-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid or 2-(4-boronophenyl)acetic acid), during which the halogen is replaced, thus the resulting coordination compound of general formula (VIII) would have <semantics>R1=<annotation encoding="application / x-tex">R^1 =< / annotation>< / semantics> COOH or C6 to C10 aryl, substituted with -COOH or -CH2COOH. The resulting carboxylate moiety can be then utilized in amide coupling reaction for synthesis of peptide conjugates. Conjugates with oligoarginines are capable of crossing cell membrane, allowing metal cages to be incorporated to the cells. Another possible post-click transformation is the replacement of halogen present within R1, R4 and / or R5 substituent by <semantics>−N3<annotation encoding="application / x-tex">-N_3< / annotation>< / semantics> group by reaction with NaN3. The resulting azide can be used for coupling of the metal cage to another alkyne-bearing moiety using copper-catalysed azide-alkyne cycloaddition (CuAAC) reaction. Another possible post-click transformation is the hydrolysis of TIPS protecting group present in R1, R4 and / or [Image disponible dans le document PDF, Image available in the PDF document] R5 substituent and protecting the triple bond (R1, R3 and / or R5 is . The hydrolysis is performed using aqueous K2CO3, and results in R1, R3 and / or R5 being \( \) . The resulting deprotected triple bond is suitable for further conjugations via reaction with the alkyne, for example click reactions with azides and forming triazole bridges (e.g. CuAAC reaction). In another embodiment, the post-click transformation may be addition reaction of methanol to R1, R4 and / or [Image disponible dans le document PDF, Image available in the PDF document] <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>, wherein <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>, <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> and / or <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics> is thus transforming the triple bond to dimethyl acetal (protected version of an aldehyde). This demonstrates conversion of one functional group (alkyne) to another (aldehyde). Aldehydes are usable for conjugation reactions based on formation of Schiff bases with amines, hydrazines and acid hydrazides. In yet another embodiment, the post-click transformation may be deuteration reaction of CH2 groups of the pendant arms in D2O in presence of DBU, transforming them into CD2 groups. This conversion does not alter the physico-chemical properties of the molecule (in terms of stability or reactivity), but changes the overall mass of the molecule, to be entirely distinguishable from the parent non-deuterated molecule using mass spectrometry. This means, that the metal ion cage with one particular metal can be used as two different mass tags. In yet another embodiment, the post-click transformation may be a selective reduction of pyridyl cycle of [Image disponible dans le document PDF, Image available in the PDF document] Z substituent, wherein Z is and R3 and R5 are as defined above, using NaBH4 or NaBD4 [Image disponible dans le document PDF, Image available in the PDF document] as the reducing agent, thus transforming the Z group into , respectively. Similarly to the deuteration of CH2 groups, this conversion changes the mass of the molecule for metal tags purposes. In yet another embodiment, the post-click transformation may be reaction of NH2 group, if present, of R1 and / or R4 and / or R5 and / or A, wherein R1 and / or R4 and / or R5 contains –NH2 or –(CH2)nNH2, with FmocCl, resulting in transformation of –NH2 group into –NHFmoc group. Fmoc group is the most commonly encountered amine protecting group used in solid-phase peptide synthesis (SPPS). Introducting of Fmoc group therefore facilitates use of the metal cages for SPPS. In yet another embodiment, the post-click transformation may be reaction of NH2 group, if present, of R1 and / or R4 and / or R5 and / or A, with a carboxyl group of another molecule of general formula (I) or of its metal complex as defined above, resulting in conjugation of two or more compounds of general formula (I) or of their metal complexes into conjugates bound via a peptide (amide) bond. In yet another embodiment, the post-click transformation may be reaction of non-coordinating –COOH group, if present, in R1 and / or R4 and / or R5 and / or A, with an amino group of an aminoacid or peptide, thus forming a peptide bond for conjugation purposes. In yet another embodiment, the post-click transformation may be S-alkylation reaction of a halogen, preferably Cl, of R1, R4 and / or R5 substituent with a thiol, resulting in trasforming the halogen into sulfide. The thiol may be e.g. Na2S, NaSH, N-Boc-cysteine or a cysteine-containing peptide and the reaction may take place in presence of DIPEA. Incorporating cysteine (aminoacid) into the structure of the coordination compound according to the present invention opens futher possibilities for amide bonds (e.g. peptide attachment). In yet another embodiment, the post-click transformation may be reaction of <Formule mathématique disponible dans le document PDF, Math available in the PDF document>$\gray$ = CH group of <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>, <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> and / or R5, wherein R1, R3 and / or R5 contains \( \) = CH, with an azide, preferably with alkyl- or arylazide, thereby forming a triazole bridge connecting the alkyl- or aryl- to R1, R3 and / or R5 group. The arylazide is preferably C6 to C10 arylazide, e.g. benzyl azide, optionally substituted with -COOH or -CH2COOH. The alkyl azide is preferably C1 to C7 alkyl azide, wherein the alkyl may be linear or branched. In yet another embodiment, the post-click transformation may be reaction of <semantics>−N3<annotation encoding="application / x-tex">-N_3< / annotation>< / semantics> group of <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> or <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>, wherein <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> or R5 contains –N3 group, with a substituent comprising a carbon-carbon triple bond, thereby forming a triazole bridge connecting the substituent with the coordination compound. The substituent comprising a triple bond may be for example C7 to C10 arylalkynyl, optionally substituted with -COOH or -CH2COOH, e.g. phenylacetylene, wherein the phenyl moiety may optionally be substituted with -COOH or -CH2COOH. In yet another embodiment, the post-clickzip transformation may be reaction of –SH group of R1 and / or R5, with a substituent comprising maleimide, thereby forming thiosuccinimide linkage connecting the substituent with the coordination compound; or reaction of -SH group of R1 and / or R5, with a substituent comprising another –SH group, thereby forming a disulfide bridge connecting the substituent with the coordination compound; or reaction of –SH group of R1 and / or R5, with alkyl- or arylhalogenide, thereby forming a thioether linkage connecting the alkyl- or aryl- to the coordination compound. In yet another embodiment, the post-clickzip transformation may be reaction of –NO2 group of R1 and / or R5, with a substituent comprising –SH group, thereby forming a thioether linkage connecting the substituent with the coordination compound. In one embodiment, the post-click transformation may include reaction with another coordination compound of the present invention, thereby forming a chain or a dimer. The coordination compound chain or dimer may contain the same metal cation in both click-zipped cages or it may contain different metal cations in each of the chelates. The advantage of the chains and dimers lies in the possibility to combine properties of the two caged chelates, such as their unique weights to produce mass tags with higher variability of weights. Typically, the coordination compounds are bound into the chain by forming a triazole bridge between R1 or R5 group of the first coordination compound and R1 or R5 group of the following coordination compound (the use [Image disponible dans le document PDF, Image available in the PDF document] of R5 group is only possible for Z being The general basic structure of the coordination compound chain is thus (IXa) or (IXb) [Image disponible dans le document PDF, Image available in the PDF document] (IXa) [Image disponible dans le document PDF, Image available in the PDF document] (IXb). In one embodiment, the coordination compounds are bound into the chain by amide bonds formed between a substituent of one coordination compound containing an amine group (R1 and / or R4 and / or R5 and / or A) and a substituent of another coordination compound containing a carboxyl group (R1 and / or R4 and / or R5 and / or A). The chain usually contains two coordination compounds according to the present invention, however it may contain three, four or more coordination compounds. In yet another embodiment the two types of linkage, described above, are possible in one chain, for example two neighbouring coordination compounds may be linked by one triazole bridge, leaving R5 or R1 substituent available for linking another coordination compound according to the present invention, either via a triazole bridge or, if amino or carboxyl groups are present, via an amide bond. In one embodiment, the coordination compound chain containing at least two coordination compounds as defined herein, is bound via a triazole bridge formed between R1 or R5 group of the first coordination compound and R1 or R5 group of the following coordination compound and / or via amide bond formed between a substituent R1 or R4 or R5 or A of one coordination compound containing an amine group and a substituent R1 or R4 or R5 or A of another coordination compound containing a carboxyl group and / or via disulfide bonds formed between a substituent R1 or R5 of one coordination compound containing –SH group, and a substituent R1 or R5 of another coordination compound containing –SH group. In one embodiment, the coordination compounds are bound into the chain by disulfide bonds (-S-S-) formed between a substituent R1 or R5 of one coordination compound containing –SH group, and a substituent R1 or R5 of another coordination compound containing –SH group. The coordination compound dimer contains two coordination compounds according to the present invention, bound together by forming a triazole bridge between R1 group of the first coordination compound and R5 group of the second coordination compound, and, at the same time, by forming a triazole bridge between R5 group of the first coordination compound and R1 group of the second coordination compound. The general structure of the coordination compound dimer is thus (X) [Image disponible dans le document PDF, Image available in the PDF document] (X). The synthesis of the coordination compound chain or dimer is based on a click reaction between an azido group of the first coordination compound and a triple bond of the second coordination compound, thereby forming a triazole bridge, linking the two coordination compound into a dimer. The triazole bridge is selected from the group comprising: [Image disponible dans le document PDF, Image available in the PDF document] 1,2,3-triazole group of formula formed between -N3 group of R1 or R4 or R5 of first coordination compound and the triple bond of R1 or R4 or R5 of the second coordination compound. Preferably, the metal cations are different, for example the metal cations are selected from Tb3+ and 176Yb3+. Yet another object of the present invention is a conjugate suitable for use as markers for drug tracing. Many drugs are based on peptides or proteins, and their biodistribution can be traced by attachment of a fluorescent or radioactive marker to the peptide or protein structure. The coordination compounds and dimers of the present invention are suitable for their attachment to the peptide or protein of a drug to be traced. The isolated cell culture or a tissue can then be analysed for the presence of the metal complex using conventional methods, such as LC-MS, which is commonly used and relatively unexpensive instrument. The cells or tissues can be entirely hydrolyzed in a strong acid without any decomposition of the coordination compound according to the present invention. The coordination compound can then be detected in a hydrolyzed sample. Such method is unexpensive and reliable thanks to the extremely high stability of the coordination compounds. LC-MS method also allows for using a plurality of different coordination compounds with different metal isotops (multiplexing), which may then be all analyzed during one LC-MS analysis. The conjugate according to the present invention contains the coordination compound according to the present invention as defined above or the coordination compound dimer or chain as defined above, conjugated to a peptide or to a protein. The conjugation takes place via an amide bond, formed between the amino group of the peptide or the protein and a carboxyl group of the coordination compound or of the chain or dimer or vice versa. Thus, the coordination compound or the chain or dimer need to contain either –NH2 or –COOH group prior to peptide or protein conjugation. Preferably, the –NH2 or –COOH group is part of the R1 and / or R4 and / or R5 group, therefore the conjugates are formed from coordination compounds or coordination compound dimers, which have R1 and / or R4 and / or R5 group selected from the group comprising –NH2; –(CH2)nNH2; –COOH; – <semantics>(CH2)nCOOH<annotation encoding="application / x-tex">(CH_2)_nCOOH< / annotation>< / semantics>; <semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics> to <semantics>C10<annotation encoding="application / x-tex">C_{10}< / annotation>< / semantics> aryl, substituted with <semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>, <semantics>−COOH<annotation encoding="application / x-tex">-COOH< / annotation>< / semantics>, <semantics>−(CH2)nNH2<annotation encoding="application / x-tex">-(CH_2)_nNH_2< / annotation>< / semantics>, or <semantics>−(CH2)nCOOH<annotation encoding="application / x-tex">-(CH_2)_nCOOH< / annotation>< / semantics>; wherein n is an integer in the range of from 1 to 3. The conjugation reaction conditions are known to the person skilled in the art, typically the reaction takes place at 25 °C in DMSO, using commonly used peptide coupling agents (preferebaly HATU, PyAOP) in the presence of organic base (triethylamine, ethyldiisopropylamine). Reaction are usually completed within several minutes. The peptide is preferably selected from the group comprising oligopeptides of 3 to 20 aminoacids; The protein is preferably selected from the group comprising antibodies, preferably monoclonal antibodies. Another object of the present invention is a method of drug tracing, preferably of tracing of peptide-based or protein-based drugs, which comprises the following steps: i) providing a cell culture or a tissue to be analyzed, containing at least one conjugate defined above, wherein the peptide or the protein is of the peptide-based or protein-based drug to be traced; ii) hydrolyzing the cell culture or tissue from step i) using a strong acid, preferably non-oxidizing aq. HCl, obtaining a hydrolyzate; iii) qualitative and / or quantitative analysis of the hydrolyzate of step ii) for the presence of the coordination compound or of the coordination compound dimer according to the present invention, preferably using LC- MS. Further object of the present invention is the in vitro use of the coordination compound or of the coordination compound dimer or of the conjugate according to the present invention in pharmacy, preferably for development and testing of new drugs, more preferably for drug marking and tracing. Another object of the present invention is the use of the coordination compounds or of the coordination compound dimers according to the present invention in medical diagnostics, preferably as MRI contrast agents. Preferably, Gd3+ coordination compounds or dimers shall be used as MRI contrast agents, as Gd has a very high relaxivity. The extremely high kinetic inertness of the coordination compounds (approximately 100x higher than for GdDOTA, a commonly used MRI contrast agent) allows for using even higher dosages and no free gadolinium, which itself is toxic for humans or animals, is released from the coordination compounds according to the present invention. The claimed coordination compounds are thus expected to be safe for use in human or animal beings. Another object of the present invention is the use of the coordination compound or the coordination compound chain or the coordination compound dimer according to the present invention, wherein M is a radionuclide, preferably selected from the group comprising 44Sc, 47Sc, 64Cu, 67Cu, 86Y, 90Y, 140Nd, 149Pm, 151Pm, 153Sm, 159Gd, 149Tb, 161Tb, 165Dy, 161Ho, 166Ho, 169Er, 167Tm, 175Yb, 177Lu, in medicine as radiodiagnostic and / or radiopharmaceutic agents. Alternatively, a radionuclide may also be present in the side chain of the coordination compound such as a radioizotope of a halogen, e.g. R1 and / or R5 may be 18F. The present invention is further demostrated by the following examples. Examples Example 1: Synthesis of intermediates of alkyne pendant arms [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD701: Pear-shape glass flask (50 mL) was charged with (6-Bromopyridin-2- yl)methanol (2.47 g; 13.1 mmol; 1.0 equiv.) and magnetic stirrer and three times secured with argon. Solid CuI (149 mg; 782 μmol; 6.0 mol%) and [Pd(PPh3)2Cl2] (225 mg; 321 μmol; 2.4 mol%) were subsequently added followed by another securing with argon (three times). Under constant flow of argon was then added dry THF (25 mL) through septum followed by addition of Ethynyltrimethylsilane (2.0 mL; 14.5 mmol; 1.1 equiv.) and TEA (5.5 mL; 39.5 mmol; 3.0 equiv.) after which the mixture changed color to dark brown. The flask was left stirring under septum (but without external argon) for 3 h at RT. The mixture was then transferred to a separatory funnel with EtOAc (150 mL) and H2O (100 mL). After shaking, the dark colored (and not entirely homogenous) organic layer was separated and the aqueous layer was further extracted with EtOAc (<semantics>5×50<annotation encoding="application / x-tex">5 \times 50< / annotation>< / semantics> mL). Combined organic layers were filtered through cotton plug and the filtrate was further dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. Resulting dark brown oily residue was purified on flash chromatography (330 g SiO2, 100% DCM to 10% EtOAc in DCM). Combined fractions with product were evaporated to dryness and further co-evaporated once with DCM. The residue was further dried on high vacuum overnight to give product in the form of free base as dark yellow oil. Yield: 2.16 g (80%; 1 step; based on (6-Bromopyridin-2-yl)methanol). NMR (DMSO-d6): 1H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 0.24 (CH3, s, 9H); 4.52 (CH2, d, 2H, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 6); 5.48 (OH, t, 1H, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 6); 7.39 <semantics>(arom.,dd,1H,3JHH=8;4JHH=1);7.46(arom.,dd,1H,3JHH=8;4JHH=1);7.80(arom.,t,1H,3JHH=8).<annotation encoding="application / x-tex">(arom., dd, 1H, {}^{3}J_{HH} = 8; {}^{4}J_{HH} = 1); 7.46 (arom., dd, 1H, {}^{3}J_{HH} = 8; {}^{4}J_{HH} = 1); 7.80 (arom., t, 1H, {}^{3}J_{HH} = 8).< / annotation>< / semantics> 13C{¹H} <semantics>δC<annotation encoding="application / x-tex">\delta_{C}< / annotation>< / semantics> −0.3 (CH3, s); 63.9 (CH2, s); 93.4 and 104.5 (C≡C; 2 × s); 120.2 (arom., s); 125.4 (arom., s); 137.2 <semantics>(arom.,s);140.8(arom.,s);162.7(arom.,s).ESI−HRMS:206.0995[M+H]+(theor.[C11H16N1O1Si1]+=<annotation encoding="application / x-tex">(arom., s); 140.8 (arom., s); 162.7 (arom., s). ESI-HRMS: 206.0995 [M+H]+ (theor. [C11H16N1O1Si1]+ =< / annotation>< / semantics> 206.0996). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD557: In a round-bottom glass flask (100 mL), TD701 (2.16 g; 10.5 mmol; 1.0 equiv.) was dissolved in DCM (40 mL). Freshly prepared solution of SOCl2 (1.50 mL; 20.7 mmol; 2.0 equiv.) in DCM (10 mL) was then added and the open flask was stirred 1 h at RT. Dil. aq. solution of NaHCO3 (50 mL) was then added and resulting biphasic mixture was vigorously stirred for additional 1 h at RT, during which bubbles of gas slowly evolved. Mixture was then transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (<semantics>4×50<annotation encoding="application / x-tex">4 \times 50< / annotation>< / semantics> mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The brown residue (already pure according to 1H NMR) was purified on flash chromatography (330 g SiO2, 60% P.E. in DCM to 20% P.E. in DCM) to remove the intensively colored impurities. Combined fractions with product were evaporated to dryness and further co-evaporated once with DCM. The residual nearly colorless oil was left in a freezer to solidify. Resulting solid was crushed and further dried on high vacuum overnight to give product in the form of free base as fine white powder. Yield: 2.14 g (87%; 1 step; based on TD701). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 0.25 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 9H); 4.76 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>, s, 2H); 7.50 (arom., dd, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^3J_{HH} = 8< / annotation>< / semantics>; <semantics>4JHH=1<annotation encoding="application / x-tex">{}^4J_{HH} = 1< / annotation>< / semantics>); 7.55 (arom., dd, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^3J_{HH} = 8< / annotation>< / semantics>; <semantics>4JHH=1<annotation encoding="application / x-tex">{}^4J_{HH} = 1< / annotation>< / semantics>); 7.86 (arom., t, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>). <semantics>13C{1H}<annotation encoding="application / x-tex">{}^{13}C\{{}^{1}H\}< / annotation>< / semantics> <semantics>δC=0.4<annotation encoding="application / x-tex">\delta_{C} = 0.4< / annotation>< / semantics> (CH3, s); 46.3 (CH2, s); 94.3 and 103.8 (C≡C; 2 × s); 123.3 (arom., s); 126.7 (arom., s); 138.1 (arom., s); 141.5 (arom., s); 157.0 (arom., s). ESI-HRMS: 224.0657 [M+H]+ (theor. <semantics>[C11H15N1Cl1Si1]+=224.0657<annotation encoding="application / x-tex">[C_{11}H_{15}N_1Cl_1Si_1]^+ = 224.0657< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD558: In a pear-shaped glass flask (100 mL), TD557 (1.05 g; 4.69 mmol; 1.0 equiv.) was dissolved in MeCN (40 mL). Freshly prepared solution of KF (406 mg; 7.0 mmol; 1.5 equiv.) in H2O (7 mL) was then added and the flask was vigorously stirred 2 h at RT. The mixture was concentrated to ~10 mL and then diluted with DCM (50 mL) and dil. aq. NaHCO3 (50 mL). The mixture was transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (<semantics>4×25<annotation encoding="application / x-tex">4 \times 25< / annotation>< / semantics> mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further briefly dried on high vacuum to give product in the form of free base as pale yellow oil. Yield: 702 mg (99%; 1 step; based on TD557). NMR (DMSO-d6): 1H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 4.37 (C=CH, s, 1H); 4.76 (CH2, s, 2H); 7.53 (arom., dd, 1H, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 8; <semantics>4JHH<annotation encoding="application / x-tex">{}^{4}J_{HH}< / annotation>< / semantics> = 1); 7.57 (arom., dd, 1H, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 8; <semantics>4JHH<annotation encoding="application / x-tex">{}^{4}J_{HH}< / annotation>< / semantics> = 1); 7.87 (arom., t, 1H, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 8). <semantics>13𝑪{1𝑯}<annotation encoding="application / x-tex">{}^{13}\mathbf{C}\{{}^{1}\mathbf{H}\}< / annotation>< / semantics> 46.3 (CH2, s); 80.6 and 82.6 (<semantics>C≡CH<annotation encoding="application / x-tex">C \equiv CH< / annotation>< / semantics>; 2 × s); 123.4 (arom., s); 126.8 (arom., s); 138.1 (arom., s); 141.3 (arom., s); 157.0 (arom., s). ESI-HRMS: <semantics>152.0262 [M+H]+ (theor. [C8H7N1Cl1]+=152.0262).<annotation encoding="application / x-tex">152.0262 \text{ [M+H]}^+ \text{ (theor. } [C_8H_7N_1Cl_1]^+ = 152.0262).< / annotation>< / semantics> [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD712: Pear-shape glass flask (10 mL) was charged with (6-Bromopyridin-2- yl)methanol (284 mg; 1.51 mmol; 1.0 equiv.) and magnetic stirrer and three times secured with argon. Solid CuI (14.5 mg; 76 μmol; 5.0 mol%) and [Pd(PPh3)2Cl2] (21 mg; 30 μmol; 2.0 mol%) were subsequently added followed by another securing with argon (three times). Under constant flow of argon was then added dry THF (4 mL) through septum followed by addition of Ethynyltriisopropylsilane (370 µL; 1.65 mmol; 1.1 equiv.) and TEA (630 µL; 4.52 mmol; 3.0 equiv.) after which the mixture changed color to dark brown. The flask was left stirring under septum (but without external argon) for 16 h at RT. The mixture was then transferred to a separatory funnel with EtOAc (30 mL) and H2O (30 mL). After shaking, the dark colored (and not entirely homogenous) organic layer was separated and the aqueous layer was further extracted with EtOAc (<semantics>5×25<annotation encoding="application / x-tex">5 \times 25< / annotation>< / semantics> mL). Combined organic layers were filtered through cotton plug and the filtrate was further dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. Resulting dark brown oily residue was purified on flash chromatography (120) g SiO2, 100% DCM to 10% EtOAc in DCM). Combined fractions with product were evaporated to dryness and further co-evaporated once with DCM. The residue was further dried on high vacuum overnight to give product in the form of free base as yellow oil. Yield: 387 mg (89%; 1 step; based on (6-Bromopyridin-2-yl)methanol). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 0.92–1.26 (i-Pr, m, 21H); 4.53 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, d, 2H, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 6); 5.48 (O<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, t, 1H, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 6); 7.40 (arom., dd, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>; <semantics>4JHH=1<annotation encoding="application / x-tex">{}^{4}J_{HH} = 1< / annotation>< / semantics>); 7.47 (arom., dd, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>; <semantics>4JHH=1<annotation encoding="application / x-tex">{}^{4}J_{HH} = 1< / annotation>< / semantics>); 7.80 (arom., t, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>). 13C{1H} <semantics>δC<annotation encoding="application / x-tex">\delta_{C}< / annotation>< / semantics> 10.7 (i-Pr, s); 18.5 (i-Pr, s); 64.0 (CH2, s); 89.4 and 106.6 (C≡C; 2 × s); 120.2 (arom., s); 125.8 (arom., s); 137.2 (arom., s); 140.9 (arom., s); 162.7 (arom., s). ESI-HRMS: 290.1932 [M+H]+ (theor. <semantics>[C17H28N1O1Si1]+=290.1935<annotation encoding="application / x-tex">[C_{17}H_{28}N_1O_1Si_1]^+ = 290.1935< / annotation>< / semantics>. [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD723: In a round-bottom glass flask (25 mL), TD712 (384 g; 1.33 mmol; 1.0 equiv.) was dissolved in DCM (5 mL). Freshly prepared solution of SOCl2 (200 μL; 2.75 mmol; 2.1 equiv.) in DCM (1 mL) was then added and the open flask was stirred 1 h at RT. Dil. aq. solution of NaHCO3 (10 mL) was then added and resulting biphasic mixture was vigorously stirred for additional 1 h at RT, during which bubbles of gas slowly evolved. Mixture was then transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (4 × 10 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The brown residue (already pure according to 1H NMR) was purified on flash chromatography (120 g SiO2, 20% DCM in P.E. to 30% DCM in P.E.) to remove the intensively colored impurities. Combined fractions with product were evaporated to dryness and further co-evaporated once with DCM. The residual colorless oil was further dried on high vacuum overnight to give product in the form of free base as colourless solid. Yield: 356 mg (87%; 1 step; based on TD712). NMR (DMSO-d6): 1H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 0.91–1.28 (i-Pr, m, 21H); 4.78 (CH2, s); 7.52 (arom., dd, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>; <semantics>4JHH=1<annotation encoding="application / x-tex">{}^{4}J_{HH} = 1< / annotation>< / semantics>); 7.57 (arom., dd, 1H, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 8; <semantics>4JHH<annotation encoding="application / x-tex">{}^{4}J_{HH}< / annotation>< / semantics> = 1); 7.86 (arom., t, 1H, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 8). ESI-HRMS: 308.1593 [M+H]+ (theor. [C17H27N1Cl1Si1]+ = 308.1596). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD530: Pear-shape glass flask (50 mL) was charged with (6-Bromopyridin- 2-yl)methanol (1.00 g; 5.35 mmol; 1.0 equiv.), N-Boc-propargylamine (1.00 g; 6.44 mmol; 1.2 equiv.) and magnetic stirrer and three times secured with argon. Solid CuI (102) mg; 536 μmol; 10.0 mol%) and [Pd(PPh3)2Cl2] (187 mg; 266 μmol; 5.0 mol%) were subsequently added followed by another securing with argon (three times). Under constant flow of argon was then added dry THF (27 mL) through septum followed by addition of TEA (2.24 mL; 16.1 mmol; 3.0 equiv.) after which the mixture changed color to dark brown. The flask was left stirring under septum (but without external argon) for 18 h at RT. The mixture was then transferred to a separatory funnel with EtOAc (30 mL) and H2O (50 mL). After shaking, the dark colored (and not entirely homogenous) organic layer was separated and the aqueous layer was further extracted with EtOAc (3 × 30 mL). Combined organic layers were filtered through cotton plug and the filtrate was further dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. Resulting dark brown oily residue was purified on flash chromatography (220 g SiO2, 100% DCM to 100% EtOAc). Combined fractions with product were evaporated to dryness and further co-evaporated once with DCM. The residue was further dried on high vacuum overnight to give product in the form of free base as yellow oil. Yield: 610 mg (43%; 1 step; based on (6-Bromopyridin-2-yl)methanol). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 1.40 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 9H); 3.99 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, d, 2H, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 6); 4.51 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, d, 2H, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 6); 5.47 <semantics>(OH,t,1H,3JHH=6);7.32(arom.,dd,1H,3JHH=8;4JHH=1);7.40(NH,t,1H,3JHH=6);7.44(arom.,dd,1H,1H,2H,2H,2H,2H,2H,2H,2H,2H,2H,2<annotation encoding="application / x-tex">(OH, t, 1H, {}^{3}J_{HH} = 6); 7.32 (arom., dd, 1H, {}^{3}J_{HH} = 8; {}^{4}J_{HH} = 1); 7.40 (NH, t, 1H, {}^{3}J_{HH} = 6); 7.44 (arom., dd, 1H, 1H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2H, 2< / annotation>< / semantics> <semantics>3JHH=8<annotation encoding="application / x-tex">^{3}J_{HH} = 8< / annotation>< / semantics>; <semantics>4JHH=1<annotation encoding="application / x-tex">^{4}J_{HH} = 1< / annotation>< / semantics>); 7.79 (arom., t, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">^{3}J_{HH} = 8< / annotation>< / semantics>). <semantics>13C{1H}<annotation encoding="application / x-tex">^{13}C\{^{1}H\}< / annotation>< / semantics> <semantics>δC<annotation encoding="application / x-tex">\delta_{C}< / annotation>< / semantics> 28.2 (CH3, s); 29.9 (CH2, s); 64.0 (CH2, s); 78.4 <semantics>(C−CH3,s)<annotation encoding="application / x-tex">(C-CH_3, s)< / annotation>< / semantics>; 81.3 and 86.9 <semantics>(C≡C;2×s)<annotation encoding="application / x-tex">(C \equiv C; 2 \times s)< / annotation>< / semantics>; 119.8 <semantics>(arom.,s)<annotation encoding="application / x-tex">(arom., s)< / annotation>< / semantics>; 125.0 <semantics>(arom.,s)<annotation encoding="application / x-tex">(arom., s)< / annotation>< / semantics>; 137.2 <semantics>(arom.,s)<annotation encoding="application / x-tex">(arom., s)< / annotation>< / semantics>; 141.1 <semantics>(arom.,s)<annotation encoding="application / x-tex">(arom., s)< / annotation>< / semantics>; 155.3 (CO, s); 162.5 (arom., s). ESI-HRMS: 263.1390 [M+H]+ (theor. <semantics>[C14H19N2O3]+=263.1390<annotation encoding="application / x-tex">[C_{14}H_{19}N_2O_3]^+ = 263.1390< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD538: In a round-bottom glass flask (250 mL), TD530 (568 mg; 2.17 mmol; 1.0 equiv.) was dissolved in DCM (20 mL) followed by addition of TEA (900 μL; 6.46 mmol; 3.0 equiv.). Freshly prepared solution of MsCl (355 μL; 4.33 mmol; 2.0 equiv.) in DCM (5 mL) was then added. Resulting solution was stirred 20 min at RT. Mixture was then diluted with DCM (50 mL) followed by addition of dil. aq. solution of NaHCO3 (50 mL). The resulting biphasic mixture was then transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (<semantics>3×50<annotation encoding="application / x-tex">3 \times 50< / annotation>< / semantics> mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. ESI-MS (LC-MS): 341.1 [M+H]+ (theor. <semantics>[C15H21N2O5S1]+=341.1<annotation encoding="application / x-tex">[C_{15}H_{21}N_2O_5S_1]^+ = 341.1< / annotation>< / semantics>). All of TD538 obtained in this way was directly used for TD539 without further purification or characterization. [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1045: Pear-shaped glass flask (25 mL) was charged with (6-Bromopyridin- 2-yl)methanol (500 mg; 2.67 mmol; 1.0 equiv.), 1,1-Dimethylpropargylamine (420 μL; 3.99 mmol; 1.5 equiv.) and magnetic stirrer and three times secured with argon. Solid CuI (21 mg; 110 <semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>mol; 4.0 mol%) and [Pd(PPh3)2Cl2] (19 mg; 27 <semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>mol; 1.0 mol%) were subsequently added followed by another securing with argon (three times). Under constant flow of argon was then added dry THF (10 mL) through septum followed by addition of TEA (1.10 mL; 7.89 mmol; 3.0 equiv.) after which the mixture changed color to dark brown. The flask was left stirring under septum (but without external argon) for 18 h at RT. The mixture was filtered with syringe microfilter (PTFE) and the solid phase was further washed with MeCN. Filtrate was evaporated to dryness and the resulting dark brown solid residue was purified on flash chromatography (120 g SiO2, 100% EtOAc to 40% EtOAc in MeOH). Combined fractions with product were evaporated to dryness and further co-evaporated once with DCM. The residue was further dried on high vacuum overnight to give product in the form of free base as yellow solidified oil. Yield: 283 mg (56%; 1 step; based on (6-Bromopyridin-2-yl)methanol). NMR (DMSO-d6): 1H δH 1.38 <semantics>(CH3,s,6H);3.17(NH2,s,2H);4.51(CH2,s,2H);5.44(OH,bs,1H);7.26(arom.,dd,1H,<math>3JHH=8;4JHH=1);<annotation encoding="application / x-tex">(CH_3, s, 6H); 3.17 (NH_2, s, 2H); 4.51 (CH_2, s, 2H); 5.44 (OH, bs, 1H); 7.26 (arom., dd, 1H, ^3J_{HH} = 8; ^4J_{HH} = 1);< / annotation>< / semantics> 7.40 (arom., dd, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>; <semantics>4JHH=1<annotation encoding="application / x-tex">{}^{4}J_{HH} = 1< / annotation>< / semantics>); 7.76 (arom., t, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>). ESI-HRMS: 191.1180 [M+H]+ (theor. <semantics>[C11H15N2O1]+=191.1180<annotation encoding="application / x-tex">[C_{11}H_{15}N_2O_1]^+ = 191.1180< / annotation>< / semantics>. [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1048: Pear-shaped glass flask (25 mL) was charged with TD1045 (280 mg; 1.47 mmol; 1.0 equiv.) followed by addition of MeCN (10 mL) and solution of Boc2O (2.0 M in dry THF; 1.0 mL; 2.00 mmol; 1.4 equiv.). The resulting mixture was stirred 16 h at RT. Mixture was then evaporated to dryness and the resulting yellow residue was purified on flash chromatography (120 g SiO2, 100% DCM to 100% EtOAc). Combined fractions with product were evaporated to dryness and further co-evaporated once with DCM. The residue was further dried on high vacuum overnight to give product in the form of free base as colourless solid. Yield: 242 mg (57%; 1 step; based on TD1045). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 1.40 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 9H), 1.53 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 6H); 4.51 <semantics>(CH2,d,2H,3JHH=4);5.44(OH,t,1H,3JHH=4);7.12(NH,bs,1H);7.25(arom.,dd,1H,3JHH=8;4JHH=1);<annotation encoding="application / x-tex">(CH_2, d, 2H, {}^3J_{HH} = 4); 5.44 (OH, t, 1H, {}^3J_{HH} = 4); 7.12 (NH, bs, 1H); 7.25 (arom., dd, 1H, {}^3J_{HH} = 8; {}^4J_{HH} = 1);< / annotation>< / semantics> 7.41 (arom., dd, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>; <semantics>4JHH=1<annotation encoding="application / x-tex">{}^{4}J_{HH} = 1< / annotation>< / semantics>); 7.77 (arom., t, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>). ESI-HRMS: 291.1704 [M+H]+ (theor. <semantics>[C16H23N2O3]+=291.1703<annotation encoding="application / x-tex">[C_{16}H_{23}N_2O_3]^+ = 291.1703< / annotation>< / semantics>. [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1050: In a glass vial (20 mL), TD1048 (19 mg; 65 μmol; 1.0 equiv.) was dissolved in DCM (3 mL) followed by addition of TEA (28 µL; 201 µmol; 3.1 equiv.). Freshly prepared solution of MsCl (10 µL; 129 µmol; 2.0 equiv.) in DCM (1 mL) was then added. Resulting solution was stirred 20 min at RT. Mixture was then diluted with DCM (15 mL) followed by addition of dil. aq. solution of NaHCO3 (15 mL). The resulting biphasic mixture was then transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (3 <semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics> 20 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. ESI-MS (LC-MS): 369.1 [M+H]+ (theor. <semantics>[C17H25N2O5S1]+=369.1<annotation encoding="application / x-tex">[C_{17}H_{25}N_2O_5S_1]^+ = 369.1< / annotation>< / semantics>). All of TD1050 obtained in this way was directly used for TD1054 (and analogically for TD1105) without further purification or characterization. Synthesis of TD966: Pear-shape glass flask (100 mL) was charged with (6-Bromopyridin-2-yl)methanol [Image disponible dans le document PDF, Image available in the PDF document] (1.00 g; 5.35 mmol; 1.0 equiv.), N-Boc-4-ethynylpiperidine (1.23 g; 5.88 mmol; 1.1 equiv.) and magnetic stirrer and three times secured with argon. Solid CuI (41 mg; 215 µmol; 4.0 mol%) and [Pd(PPh3)2Cl2] (75 mg; 107 μmol; 2.0 mol%) were subsequently added followed by another securing with argon (three times). Under constant flow of argon was then added dry THF (40 mL) through septum followed by addition of TEA (2.20 mL; 15.7 mmol; 3.0 equiv.) after which the mixture changed color to dark brown. The flask was left stirring under septum (but without external argon) for 2 d at RT. The mixture was then transferred to a separatory funnel with EtOAc (30 mL) and H2O (50 mL). After shaking, the dark colored (and not entirely homogenous) organic layer was separated and the aqueous layer was further extracted with EtOAc (3 × 30 mL). Combined organic layers were filtered through cotton plug and the filtrate was further dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. Resulting dark brown oily residue was purified on flash chromatography (220) g SiO2, 100% DCM to 100% EtOAc). Combined fractions with product were evaporated to dryness and further co-evaporated once with DCM. The residue was further dried on high vacuum overnight to give product in the form of free base as yellow oil. Yield: 1.47 g (87%; 1 step; based on (6-Bromopyridin-2-yl)methanol). NMR (DMSO-d6): 1H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 1.40 (CH3, s, 9H); 1.44–1.57 (CH2, m, 2H); 1.75–1.89 (CH2, m, 2H); 2.87 (CH–C≡C tt, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>, <semantics>3JHH=4<annotation encoding="application / x-tex">{}^{3}J_{HH} = 4< / annotation>< / semantics>); 3.01–3.17 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, m, 2H); 3.59–3.73 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, m, 2H); 4.51 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>–O, d, 2H, <semantics>3JHH=6<annotation encoding="application / x-tex">{}^{3}J_{HH} = 6< / annotation>< / semantics>); 5.44 <semantics>(OH,t,1H,3JHH=6);7.32(arom.,dd,1H,3JHH=8;4JHH=1);7.41(arom.,dd,1H,3JHH=8;4JHH=1);7.76<annotation encoding="application / x-tex">(OH, t, 1H, {}^{3}J_{HH} = 6); 7.32 (arom., dd, 1H, {}^{3}J_{HH} = 8; {}^{4}J_{HH} = 1); 7.41 (arom., dd, 1H, {}^{3}J_{HH} = 8; {}^{4}J_{HH} = 1); 7.76< / annotation>< / semantics> (arom., t, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>). ESI-HRMS: 317.1860 [M+H]+ (theor. [C18H25N2O3]+ = 317.1860). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1117: In a glass vial (20 mL), TD952 (50.0 mg; 158 µmol; 1.0 equiv.) was dissolved in DCM (6 mL) followed by addition of TEA (66 µL; 473 µmol; 3.0 equiv.) and neat MsCl (25 μL; 323 μmol; 2.0 equiv.). Resulting solution was stirred 20 min at RT followed by addition of DCM (10 mL) dil. aq. solution of NaHCO3 (10 mL). The resulting biphasic mixture was then transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (4 × 10 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. ESI-MS (LC-MS): 395.2 [M+H]+ (theor. <semantics>[C19H27N2O5S1]+=395.2<annotation encoding="application / x-tex">[C_{19}H_{27}N_2O_5S_1]^+ = 395.2< / annotation>< / semantics>). All of TD1117 obtained in this way was directly used for TD1118 without further purification or characterization. [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD936: Glass vial (4 mL) was charged with (6-Bromopyridin-2-yl)methanol (135 mg; 722 μmol; 1.0 equiv.), CuI (5.5 mg; 29 μmol; 4.0 mol%), [Pd(PPh3)2Cl2] (10.0 mg; 14 µmol; 2.0 mol%) and magnetic stirrer and three times secured with argon. Under constant flow of argon was then added dry THF (3 mL) through septum followed by addition of phenylacetylene (95 μL; 865 μmol; 1.2 equiv.) and TEA (300 μL; 2.15 mmol; 3.0 equiv.) after which the mixture changed color to dark brown. The vial was left stirring under septum (but without external argon) for 16 h at RT. The mixture was then filtered through syringe microfilter (PTFE) followed by washing with MeCN. Filtrate was evaporated to dryness, re-dissolved in MeCN (3 mL) and directly purified by preparative HPLC (C18; H2O–MeCN gradient with TFA additive). Fractions containing product were neutralized with dil. aq. NaHCO3 and evaporated to dryness. Residue was dissolved in a mixture of DCM (50 mL) and H2O (50 mL) and transferred to a separatory funnel. After brief shaking, the bottom phase was separated and the aq. layer was further extracted with DCM (4 × 25 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residual solid was briefly dried on high vacuum to give product in the form of free base as a yellow oil. Yield: 141 mg (93%; 1 step; based on (6-Bromopyridin-2-yl)methanol). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 4.57 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, d, 2H, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 6); 5.50 (O<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, t, 1H, <semantics>3JHH=6<annotation encoding="application / x-tex">{}^{3}J_{HH} = 6< / annotation>< / semantics>); 7.42–7.54 (arom., Ph, m, 2+3H); 7.57–7.64 (Ph, m, 2H); 7.85 (arom., t, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>). ESI- HRMS: 210.0913 [M+H]+ (theor. <semantics>[C14H12N1O1]+=210.0913<annotation encoding="application / x-tex">[C_{14}H_{12}N_1O_1]^+ = 210.0913< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD939: In a glass vial (20 mL), TD936 (22 mg; 105 μmol; 1.0 equiv.) was dissolved in DCM (6 mL) followed by addition of TEA (44 µL; 316 µmol; 3.0 equiv.). and neat MsCl (16 μL; 207 μmol; 2.0 equiv.). Resulting solution was stirred 20 min at RT followed by addition of dil. aq. solution of NaHCO3 (5 mL). The resulting biphasic mixture was then transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (<semantics>4×25<annotation encoding="application / x-tex">4 \times 25< / annotation>< / semantics> mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. ESI-MS (LC-MS): 288.1 [M+H]+ (theor. <semantics>[C15H14N1O3S1]+=288.1<annotation encoding="application / x-tex">[C_{15}H_{14}N_1O_3S_1]^+ = 288.1< / annotation>< / semantics>). All of TD939 obtained in this way was directly used for TD944 without further purification or characterization. [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD937: Glass vial (4 mL) was charged with (6-Bromopyridin-2-yl)methanol (135 mg; 722 μmol; 1.0 equiv.), CuI (5.5 mg; 29 μmol; 4.0 mol%), [Pd(PPh3)2Cl2] (10.0 mg; 14 µmol; 2.0 mol%) and magnetic stirrer and three times secured with argon. Under constant flow of argon was then added dry THF (3 mL) through septum followed by addition of Cyclopropylacetylene (75 μL; 886 μmol; 1.2 equiv.) and TEA (300 μL; 2.15 mmol; 3.0 equiv.) after which the mixture changed color to dark brown. The vial was left stirring under septum (but without external argon) for 16 h at RT. The mixture was then filtered through syringe microfilter (PTFE) followed by washing with MeCN. Filtrate was evaporated to dryness, re-dissolved in MeCN (3 mL) and directly purified by preparative HPLC (C18; H2O–MeCN gradient with TFA additive). Fractions containing product were neutralized with dil. aq. NaHCO3 and evaporated to dryness. Residue was dissolved in a mixture of DCM (50 mL) and H2O (50 mL) and transferred to a separatory funnel. After brief shaking, the bottom phase was separated and the aq. layer was further extracted with DCM (<semantics>4×25<annotation encoding="application / x-tex">4 \times 25< / annotation>< / semantics> mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residual solid was briefly dried on high vacuum to give product in the form of free base as a yellow oil. Yield: 98 mg (78%; 1 step; based on (6-Bromopyridin-2-yl)methanol). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 0.69–0.83 (CH2–CH, m, 2H); 0.83–0.99 <semantics>(CH2−CH,m,2H);1.56(CH,tt,3JHH=8,3JHH=5);4.49(CH2,d,2H,3JHH=6);5.42(OH,t,1H,3JHH=6);<annotation encoding="application / x-tex">(CH_2-CH, m, 2H); 1.56 (CH, tt, {}^3J_{HH} = 8, {}^3J_{HH} = 5); 4.49 (CH_2, d, 2H, {}^3J_{HH} = 6); 5.42 (OH, t, 1H, {}^3J_{HH} = 6);< / annotation>< / semantics> 7.27 (arom., dd, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>, <semantics>4JHH=1<annotation encoding="application / x-tex">{}^{4}J_{HH} = 1< / annotation>< / semantics>); 7.38 (arom., dd, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>, <semantics>4JHH=1<annotation encoding="application / x-tex">{}^{4}J_{HH} = 1< / annotation>< / semantics>); 7.74 (arom., t, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>). ESI-HRMS: 174.0913 [M+H]+ (theor. <semantics>[C11H12N1O1]+=174.0913<annotation encoding="application / x-tex">[C_{11}H_{12}N_1O_1]^+ = 174.0913< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD940: In a glass vial (20 mL), TD937 (26 mg; 150 µmol; 1.0 equiv.) was dissolved in DCM (9 mL) followed by addition of TEA (63 µL; 452 µmol; 3.0 equiv.) and neat MsCl (23 μL; 297 μmol; 2.0 equiv.). Resulting solution was stirred 20 min at RT followed by addition of dil. aq. solution of NaHCO3 (5 mL). The resulting biphasic mixture was then transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (<semantics>4×25<annotation encoding="application / x-tex">4 \times 25< / annotation>< / semantics> mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. ESI-MS (LC-MS): 252.0 [M+H]+ (theor. <semantics>[C12H14N1O3S1]+=252.1<annotation encoding="application / x-tex">[C_{12}H_{14}N_1O_3S_1]^+ = 252.1< / annotation>< / semantics>). All of TD940 obtained in this way was directly used for TD943 without further purification or characterization. [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD952: Glass vial (4 mL) was charged with (6-Bromopyridin-2-yl)methanol (150 mg; 802 μmol; 1.0 equiv.), CuI (6.1 mg; 32 μmol; 4.0 mol%), [Pd(PPh3)2Cl2] (11.5 mg; 16 µmol; 2.0 mol%) and magnetic stirrer and three times secured with argon. Under constant flow of argon was then added dry THF (3 mL) through septum followed by addition of tert- butylacetylene (200 µL; 1.62 mmol; 2.0 equiv.) and TEA (340 µL; 2.44 mmol; 3.0 equiv.) after which the mixture changed color to dark brown. The vial was left stirring under septum (but without external argon) for 24 h at RT. The mixture was then filtered through syringe microfilter (PTFE) followed by washing with MeCN. Filtrate was evaporated to dryness, re-dissolved in MeCN (3 mL) and directly purified by preparative HPLC (C18; H2O–MeCN gradient with TFA additive). Fractions containing product were neutralized with dil. aq. NaHCO3 and evaporated to dryness. Residue was dissolved in a mixture of DCM (50 mL) and H2O (50 mL) and transferred to a separatory funnel. After brief shaking, the bottom phase was separated and the aq. layer was further extracted with DCM (<semantics>4×25<annotation encoding="application / x-tex">4 \times 25< / annotation>< / semantics> mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residual solid was briefly dried on high vacuum to give product in the form of free base as a yellow oil. Yield: 146 mg (96%; 1 step; based on (6-Bromopyridin-2-yl)methanol). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 1.30 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 9H); 4.51 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, d, 2H, <semantics>3JHH=6<annotation encoding="application / x-tex">^{3}J_{HH} = 6< / annotation>< / semantics>); 5.43 (OH, t, 1H, <semantics>3JHH=6<annotation encoding="application / x-tex">^{3}J_{HH} = 6< / annotation>< / semantics>); 7.26 (arom., dd, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">^{3}J_{HH} = 8< / annotation>< / semantics>, <semantics>4JHH=1<annotation encoding="application / x-tex">^{4}J_{HH} = 1< / annotation>< / semantics>); 7.39 (arom., dd, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">^{3}J_{HH} = 8< / annotation>< / semantics>, <semantics>4JHH=1<annotation encoding="application / x-tex">^{4}J_{HH} = 1< / annotation>< / semantics>); 7.74 (arom., t, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">^{3}J_{HH} = 8< / annotation>< / semantics>). ESI-HRMS: 190.1227 [M+H]+ (theor. [C12H16N1O1]+ = 190.1226). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD956: In a glass vial (20 mL), TD952 (8 mg; 42 µmol; 1.0 equiv.) was dissolved in DCM (3 mL) followed by addition of TEA (18 µL; 129 µmol; 3.0 equiv.) and neat MsCl (6.5 μL; 84 μmol; 2.0 equiv.). Resulting solution was stirred 20 min at RT followed by addition of DCM (5 mL) dil. aq. solution of NaHCO3 (5 mL). The resulting biphasic mixture was then transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (4 × 10 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. ESI-MS (LC-MS): 268.1 [M+H]+ (theor. <semantics>[C13H18N1O3S1]+=268.1<annotation encoding="application / x-tex">[C_{13}H_{18}N_1O_3S_1]^+ = 268.1< / annotation>< / semantics>). All of TD956 obtained in this way was directly used for TD959 without further purification or characterization. Synthesis of TD965: Glass vial (4 mL) was charged with (6-Bromopyridin-2-yl)methanol [Image disponible dans le document PDF, Image available in the PDF document] (53 mg; 283 μmol; 1.0 equiv.), I-Ethynyladamantane (50 mg; 312 μmol; 1.1 equiv.), CuI (2.7 mg; 14 μmol; 5.0 mol%), [Pd(PPh3)2Cl2] (5.0 mg; 7 μmol; 2.5 mol%) and magnetic stirrer and three times secured with argon. Under constant flow of argon was then added dry THF (1.5 mL) through septum followed by addition of TEA (120 µL; 861 µmol; 3.0 equiv.) after which the mixture changed color to dark brown. The vial was left stirring under septum (but without external argon) for 2 d at RT. The mixture was then filtered through syringe microfilter (PTFE) followed by washing with MeCN. Filtrate was evaporated to dryness, re-dissolved in MeCN (3 mL) and directly purified by preparative HPLC (C18; H2O–MeCN gradient with TFA additive). Fractions containing product were neutralized with dil. aq. NaHCO3 and evaporated to dryness. Residue was dissolved in a mixture of DCM (25 mL) and H2O (25 mL) and transferred to a separatory funnel. After brief shaking, the bottom phase was separated and the aq. layer was further extracted with DCM (<semantics>4×10 mL<annotation encoding="application / x-tex">4 \times 10 \text{ mL}< / annotation>< / semantics>). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residual solid was briefly dried on high vacuum to give product in the form of free base as a colourless oil. Yield: 67 mg (89%; 1 step; based on (6-Bromopyridin-2-yl)methanol). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 1.61–1.76 (Adm., m, 6H); 1.82–1.93 <semantics>(Adm.,m,6H)<annotation encoding="application / x-tex">(Adm., m, 6H)< / annotation>< / semantics>; 1.94–2.00 <semantics>(Adm.,m,3H)<annotation encoding="application / x-tex">(Adm., m, 3H)< / annotation>< / semantics>; 4.50 <semantics>(CH2,d,2H,3JHH=6)<annotation encoding="application / x-tex">(CH_2, d, 2H, {}^3J_{HH} = 6)< / annotation>< / semantics>; 5.43 <semantics>(OH,t,1H,3JHH=6)<annotation encoding="application / x-tex">(OH, t, 1H, {}^3J_{HH} = 6)< / annotation>< / semantics>; 7.25 <semantics>(arom.,m,6H)<annotation encoding="application / x-tex">(arom., m, 6H)< / annotation>< / semantics>); 1.94–2.00 <semantics>(Adm.,m,3H)<annotation encoding="application / x-tex">(Adm., m, 3H)< / annotation>< / semantics>; 4.50 <semantics>(CH2,d,2H,3JHH=6)<annotation encoding="application / x-tex">(CH_2, d, 2H, {}^3J_{HH} = 6)< / annotation>< / semantics>; 5.43 <semantics>(OH,t,<annotation encoding="application / x-tex">(OH, t,< / annotation>< / semantics> dd, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>, <semantics>4JHH=1<annotation encoding="application / x-tex">{}^{4}J_{HH} = 1< / annotation>< / semantics>); 7.38 (arom., dd, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>, <semantics>4JHH=1<annotation encoding="application / x-tex">{}^{4}J_{HH} = 1< / annotation>< / semantics>); 7.74 (arom., t, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>). ESI-HRMS: <semantics>268.1694 [M+H]+ (theor. [C18H22N1O1]+=268.1696).<annotation encoding="application / x-tex">268.1694 \text{ [M+H]}^+ \text{ (theor. } [C_{18}H_{22}N_1O_1]^+ = 268.1696).< / annotation>< / semantics> [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD990: In a glass vial (20 mL), TD965 (21 mg; 79 µmol; 1.0 equiv.) was dissolved in DCM (3 mL) followed by addition of TEA (33 µL; 237 µmol; 3.0 equiv.) and neat MsCl (12 μL; 155 μmol; 2.0 equiv.). Resulting solution was stirred 20 min at RT followed by addition of DCM (10 mL) dil. aq. solution of NaHCO3 (10 mL). The resulting biphasic mixture was then transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (<semantics>3×15<annotation encoding="application / x-tex">3 \times 15< / annotation>< / semantics> mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. ESI-MS (LC-MS): 346.1 [M+H]+ (theor. <semantics>[C19H24N1O3S1]+=346.1<annotation encoding="application / x-tex">[C_{19}H_{24}N_1O_3S_1]^+ = 346.1< / annotation>< / semantics>). All of TD990 obtained in this way was directly used for TD992 without further purification or characterization. [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1194: In a glass vial (4 mL), TD558 (110 mg; 726 µmol; 1.0 equiv.) was dissolved in MeCN (3.3 mL) followed by addition of NIS (180 mg; 800 µmol; 1.1 equiv.) and AcOH (50 μL; 875 μmol; 1.2 equiv.) and the resulting mixture was stirred 3 h at 80 °C. Mixture was then directly purified by preparative HPLC (C18; H2O–MeCN gradient with FA additive). Fractions containing product were joined and diluted with DCM (50 mL). The resulting biphasic mixture was transferred to a separatory funnel followed by addition of dil. aq. NaHCO3 and aq. Na2S3O3. After brief shaking, the bottom phase was separated and the aq. layer was further extracted with DCM (<semantics>3×25<annotation encoding="application / x-tex">3 \times 25< / annotation>< / semantics> mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was briefly dried on high vacuum to give product in the form of free base as a pale red solid. Yield: 61.5 mg (31%; 1 step; based on TD558). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 4.74 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, s, 2H); 7.48 (arom., dd, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">^{3}J_{HH} = 8< / annotation>< / semantics>, <semantics>4JHH=1<annotation encoding="application / x-tex">^{4}J_{HH} = 1< / annotation>< / semantics>); 7.54 (arom., dd, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">^{3}J_{HH} = 8< / annotation>< / semantics>, <semantics>4JHH=1<annotation encoding="application / x-tex">^{4}J_{HH} = 1< / annotation>< / semantics>); 7.85 (arom., t, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">^{3}J_{HH} = 8< / annotation>< / semantics>). ESI-HRMS: 277.9230 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics> (theor. <semantics>[C8H6N1I1CI1]+=277.9228<annotation encoding="application / x-tex">[C_8H_6N_1I_1CI_1]^+ = 277.9228< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1178: Glass vial (20 mL) was charged with CuI (60.0 mg; 315 µmol; 40 mol%), Phen (114 mg; 633 μmol; 80.0 mol%), KHCO3 (159 mg; 1.59 mmol; 2.0 equiv.) and magnetic stirrer and three times secured with argon. Under constant flow of argon was then added solution of TD558 (120 mg; 792 μmol; 1.0 equiv.) and Togni I (288 mg; 872 μmol; 1.1 equiv.) in dry DCM (8 mL) through septum and the resulting mixture was stirred 2 d at RT. Mixture was then filtered through syringe microfilter (PTFE) and the solid phase was further washed with DCM. Filtrate was evaporated to dryness and the residue was resuspended in MeCN (3 mL). Mixture was again filtered through syringe microfilter (PTFE) and the filtrate was purified by preparative HPLC (C18; H2O–MeCN gradient with FA additive). Fractions containing product were joined and diluted with DCM (50 mL). The resulting biphasic mixture was transferred to a separatory funnel followed by addition of dil. aq. NaHCO3. After brief shaking, the bottom phase was separated and the aq. layer was further extracted with DCM (<semantics>3×25<annotation encoding="application / x-tex">3 \times 25< / annotation>< / semantics> mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The resulting yellow oil was briefly dried on high vacuum (until the oil crystallized) to give product in the form of free base as pale yellow solid (portion of the product sublimed as colourless crystals on the upper part of the flask). Yield: 48.5 mg (28%; 1 step; based on TD558). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 4.83 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, s, 2H); 7.78 <semantics>(arom.,dd,1H,3JHH=8,4JHH=1);7.88(arom.,dd,1H,3JHH=8,4JHH=1);8.04(arom.,t,1H,3JHH=8).<annotation encoding="application / x-tex">(arom., dd, 1H, {}^{3}J_{HH} = 8, {}^{4}J_{HH} = 1); 7.88 (arom., dd, 1H, {}^{3}J_{HH} = 8, {}^{4}J_{HH} = 1); 8.04 (arom., t, 1H, {}^{3}J_{HH} = 8).< / annotation>< / semantics> 19F{1H} <semantics>δF<annotation encoding="application / x-tex">\delta_F< / annotation>< / semantics> -49.2 (s). ESI-HRMS: 220.0140 [M+H]+ (theor. [C9H6N1F3Cl1]+ = 220.0135). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD797: In a round-bottom glass flask (50 mL), Methyl 4,6- dibromopicolinate (200 mg; 678 μmol; 1.0 equiv.) was dissolved in a mixture of THF (4 mL) and MeOH (2 mL). To the resulting slightly yellow solution was added portion wise (over course of 10 min, with no stopper on the flask) solid NaBH4 (205 mg; 5.42 mmol; 8.0 equiv.) during which hydrogen gas evolved intensively and the color of the mixture changed to nearly colorless. Mixture was then transferred to a separatory funnel and diluted with DCM (100 mL) and H2O (100 mL). After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (3 × 50 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as white solid. Yield: 179 mg (99%; 1 step; based on Methyl 4,6-dibromopicolinate). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 4.53 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, s, 2H); 5.68 (OH, bs, 1H); 7.67 (arom., m, 1H); 7.89 (arom., m, 1H). ESI-HRMS: 265.8809 [M+H]+ (theor. <semantics>[C6H6N1O1Br2]+=265.8811<annotation encoding="application / x-tex">[C_6H_6N_1O_1Br_2]^+ = 265.8811< / annotation>< / semantics>. [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD804: Glass vial (4 mL) was charged with TD797 (100 mg; 375 μmol; 1.0 equiv.) and magnetic stirrer and three times secured with argon. Solid CuI (4.3 mg; 23 μmol; 6.0 mol%) and [Pd(PPh3)2Cl2] (8.0 mg; 11 μmol; 3.0 mol%) were subsequently added followed by another securing with argon (three times). Under constant flow of argon was then added dry THF (1.5 mL) through septum followed by addition of Ethynyltrimethylsilane (160 µL; 1.16 mmol; 3.1 equiv.) and TEA (160 µL; 1.15 mmol; 3.1 equiv.) after which the mixture changed color to dark brown. The flask was left stirring under septum (but without external argon) for 16 h at RT. The mixture was then transferred to a separatory funnel with EtOAc (50 mL) and H2O (50 mL). After shaking, the dark colored organic layer was separated and the aqueous layer was further extracted with EtOAc (3 × 25 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. Resulting dark brown oily residue was purified on flash chromatography (120 g SiO2, 100% DCM to 20% EtOAc in DCM). Combined fractions with product were evaporated to dryness and further co-evaporated once with DCM. The residue was further dried on high vacuum overnight to give product in the form of free base as dark brown oil. Yield: 99 mg (88%; 1 step; based on TD797). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 0.24 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 9H); 0.25 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 9H); 4.51 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>, d, 2H, <semantics>3JHH<annotation encoding="application / x-tex">^3J_{HH}< / annotation>< / semantics> = 6); 5.53 (O<semantics>H<annotation encoding="application / x-tex">H< / annotation>< / semantics>, t, 1H, <semantics>3JHH<annotation encoding="application / x-tex">^3J_{HH}< / annotation>< / semantics> = 6); 7.40 (arom., d, 1H, <semantics>4JHH<annotation encoding="application / x-tex">^4J_{HH}< / annotation>< / semantics> = 2); 7.42 (arom., d, 1H, <semantics>4JHH<annotation encoding="application / x-tex">^4J_{HH}< / annotation>< / semantics> = 2). ESI-HRMS: 302.1389 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics> (theor. <semantics>[C16H24N1O1Si2]+=302.1391<annotation encoding="application / x-tex">[C_{16}H_{24}N_1O_1Si_2]^+ = 302.1391< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD806: In a pear-shaped glass flask (50 mL), TD804 (98 mg; 325 μmol; 1.0 equiv.) was dissolved in DCM (3 mL). Freshly prepared solution of SOCl2 (47 μL; 647 μmol; 2.0 equiv.) in DCM (1 mL) was then added and the open flask was stirred 1 h at RT. Reaction mixture was diluted with DCM (16 mL) and dil. aq. solution of NaHCO3 (20 mL) was then added and resulting biphasic mixture was vigorously stirred for additional 1 h at RT, during which bubbles of gas slowly evolved. Mixture was then transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (3 <semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics> 20 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as brown oil. Yield: 102 mg (98%; 1 step; based on TD804). NMR (DMSO-d6): 1H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 0.25 (C<semantics>H3<annotation encoding="application / x-tex">H_3< / annotation>< / semantics>, s, 18H); 4.74 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>, s, 2H); 7.53 (arom., d, 1H, <semantics>4JHH<annotation encoding="application / x-tex">^4J_{HH}< / annotation>< / semantics> = 2); 7.60 (arom., d, 1H, <semantics>4JHH=2<annotation encoding="application / x-tex">{}^{4}J_{HH} = 2< / annotation>< / semantics>). ESI-HRMS: 320.1051 [M+H]+ (theor. [C16H23N1O1Cl1Si2]+ = 320.1052). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD807: In a round-bottom glass flask (50 mL), TD806 (101 mg; 316 µmol; 1.0 equiv.) was dissolved in MeCN (5 mL). Freshly prepared solution of KF (46.4 mg; 800 μmol; 2.5 equiv.) in H2O (800 μL) was then added and the flask was stirred 5 h at RT. The mixture was concentrated to ~1 ml and diluted with DCM (50 mL) and dil. aq. NaHCO3 (50 mL). The mixture was transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (<semantics>3×25<annotation encoding="application / x-tex">3 \times 25< / annotation>< / semantics> mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as brown solid. Yield: 48 mg <semantics>(87%;1 step; based on TD806)<annotation encoding="application / x-tex">(87\%; 1 \text{ step}; \text{ based on TD806})< / annotation>< / semantics>. NMR (DMSO-d6): <semantics>1H<annotation encoding="application / x-tex">{}^{1}\text{H}< / annotation>< / semantics> <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 4.48 (C\equiv CH, s, 1H); 4.75 (C\equiv CH, s, 1H); 4.76 (CH2, s, 2H); 7.61 (arom., d, 1H, <semantics>4JHH=1<annotation encoding="application / x-tex">{}^{4}J_{HH} = 1< / annotation>< / semantics>); 7.65 (arom., d, 1H, <semantics>4JHH=1<annotation encoding="application / x-tex">{}^{4}J_{HH} = 1< / annotation>< / semantics>). ESI-HRMS: 176.0267 [M+H]+ (theor. <semantics>[C10H7N1Cl1]+=176.0267<annotation encoding="application / x-tex">[C_{10}H_7N_1Cl_1]^+ = 176.0267< / annotation>< / semantics>. [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD662: In a glass vial (4 mL), Dipropargylamine (116 µL; 1.12 mmol; 1.0 equiv.) was dissolved in MeCN (2.5 mL) followed by addition of neat 1,2-Dibromoethane (965 μL; 11.2 mmol; 10 equiv.) and NaHCO3 (113 mg; 1.35 mmol; 1.2 equiv.) and the resulting mixture was stirred 2 days at 80 °C. Mixture was then diluted with DCM (50 mL) followed by addition of dil. aq. solution of NaHCO3 (50 mL). The resulting biphasic mixture was then transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (3 × 25 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. Residue was further purified by column chromatography (SiO2; 25) g; DCM). Combined fractions with product were evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as nearly colorless oil. Yield: 69 mg (31%; 1 step; based on Dipropargylamine). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 2.86 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, t, 2H, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 7); 3.21 (C=C<semantics>H<annotation encoding="application / x-tex">H< / annotation>< / semantics>, t, 2H, <semantics>4JHH<annotation encoding="application / x-tex">{}^{4}J_{HH}< / annotation>< / semantics> = 2); 3.21 (CH2, t, 4H, <semantics>4JHH<annotation encoding="application / x-tex">{}^{4}J_{HH}< / annotation>< / semantics> = 2); 3.55 (CH2, t, 2H, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 7). <semantics>13𝑪{1𝑯}<annotation encoding="application / x-tex">{}^{13}\mathbf{C}\{{}^{1}\mathbf{H}\}< / annotation>< / semantics> <semantics>δC<annotation encoding="application / x-tex">\delta_{C}< / annotation>< / semantics> 30.3 (CH2, s); 41.6 (CH2, s); 53.9 <semantics>(CH2,s)<annotation encoding="application / x-tex">(CH_2, s)< / annotation>< / semantics>; 76.4 and 78.5 <semantics>(C≡CH,2×s)<annotation encoding="application / x-tex">(C \equiv CH, 2 \times s)< / annotation>< / semantics>. ESI-HRMS: 200.0070 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics> (theor. <semantics>[C8H11N1Br1]+=200.0070<annotation encoding="application / x-tex">[C_8H_{11}N_1Br_1]^+ = 200.0070< / annotation>< / semantics>). Example 2: Synthesis of intermediates of azide pendant arms [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD406: In a round-bottom glass flask (250 mL), 2,6- Bis(chloromethyl)pyridine (6.17 g; 35.0 mmol; 1.2 equiv.) was dissolved in MeCN (80 mL) followed by addition of solid NaN3 (1.90 g; 29.2 mmol; 1.0 equiv.) and anhydrous K2CO3 (4.04 g; 29.2 mmol; 1.0 equiv.) and the resulting suspension was stirred 5 days at 50 °C. The mixture was filtered on glass frit S3 and the solid residue was washed with MeCN. Filtrate was evaporated to dryness and the orange oily residue was purified by column chromatography (SiO2, 30% P.E. in DCM to 100%) DCM). Fractions with product were combined and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as faint yellow oil. Yield: 2.62 g (49%; 1 step; based on NaN3). Recovery: 2.21 g of 2,6-Bis(chloromethyl)pyridine (36% of the initial amount used). NMR (DMSO-d6): 1H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 4.53 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>, s, 2H); 4.78 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>, s, 2H); 7.40 (arom., d, 1H, <semantics>3JHH<annotation encoding="application / x-tex">^3J_{HH}< / annotation>< / semantics> = 8; <semantics>4JHH<annotation encoding="application / x-tex">^4J_{HH}< / annotation>< / semantics> = 1); 7.52 (arom., d, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>; <semantics>4JHH=1<annotation encoding="application / x-tex">{}^{4}J_{HH} = 1< / annotation>< / semantics>); 7.89 (arom., t, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>). <semantics>13𝑪{1𝑯}δC46.6(CH2,s)<annotation encoding="application / x-tex">{}^{13}\mathbf{C}\{{}^{1}\mathbf{H}\}\ \delta_{C}\ 46.6\ (CH_{2}, s)< / annotation>< / semantics>; 54.2 (CH2, s); 121.9 (arom., s); 122.6 (arom., s); 138.5 (arom., s); 155.7 (arom., s); 156.3 (arom., s). ESI-HRMS: 183.0433 [M+H]+ (theor. <semantics>[C7H8N4Cl1]+=183.0432<annotation encoding="application / x-tex">[C_7H_8N_4Cl_1]^+ = 183.0432< / annotation>< / semantics>. [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD595: In a glass vial (20 mL), TD406 (30 mg; 162 µmol; 1.0 equiv.) was dissolved in DCM (5 mL) followed by addition of freshly prepared solution of MCPBA (77%; 72 mg; 320 µmol; 2.0 equiv.) in DCM (1 mL). The resulting solution was stirred 3 h at RT. Mixture was then diluted with DCM (20 mL) and dil. aq. NaHCO3 (25 mL) and transferred to a separatory funnel. After shaking, the bottom layer was separated and aqueous layer was further extracted with DCM (3 × 20 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. ESI-MS (LC-MS): 199.0 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics> (theor. <semantics>[C7H8N4O1Cl1]+=199.0<annotation encoding="application / x-tex">[C_7H_8N_4O_1Cl_1]^+ = 199.0< / annotation>< / semantics>). All of TD595 obtained in this way was directly used for TD596 without further purification or characterization. [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD726: In a round-bottom glass flask (1000 mL), Dimethyl 4- chloropyridine-2,6-dicarboxylate (15.0 g; 65.3 mmol; 1.0 equiv.) was gradually dissolved in a mixture of THF (540 mL) and MeOH (120 mL). The resulting slightly yellow solution - - was cooled with an ice bath (<semantics>∼<annotation encoding="application / x-tex">\sim< / annotation>< / semantics>5 °C) followed by portion wise additions (over course of 1 h, with no stopper on the flask) of solid NaBH4 (12.4 g; 328 mmol; 5.0 equiv.) during which hydrogen gas evolved intensively and the color of the mixture changed to red, orange and eventually yellow. After the addition, the flask was allowed to warm up to RT and was further stirred 16 h at RT. Resulting faint yellow opalescent solution was filtered on glass frit (S3), the filtrate was evaporated to dryness and further co-evaporated with DCM (as a suspension). Residue was dissolved in boiling H2O (~600 mL) and the resulting highly alkaline solution was continuously extracted by DCM overnight. The organic layer (containing partly crystallized product) was evaporated to dryness. The residue was mechanically crushed and further dried on high vacuum (till constant mass) to give product in the form of free base as nearly colorless microcrystalline powder. Yield: 10.84 g (96%; 1 step; based on Dimethyl 4-chloropyridine-2,6-dicarboxylate). NMR (DMSO-d6): 1H δH 4.53 (CH2, d, 4H, <semantics>3JHH=6<annotation encoding="application / x-tex">{}^{3}J_{HH} = 6< / annotation>< / semantics>); 5.54 (OH, t, 2H, <semantics>3JHH=6<annotation encoding="application / x-tex">{}^{3}J_{HH} = 6< / annotation>< / semantics>); 7.36 (arom., s, 2H). <semantics>13𝑪{1𝑯}<annotation encoding="application / x-tex">{}^{13}\mathbf{C}\{{}^{1}\mathbf{H}\}< / annotation>< / semantics> <semantics>δC<annotation encoding="application / x-tex">\delta_{C}< / annotation>< / semantics> 63.7 (CH2, s); 118.0 <semantics>(arom.,s);144.0(arom.,s);163.5(arom.,s).<annotation encoding="application / x-tex">(arom., s); 144.0 (arom., s); 163.5 (arom., s).< / annotation>< / semantics> ESI-HRMS: 174.0317 [M+H]+ (theor. [C7H9N1O2Cl1]+ = 174.0316). EA (<semantics>C7H8N1O2Cl1<annotation encoding="application / x-tex">C_7H_8N_1O_2Cl_1< / annotation>< / semantics>, <semantics>MR=173.6<annotation encoding="application / x-tex">M_R = 173.6< / annotation>< / semantics>): C 48.4 (48.5); H 4.7 (4.5); N 7.7 (8.1); Cl 20.4 (21.2). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD759: In a round-bottom glass flask (100 mL), TD726 (626 mg; 3.61 mmol; 1.0 equiv.) was suspended in DCM (20 mL). Freshly prepared solution of SOCl2 (780 μL; 10.7 mmol; 3.0 equiv.) in DCM (10 mL) was then added and the open flask was stirred 90 min at RT, producing clear solution. Dil. aq. solution of NaHCO3 (40 mL) was then added and resulting biphasic mixture was vigorously stirred for additional 1 h at RT, during which bubbles of gas slowly evolved. Mixture was then transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (<semantics>3×50<annotation encoding="application / x-tex">3 \times 50< / annotation>< / semantics> mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The resulting crystalized residue was crushed and further dried on high vacuum overnight to give product in the form of free base as nearly colorless microcrystalline powder. Yield: 711 mg (94%; 1 step; based on TD726). NMR (DMSO-d6): 1H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 4.79 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>, s, 4H); 7.70 (arom., s, 2H). 13C{1H} <semantics>δC<annotation encoding="application / x-tex">\delta_{C}< / annotation>< / semantics> 45.7 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>, s); 122.8 (arom., s); 144.4 (arom., s); 158.2 (arom., s). ESI-HRMS: 209.9638 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics> (theor. <semantics>[C7H7N1Cl3]+=209.9639<annotation encoding="application / x-tex">[C_7H_7N_1Cl_3]^+ = 209.9639< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD760: In a glass vial (20 mL), TD759 (708 mg; 3.36 mmol; 1.3 equiv.) was dissolved in MeCN (20 mL) followed by addition of solid NaN3 (168 mg; 2.58 mmol; 1.0 equiv.) and dried K2CO3 (360 mg; 2.61 mmol; 1.0 equiv.) and the resulting suspension was stirred 24 h at 80 °C. The mixture was filtered on through syringe microfilter (PTFE) and the solid residue was washed with MeCN. Filtrate was evaporated to dryness and yellow oily residue was purified by column chromatography (SiO2, 40% P.E. in DCM to 10% P.E. in DCM). Fractions with product were combined and evaporated to dryness. The residue was further dried on high vacuum 1 h to give product in the form of free base as faint yellow oil. Yield: 323 mg (58%; 1 step; based on NaN3). Recovery: 218 mg of TD759 (31% of the initial amount used). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 4.56 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, s, 2H); 4.78 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, s, 2H); 7.58 <semantics>(arom.,d,1H,4JHH=2);7.69(arom.,d,1H,4JHH=8).<annotation encoding="application / x-tex">(arom., d, 1H, {}^{4}J_{HH} = 2); 7.69 (arom., d, 1H, {}^{4}J_{HH} = 8).< / annotation>< / semantics> 13C{1H} <semantics>δC<annotation encoding="application / x-tex">\delta_{C}< / annotation>< / semantics> 45.8 (CH2, s); 53.6 (CH2, s); 121.9 (arom., s); 122.5 (arom., s); 144.4 (arom., s); 157.9 (arom., s); 158.2 (arom., s). ESI-HRMS: 217.0040 [M+H]+ (theor. <semantics>[C7H7N4Cl2]+=217.0042<annotation encoding="application / x-tex">[C_7H_7N_4Cl_2]^+ = 217.0042< / annotation>< / semantics>. [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1146: In a glass vial (20 mL), TD726 (495 mg; 2.85 mmol; 1.0 equiv.) was dissolved in DMF (11.0 mL; 143 mmol; 50 equiv.) followed by addition of freshly ground KOH (1.6 g; 28.5 mmol; 10 equiv.). The resulting suspension was stirred 3 days at 100 °C in the presence of air (vial septum was punctured by two thick needles). The mixture was then filtered through syringe microfilter (PTFE; the solids were washed with DMF). Filtrate was evaporated to dryness and purified by preparative HPLC (C18; H2O–MeCN gradient with TFA additive). Fractions with product were combined and directly lyophilized to give product in the form of trifluoroacetate salt as white foam. Yield: 187 mg (22%; 1 step; based on TD726). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 3.18 (C<semantics>H3<annotation encoding="application / x-tex">H_3< / annotation>< / semantics>, s, 6H); 4.59 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>, d, 4H, <semantics>3JHH=6<annotation encoding="application / x-tex">^3J_{HH} = 6< / annotation>< / semantics>); 5.91 (O<semantics>H<annotation encoding="application / x-tex">H< / annotation>< / semantics>, t, 2H, <semantics>3JHH=6<annotation encoding="application / x-tex">^3J_{HH} = 6< / annotation>< / semantics>); 6.84 (arom., s, 2H). ESI-HRMS: 183.1128 [M+H]+ (theor. <semantics>[C9H15N2O2]+=183.1128<annotation encoding="application / x-tex">[C_9H_{15}N_2O_2]^+ = 183.1128< / annotation>< / semantics>). EA (<semantics>C9H14N2O2⋅1.0<annotation encoding="application / x-tex">C_9H_{14}N_2O_2 \cdot 1.0< / annotation>< / semantics>TFA, <semantics>MR=296.2<annotation encoding="application / x-tex">M_R = 296.2< / annotation>< / semantics>): C 44.6 (44.1); H 5.1 (4.9); N 9.5 (9.1); F 19.2 (18.2). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1154: In a round-bottom glass flask (100 mL), TD1146·1.0TFA (173.3 mg; 585 µmol; 1.0 equiv.) was suspended in DCM (17 mL) followed by addition of neat SOCl2 (780 μL; 2.34 mmol; 4.0 equiv.). The resulting mixture was stirred 90 min at RT, producing clear solution. Dil. aq. solution of NaHCO3 (20 mL) was then added and resulting biphasic mixture was vigorously stirred for additional 1 h RT, during which bubbles of gas slowly evolved. Mixture was then transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (<semantics>3×25<annotation encoding="application / x-tex">3 \times 25< / annotation>< / semantics> mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as white solid. Yield: 105.6 mg (82%; 1 step; based on TD726). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 2.98 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 6H); 4.60 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, s, 4H); 6.73 (arom., s, 2H). ESI-HRMS: 219.0450 [M+H]+ (theor. <semantics>[C9H13N2Cl2]+=219.0450<annotation encoding="application / x-tex">[C_9H_{13}N_2Cl_2]^+ = 219.0450< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1163: In a glass vial (20 mL), TD1154 (103.9 mg; 474 µmol; 1.3 equiv.) was dissolved in MeCN (7 mL) followed by addition of solid NaN3 (23.7 mg; 365 μmol; 1.0 equiv.) and dried K2CO3 (50.3 mg; 364 μmol; 1.0 equiv.) and the resulting suspension was stirred 24 h at 70 °C. The mixture was filtered on through syringe microfilter (PTFE) and the solid residue was washed with MeCN. Filtrate was evaporated to dryness and the residue was purified by column chromatography (SiO2, 5% EtOAc in DCM to 10% EtOAc in DCM). Fractions with product were combined and evaporated to dryness. The residue was further dried on high vacuum 1 h to give product in the form of free base as colourless oil. Yield: 33.8 mg (41%; 1 step; based on NaN3). Recovery: 11.0 mg of TD1154 (11% of the initial amount used). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 2.99 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 6H); 4.32 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, s, 2H); 4.60 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>, s, 2H); 6.60 (arom., d, 1H, <semantics>4JHH=2<annotation encoding="application / x-tex">{}^4J_{HH} = 2< / annotation>< / semantics>); 6.73 (arom., d, 1H, <semantics>4JHH=2<annotation encoding="application / x-tex">{}^4J_{HH} = 2< / annotation>< / semantics>). ESI-HRMS: 226.0853 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics> (theor. <semantics>[C9H13N5Cl1]+=226.0854<annotation encoding="application / x-tex">[C_9H_{13}N_5Cl_1]^+ = 226.0854< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1024: Glass vial (100 mL) was charged with CuI (70 mg; 0.37 mmol; 4.0 mol%) and [Pd(PPh3)2Cl2] (125 mg; 0.18 mmol; 2.0 mol%) and magnetic stirrer and three times secured with argon. Solution of Dimethyl 4- iodopyridine-2,6-dicarboxylate (2.93 g; 9.13 mmol; 1.0 equiv.) in mixture of dry THF (40 ml), dry Toluene (40 ml) and dry DMF (2 mL) was subsequently added through septum followed by addition of Ethynyltriisopropylsilane (2.25 mL; 10.0 mmol; 1.1 equiv.) and TEA (3.80 mL; 27.3 mmol; 3.0 equiv.) after which the mixture changed color to pale red. The flask was left stirring under septum (but without external argon) for 20 h at RT. The resulting dark mixture was filtered through syringe microfilter (PTFE) and the filtrate was evaporated to dryness. Residue was dissolved in DCM (250 mL) and the resulting red solution was washed once with aq. solution of Na2S2O3. The organic layer was separated, dried with Na2SO4, filtered through glass frit (S3) and evaporated to dryness. Residue was purified on flash chromatography (220 g SiO2, 100% DCM to 20% EtOAc in DCM). Combined fractions with product were evaporated to dryness and further co-evaporated once with DCM. The residue was further dried on high vacuum overnight to give pre-purified product in the form of free base as orange oil. Yield: 3.16 g (92%; 1 step; based on Dimethyl 4-iodopyridine-2,6-dicarboxylate). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 0.92–1.27 (i-Pr, m, 21H); 3.92 (C<semantics>H3<annotation encoding="application / x-tex">H_3< / annotation>< / semantics>, s, 6H); 8.16 (arom., s, 2H). 13C{1H} <semantics>δC<annotation encoding="application / x-tex">\delta_C< / annotation>< / semantics> 10.6 (i-Pr, s); 18.4 (i-Pr, s); 52.9 (C<semantics>H3<annotation encoding="application / x-tex">H_3< / annotation>< / semantics>, s); 99.0 (C<semantics>≡C<annotation encoding="application / x-tex">\equiv C< / annotation>< / semantics>- Si, s); <semantics>102.5<annotation encoding="application / x-tex">102.5< / annotation>< / semantics> (C=<semantics>C<annotation encoding="application / x-tex">C< / annotation>< / semantics>-arom.; s); <semantics>129.3<annotation encoding="application / x-tex">129.3< / annotation>< / semantics> (arom., s); <semantics>132.7<annotation encoding="application / x-tex">132.7< / annotation>< / semantics> (arom., s); <semantics>148.4<annotation encoding="application / x-tex">148.4< / annotation>< / semantics> (arom., s); <semantics>164.0<annotation encoding="application / x-tex">164.0< / annotation>< / semantics> (CO, s). ESI-HRMS: <semantics>376.1939[M+H]+ (theor. [C20H30N1O4Si1]+=376.1939).<annotation encoding="application / x-tex">376.1939 [M+H]^+ \text{ (theor. } [C_{20}H_{30}N_1O_4Si_1]^+ = 376.1939).< / annotation>< / semantics> [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD808: In a round-bottom glass flask (250 mL), TD1024 (3.15 g; 8.39 mmol; 1.0 equiv.) was dissolved in a mixture of THF (60 mL) and MeOH (30 mL). Then, solid NaBH4 (2.55 g; 67.4 mmol; 8 equiv.) was added portion wise over the course of 1 h (during which hydrogen gas evolved intensively) and the color of the mixture changed to dark red. After the addition, the flask was further stirred 1 h at RT. The mixture was evaporated to dryness. Residue was resuspended in DCM (200 mL) and H2O (200 mL) and transferred to a separatory funnel. After shaking, the bottom phase (as a suspension) was separated. Aqueous phase was further extracted with DCM (<semantics>3×100 mL<annotation encoding="application / x-tex">3 \times 100 \text{ mL}< / annotation>< / semantics>). Combined organic layers were diluted with EtOAc (500 mL). The resulting brown solution was then dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as pale brown solid. Yield: 2.61 g (97%; 1 step; based on TD1024). NMR (DMSO-d6): 1H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 1.04–1.17 (i-Pr, m, 21H); 4.51 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>, d, 4H, <semantics>3JHH<annotation encoding="application / x-tex">^3J_{HH}< / annotation>< / semantics> = 6); 5.48 (O<semantics>H<annotation encoding="application / x-tex">H< / annotation>< / semantics>, t, 2H, <semantics>3JHH<annotation encoding="application / x-tex">^3J_{HH}< / annotation>< / semantics> = 6); 7.31 (arom., s, 2H). 13C{¹H} δC 10.6 (i-Pr, s); 18.5 (i-Pr, s); 63.9 (CH2, s); 94.6 (<semantics>C<annotation encoding="application / x-tex">C< / annotation>< / semantics>≡C−Si, s); 105.1 (<semantics>C<annotation encoding="application / x-tex">C< / annotation>< / semantics>≡C−arom.; s); 119.8 (arom., s); 130.8 (arom., s); 161.9 (arom., s). ESI-HRMS: 320.2036 [M+H]+ (theor. <semantics>[C18H30N1O2]+=320.2040<annotation encoding="application / x-tex">[C_{18}H_{30}N_1O_2]^+ = 320.2040< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD815: In a round-bottom glass flask (250 mL), pre-purified TD808 (2.61 g; 8.17 mmol; 1.0 equiv.) was suspended in DCM (100 mL). Freshly prepared solution of SOCl2 (1.80 mL; 24.8 mmol; 3.0 equiv.) in DCM (10 mL) was then added and the open flask was stirred 1 h at RT. Dil. aq. solution of NaHCO3 (100 mL) was then added and resulting biphasic mixture was vigorously stirred for additional 1 h at RT, during which bubbles of gas slowly evolved. Mixture was then transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (<semantics>3×75<annotation encoding="application / x-tex">3 \times 75< / annotation>< / semantics> mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as yellow oil. Yield: 2.87 g (99%; 1 step; based on TD808). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 0.97–1.20 (i-Pr, m, 21H); 4.78 (CH2, s, 4H); 7.59 (arom., s, 2H). <semantics>13<annotation encoding="application / x-tex">{}^{13}< / annotation>< / semantics>C{<semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H} <semantics>δC<annotation encoding="application / x-tex">\delta_{C}< / annotation>< / semantics> 10.6 (i-Pr, s); 18.4 (i-Pr, s); 45.9 (CH2, s); 96.6 (C<semantics>≡<annotation encoding="application / x-tex">\equiv< / annotation>< / semantics>C-Si, s); 103.5 (C<semantics>≡<annotation encoding="application / x-tex">\equiv< / annotation>< / semantics>C-arom.; s); 124.6 (arom., s); 132.0 (arom., s); 157.1 (arom., s). ESI-HRMS: 356.1368 [M+H]+ (theor. <semantics>[C18H28N1Cl2Si1]+=356.1368<annotation encoding="application / x-tex">[C_{18}H_{28}N_1Cl_2Si_1]^+ = 356.1368< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD817: In a round-bottom glass flask (250 mL), TD815 (2.86 g; 8.02 mmol; 1.2 equiv.) was dissolved in MeCN (130 mL) followed by addition of solid NaN3 (435 mg; 6.69 mmol; 1.0 equiv.) and dried K2CO3 (920 mg; 6.67 mmol; 1.0 equiv.) and the resulting suspension was stirred 16 h at 80 °C. The mixture was filtered through syringe microfilter (PTFE) and the solid residue was washed with MeCN. Filtrate was evaporated to dryness and orange oily residue was purified by column chromatography (220 g SiO2, 30% P.E. in DCM to 10% P.E. in DCM). Fractions with product were combined and evaporated to dryness. The residue was further dried on high vacuum 1 h to give product in the form of free base as faint yellow oil. Yield: 1.23 g (51%; 1 step; based on NaN3). Recovery: 709 mg of TD815 (25% of the initial amount used). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 1.01–1.21 (i-Pr, m, 21H); 4.55 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>, s, 2H); 4.78 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>, s, 2H); 7.47 <semantics>(arom.,d,1H,4JHH=1);7.58(arom.,d,1H,4JHH=1).13𝑪{1𝑯}δC10.6(i−Pr,s);18.4(i−Pr,s);46.0(CH2,s);<annotation encoding="application / x-tex">(arom., d, 1H, {}^{4}J_{HH} = 1); 7.58 (arom., d, 1H, {}^{4}J_{HH} = 1). {}^{13}\mathbf{C} \{ {}^{1}\mathbf{H} \} \delta_{C} 10.6 (i-Pr, s); 18.4 (i-Pr, s); 46.0 (CH2, s);< / annotation>< / semantics> 53.7 (CH2, s); 96.5 (C<semantics>≡<annotation encoding="application / x-tex">\equiv< / annotation>< / semantics>C–Si, s); 103.7 (C<semantics>≡<annotation encoding="application / x-tex">\equiv< / annotation>< / semantics>C–arom.; s); 123.7 (arom., s); 124.3 (arom., s); 131.8 (arom., s); 156.6 (arom., s); 157.1 (arom., s). ESI-HRMS: 363.1763 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics> (theor. <semantics>[C18H28N4Cl1Si1]+=363.1766<annotation encoding="application / x-tex">[C_{18}H_{28}N_4Cl_1Si_1]^+ = 363.1766< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1052: In a glass vial (20 mL), Dimethyl 4-iodopyridine-2,6- dicarboxylate (500 mg; 1.56 mmol; 1.0 equiv.), CuI (600 mg; 3.15 mmol, 2.0 equiv.) and [(dppf)PdCl2] (7.0 mg, 10 μmol; 0.6 mol%) were dissolved in dry DMF (8 mL) followed by addition of Methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (600 mg; 3.12 mmol; 2.0 equiv.) in dry DMF (2 mL). The resulting dark mixture was stirred 16 h at 100 °C. After cooling down, the mixture was diluted with DCM (10 mL) and filtered through syringe microfilter (PTFE). The solids were further washed with DCM. Filtrate was further diluted with DCM (50 mL) and washed with dil. aq. NaHCO3 (<semantics>5×25<annotation encoding="application / x-tex">5 \times 25< / annotation>< / semantics> mL). Organic layer was dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. Residue was purified by column chromatography (120 g SiO2, 100 % DCM to 15% EtOAc in DCM). Fractions with product were combined and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as colorless solid. Yield: 366 mg (89%; 1 step; based on Dimethyl 4-iodopyridine-2,6-dicarboxylate). NMR (DMSO-d6): 1H δH 3.97 <semantics>(CH3,s,6H);8.49(arom.,q,2H,4JHF=1).19F{1H}δF−63.4(s).<annotation encoding="application / x-tex">(CH_3, s, 6H); 8.49 (arom., q, 2H, {}^4J_{HF} = 1). {}^{19}F\{{}^{1}H\} \delta_F -63.4 (s).< / annotation>< / semantics> ESI-HRMS: 264.0480 [M+H]+ (theor. <semantics>[C10H9N1O4F3]+=264.0478<annotation encoding="application / x-tex">[C_{10}H_9N_1O_4F_3]^+ = 264.0478< / annotation>< / semantics>. [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1053: In a round-bottom glass flask (100 mL), TD1052 (365 mg; 1.39 mmol; 1.0 equiv.) was dissolved in a mixture of MeOH (5 mL) and THF (10 mL). The resulting colourless solution was cooled with an ice bath (~5 °C) followed by portion wise additions (over course of 30 min, with no stopper on the flask) of solid NaBH4 (420 mg; 11.1 mmol; 8.0 equiv.) during which hydrogen gas evolved intensively and the color of the mixture changed to red and orange. After the addition, the flask was allowed to warm up to RT and was further stirred 30 min at RT. Resulting yellow solution was evaporated to dryness. Residue was purified by column chromatography (120 g SiO2, solid load technique, 100 % EtOAc to 15% MeOH in EtOAc). Fractions with product were combined and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as yellow oil. Yield: 171 mg (60%; 1 step; based on TD1052). NMR (DMSO-d6): 1H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 4.62 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>, s, 4H); 5.65 (O<semantics>H<annotation encoding="application / x-tex">H< / annotation>< / semantics>, s, 2H); 7.60 (arom., q, 2H, <semantics>4JHF<annotation encoding="application / x-tex">^4J_{HF}< / annotation>< / semantics> = 1). 19F{1H} <semantics>δF<annotation encoding="application / x-tex">\delta_{F}< / annotation>< / semantics> -63.6 (s). ESI-HRMS: 208.0580 [M+H]+ (theor. <semantics>[C8H9N1O2F3]+=208.0580<annotation encoding="application / x-tex">[C_8H_9N_1O_2F_3]^+ = 208.0580< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1055: In a round-bottom glass flask (100 mL), TD1053 (169 mg; 816 μmol; 1.0 equiv.) was dissolved in DCM (20 mL). Freshly prepared solution of SOCl2 (237 µL; 3.26 mmol; 4.0 equiv.) in DCM (5 mL) was then added and the resulting mixture was stirred 16 h at RT. Dil. aq. solution of NaHCO3 (25 mL) was then added and resulting biphasic mixture was vigorously stirred for additional 10 min at RT, during which bubbles of gas slowly evolved. Mixture was then transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (3 × 25 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as yellow oil. Yield: 168 mg (84%; 1 step; based on TD1053). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 4.90 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, s, 4H); 7.94 (arom., s, 2H). <semantics>19<annotation encoding="application / x-tex">{}^{19}< / annotation>< / semantics>F{<semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H} <semantics>δF<annotation encoding="application / x-tex">\delta_{F}< / annotation>< / semantics> -63.4 (s). APCI-HRMS: <Formule mathématique disponible dans le document PDF, Math available in the PDF document>243.9902 \text{ [M+H]}^+ \text{ (theor. } [C_8H_7N_1F_3Cl_2]}^+ = 243.9902 \text{)}. [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1057: In a glass vial (4 mL), TD1055 (143 mg; 586 µmol; 1.8 equiv.) was dissolved in MeCN (3.5 mL) followed by addition of solid NaN3 (21.5 mg; 331 µmol; 1.0 equiv.) and dried K2CO3 (46 mg; 333 µmol; 1.0 equiv.) and the resulting suspension was stirred 3 d at 70 °C. The mixture was filtered through syringe microfilter (PTFE) and the solid residue was washed with MeCN. Filtrate was evaporated to dryness and orange oily residue was purified by column chromatography (80 g SiO2, 30% P.E. in DCM to 40% DCM in P.E.). Fractions with product were combined and evaporated to dryness. The residue was further dried on high vacuum 1 h to give product in the form of free base as colourless oil. Yield: 43.9 g (53%; 1 step; based on NaN3). Recovery: 32.1 mg of TD1055 (22% of the initial amount used). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 4.69 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, s, 2H); 4.90 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, s, 2H); 7.81 (arom., d, 1H, <semantics>4JHH=1<annotation encoding="application / x-tex">{}^4J_{HH} = 1< / annotation>< / semantics>); 7.93 (arom., d, 1H, <semantics>4JHH=1<annotation encoding="application / x-tex">{}^4J_{HH} = 1< / annotation>< / semantics>). <semantics>19F{1H}<annotation encoding="application / x-tex">{}^{19}F\{{}^1H\}< / annotation>< / semantics> <semantics>δF<annotation encoding="application / x-tex">\delta_F< / annotation>< / semantics> -63.4 (s). APCI-HRMS: 251.0306 [M+H]+ (theor. <semantics>[C8H7N4F3Cl1]+=251.0306<annotation encoding="application / x-tex">[C_8H_7N_4F_3Cl_1]^+ = 251.0306< / annotation>< / semantics>). Synthesis of TD549: Pear-shape glass flask (250 mL) was charged with Dimethyl 4-chloropyridine-2,6- [Image disponible dans le document PDF, Image available in the PDF document] dicarboxylate (5.00 g; 21.8 mmol; 1.0 equiv.), Phenylboronic acid (3.20 g; 26.2 mmol; 1.2 equiv.) and XPhos Pd G2 (510 mg; 648 µmol; 3.0 mol%) and was then three times secured with argon. Under constant flow of argon was then added dry DMF (110 mL) through septum followed by addition of freshly dried (using heat gun under high vacuum) Cs2CO3 (15.6 g; 47.9 mmol; 2.2 equiv.; the flask was briefly opened for addition). The mixture was then stirred 20 h under septum (but without external argon) at 80 °C. Resulting dark mixture was filtered through glass frit (S3) and the filtrate was poured to a stirred beaker with H2O (500 mL). Precipitate was collected on glass frit (S2), washed with H2O and further dried on high vacuum overnight to give product in the form of free base as off white solid. Yield: 3.01 g (51%; 1 step; based on Dimethyl 4-chloropyridine- 2,6-dicarboxylate). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 3.95 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 6H); 7.45–7.57 (<semantics>Ph<annotation encoding="application / x-tex">Ph< / annotation>< / semantics>, m, 3H); 7.82–8.00 (<semantics>Ph<annotation encoding="application / x-tex">Ph< / annotation>< / semantics>, m, 2H); 8.48 (arom., s, 2H); <semantics>13<annotation encoding="application / x-tex">{}^{13}< / annotation>< / semantics>C{<semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H} <semantics>δC<annotation encoding="application / x-tex">\delta_{C}< / annotation>< / semantics> 52.7 (CH3, s); 125.0 (arom., s); 127.2 (Ph., s); 129.5 (Ph., s); 130.2 (Ph., s); 135.5 (Ph., s); 148.6 (arom., s); 150.0 (arom., s); 164.7 (CO., s). ESI-HRMS: 272.0916 [M+H]+ (theor. <semantics>[C15H14N1O4]+=272.0917<annotation encoding="application / x-tex">[C_{15}H_{14}N_1O_4]^+ = 272.0917< / annotation>< / semantics>. [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD563: In a round-bottom glass flask (500 mL), TD549 (2.98 g; 11.0 mmol; 1.0 equiv.) was dissolved in a mixture of MeOH (100 mL) and THF (100 mL). The resulting slightly yellow solution was cooled with an ice bath (<semantics>∼<annotation encoding="application / x-tex">\sim< / annotation>< / semantics>5 °C) followed by portion wise additions (over course of 30 min, with no stopper on the flask) of solid NaBH4 (2.90 g; 76.7 mmol; 9.0 equiv.) during which hydrogen gas evolved intensively and the color of the mixture changed to red and orange. After the addition, the flask was allowed to warm up to RT and was further stirred 30 min at RT. Resulting faint yellow opalescent solution was filtered through syringe microfilter (PTFE). The filtrate was evaporated to dryness and further co-evaporated with DCM (as a suspension). Residue was dissolved in a mixture of H2O (300 mL) and DCM (300 mL) and transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (8 × 75 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The resulting crystalized residue was crushed and further dried on high vacuum overnight to give product in the form of free base as nearly colorless solid. Yield: 2.29 g (97%; 1 step; based on TD549). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 4.59 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, s, 4H); 5.45 (O<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, s, 2H); 7.45–7.57 (<semantics>Ph2<annotation encoding="application / x-tex">Ph_{2}< / annotation>< / semantics>, m, 3H); 7.60 (<semantics>arom1<annotation encoding="application / x-tex">arom_{1}< / annotation>< / semantics>, s, 2H); 7.68–7.82 (Ph, m, 2H). <semantics>13<annotation encoding="application / x-tex">{}^{13}< / annotation>< / semantics>C{<semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H} <semantics>δC<annotation encoding="application / x-tex">\delta_{C}< / annotation>< / semantics> 64.2 (CH2, s); 115.7 (arom., s); 126.7 (Ph, s); 129.1 (Ph, s); 129.3 <semantics>(Ph,s)<annotation encoding="application / x-tex">(Ph, s)< / annotation>< / semantics>; 138.1 <semantics>(Ph,s)<annotation encoding="application / x-tex">(Ph, s)< / annotation>< / semantics>; 148.2 <semantics>(arom.,s)<annotation encoding="application / x-tex">(arom., s)< / annotation>< / semantics>; 161.7 <semantics>(arom.,s)<annotation encoding="application / x-tex">(arom., s)< / annotation>< / semantics>. ESI-HRMS: 216.1022 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics> (theor. <semantics>[C13H14N1O2]+<annotation encoding="application / x-tex">[C_{13}H_{14}N_1O_2]^+< / annotation>< / semantics> <semantics>=216.1019<annotation encoding="application / x-tex">= 216.1019< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD564: In a round-bottom glass flask (500 mL), TD563 (2.25 g; 10.5 mmol; 1.0 equiv.) was dissolved (with gentle heating) in DCM (250 mL). Freshly prepared solution of SOCl2 (2.27 mL; 31.3 mmol; 3.0 equiv.) in DCM (10 mL) was then added, after which precipitate started to form. After 1 h of stirring at RT, all of the previously formed precipitate was dissolved again. Dil. aq. solution of NaHCO3 (150 mL) was then added to the clear yellow solution and the resulting biphasic mixture was vigorously stirred for additional 1 h at RT, during which bubbles of gas slowly evolved. Mixture was then transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (3 <semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics> 100 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as faint yellow solid. Yield: 2.59 g (98%; 1 step; based on TD563). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 4.88 <semantics>(CH2,s,4H);7.47−7.58(Ph,m,3H);7.77−7.85(Ph,m,2H);7.86(arom.,s,2H).<annotation encoding="application / x-tex">(CH_2, s, 4H); 7.47-7.58 (Ph, m, 3H); 7.77-7.85 (Ph, m, 2H); 7.86 (arom., s, 2H).< / annotation>< / semantics> 13C{1H} <semantics>δC<annotation encoding="application / x-tex">\delta_C< / annotation>< / semantics> 46.6 (CH2, s); 120.3 (arom., s); 126.9 (Ph, s); 129.3 (Ph, s); 129.7 (Ph, s); 136.5 (Ph, s); 149.5 (arom., s); 157.1 (arom., s); 157.1 (arom., s); ESI-HRMS: 252.0342 [M+H]+ (theor. <semantics>[C13H12N1Cl2]+=252.0341<annotation encoding="application / x-tex">[C_{13}H_{12}N_1Cl_2]^+ = 252.0341< / annotation>< / semantics>). Synthesis of TD566: In a pear-shaped glass flask (100 mL), TD564 (1.60 g; 6.35 mmol; 1.3 equiv.) was [Image disponible dans le document PDF, Image available in the PDF document] dissolved (with gentle heating) in MeCN (60 mL) followed by addition of solid NaN3 <semantics>(320 mg;4.92 mmol;1.0 equiv.)<annotation encoding="application / x-tex">(320 \text{ mg}; 4.92 \text{ mmol}; 1.0 \text{ equiv.})< / annotation>< / semantics> and dried <semantics>K2CO3<annotation encoding="application / x-tex">K_2CO_3< / annotation>< / semantics> (680 mg; 4.93 mmol; 1.0 equiv.) and the resulting suspension was stirred 24 h at 80 °C. The mixture was filtered on glass frit S3 and the solid residue was washed with MeCN. Filtrate was evaporated to dryness and the orange oily residue was purified by column chromatography (SiO2, 15% P.E. in DCM to 100% DCM). Fractions with product were combined and evaporated to dryness. The residue was further dried 1 h on high vacuum to give product in the form of free base as white solid. Yield: 691 mg (54%; 1 step; based on NaN3). Recovery: 613 mg of TD564 (38% of the initial amount used). NMR (DMSO-d6): 1H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 4.59 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>, s, 2H); 4.84 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>, s, 2H); 7.46–7.60 (<semantics>Ph<annotation encoding="application / x-tex">Ph< / annotation>< / semantics>, m, 3H); 7.74 (<semantics>arom.<annotation encoding="application / x-tex">arom.< / annotation>< / semantics>, d, 1H, <semantics>4JHH=2<annotation encoding="application / x-tex">{}^4J_{HH} = 2< / annotation>< / semantics>); 7.77–7.85 (<semantics>Ph<annotation encoding="application / x-tex">Ph< / annotation>< / semantics>, m, 2H); 7.86 (<semantics>arom.<annotation encoding="application / x-tex">arom.< / annotation>< / semantics>, d, 1H, <semantics>4JHH=2<annotation encoding="application / x-tex">{}^{4}J_{HH} = 2< / annotation>< / semantics>). <semantics>13C{1H}<annotation encoding="application / x-tex">{}^{13}C\{{}^{1}H\}< / annotation>< / semantics> <semantics>δC<annotation encoding="application / x-tex">\delta_{C}< / annotation>< / semantics> 46.7 (CH2, s); 54.2 (CH2, s); 119.4 (arom., s); 120.0 (arom., s); 126.9 (Ph, s); 129.3 (Ph, s); 129.7 (Ph, s); 136.6 (Ph, s); 149.3 (arom., s); 156.6 (arom., s); 157.1 (arom., s). ESI-HRMS: 259.0747 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics> (theor. <semantics>[C13H12N4Cl1]+=259.0745<annotation encoding="application / x-tex">[C_{13}H_{12}N_4Cl_1]^+ = 259.0745< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1083: In a round-bottom glass flask (100 mL), methyl isonicotinate (250 mg; 1.83 mmol; 1.0 equiv.) was dissolved in MeOH (10 mL) followed by addition of conc. H2SO4 (25 μL). The resulting mixture was stirred 30 min at 55 °C. After cooling down, solution of <semantics>(NH4)2S2O8<annotation encoding="application / x-tex">(NH_4)_2S_2O_8< / annotation>< / semantics> (4.16 g; 18.2 mmol; 10 equiv.) in H2O (10 mL) was added dropwise and the resulting mixture was then further stirred 16 h at 55 °C. Reaction was then carefully quenched by aq. NaHCO3. Mixture was then transferred to a separatory funnel and extracted with EtOAc (<semantics>5×50<annotation encoding="application / x-tex">5 \times 50< / annotation>< / semantics> mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. Residue was purified by preparative HPLC (C18; H2O–MeCN gradient with FA additive). Fractions with product were joined and directly lyophilized to give product in the form of free base as white fluffy solid. Yield: 99.5 mg (28%; 1 step; based on methyl isonicotinate). NMR (DMSO- d6): 1H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 3.92 (C<semantics>H3<annotation encoding="application / x-tex">H_3< / annotation>< / semantics>, s, 3H); 4.60 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>, d, 4H, <semantics>3JHH<annotation encoding="application / x-tex">^3J_{HH}< / annotation>< / semantics> = 6); 5.58 (O<semantics>H<annotation encoding="application / x-tex">H< / annotation>< / semantics>, t, 2H, <semantics>3JHH<annotation encoding="application / x-tex">^3J_{HH}< / annotation>< / semantics> = 6); 7.80 (arom., s, 2H). ESI- HRMS: 198.0759 [M+H]+ (theor. <semantics>[C9H12N1O4]+=198.0761<annotation encoding="application / x-tex">[C_9H_{12}N_1O_4]^+ = 198.0761< / annotation>< / semantics>). EA <semantics>(C9H11N1O4,MR=197.2)<annotation encoding="application / x-tex">(C_9H_{11}N_1O_4, M_R = 197.2)< / annotation>< / semantics>: C 54.8 (54.8); H 5.6 (5.5); N 7.1 (7.0). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1087: In a round-bottom glass flask (50 mL), TD1083 (96.2 mg; 488 μmol; 1.0 equiv.) was dissolved in DCM (20 mL) followed by addition of SOCI2 (106 μL; 1.46 mmol; 3.0 equiv.). The mixture was stirred 1 h at RT. Mixture was then quenched by addition of dil. aq. solution of NaHCO3 (20 mL). The resulting biphasic mixture was vigorously stirred for additional 1 h at RT, during which bubbles of gas slowly evolved. Mixture was then transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (<semantics>3×30 mL<annotation encoding="application / x-tex">3 \times 30 \text{ mL}< / annotation>< / semantics>). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight (where product slowly crystallized) to give product in the form of free base as bright yellow solid. Yield: 112.8 mg (99%; 1 step; based on TD1083). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 3.92 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 3H); 4.90 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, s, 4H); 7.98 (arom., s, 2H). ESI-HRMS: 234.0085 [M+H]+ (theor. <semantics>[C9H10N1O2Cl2]+=234.0083<annotation encoding="application / x-tex">[C_9H_{10}N_1O_2Cl_2]^+ = 234.0083< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1089: In a glass vial (4 mL), TD1087 (112.0 mg; 478 µmol; 1.2 equiv.) was dissolved in MeCN (2 mL) followed by addition of solid NaN3 (26.0 mg; 400 <semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>mol; 1.0 equiv.) and dried <semantics>K2CO3<annotation encoding="application / x-tex">K_2CO_3< / annotation>< / semantics> (55.0 mg; 400 <semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>mol; 1.0 equiv.) and the resulting suspension was stirred 2 h at 70 °C. The mixture was filtered on through syringe microfilter (PTFE) and the solid residue was washed with MeCN. Filtrate was evaporated to dryness and oily residue was purified by column chromatography (SiO2, DCM to 10% EtOAc in DCM). Fractions with product were combined and evaporated to dryness. The residue was further dried on high vacuum overnight to give pre-purified product (containing <semantics>∼20%<annotation encoding="application / x-tex">\sim 20\%< / annotation>< / semantics> of bis azide byproduct) in the form of free base as yellow oil. Yield: 49.6 mg. ESI-HRMS: 241.0490 [M+H]+ (theor. <semantics>[C9H10N4O2Cl1]+=241.0487<annotation encoding="application / x-tex">[C_9H_{10}N_4O_2Cl_1]^+ = 241.0487< / annotation>< / semantics>). Part of TD1089 obtained in this way was directly used for TD1092 without further purification or characterization. [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1101: In a round-bottom glass flask (100 mL), isopropyl isonicotinate (600 mg; 3.63 mmol; 1.0 equiv.) was dissolved in MeOH (20 mL) followed by addition of conc. <semantics>H2SO4<annotation encoding="application / x-tex">H_2SO_4< / annotation>< / semantics> (50 <semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>L). Then, solution of <semantics>(NH4)2S2O8<annotation encoding="application / x-tex">(NH_4)_2S_2O_8< / annotation>< / semantics> (8.32 g; 36.5 mmol; 10 equiv.) in H2O (20 mL) was added dropwise and the resulting mixture was further stirred 16 h at 70 °C. Reaction was then carefully neutralized by aq. NaHCO3. Mixture was then transferred to a separatory funnel and extracted with EtOAc (<semantics>5×50<annotation encoding="application / x-tex">5 \times 50< / annotation>< / semantics> mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. Residue was purified by preparative HPLC (C18; H2O–MeCN gradient with FA additive). Fractions with product were joined and directly lyophilized to give product in the form of free base as white fluffy solid. Yield: 284 mg (35%; 1 step; based on isopropyl isonicotinate). NMR (DMSO-d6): 1H <semantics>δH<annotation encoding="application / x-tex">\delta_H< / annotation>< / semantics> 1.34 (CH3, d, 6H, 3<semantics>JHH<annotation encoding="application / x-tex">J_{HH}< / annotation>< / semantics> = 6); 4.59 (CH2, d, 4H, <semantics>3JHH=6<annotation encoding="application / x-tex">^{3}J_{HH} = 6< / annotation>< / semantics>); 5.19 (CH, hept, 1H, <semantics>3JHH=6<annotation encoding="application / x-tex">^{3}J_{HH} = 6< / annotation>< / semantics>); 5.57 (OH, t, 2H, <semantics>3JHH=6<annotation encoding="application / x-tex">^{3}J_{HH} = 6< / annotation>< / semantics>); 7.78 (arom., s, 2H). ESI-HRMS: 226.1076 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics> (theor. <semantics>[C11H16N1O4]+=226.1074<annotation encoding="application / x-tex">[C_{11}H_{16}N_1O_4]^+ = 226.1074< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1109: In a round-bottom glass flask (100 mL), TD1101 (283 mg; 1.26 mmol; 1.0 equiv.) was dissolved in DCM (40 mL) followed by addition of SOCl2 (275 μL; 3.79 mmol; 3.0 equiv.). The mixture was stirred 1 h at RT. Mixture was then quenched by addition of dil. aq. solution of NaHCO3 (40 mL). The resulting biphasic mixture was vigorously stirred for additional 1 h at RT, during which bubbles of gas slowly evolved. Mixture was then transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (<semantics>3×50<annotation encoding="application / x-tex">3 \times 50< / annotation>< / semantics> mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight (where product slowly crystallized) to give product in the form of free base as pale yellow solid. Yield: 322 mg (98%; 1 step; based on TD1101). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 1.35 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, d, 6H, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 6); 4.90 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, s, 4H); 5.20 (CH, hept, 1H, <semantics>3JHH=6<annotation encoding="application / x-tex">{}^{3}J_{HH} = 6< / annotation>< / semantics>); 7.96 (arom., s, 2H). ESI-HRMS: 262.0399 [M+H]+ (theor. [C11H14N1O2Cl2]+ = 262.0396). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1112: In a glass vial (20 mL), TD1109 (321 mg; 1.23 mmol; 1.2 equiv.) was dissolved in MeCN (6 mL) followed by addition of solid NaN3 (66.5 mg; 1.02 mmol; 1.0 equiv.) and dried <semantics>K2CO3<annotation encoding="application / x-tex">K_2CO_3< / annotation>< / semantics> (141 mg; 1.02 mmol; 1.0 equiv.) and the resulting suspension was stirred 16 h at 70 °C. The mixture was filtered on through syringe microfilter (PTFE) and the solid residue was washed with MeCN. Filtrate was evaporated to dryness and oily residue was purified by column chromatography (SiO2, DCM to 3% EtOAc in DCM). Fractions with product were combined and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as colourless oil. Yield: 116 mg (42%; 1 step; based on NaN3). Recovery: 124 mg of TD1109 (39% of the initial amount used). NMR (DMSO-d6): 1H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 1.35 (C<semantics>H3<annotation encoding="application / x-tex">H_3< / annotation>< / semantics>, d, 6H, <semantics>3JHH<annotation encoding="application / x-tex">^3J_{HH}< / annotation>< / semantics> = 6); 4.67 (CH2, s, 2H); 4.89 (CH2, s, 4H); 5.19 (CH, hept, 1H, <semantics>3JHH=6<annotation encoding="application / x-tex">{}^{3}J_{HH} = 6< / annotation>< / semantics>); 7.83 (arom., d, 1H, <semantics>4JHH=1<annotation encoding="application / x-tex">{}^{4}J_{HH} = 1< / annotation>< / semantics>).7.95 (arom., d, 1H, <semantics>4JHH=1<annotation encoding="application / x-tex">{}^{4}J_{HH} = 1< / annotation>< / semantics>). ESI-HRMS: 269.0800 [M+H]+ (theor. [C11H14N4O2Cl1]+ = 269.0800). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1119: In a glass vial (40 mL), tert-butyl isonicotinate (486 mg; 2.71 mmol; 1.0 equiv.) was dissolved in MeOH (15 mL) followed by addition of conc. <semantics>H2SO4<annotation encoding="application / x-tex">H_2SO_4< / annotation>< / semantics> (40 µL). Then, solution of <semantics>(NH4)2S2O8<annotation encoding="application / x-tex">(NH_4)_2S_2O_8< / annotation>< / semantics> (6.20 g; 27.2 mmol; 10 equiv.) in <semantics>H2O<annotation encoding="application / x-tex">H_2O< / annotation>< / semantics> (15 mL) was added dropwise and the resulting mixture was further stirred 30 min at 80 °C. Reaction was then carefully neutralized by aq. NaHCO3. Mixture was then transferred to a separatory funnel and extracted with EtOAc (5 <semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics> 30 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. Residue was purified by preparative HPLC (C18; H2O-MeCN gradient with FA additive). Fractions with product were joined and directly lyophilized to give product in the form of free base as white fluffy solid. Yield: 161 mg (25%; 1 step; based on tert-butyl isonicotinate). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 1.57 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 9H); 4.58 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, d, 4H, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 4); 5.54 (O<semantics>H<annotation encoding="application / x-tex">H< / annotation>< / semantics>, t, 2H, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 4); 7.73 (arom., s, 2H). ESI-HRMS: 240.1230 [M+H]+ (theor. <semantics>[C12H18N1O4]+<annotation encoding="application / x-tex">[C_{12}H_{18}N_1O_4]^+< / annotation>< / semantics> = 240.1230). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1129: In a round-bottom glass flask (100 mL), TD1119 (159 mg; 664 μmol; 1.0 equiv.) was dissolved in DCM (20 mL) followed by addition of SOCl2 (145 μL; 2.00 mmol; 3.0 equiv.). The mixture was stirred 1 h at RT. Mixture was then quenched by addition of dil. aq. solution of NaHCO3 (20 mL). The resulting biphasic mixture was vigorously stirred for additional 1 h at RT, during which bubbles of gas slowly evolved. Mixture was then transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (3 × 25 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight (where product slowly crystallized) to give product in the form of free base as faint yellow solid. Yield: 175 mg (95%; 1 step; based on TD1119). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 1.57 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 9H); 4.89 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, s, 4H); 7.91 (arom., s, 2H). ESI-HRMS: <semantics>276.0552 [M+H]+<annotation encoding="application / x-tex">276.0552 \text{ [M+H]}^+< / annotation>< / semantics> (theor. <semantics>[C12H16N1O2Cl2]+=276.0553<annotation encoding="application / x-tex">[C_{12}H_{16}N_1O_2Cl_2]^+ = 276.0553< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1130: In a glass vial (4 mL), TD1129 (174.0 mg; 630 μmol; 1.2 equiv.) was dissolved in MeCN (3 mL) followed by addition of solid NaN3 (34.0 mg; 523 <semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>mol; 1.0 equiv.) and dried <semantics>K2CO3<annotation encoding="application / x-tex">K_2CO_3< / annotation>< / semantics> (72.0 mg; 522 <semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>mol; 1.0 equiv.) and the resulting suspension was stirred 6 h at 70 °C. The mixture was filtered on through syringe microfilter (PTFE) and the solid residue was washed with MeCN. Filtrate was evaporated to dryness and oily residue was purified by column chromatography (SiO2, DCM to 3% EtOAc in DCM). Fractions with product were combined and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as colourless oil. Yield: 58.2 mg (39%; 1 step; based on NaN3). Recovery: 90.5 mg of TD1129 (52% of the initial amount used). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 1.57 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 9H); 4.66 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, s, 2H); 4.89 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>, s, 2H); 7.79 (arom., d, 1H, <semantics>4JHH=2<annotation encoding="application / x-tex">{}^4J_{HH} = 2< / annotation>< / semantics>).7.91 (arom., d, 1H, <semantics>4JHH=2<annotation encoding="application / x-tex">{}^4J_{HH} = 2< / annotation>< / semantics>). ESI-HRMS: 305.0772 <semantics>[M+Na]+<annotation encoding="application / x-tex">[M+Na]^+< / annotation>< / semantics> (theor. <semantics>[C12H15N4O2Cl1Na1]+=305.0776<annotation encoding="application / x-tex">[C_{12}H_{15}N_4O_2Cl_1Na_1]^+ = 305.0776< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD725: Glass vial (40 mL) was charged with TD726 (628 mg; 3.62 mmol; 1.0 equiv.), (4-(tert-Butoxycarbonyl)phenyl)boronic acid (880 mg; 3.96 mmol; 1.1 equiv.) and XPhos Pd G2 (57 mg; 7.2 μmol; 2.0 mol%) and was then three times secured with argon. Under constant flow of argon was then added dry 1,4-Dioxane (16 mL) through septum followed by addition of freshly prepared (and briefly washed with argon prior addition) solution of K3PO4·H2O (920 mg; 4.00 mmol; 1.1 equiv.) in H2O (8 mL). The mixture was then stirred 16 h under septum (but without external argon) at 80 °C. Resulting dark mixture was transferred to a separatory funnel and diluted with EtOAc (40 mL) and H2O (50 ml). After shaking, upper layer was separated and aqueous layer was further extracted with EtOAc (5 × 30 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. Residue was purified on flash chromatography (120 g SiO2, 100% EtOAc to 30% MeOH in EtOAc). Combined fractions with product were evaporated to dryness and further co-evaporated once with DCM. The residue was further dried on high vacuum overnight to give pre-purified product in the form of free base as off-white powder. Yield: 1.04 g. NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 1.57 (CH3, s, 9H); 4.61 (CH2, d, 4H, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 6); 5.48 (OH, t, 2H, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 6); 7.64 (arom., s, 2H); 7.88 (arom., dm, 2H, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 9); 8.04 (arom., dm, 2H, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 9). <semantics>13<annotation encoding="application / x-tex">{}^{13}< / annotation>< / semantics>C<semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H<semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics> <semantics>δC<annotation encoding="application / x-tex">\delta_{C}< / annotation>< / semantics> 27.8 (CH3, s); 64.2 (CH2, s); 81.0 (C–CH3, s); 115.8 (arom., s); 127.0 (arom., s); 129.9 (arom., s); 131.6 (arom., s); 142.2 (arom., s); 147.0 (arom., s); 162.0 (arom., s); 164.6 (CO, s). ESI-HRMS: 316.1539 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics> (theor. <semantics>[C18H22N1O4]+=316.1543<annotation encoding="application / x-tex">[C_{18}H_{22}N_1O_4]^+ = 316.1543< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD730: In a round-bottom glass flask (250 mL), pre-purified TD725 (1.04 g; <semantics>≤<annotation encoding="application / x-tex">\leq< / annotation>< / semantics>3.30 mmol; 1.0 equiv.) was suspended in DCM (35 mL). Freshly prepared solution of SOCl2 (721 μL; 9.93 mmol; ≥3.0 equiv.) in DCM (5 mL) was then added. Clear solution was quickly formed and the open flask was stirred 1 h at RT. Mixture was then quenched by addition of dil. aq. solution of NaHCO3 (60 mL). The resulting biphasic mixture was vigorously stirred for additional 1 h at RT, during which bubbles of gas slowly evolved. Mixture was then transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (5 <semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics> 30 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was purified on flash chromatography (120 g SiO2, 100% DCM to 20% EtOAc in DCM). Combined fractions with product were evaporated to dryness and further co-evaporated once with DCM. The residual faint yellow oil slowly crystallized. The solid was crushed and further dried on high vacuum overnight to give product in the form of free base as off-white powder. Yield: 839 mg (66%; 2 steps; based on TD726). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 1.58 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 9H); 4.86 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, s, 4H); 7.92 (arom., s, 2H); 7.94 (arom., dm, 2H, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 9); 8.05 (arom., dm, 2H, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 9). <semantics>13𝑪{1𝑯}<annotation encoding="application / x-tex">{}^{13}\mathbf{C}\{{}^{1}\mathbf{H}\}< / annotation>< / semantics> <semantics>δC<annotation encoding="application / x-tex">\delta_{C}< / annotation>< / semantics> 27.8 (CH3, s); 46.5 (CH2, s); 81.2 (C–CH3, s); 120.6 (arom., s); 127.2 (arom., s); 129.9 (arom., s); 132.1 (arom., s); 140.6 (arom., s); 148.3 (arom., s); 157.3 (arom., s); 164.5 (CO, s). ESI-HRMS: 352.0866 [M+H]+ (theor. <semantics>[C18H20N1O2Cl2]+=352.0866<annotation encoding="application / x-tex">[C_{18}H_{20}N_1O_2Cl_2]^+ = 352.0866< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD733: In a glass vial (20 mL), TD730 (837 mg; 2.38 mmol; 1.3 equiv.) was dissolved in MeCN (18 mL) followed by addition of solid NaN3 (119 mg; 1.83 mmol; 1.0 equiv.) and dried K2CO3 (253 mg; 1.83 mmol; 1.0 equiv.) and the resulting suspension was stirred 24 h at 80 °C. The mixture was filtered on through syringe microfilter (PTFE) and the solid residue was washed with MeCN. Filtrate was evaporated to dryness and oily residue was purified by column chromatography (SiO2, 20% Pentane in DCM to 1% EtOAc in DCM). Fractions with product were combined and evaporated to dryness. The resulting nearly colorless oil was further dried on high vacuum overnight (where product slowly crystallized) to give product in the form of free base as colorless solid. Yield: 230 mg (35%; 1 step; based on NaN3). Recovery: 442 mg of TD730 (53% of the initial amount used). NMR (DMSO-d6): 1H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 1.57 (CH3, s, 9H); 4.62 (CH2, s, 2H); 4.86 (CH2, s, 2H); 7.80 (arom., d, 1H, <semantics>4JHH<annotation encoding="application / x-tex">^4J_{HH}< / annotation>< / semantics> = 2); 7.91 (arom., d, 1H, <semantics>4JHH=2<annotation encoding="application / x-tex">^{4}J_{HH} = 2< / annotation>< / semantics>); 7.94 (arom., dm, 2H, <semantics>3JHH=9<annotation encoding="application / x-tex">^{3}J_{HH} = 9< / annotation>< / semantics>); 8.05 (arom., dm, 2H, <semantics>3JHH=9<annotation encoding="application / x-tex">^{3}J_{HH} = 9< / annotation>< / semantics>). <semantics>13C{1H}<annotation encoding="application / x-tex">^{13}C\{^{1}H\}< / annotation>< / semantics> <semantics>δC<annotation encoding="application / x-tex">\delta_{C}< / annotation>< / semantics> 27.8 (CH3, s); 46.6 (CH2, s); 54.2 (CH2, s); 81.2 (C–CH3, s); 119.6 (arom., s); 120.3 (arom., s); 127.2 (arom., s); 129.9 (arom., s); 132.1 (arom., s); 140.7 (arom., s); 148.1 (arom., s); 156.8 (arom., s); 157.3 (arom., s); 164.5 (CO, s). ESI-HRMS: 359.1270 [M+H]+ (theor. <semantics>[C18H20N4O2Cl1]+=359.1269<annotation encoding="application / x-tex">[C_{18}H_{20}N_4O_2Cl_1]^+ = 359.1269< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1425: Glass vial (40 mL) was charged methyl 2-bromo-6- methylisonicotinate (1.00 g; 4.35 mmol; 1.0 equiv.), NBS (recrystallized from boiling <semantics>H2O<annotation encoding="application / x-tex">H_2O< / annotation>< / semantics>; 770 mg; 4.33 mmol; 1.0 equiv.), (BnO)2 (53 mg; 219 µmol; 5 mol%) and magnetic stirrer and three times secured with argon. Under constant flow of argon was then added CCl4 (21 mL) through septum. The vial was left stirring under septum (but without external argon) for 24 h at 75 °C. After cooling down, the mixture was filtered through syringe microfilter (PTFE) and the solids were washed with DCM. Filtrate was evaporated to dryness, re-suspended in c-Hex (25 ml) and filtered through syringe microfilter (PTFE). Filtrate was evaporated to dryness and the residue was purified by flash chromatography (120 g SiO2, 100% c-Hex to 80% DCM in c-Hex). Combined fractions with product were evaporated to dryness. The residual oil was further dried on high vacuum overnight (where the product crystallized) to give product in the form of free base as faint yellow solid. Yield: 571 mg (43%; 1 step; based on methyl 2-bromo-6-methylisonicotinate). Recovery: 314 mg of methyl 2-bromo-6-methylisonicotinate (31% of the initial amount used). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 3.91 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 3H); 4.79 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, s, 2H); 7.94 (arom., d, 1H, <semantics>4JHH=1<annotation encoding="application / x-tex">{}^{4}J_{HH} = 1< / annotation>< / semantics>); 8.05 (arom., d, 1H, <semantics>4JHH=1<annotation encoding="application / x-tex">{}^{4}J_{HH} = 1< / annotation>< / semantics>). ESI-HRMS: 307.8916 [M+H]+ (theor. [C8H8N1O2Br2]+ = 307.8916). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1428: Pear-shaped glass flask (25 mL) was charged with TD1425 (523 mg; 1.69 mmol; 1.0 equiv.), N-Boc-1,1-dimethylpropargylamine (310 mg; 1.69 mmol; 1.0 equiv.) and magnetic stirrer and three times secured with argon. Solid CuI (13.0 mg; 68 μmol; 4.0 mol%) and [Pd(PPh3)2Cl2] (24 mg; 34 μmol; 2.0 mol%) were subsequently added followed by another securing with argon (three times). Under constant flow of argon was then added dry THF (7.5 mL) through septum followed by addition of DIPEA (885 µL; 5.08 mmol; 3.0 equiv.). The flask was left stirring under septum (but without external argon) for 2 d at RT. The mixture was evaporated to dryness, re-suspended in DCM (15 mL) and filtered through syringe microfilter (PTFE) and the solid phase was further washed with DCM. Filtrate was purified on flash chromatography (120 g SiO2, 10% EtOAc in c-Hex to 50% EtOAc in c-Hex). Combined fractions with product were evaporated to dryness and once re-purified on flash chromatography (80 g SiO2, 100% DCM to 5% EtOAc in DCM). Combined fractions with product were evaporated to dryness and further co-evaporated once with DCM. The residue was further dried on high vacuum overnight to give product in the form of free base as faint yellow solidified oil. Yield: 175 mg (25%; 1 step; based on TD1425). NMR (DMSO- d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 1.42 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>-C-O, s, 9H); 1.56 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>-C-N, s, 6H); 3.91 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>-O, s, 3H); 4.79 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, s, 2H); 7.23 (N<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>-C-N, s, 6H); 3.91 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>-O, s, 3H); 4.79 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, s, 2H); 7.23 (N<Formule mathématique disponible dans le document PDF, Math available in the PDF document>$H_$ bs, 1H); 7.71 (arom., d, 1H, <semantics>4JHH=1<annotation encoding="application / x-tex">{}^{4}J_{HH} = 1< / annotation>< / semantics>); 7.97 (arom., d, 1H, <semantics>4JHH=1<annotation encoding="application / x-tex">{}^{4}J_{HH} = 1< / annotation>< / semantics>). ESI-HRMS: 411.0913 [M+H]+ (theor. <semantics>[C18H24N2O4Br1]+=411.0914<annotation encoding="application / x-tex">[C_{18}H_{24}N_2O_4Br_1]^+ = 411.0914< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1386: In a round-bottom glass flask (100 mL), pyridine-2,6- diyldimethanol (2.00 g; 14.4 mmol; 1.0 equiv.) and Imidazole (0.98 g; 14.4 mmol; 1.0 equiv.) were dissolved in DMF (20 mL) followed by addition of TBDMSCI (2.17 g; 14.4 mmol; 1.0 equiv.). The resulting solution was stirred 2 h at RT. Mixture was evaporated to dryness and the residue dissolved in a mixture of DCM (50 mL) and dil. aq. NaHCO3 (50 mL) and transferred to a separatory funnel. After brief shaking, the bottom phase was separated and the aq. layer was further extracted with DCM (5 <semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics> 30 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. Residue was purified by column chromatography (100 g SiO2, DCM to 50% EtOAc in DCM). Fractions with product were combined and evaporated to dryness and once co-evaporated with DCM. The residue was further dried on high vacuum overnight to give product in the form of free base as nearly colorless oil. Yield: 1.54 g (42%; 1 step; based on pyridine-2,6- diyldimethanol). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 0.09 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 6H); 0.92 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 9H); 4.51 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, d, 2H, <semantics>3JHH=5<annotation encoding="application / x-tex">{}^{3}J_{HH} = 5< / annotation>< / semantics>); 4.71 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>, s, 2H); 5.37 (O<semantics>H<annotation encoding="application / x-tex">H< / annotation>< / semantics>, t, 1H, <semantics>3JHH=5<annotation encoding="application / x-tex">{}^3J_{HH} = 5< / annotation>< / semantics>); 7.28 (arom., dd, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^3J_{HH} = 8< / annotation>< / semantics>; <semantics>4JHH=1<annotation encoding="application / x-tex">{}^4J_{HH} = 1< / annotation>< / semantics>); 7.34 (arom., dd, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">^{3}J_{HH} = 8< / annotation>< / semantics>; <semantics>4JHH=1<annotation encoding="application / x-tex">^{4}J_{HH} = 1< / annotation>< / semantics>); 7.81 (arom., t, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">^{3}J_{HH} = 8< / annotation>< / semantics>). ESI-HRMS: 254.1569 [M+H]+ (theor. [C13H24N1O2Si1]+ = 254.1571). [Image disponible dans le document PDF, Image available in the PDF document] OTBDMS Synthesis of TD1389: In a round-bottom glass flask (250 mL), TD1386 (1.54 g; 6.08 mmol; 1.0 equiv.) was dissolved in DCM (60 mL) followed by addition of SOCI2 (885 μL; 12.0 mmol; 2.0 equiv.). The mixture was stirred 1 h at RT. Mixture was then quenched by addition of dil. aq. solution of NaHCO3 (60 mL). The resulting biphasic mixture was vigorously stirred for additional 30 min at RT, during which bubbles of gas slowly evolved. Mixture was then transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (3 <semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics> 50 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as nearly colorless oil. Yield: 1.63 g (99%; 1 step; based on TD1386). NMR (DMSO-d6): 1H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 0.10 (CH3, s, 6H); 0.92 (CH3, s, 9H); 4.74 (CH2, s, 2H); 4.75 <semantics>(CH2,s,2H);7.40(arom.,dd,1H,3JHH=8;4JHH=1);7.42(arom.,dd,1H,3JHH=8;4JHH=1);7.87(arom.,t,t)<annotation encoding="application / x-tex">(CH_2, s, 2H); 7.40 (arom., dd, 1H, {}^3J_{HH} = 8; {}^4J_{HH} = 1); 7.42 (arom., dd, 1H, {}^3J_{HH} = 8; {}^4J_{HH} = 1); 7.87 (arom., t, t)< / annotation>< / semantics> 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>). ESI-HRMS: 272.1231 [M+H]+ (theor. [C13H23N1O1Cl1Si1]+ = 272.1232). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1390: In a glass flask (20 mL), KCN (390 mg; 5.99 mmol; 1.05 equiv.) was dissolved in H2O (2 mL) followed by addition of TD1389 (1.55 g; 5.70 mmol; 1.0 equiv.) in DMF (6 mL). The resulting mixture was vigorously stirred for 70 min at 100 °C. After cooling to RT, mixture was diluted with H2O (4 mL) and MeCN (8 mL) and filtered through syringe microfilter (PTFE). Filtrate was directly purified by preparative HPLC (C18; H2O– MeCN gradient with FA additive). Fractions with product were combined, neutralized with dil. aq. NaHCO3 and evaporated to dryness. Residue was dissolved in DCM (100 mL) and H2O (100 mL) and transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (4 × 50 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residual pale yellow oil was left in a freezer to solidify. Resulting solid was crushed and further dried on high vacuum overnight to give product in the form of free base as faint yellow powder. Yield: 1.23 g (82%; 1 step; based on TD1389). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 0.10 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 6H); 0.92 <semantics>(CH3,s,9H);4.17(CH2,s,2H);4.75(CH2,s,2H);7.30(arom.,dd,1H,<math>3JHH=8;4JHH=1);7.40(arom.,dd,1H,3JHH=8;4JHH=1);7.40(arom.,dd,1H,3JHH=8;4JHH=1);7.<annotation encoding="application / x-tex">(CH_3, s, 9H); 4.17 (CH_2, s, 2H); 4.75 (CH_2, s, 2H); 7.30 (arom., dd, 1H, {}^3J_{HH} = 8; {}^4J_{HH} = 1); 7.40 (arom., dd, 1H, {}^3J_{HH} = 8; {}^4J_{HH} = 1); 7.40 (arom., dd, 1H, {}^3J_{HH} = 8; {}^4J_{HH} = 1); 7.< / annotation>< / semantics> 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>; <semantics>4JHH=1<annotation encoding="application / x-tex">{}^{4}J_{HH} = 1< / annotation>< / semantics>); 7.86 (arom., t, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>). ESI-HRMS: 263.1573 [M+H]+ (theor. [C14H23N2O1Si1]+ <semantics>=263.1574<annotation encoding="application / x-tex">= 263.1574< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1393: In a pear-shaped glass flask (100 mL), TD1390 (700 mg; 2.67 mmol; 1.00 equiv.) was dissolved in MeOH (2.70 mL; 66.7 mmol; 25 equiv.) followed by addition of TMSCl (2.37 mL; 18.7 mmol; 7.0 equiv.). The resulting mixture was vigorously stirred for 2 h at 60 °C. After cooling to RT, mixture was quenched with H2O (4 mL) and partly neutralized (to pH 3–4) by slow addition of sat. aq. NaHCO3 (5 mL). Resulting biphasic mixture was carefully evaporated to dryness followed by addition of H2O (10 mL) to the residue. Mixture was then filtered through syringe microfilter (RC) and the filtrate was directly purified by preparative HPLC (C18; H2O–MeCN gradient with FA additive). Fractions with product were combined, neutralized with dil. aq. NaHCO3 and evaporated to dryness. Residue was dissolved in DCM (100 mL) and H2O (100 mL) and transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (<semantics>4×50<annotation encoding="application / x-tex">4 \times 50< / annotation>< / semantics> mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further briefly dried on high vacuum to give product in the form of free base as faint yellow oil. Yield: 404 mg (84%; 1 step; based on TD1390). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 3.61 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 3H); 3.81 <semantics>(CH2,s,2H);4.51(CH2,d,2H,3JHH=5);5.39(OH,t,1H,3JHH=5);7.20(arom.,dd,1H,3JHH=8;4JHH=1);<annotation encoding="application / x-tex">(CH_2, s, 2H); 4.51 (CH_2, d, 2H, {}^3J_{HH} = 5); 5.39 (OH, t, 1H, {}^3J_{HH} = 5); 7.20 (arom., dd, 1H, {}^3J_{HH} = 8; {}^4J_{HH} = 1);< / annotation>< / semantics> 7.36 (arom., dd, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>; <semantics>4JHH=1<annotation encoding="application / x-tex">{}^{4}J_{HH} = 1< / annotation>< / semantics>); 7.76 (arom., t, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>). ESI-HRMS: 182.0811 [M+H]+ (theor. <semantics>[C9H12N1O3]+=182.0812<annotation encoding="application / x-tex">[C_9H_{12}N_1O_3]^+ = 182.0812< / annotation>< / semantics>. [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1395: In a round-bottom glass flask (50 mL), TD1393 (340 mg; 1.88 mmol; 1.0 equiv.) and Imidazole (190 mg; 2.79 mmol; 1.5 equiv.) were dissolved in DMF (6 mL) followed by addition of TBDMSCI (425 mg; 2.82 mmol; 1.5 equiv.). The resulting solution was stirred 16 h at RT. Mixture was directly purified by preparative HPLC (C18; H2O–MeCN gradient with FA additive). Fractions with product were combined, neutralized with dil. aq. NaHCO3 and evaporated to dryness. Residue was dissolved in DCM (50 mL) and H2O (50 mL) and transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (4 <semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics> 25 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as faint yellow oil. Yield: 537 mg (97%; 1 step; based on TD1393). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 0.09 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 6H); 0.91 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 9H); 3.61 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 3H); 3.81 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, s, 2H); <Formule mathématique disponible dans le document PDF, Math available in the PDF document>4.70 \text{ (C}H_2, \text{ s, 2H)}; 7.23 \text{ (arom., dd, 1H, }^3J_{HH} = 8; ^4J_{HH} = 1); 7.32 \text{ (arom., dd, 1H, }^3J_{HH} = 8; ^4J_{HH} = 1); 7.79 \text{ (arom., dd, 1H, }^3J_{HH} = 8; ^4J_{HH} = 1); 7.79 \text{ (arom., dd, 1H, }^3J_{ t, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>). ESI-HRMS: 296.1676 [M+H]+ (theor. [C15H26N1O3Si1]+ = 296.1677). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1396: In a round-bottom glass flask (100 mL), TD1395 (537 mg; 1.82 mmol; 1.0 equiv.) was dissolved in a mixture of THF (9 mL) and MeOH (9 mL). To the resulting colourless solution was added portion wise (over course of 10 min, with no stopper on the flask) solid NaBH4 (2.06 g; 54.5 mmol; 30 equiv.) during which hydrogen gas evolved intensively. Mixture was further stirred 1 h at RT, during which was twice diluted with MeOH (9 mL each) to ensure stirring. Mixture was then diluted with DCM (100 mL) and H2O (100 mL) and transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (4 <semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics> 25 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as nearly colourless oil. Yield: 483 mg (99%; 1 step; based on TD1395). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 0.09 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 6H); 0.92 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 9H); 2.84 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>, t, 2H, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 7); 3.71 <semantics>(CH2,td,2H,3JHH=7,3JHH=5);4.62(OH,t,1H,3JHH=5);4.71(CH2,s,2H);7.14(arom.,dd,1H,3JHH=8;<annotation encoding="application / x-tex">(CH_2, td, 2H, {}^3J_{HH} = 7, {}^3J_{HH} = 5); 4.62 (OH, t, 1H, {}^3J_{HH} = 5); 4.71 (CH_2, s, 2H); 7.14 (arom., dd, 1H, {}^3J_{HH} = 8;< / annotation>< / semantics> <semantics>4JHH=1<annotation encoding="application / x-tex">^{4}J_{HH} = 1< / annotation>< / semantics>); 7.24 (arom., dd, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">^{3}J_{HH} = 8< / annotation>< / semantics>; <semantics>4JHH=1<annotation encoding="application / x-tex">^{4}J_{HH} = 1< / annotation>< / semantics>); 7.70 (arom., t, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">^{3}J_{HH} = 8< / annotation>< / semantics>). ESI-HRMS: 268.1726 [M+H]+ (theor. <semantics>[C14H26N1O2Si1]+=268.1727<annotation encoding="application / x-tex">[C_{14}H_{26}N_1O_2Si_1]^+ = 268.1727< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1401: In a round-bottom glass flask (50 mL), TD1396 (94 mg; 352 µmol; 1.0 equiv.) was dissolved in DCM (3.5 mL) followed by addition of SOCl2 (51 μL; 702 μmol; 2.0 equiv.). The mixture was stirred 3 h at RT. Mixture was then diluted with DCM (20 mL) and quenched by addition of dil. aq. solution of NaHCO3 (10 mL). The resulting biphasic mixture was vigorously stirred for additional 30 min at RT, during which bubbles of gas slowly evolved. Mixture was then transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (<semantics>3×15<annotation encoding="application / x-tex">3 \times 15< / annotation>< / semantics> mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was dissolved in DMF (1.7 mL) followed by addition of solid NaN3 (46 mg; 708 µmol; 2.0 equiv.). The resulting mixture was stirred at 80 °C overnight. After cooling, the mixture was directly purified by preparative HPLC (C18; H2O–MeCN gradient with FA additive). Fractions with product were combined, neutralized with dil. aq. NaHCO3 and evaporated to dryness. Residue was dissolved in DCM (25 mL) and H2O (25 mL) and transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (4 × 10 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as colorless oil. Yield: 17.6 mg (28%; 2 steps; based on TD1396). NMR (DMSO-d6): 1H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 2.98 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>, t, 2H, <semantics>3JHH<annotation encoding="application / x-tex">^3J_{HH}< / annotation>< / semantics> = 7); 3.69 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>, td, 2H, <semantics>3JHH<annotation encoding="application / x-tex">^3J_{HH}< / annotation>< / semantics> = 7, <semantics>3JHH<annotation encoding="application / x-tex">^3J_{HH}< / annotation>< / semantics> = 5); 4.53 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>, d, 2H, <semantics>3JHH<annotation encoding="application / x-tex">^3J_{HH}< / annotation>< / semantics> = 6); 5.37 (O<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>) t, 1H, <semantics>3JHH=6<annotation encoding="application / x-tex">{}^{3}J_{HH} = 6< / annotation>< / semantics>); 7.18 (arom., dd, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>; <semantics>4JHH=1<annotation encoding="application / x-tex">{}^{4}J_{HH} = 1< / annotation>< / semantics>); 7.32 (arom., dd, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>; <semantics>4JHH=1<annotation encoding="application / x-tex">{}^{4}J_{HH} = 1< / annotation>< / semantics>); 7.73 (arom., t, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>). ESI-HRMS: 201.0746 [M+Na]+ (theor. [C8H10N4O1Na1]+ = 201.0747). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1406: In a round-bottom glass flask (25 mL), TD1401 (16.5 mg; 92.6 µmol; 1.0 equiv.) was dissolved in DCM (1.85 mL) followed by addition of SOCl2 (13.5 µL; 186 μmol; 2.0 equiv.). The mixture was stirred 1 h at RT. Mixture was then diluted with DCM (10 mL) and quenched by addition of dil. aq. solution of NaHCO3 (10 mL). The resulting biphasic mixture was vigorously stirred for additional 30 min at RT, during which bubbles of gas slowly evolved. Mixture was then transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (3 × 10 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as colourless solid. Yield: 17.7 mg (97%; 1 step; based on TD1401). NMR (DMSO-d6): 1H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 3.02 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>, t, 2H, <semantics>3JHH<annotation encoding="application / x-tex">^3J_{HH}< / annotation>< / semantics> = 7); 3.71 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>, td, 2H, <semantics>3JHH<annotation encoding="application / x-tex">^3J_{HH}< / annotation>< / semantics> = 7, <semantics>3JHH=5<annotation encoding="application / x-tex">^{3}J_{HH} = 5< / annotation>< / semantics>); 4.75 (CH2, s, 2H); 7.32 (arom., dd, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">^{3}J_{HH} = 8< / annotation>< / semantics>; <semantics>4JHH=1<annotation encoding="application / x-tex">^{4}J_{HH} = 1< / annotation>< / semantics>); 7.41 (arom., dd, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">^{3}J_{HH} = 8< / annotation>< / semantics>; <semantics>4JHH=1<annotation encoding="application / x-tex">^{4}J_{HH} = 1< / annotation>< / semantics>); 7.79 (arom., t, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>). ESI-HRMS: 197.0589 [M+H]+ (theor. [C8H10N4Cl1]+ = 197.0589). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1339: Pear-shaped glass flask (250 mL) was charged with ethyl l-lactate (3.54 g; 30.0 mmol; 1.00 equiv.) and magnetic stirrer and three times briefly secured with argon. Under constant flow of argon was then added dry DCM (100 mL) through septum and the mixture was cooled with an ice bath (5 °C) followed by dropwise addition of triflic anhydride (5.3 mL; 31.5 mmol; 1.05 equiv.) and immediately followed by dropwise addition of dry pyridine (2.54 ml; 31.5 mmol; 1.05 equiv.). The resulting mixture was stirred at 5 °C for 30 min. Resulting suspension was then directly purified by column chromatography (140 g SiO2, DCM). Combined fractions with product were evaporated to dryness and briefly dried on high vacuum to give product as faintly pinkish oil. Yield: 5.90 g (79%; 1 step; based on ethyl l-lactate). NMR (DMSO-d6): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 1.26 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>-CH2, t, 3H, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 7); 1.51 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>-CH, d, 3H, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 7); 4.19–4.31 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>, m, 2H); 5.27 (C<semantics>H<annotation encoding="application / x-tex">H< / annotation>< / semantics>, q, 1H, <semantics>3JHH=7<annotation encoding="application / x-tex">{}^3J_{HH} = 7< / annotation>< / semantics>). <semantics>19F{1H}<annotation encoding="application / x-tex">{}^{19}F\{{}^{1}H\}< / annotation>< / semantics> <semantics>δF=77.7<annotation encoding="application / x-tex">\delta_F = 77.7< / annotation>< / semantics> (s). CI-HRMS: 251.0193 [M+H]+ (theor. <semantics>[C6H10O5S1F3]+=251.0196<annotation encoding="application / x-tex">[C_6H_{10}O_5S_1F_3]^+ = 251.0196< / annotation>< / semantics>. [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1488: Pear-shaped glass flask (25 mL) was charged with dimethyl L- malate (200 mg; 1.23 mmol; 1.00 equiv.) and magnetic stirrer and three times briefly secured with argon. Under constant flow of argon was then added dry DCM (4 mL) through septum and the mixture was cooled with an ice bath (5 °C) followed by dropwise addition of triflic anhydride (220 µL; 1.31 mmol; 1.06 equiv.) and immediately followed by dropwise addition of dry pyridine (105 µL; 1.30 mmol; 1.06 equiv.). The resulting mixture was stirred at RT for 30 min. Resulting suspension was then directly purified by column chromatography (30 g SiO2, DCM). Combined fractions with product were evaporated to dryness and briefly dried on high vacuum to give product as colourless oil. Yield: 258 mg (77%; 1 step; based on dimethyl L- malate). NMR (DMSO-d6): 1H <semantics>δH<annotation encoding="application / x-tex">\delta_H< / annotation>< / semantics> 3.08 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>, dd, 1H, 2<semantics>JHH<annotation encoding="application / x-tex">J_{HH}< / annotation>< / semantics> = 17, 3<semantics>JHH<annotation encoding="application / x-tex">J_{HH}< / annotation>< / semantics> = 5); 3.13 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>, dd, 1H, 2<semantics>JHH<annotation encoding="application / x-tex">J_{HH}< / annotation>< / semantics> = 17, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 6); 4.65 (CH3, s, 3H); 3.78 (CH3, s, 3H); 5.48 (CH, dd, 1H, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 6, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 5). <semantics>19F{1H}<annotation encoding="application / x-tex">{}^{19}F\{{}^{1}H\}< / annotation>< / semantics> <semantics>δF=77.7<annotation encoding="application / x-tex">\delta_F = 77.7< / annotation>< / semantics> (s). ESI-HRMS: 316.9910 [M+Na]+ (theor. [C7H9O7F3S1Na1]+ = 316.9913). Example 3: Synthesis of protected macrocyclic intermediates [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD680: In a pear-shape glass flask (250 mL), Cbz2cyclen (free base; 1.54 g; 3.50 mmol; 1.6 equiv.) was dissolved in MeCN (100 mL) followed by addition of dried K2CO3 (300 mg; 2.17 mmol; 1.0 equiv.). To the vigorously stirred reaction mixture, solution of tert-Butyl bromoacetate (427 mg; 2.19 mmol; 1.0 equiv.) in dry MeCN (25 mL) was added dropwise (over the course of 2 h). Solids were filtered off using syringe microfilter (PTFE) and filtrate was evaporated to dryness. Residue was purified by preparative HPLC (C18; H2O–MeCN gradient with FA additive). Fractions with product were combined, neutralized with dil. aq. NaHCO3 and evaporated to dryness. Residue was dissolved in DCM (150 mL) and H2O (150 mL) and transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (3 × 75 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as nearly colorless oil. Yield: 624 mg (51%; 1 step; based on tert-Butyl bromoacetate). NMR (CD3CN): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 1.32–1.49 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, m, 9H); 2.57–2.76 (mc, m, 4H); 2.81–2.98 (mc, m, 4H); 3.23–3.64 (mc, CH2–CO, m, 8+2H); 5.00–5.15 (CH2–Ph, m, 4H); 7.19–7.48 (Ph, m, 10H). ESI-HRMS: 555.3171 [M+H]+ (theor. <semantics>[C30H43N4O6]+=555.3177<annotation encoding="application / x-tex">[C_{30}H_{43}N_4O_6]^+ = 555.3177< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD686: In a glass vial (4 mL), TD680 (150 mg; 270 µmol; 1.0 equiv.) was dissolved in MeCN (3 mL) followed by addition of Boc2O (2.0 M solution in THF; 200 μL; 400 μmol; 1.5 equiv.). Resulting mixture was stirred 16 h at RT. Reaction mixture was directly purified by preparative HPLC (C18; H2O–MeCN gradient with FA additive). Fractions with product were combined, immediately neutralized with dil. aq. NaHCO3 and evaporated to dryness. Residue was dissolved in DCM (50 mL) and H2O (50 mL) and transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (3 <semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics> 25 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as colorless oil. Yield: 170 mg (96%; 1 step; based on TD680). NMR (CD3CN): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 1.17–1.56 <semantics>(CH3,m,18H);2.62−2.99(mc,m,4H);3.10−3.53(mc,CH2−CO,m,12+2H);4.96−5.16(CH2−Ph,m,4H);<annotation encoding="application / x-tex">(CH_3, m, 18H); 2.62-2.99 (mc, m, 4H); 3.10-3.53 (mc, CH_2-CO, m, 12+2H); 4.96-5.16 (CH_2-Ph, m, 4H);< / annotation>< / semantics> 7.20–7.47 (Ph, m, 10H). ESI-HRMS: 655.3691 [M+H]+ (theor. <semantics>[C35H51N4O8]+=655.3701<annotation encoding="application / x-tex">[C_{35}H_{51}N_4O_8]^+ = 655.3701< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD691: Pear-shape glass flask (25 mL) was charged with TD686 (170 mg; 260 µmol) and magnetic stirrer and three times secured with argon. Solid Pd@C (17 mg) was then added followed by another securing with argon (three times). Under constant flow of argon was then added MeOH (10 mL) through septum. Argon input was then removed and H2 gas (from balloon) was allowed to bubble through the mixture for 30 min at RT. Catalyst was then filtered off using syringe microfilter (PTFE; filter was further washed with MeOH). Filtrate was evaporated to dryness and once co-evaporated with DCM. The residue was further dried on high vacuum overnight to give product in the form of free base as colorless oil. Yield: 100 mg (≥99%; 1 step; based on TD686). ESI-MS (LC- MS): 387.3 [M+H]+ (theor. <semantics>[C19H39N4O4]+=387.3<annotation encoding="application / x-tex">[C_{19}H_{39}N_4O_4]^+ = 387.3< / annotation>< / semantics>). All of TD691 was directly used for TD692 without further characterization. [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1106: In a pear-shape glass flask (50 mL), Cbz2cyclen (free base; 500 mg; 1.14 mmol; 1.0 equiv.) was dissolved in MeCN (10 mL) followed by addition of dried K2CO3 (870 mg; 5.69 mmol; 5.0 equiv.) and Methyl bromoacetate (235 μL; 2.51 mmol; 2.2 equiv.) in MeCN (5 mL). The resulting suspension was stirred 2 d at RT. Solids were filtered off using syringe microfilter (PTFE) and filtrate was evaporated to dryness. Residue was purified by preparative HPLC (C18; H2O–MeCN gradient with FA additive). Fractions with product were combined, neutralized with dil. aq. NaHCO3 and evaporated to dryness. Residue was dissolved in DCM (50 mL) and H2O (50 mL) and transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (<semantics>3×50<annotation encoding="application / x-tex">3 \times 50< / annotation>< / semantics> mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as colorless oil. Yield: 422 mg (64%; 1 step; based on Cbz2cyclen). NMR (CD3CN): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 2.63–2.88 (mc, m, 8H); 3.19– 3.49 (<semantics>mc<annotation encoding="application / x-tex">mc< / annotation>< / semantics>, <semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>–<semantics>CO<annotation encoding="application / x-tex">CO< / annotation>< / semantics>, <semantics>m<annotation encoding="application / x-tex">m< / annotation>< / semantics>, 8+4H); 3.59 (<semantics>CH3<annotation encoding="application / x-tex">CH_3< / annotation>< / semantics>, <semantics>s<annotation encoding="application / x-tex">s< / annotation>< / semantics>, 6H); 5.07 (<semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>–<semantics>Ph<annotation encoding="application / x-tex">Ph< / annotation>< / semantics>, <semantics>s<annotation encoding="application / x-tex">s< / annotation>< / semantics>, 4H); 7.21–7.41 (<semantics>Ph<annotation encoding="application / x-tex">Ph< / annotation>< / semantics>, <semantics>m<annotation encoding="application / x-tex">m< / annotation>< / semantics>, 10H). ESI-LCMS: 585.3 [M+H]+ (theor. <semantics>[C30H41N4O8]+=585.3<annotation encoding="application / x-tex">[C_{30}H_{41}N_4O_8]^+ = 585.3< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1116: Pear-shape glass flask (50 mL) was charged with Pd@C (42 mg) and magnetic stirrer and three times secured with argon. Under constant flow of argon was then added solution of TD1106 (418 mg; 715 µmol) in MeOH (25 mL) through septum. Argon input was then removed and <semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics> gas (from balloon) was allowed to bubble through the mixture for 1 h at RT. Catalyst was then filtered off using syringe microfilter (PTFE; filter was further washed with MeOH). Filtrate was evaporated to dryness and once co-evaporated with DCM. The residue was further dried on high vacuum overnight to give product in the form of free base as colorless oil that crystallized on standing. Yield: 223 mg (99%; 1 step; based on TD1106). NMR (CD3CN): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 2.48— 2.57 (mc, m, 8H); 2.63–2.74 (mc, m, 8H); 3.36 (CH2–CO, s, 4H); 3.64 (CH3, s, 6H). ESI-MS (LC-MS): 317.2 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics> (theor. <semantics>[C14H29N4O4]+=317.2<annotation encoding="application / x-tex">[C_{14}H_{29}N_4O_4]^+ = 317.2< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD687: In a glass vial (2 mL), TD680 (150 mg; 270 µmol; 1.0 equiv.) and P(OEt)3 (232 μL; 1.35 mmol; 5.0 equiv.) were mixed together followed by addition of solid <semantics>(CH2O)n<annotation encoding="application / x-tex">(CH_2O)_n< / annotation>< / semantics> (12 mg; 400 µmol; 1.5 equiv.). The resulting suspension was stirred 3 d at RT. Reaction mixture was then diluted with MeCN (700 µL) and filtered through syringe microfilter (PTFE). Filter was further washed with MeCN. Filtrate was then directly purified by preparative HPLC (C18; H2O–MeCN gradient with FA additive). Fractions with product were combined, immediately neutralized with dil. aq. NaHCO3 and evaporated to dryness. Residue was dissolved in DCM (25 mL) and H2O (25 mL) and transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (3 <semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics> 25 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as slightly yellow oil. Yield: 167 mg (87%; 1 step; based on TD680). ESI-MS (LC-MS): 705.4 [M+H]+ (theor. <semantics>[C35H54N4O9P1]+=705.4<annotation encoding="application / x-tex">[C_{35}H_{54}N_4O_9P_1]^+ = 705.4< / annotation>< / semantics>). All of TD687 was directly used for TD695 without further characterization. [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD695: Pear-shape glass flask (25 mL) was charged with TD687 (167 mg; 237 umol) and magnetic stirrer and three times secured with argon. Solid Pd@C (17 mg) was then added followed by another securing with argon (three times). Under constant flow of argon was then added MeOH (10 mL) through septum. Argon input was then removed and H2 gas (from balloon) was allowed to bubble through the mixture for 30 min at RT. The reaction mixture was further stirred under hydrogen atmosphere (from balloon) 16 h at RT. Catalyst was then filtered off using syringe microfilter (PTFE; filter was further washed with MeOH). Filtrate was evaporated to dryness and once co-evaporated with DCM. The residue was further dried on high vacuum overnight to give product in the form of free base as slightly yellow oil. Yield: 100 mg (97%; 1 step; based on TD686). ESI-MS (LC-MS): 437.2 [M+H]+ (theor. <semantics>[C19H41N4O5P1]+=437.3<annotation encoding="application / x-tex">[C_{19}H_{41}N_4O_5P_1]^+ = 437.3< / annotation>< / semantics>). All of TD695 was directly used for TD700 without further characterization. [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD913: In a glass vial (20 mL), Cbz2cyclen (free base; 242 mg; 549 µmol; 1.0 equiv.) was dissolved in MeCN (12 mL) followed by addition of solid (<semantics>CH2O<annotation encoding="application / x-tex">CH_2O< / annotation>< / semantics>)n (50 mg; 1.67 mmol; 3.0 equiv.) and PhP(OMe)2 (350 <semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>L; 2.2 mmol; 4.0 equiv.). The resulting suspension was stirred 24 h at 80°C. Reaction mixture was then filtered through syringe microfilter (PTFE) and the filtrate was evaporated to dryness. Residue was purified by preparative HPLC (C18; H2O–MeCN gradient with TFA additive). Fractions with product were combined, neutralized with dil. aq. NaHCO3 and evaporated to dryness. Residue was dissolved in DCM (75 mL) and H2O (75 mL) and transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (3 × 25 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as nearly colourless oil. Yield: 259 mg (61%; 1 step; based on Cbz2cyclen). NMR (CD3CN): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 2.30–3.38 (mc, CH2–P, m, 16+4H); 3.47 <semantics>(CH3,d,6H,3JHP=11);5.00−5.12(CH2−Ph,m,4H);7.27−7.40(Ph,m,10H);7.40−7.51(Ph,m,4H);7.51−<annotation encoding="application / x-tex">(CH_3, d, 6H, {}^3J_{HP} = 11); 5.00-5.12 (CH_2-Ph, m, 4H); 7.27-7.40 (Ph, m, 10H); 7.40-7.51 (Ph, m, 4H); 7.51-< / annotation>< / semantics> 7.60 (Ph, m, 2H); 7.60–7.82 (Ph, m, 4H). 31P <semantics>δP<annotation encoding="application / x-tex">\delta_P< / annotation>< / semantics> 42.8 (m). ESI-HRMS: 777.3178 [M+H]+ (theor. <semantics>[C40H51N4O8P2]+=777.3177<annotation encoding="application / x-tex">[C_{40}H_{51}N_4O_8P_2]^+ = 777.3177< / annotation>< / semantics>. [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD910: Pear-shape glass flask (50 mL) was charged with TD913 (250 mg; 322 μmol) and magnetic stirrer and three times secured with argon. Solid Pd@C (50 mg) was then added followed by another securing with argon (three times). Under constant flow of argon was then added MeOH (25 mL) through septum. Argon input was then removed and H2 gas (from balloon) was allowed to bubble through the mixture for 2 h at RT. Catalyst was then filtered off using syringe microfilter (PTFE; filter was further washed with MeOH). Filtrate was evaporated to dryness and once co-evaporated with DCM. The residue was further dried on high vacuum overnight to give product in the form of free base as nearly colourless oil. Yield: 161 mg (98%; 1 step; based on TD913). NMR (CD3CN): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 2.28–3.14 (<semantics>mc<annotation encoding="application / x-tex">mc< / annotation>< / semantics>, <semantics>CH2<annotation encoding="application / x-tex">CH_{2}< / annotation>< / semantics>–P, m, 16+4H); 3.53 (<semantics>CH3<annotation encoding="application / x-tex">CH_{3}< / annotation>< / semantics>, d, 3H, <semantics>3JHP=11<annotation encoding="application / x-tex">{}^{3}J_{HP} = 11< / annotation>< / semantics>); 3.54 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, d, 3H, <semantics>3JHP=11<annotation encoding="application / x-tex">{}^{3}J_{HP} = 11< / annotation>< / semantics>); 7.46–7.63 (<semantics>Ph<annotation encoding="application / x-tex">Ph< / annotation>< / semantics>, m, 6H); 7.71–7.83 (<semantics>Ph<annotation encoding="application / x-tex">Ph< / annotation>< / semantics>, m, 4H). <semantics>31𝑷<annotation encoding="application / x-tex">{}^{31}\mathbf{P}< / annotation>< / semantics> <semantics>δP<annotation encoding="application / x-tex">\delta_{P}< / annotation>< / semantics> 43.3 (m). ESI-HRMS: 509.2438 [M+H]+ (theor. <semantics>[C24H39N4O4P2]+=509.2441<annotation encoding="application / x-tex">[C_{24}H_{39}N_4O_4P_2]^+ = 509.2441< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD571: In a glass vial (4 mL), Cbz2cyclen (free base; 1.00 g; 2.27 mmol; 1.0 equiv.) and P(OEt)3 (2.00 mL; 11.7 mmol; 5.1 equiv.) were mixed together followed by addition of solid (<semantics>CH2O<annotation encoding="application / x-tex">CH_2O< / annotation>< / semantics>)n (164 mg; 5.47 mmol; 2.4 equiv.). The resulting suspension was stirred 24 h at RT. Reaction mixture was then evaporated to dryness and the residue was purified by column chromatography (SiO2; 80 g; DCM–MeOH–aq. NH3 150:10:1). Fractions with product were combined and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as slightly yellow oil. Yield: 1.29 g (77%; 1 step; based on Cbz2cyclen). ESI-MS (LC-MS): 741.3 [M+H]+ (theor. <semantics>[C34H55N4O10P2]+=741.3<annotation encoding="application / x-tex">[C_{34}H_{55}N_4O_{10}P_2]^+ = 741.3< / annotation>< / semantics>). All of TD571 was directly used for TD573 without further characterization. [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD573: Pear-shape glass flask (100 mL) was charged with TD571 (1.29 g; 1.74 mmol) and magnetic stirrer and three times secured with argon. Solid Pd@C (129 mg) was then added followed by another securing with argon (three times). Under constant flow of argon was then added EtOH (96%, 70 mL) through septum. Argon input was then removed and H2 gas (from balloon) was allowed to bubble through the mixture for 30 min at RT. The reaction mixture was further stirred under hydrogen atmosphere (from balloon) 16 h at RT. Catalyst was then filtered off using syringe microfilter (PTFE; filter was further washed with EtOH). Filtrate was evaporated to dryness and once co-evaporated with DCM. The residue was further dried on high vacuum overnight to give product in the form of free base as slightly yellow oil. Yield: 776 mg (95%; 1 step; based on TD571). ESI-MS (LC-MS): 473.2 [M+H]+ (theor. <semantics>[C18H43N4O4P2]+=473.3<annotation encoding="application / x-tex">[C_{18}H_{43}N_4O_4P_2]^+ = 473.3< / annotation>< / semantics>). Major portion of TD573 was directly used for TD579 without further characterization. [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD423: In a pear-shape glass flask (25 mL), tBuDO2A (free base; 410 mg; 1.03 mmol; 1.4 equiv.) was dissolved in dry MeCN (8 mL) followed by addition of Cs2CO3 (840 mg; 2.58 mmol; 3.4 equiv.) and of KI (172 mg; 1.04 mmol; 1.4 equiv.). Solution of 2-Chloro-N-(prop-2-yn-1-yl)acetamide (100 mg; 760 µmol; 1.0 equiv.) in dry MeCN (2 mL) was added and the resulting mixture was stirred 3 d at RT. Solids were filtered off using syringe microfilter (PTFE) and filtrate was evaporated to dryness. Residue was purified by preparative HPLC (C18; H2O–MeCN gradient with FA additive). Fractions with product were combined, neutralized with dil. aq. NaHCO3 and evaporated to dryness. Residue was dissolved in DCM (100 mL) and H2O (100 mL) and transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (<semantics>3×50<annotation encoding="application / x-tex">3 \times 50< / annotation>< / semantics> mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness to give pre- purified product in the form of free base as yellow oil. Yield: 180 mg (~75% of TD423 in a mixture with ~25% of bis(substituted) by-product). ESI-MS (LC-MS): 496.4 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics> (theor. <semantics>[C25H46N5O5]+=496.3<annotation encoding="application / x-tex">[C_{25}H_{46}N_5O_5]^+ = 496.3< / annotation>< / semantics>). All of TD423 was directly used for TD425 without further purification and characterization. [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD635: In a pear-shape glass flask (250 mL), tBuDO2A (free base; 1.21 g; 3.02 mmol; 2.3 equiv.) was dissolved in MeCN (150 mL). To the vigorously stirred reaction mixture, solution of TD558 (1202 mg; 1.33 mmol; 1.0 equiv.) in MeCN (100 mL) was added dropwise (over the course of 2 h). Resulting mixture was further stirred 2 d at RT after which was evaporated to dryness. Residue was purified by preparative HPLC (C18; H2O–MeCN gradient with FA additive). Fractions with product were ΙV combined, neutralized with dil. aq. NaHCO3 and evaporated to dryness. Residue was dissolved in DCM (100 mL) and H2O (100 mL) and transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (4 × 50 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as faint yellow oil that crystallized on standing. Yield: 453 mg (66%; 1 step; based on TD558). NMR (CD3CN): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 1.39 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 18H); 2.53 (mc, m, 4H); 2.61 (mc, m, 4H); 2.73 (mc, m, 4H); 2.77 (mc, m, 4H); 3.01 (CH2–CO, s, 4H); 3.44 <semantics>(C=CH,s,1H);3.66(CH2−arom.,s,2H);7.38(arom.,dd,1H,<math>3JHH=8,4JHH=1);7.70(arom.,t,1H,<math>3JHH=8,4JHH=1);7.70(arom.,t,1H,3JHH=1);7.70(arom.,t,1H,3JHH=1);7.70(<annotation encoding="application / x-tex">(C = CH, s, 1H); 3.66 (CH_2-arom., s, 2H); 7.38 (arom., dd, 1H, ^3J_{HH} = 8, ^4J_{HH} = 1); 7.70 (arom., t, 1H, ^3J_{HH} = 8, ^4J_{HH} = 1); 7.70 (arom., t, 1H, ^3J_{HH} = 1); 7.70 (arom., t, 1H, ^3J_{HH} = 1); 7.70 (< / annotation>< / semantics> 8); 7.76 (arom., dd, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>, <semantics>4JHH=1<annotation encoding="application / x-tex">{}^{4}J_{HH} = 1< / annotation>< / semantics>). <semantics>13𝑪{1𝑯}δC28.4(CH3,s)<annotation encoding="application / x-tex">{}^{13}\mathbf{C}\{{}^{1}\mathbf{H}\}\ \delta_{C}\ 28.4\ (CH_{3}, s)< / annotation>< / semantics>; 48.2 (mc, s); 51.8 (mc, s); 52.6 (mc, s); 54.9 (<semantics>mc<annotation encoding="application / x-tex">mc< / annotation>< / semantics>, s); 57.6 (<semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>–<semantics>CO<annotation encoding="application / x-tex">CO< / annotation>< / semantics>, s); 59.3 (<semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>–<semantics>arom<annotation encoding="application / x-tex">arom< / annotation>< / semantics>., s); 78.0 (<semantics>C≡CH<annotation encoding="application / x-tex">C\equiv CH< / annotation>< / semantics>, s); 81.3 (<semantics>C<annotation encoding="application / x-tex">C< / annotation>< / semantics>–<semantics>CH3<annotation encoding="application / x-tex">CH_3< / annotation>< / semantics>, s); 84.0 (<semantics>C≡CH<annotation encoding="application / x-tex">C\equiv CH< / annotation>< / semantics>, s); 124.9 (arom., s); 126.5 (arom., s); 137.8 (arom., s); 141.6 (arom., s); 162.8 (arom., s); 172.0 (CO, s). ESI-HRMS: <semantics>516.3542 [M+H]+ (theor. [C28H46N5O4]+=516.3544).<annotation encoding="application / x-tex">516.3542 \text{ [M+H]}^+ \text{ (theor. } [C_{28}H_{46}N_5O_4]^+ = 516.3544).< / annotation>< / semantics> [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD539: In a pear-shape glass flask (100 mL), tBuDO2A (free base; 1.73 g; 4.32 mmol; <semantics>≥<annotation encoding="application / x-tex">\geq< / annotation>< / semantics>2.0 equiv.) was dissolved in dry MeCN (15 mL) followed by addition of dried <semantics>K2CO3<annotation encoding="application / x-tex">K_2CO_3< / annotation>< / semantics> (900 mg; 6.52 mmol; <semantics>≥<annotation encoding="application / x-tex">\geq< / annotation>< / semantics>3.0 equiv.). To the vigorously stirred reaction mixture, solution of freshly prepared and isolated TD538 (≤2.17 mmol; 1.0 equiv.) in dry MeCN (10 mL) was added dropwise (over the course of 15 min). Resulting mixture was further stirred 20 h at RT. Solids were filtered off using syringe microfilter (PTFE) and filtrate was evaporated to dryness. Residue was purified by preparative HPLC (C18; H2O–MeCN gradient with FA additive). Fractions with product were combined, neutralized with dil. aq. NaHCO3 and evaporated to dryness. Residue was dissolved in DCM (150 mL) and H2O (150 mL) and transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (3 × 100 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as yellow solidified oil. Yield: 653 mg (47%; 2 steps; based on TD530). NMR (CD3CN): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 1.39 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 18H); 1.43 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 9H); 2.51–2.84 (<semantics>mc<annotation encoding="application / x-tex">mc< / annotation>< / semantics>, m, 16H); 3.01 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>-CO, s, 4H); 3.64 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>-arom., s, 2H); 4.05 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>-C<semantics>≡<annotation encoding="application / x-tex">\equiv< / annotation>< / semantics>C, bd, 2H, <semantics>3JHH=5<annotation encoding="application / x-tex">^3J_{HH} = 5< / annotation>< / semantics>); 5.97 (N<semantics>H<annotation encoding="application / x-tex">H< / annotation>< / semantics>-CO, bt, 1H, <semantics>3JHH=5<annotation encoding="application / x-tex">{}^{3}J_{HH} = 5< / annotation>< / semantics>); 7.27 (arom., dd, 1H, <semantics>3JHH=7<annotation encoding="application / x-tex">{}^{3}J_{HH} = 7< / annotation>< / semantics>, <semantics>4JHH=2<annotation encoding="application / x-tex">{}^{4}J_{HH} = 2< / annotation>< / semantics>); 7.66–7.75 (arom., m, 2H). <semantics>13𝑪{1𝑯}δC28.4(CH3,s)<annotation encoding="application / x-tex">{}^{13}\mathbf{C}\{{}^{1}\mathbf{H}\}\ \delta_{C}\ 28.4\ (CH_{3},\ s)< / annotation>< / semantics>; 28.6 (CH3, s); 31.2 (CH2-C<semantics>≡<annotation encoding="application / x-tex">\equiv< / annotation>< / semantics>C, bs); 48.1 (mc, s); 51.8 (mc, s); 52.8 (mc, s); 55.1 (mc, s); 57.6 (CH2-CO, s); 59.6 (CH2-arom., s); 81.3 (C-CH3, <semantics>2×s<annotation encoding="application / x-tex">2 \times s< / annotation>< / semantics>); 82.6 and 87.0 (C=C, <semantics>2×s<annotation encoding="application / x-tex">2 \times s< / annotation>< / semantics>); 124.3 (arom., s); 126.0 (arom., s); 137.7 (arom., s); 142.3 (arom., s); 162.7 (arom., s); 172.0 (CO, s). ESI-HRMS: 645.4331 [M+H]+ (theor. <semantics>[C34H57N6O6]+=645.4334<annotation encoding="application / x-tex">[C_{34}H_{57}N_6O_6]^+ = 645.4334< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD1118: In a pear-shape glass flask (50 mL), tBuDO2A (free base; 160 mg; 399 <semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>mol; <semantics>≥<annotation encoding="application / x-tex">\geq< / annotation>< / semantics>2.5 equiv.) was dissolved in MeCN (10 mL) followed by addition of dried <semantics>K2CO3<annotation encoding="application / x-tex">K_2CO_3< / annotation>< / semantics> (65 mg; 470 µmol; <semantics>≥<annotation encoding="application / x-tex">\geq< / annotation>< / semantics>3 equiv.). To the vigorously stirred reaction mixture, solution of freshly prepared and isolated TD1117 (≤470 mmol; 1.0 equiv.) in MeCN (10 mL) was added dropwise (over the course of 5 min). Resulting mixture was further stirred 16 h at RT. Solids were filtered off using syringe microfilter (PTFE) and filtrate was evaporated to dryness. Residue was purified by preparative HPLC (C18; H2O- MeCN gradient with FA additive). Fractions with product were combined, neutralized with dil. aq. NaHCO3 and evaporated to dryness. Residue was dissolved in DCM (50 mL) and H2O (50 mL) and transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (<semantics>3×30<annotation encoding="application / x-tex">3 \times 30< / annotation>< / semantics> mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as colourless solidified oil. Yield: 62.2 mg (57%; 2 steps; based on TD966). NMR (CD3CN): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 1.40 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 18H); 1.43 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 9H); 1.53–1.64 <semantics>(CH2,m,2H);1.82−1.91(CH2,m,2H);2.47−2.79(mc,m,16H);2.79−2.88(CH−C=C,m,1H);3.01(CH2−CO,m,2H);2.47−2.79(mc,m,16H);2.79−2.88(CH−C=C,m,1H);3.01(CH2−CO,m,2H);2.47−2.79(mc,m,2H);2.47−2.79<annotation encoding="application / x-tex">(CH_2, m, 2H); 1.82-1.91 (CH_2, m, 2H); 2.47-2.79 (mc, m, 16H); 2.79-2.88 (CH-C=C, m, 1H); 3.01 (CH_2-CO, m, 2H); 2.47-2.79 (mc, m, 16H); 2.79-2.88 (CH-C=C, m, 1H); 3.01 (CH_2-CO, m, 2H); 2.47-2.79 (mc, m, 2H); 2.47-2.79< / annotation>< / semantics> s, 4H); <semantics>3.06−3.18<annotation encoding="application / x-tex">3.06-3.18< / annotation>< / semantics> (CH2, m, 2H); <semantics>3.63<annotation encoding="application / x-tex">3.63< / annotation>< / semantics> (CH2-arom., s, 2H); <semantics>3.71−3.82<annotation encoding="application / x-tex">3.71-3.82< / annotation>< / semantics> (CH2, m, 2H); <semantics>7.27<annotation encoding="application / x-tex">7.27< / annotation>< / semantics> (arom., dd, 1H, <semantics>3JHH<annotation encoding="application / x-tex">^3J_{HH}< / annotation>< / semantics> = 7, <semantics>4JHH<annotation encoding="application / x-tex">{}^{4}J_{HH}< / annotation>< / semantics> = 2); 7.62–7.72 (arom., m, 2H). ESI-HRMS: 699.4801 [M+H]+ (theor. [C38H63N6O6]+ = 699.4804). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD692: In a pear-shape glass flask (250 mL), TD681 (100 mg; 259 µmol; 1.5 equiv.) was dissolved in MeCN (25 mL). To the vigorously stirred reaction mixture, solution of TD558 (26 mg; 172 µmol; 1.0 equiv.) in MeCN (25 mL) was added dropwise (over the course of 1 h). Resulting mixture was further stirred 2 d at RT. Solids were filtered off using syringe microfilter (PTFE) and filtrate was evaporated to dryness. Residue was purified by preparative HPLC (C18; H2O–MeCN gradient with FA additive). Fractions with product were combined, immediately neutralized with dil. aq. NaHCO3 and evaporated to dryness. Residue was dissolved in DCM (25 mL) and H2O (25 mL) and transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (3 × 25 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as yellow oil. Yield: 38 mg (44%; 1 step; based on TD558). ESI-MS (LC-MS): 502.4 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics> (theor. <semantics>[C27H44N5O4]+=502.3<annotation encoding="application / x-tex">[C_{27}H_{44}N_5O_4]^+ = 502.3< / annotation>< / semantics>). All of TD692 was directly used for TD703 without further characterization. [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD700: In a pear-shape glass flask (100 mL), TD695 (100 mg; 229 μmol; 1.5 equiv.) was dissolved in MeCN (25 mL) followed by addition of dried K2CO3 (21 mg; 152 μmol; 1.0 equiv.). To the vigorously stirred reaction mixture, solution of TD558 (23 mg; 152 µmol; 1.0 equiv.) in MeCN (25 mL) was added dropwise (over the course of 1 h). Resulting mixture was further stirred 16 h at RT. Solids were filtered off using syringe microfilter (PTFE) and filtrate was evaporated to dryness. Residue was purified by preparative HPLC (C18; H2O–MeCN gradient with FA additive). Fractions with product were combined, neutralized with dil. aq. NaHCO3 and evaporated to dryness. Residue was dissolved in DCM (75 mL) and H2O (75 mL) and transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (<semantics>3×25<annotation encoding="application / x-tex">3 \times 25< / annotation>< / semantics> mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as yellow oil. Yield: 20 mg (24%; 1 step; based on TD558). ESI-MS (LC-MS): 552.3 [M+H]+ (theor. <semantics>[C27H47N5O5P1]+=552.3<annotation encoding="application / x-tex">[C_{27}H_{47}N_5O_5P_1]^+ = 552.3< / annotation>< / semantics>). All of TD700 was directly used for TD705 without further characterization. [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD579: In a pear-shape glass flask (25 mL), TD573 (600 mg; 1.27 mmol; 2.0 equiv.) was dissolved in MeCN (10 mL). To the vigorously stirred reaction mixture, solution of TD558 (30 mg; 488 µmol; 1.0 equiv.) in MeCN (10 mL) was added dropwise (over the course of 30 min). Resulting mixture was further stirred 16 h at RT. Solids were filtered off using syringe microfilter (PTFE) and filtrate was evaporated to dryness. Residue was purified by preparative HPLC (C18; H2O–MeCN gradient with FA additive). Fractions with product were combined, neutralized with dil. aq. NaHCO3 and evaporated to dryness. Residue was dissolved in DCM (125 mL), H2O (125 mL) and aq. NaOH (1%; 20 mL) and transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (<semantics>3×50<annotation encoding="application / x-tex">3 \times 50< / annotation>< / semantics> mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as yellow oil. Yield: 137 mg (48%; 1 step; based on TD558). ESI-MS (LC-MS): 588.3 [M+H]+ (theor. <semantics>[C26H48N5O6P2]+=588.3<annotation encoding="application / x-tex">[C_{26}H_{48}N_5O_6P_2]^+ = 588.3< / annotation>< / semantics>). TD579 was directly used for TD575 and TD580 and without further characterization. [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD799: In a pear-shape glass flask (100 mL), tBuDO2Prop (free base; 165 mg; 385 µmol; 2.0 equiv.) was dissolved in MeCN (30 mL). To the vigorously stirred reaction mixture, solution of TD558 (29 mg; 191 µmol; 1.0 equiv.) in MeCN (30 mL) was added dropwise (over the course of 6 h). Resulting mixture was further stirred 10 h at RT. Solids were filtered off using syringe microfilter (PTFE) and filtrate was evaporated to dryness. Residue was purified by preparative HPLC (C18; H2O–MeCN gradient with FA additive). Fractions with product were combined, neutralized with dil. aq. NaHCO3 and evaporated to dryness. Residue was dissolved in DCM (50 mL) and H2O (50 mL) and transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (3 <semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics> 25 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as slightly yellow oil. Yield: 47 mg (45%; 1 step; based on TD558). NMR (CD3CN): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 1.38 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 18H); 2.19–2.25 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>–CO, m, 4H); 2.44–2.64 (<semantics>mc<annotation encoding="application / x-tex">mc< / annotation>< / semantics>, <semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>-<semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>-<semantics>CO<annotation encoding="application / x-tex">CO< / annotation>< / semantics>, m, 16+4H); 3.41 (<semantics>C≡CH<annotation encoding="application / x-tex">C\equiv CH< / annotation>< / semantics>, s, 1H); 3.66 (<semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>-arom., s, 2H); 7.36 (<semantics>arom.<annotation encoding="application / x-tex">arom.< / annotation>< / semantics>, dd, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">^3J_{HH} = 8< / annotation>< / semantics>, <semantics>4JHH<annotation encoding="application / x-tex">^4J_{HH}< / annotation>< / semantics> = 1); 7.70 (arom., t, 1H, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 8); 7.77 (arom., bd, 1H, <semantics>3JHH<annotation encoding="application / x-tex">{}^{3}J_{HH}< / annotation>< / semantics> = 8). ESI-HRMS: 544.3854 [M+H]+ (theor. <semantics>[C30H50N5O4]+=544.3857<annotation encoding="application / x-tex">[C_{30}H_{50}N_5O_4]^+ = 544.3857< / annotation>< / semantics>. [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD663: In a pear-shape glass flask (50 mL), tBuDO2A (free base; 210 mg; 524 µmol; 2.7 equiv.) was dissolved in MeCN (15 mL) followed by addition of dried K2CO3 (27 mg; 195 µmol; 1.0 equiv.). To the vigorously stirred reaction mixture, solution of TD566 (50 mg; 193 µmol; 1.0 equiv.) in MeCN (15 mL) was added dropwise (over the course of 15 min). Resulting mixture was further stirred 2 d at RT. Solids were filtered off using syringe microfilter (PTFE) and filtrate was evaporated to dryness. Residue was purified by preparative HPLC (C18; H2O–MeCN gradient with FA additive). Fractions with product were combined, neutralized with dil. aq. NaHCO3 and evaporated to dryness. Residue was dissolved in DCM (50 mL) and H2O (50 mL) and transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (3 <semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics> 25 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as nearly colorless oil. Yield: 83 mg (69%; 1 step; based on TD566). NMR (CD3CN): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 1.33 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 18H); 2.62 (<semantics>mc<annotation encoding="application / x-tex">mc< / annotation>< / semantics>, m, 4H); 2.66 (<semantics>mc<annotation encoding="application / x-tex">mc< / annotation>< / semantics>, m, 4H); 2.74 (<semantics>mc<annotation encoding="application / x-tex">mc< / annotation>< / semantics>, m, 4H); <semantics>2.80(mc,m,4H)<annotation encoding="application / x-tex">2.80 (mc, m, 4H)< / annotation>< / semantics>; <semantics>2.82(CH2−CO,s,4H)<annotation encoding="application / x-tex">2.82 (CH_2-CO, s, 4H)< / annotation>< / semantics>; <semantics>3.74(CH2−arom.,s,2H)<annotation encoding="application / x-tex">3.74 (CH_2-arom., s, 2H)< / annotation>< / semantics>; <semantics>4.46(CH2−N3,s,2H)<annotation encoding="application / x-tex">4.46 (CH_2-N_3, s, 2H)< / annotation>< / semantics>; <semantics>2.46−7.58(Ph,arom.,s,2H)<annotation encoding="application / x-tex">2.46-7.58 (Ph, arom., s, 2H)< / annotation>< / semantics> m, 3+1H); 7.78–7.87 (Ph, m, 2H); 8.18 (arom., bs, 1H). ESI-HRMS: <semantics>623.4022 [M+H]+<annotation encoding="application / x-tex">623.4022 \text{ [M+H]}^+< / annotation>< / semantics> (theor. <semantics>[C33H51N8O4]+<annotation encoding="application / x-tex">[C_{33}H_{51}N_8O_4]^+< / annotation>< / semantics> <semantics>=623.4028<annotation encoding="application / x-tex">= 623.4028< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD711: In a pear-shape glass flask (100 mL), tBuDO2A (free base; 564 mg; 1.41 mmol; 2.5 equiv.) was dissolved in MeCN (40 mL). To the vigorously stirred reaction mixture, solution of TD406 (103 mg; 564 µmol; 1.0 equiv.) in MeCN (40 mL) was added dropwise (over the course of 2 h). Resulting mixture was further stirred 3 d at RT. Solids were filtered off using syringe microfilter (PTFE) and filtrate was evaporated to dryness. Residue was purified by preparative HPLC (C18; H2O–MeCN gradient with FA additive). Fractions with product were combined, neutralized with dil. aq. NaHCO3 and evaporated to dryness. Residue was dissolved in DCM (100 mL) and H2O (100 mL) and transferred to a separatory funnel. After shaking, the bottom phase was separated. Aqueous phase was further extracted with DCM (3 × 50 mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as nearly colourless oil. Yield: 217 mg (70%; 1 step; based on TD406). NMR (CD3CN): <semantics>1<annotation encoding="application / x-tex">{}^{1}< / annotation>< / semantics>H <semantics>δH<annotation encoding="application / x-tex">\delta_{H}< / annotation>< / semantics> 1.39 (C<semantics>H3<annotation encoding="application / x-tex">H_{3}< / annotation>< / semantics>, s, 18H); 2.55 (<semantics>mc<annotation encoding="application / x-tex">mc< / annotation>< / semantics>, m, 4H); 2.60 (<semantics>mc<annotation encoding="application / x-tex">mc< / annotation>< / semantics>, m, 4H); 2.76 (<semantics>mc<annotation encoding="application / x-tex">mc< / annotation>< / semantics>, m, 8H); 3.03 (C<semantics>H2<annotation encoding="application / x-tex">H_{2}< / annotation>< / semantics>–CO, s, 4H); 3.70 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>-arom., s, 2H); 4.39 (C<semantics>H2<annotation encoding="application / x-tex">H_2< / annotation>< / semantics>-N3, s, 2H); 7.21 (arom., dd, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^3J_{HH} = 8< / annotation>< / semantics>, <semantics>4JHH=1<annotation encoding="application / x-tex">{}^4J_{HH} = 1< / annotation>< / semantics>); 7.67 (arom., dd, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>, <semantics>4JHH=1<annotation encoding="application / x-tex">{}^{4}J_{HH} = 1< / annotation>< / semantics>); 7.73 (arom., t, 1H, <semantics>3JHH=8<annotation encoding="application / x-tex">{}^{3}J_{HH} = 8< / annotation>< / semantics>). <semantics>13𝑪{1𝑯}δC28.4(CH3,s)<annotation encoding="application / x-tex">{}^{13}\mathbf{C}\{{}^{1}\mathbf{H}\}\ \delta_{C}\ 28.4\ (CH_{3}, s)< / annotation>< / semantics>; 48.3 (mc, s); 51.8 (mc, s); 52.7 (mc, s); 54.7 (mc, s); 56.1 (CH2–N3, s); 57.7 (CH2–CO, s); 59.0 (CH2–arom., s); 81.2 (C–CH3, s); 121.2 (arom., s); 124.1 (arom., s); 138.2 (arom., s); 155.6 (arom., s); 161.9 (arom., s); 172.0 (CO, s). ESI-HRMS: 547.3716 <semantics>[M+H]+<annotation encoding="application / x-tex">[M+H]^+< / annotation>< / semantics> (theor. <semantics>[C27H47N8O4]+=547.3715<annotation encoding="application / x-tex">[C_{27}H_{47}N_8O_4]^+ = 547.3715< / annotation>< / semantics>). [Image disponible dans le document PDF, Image available in the PDF document] Synthesis of TD596: In a pear-shape glass flask (25 mL), tBuDO2A (free base; 162 mg; 405 <semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>mol; <semantics>≥<annotation encoding="application / x-tex">\geq< / annotation>< / semantics>2.5 equiv.) was dissolved in MeCN (10 mL). To the vigorously stirred reaction mixture, solution of crude TD633 (≤162 µmol; 1.0 equiv.) in MeCN (10 mL) was added dropwise (over the course of 15 min). Resulting mixture was further stirred 2 d at RT. Solids were filtered off using syringe microfilter (PTFE) and filtrate was evaporated to dryness. Residue was purified by preparative HPLC (C18; H2O–MeCN gradient with FA additive). Fractions with product were combined, neutralized with dil. aq. NaHCO3 and evaporated to dryness. Residue was dissolved in DCM (50 mL) and H2O (50 mL) and transferred to a separatory funnel. After shaking, the bottom phase was separated and the aqueous phase was further extracted with DCM (<semantics>3×25<annotation encoding="application / x-tex">3 \times 25< / annotation>< / semantics> mL). Combined organic layers were dried with anhydrous Na2SO4, filtered through glass frit (S3) and evaporated to dryness. The residue was further dried on high vacuum overnight to give product in the form of free base as nearly colorless oil. Yield: 44 mg (48%; 2 steps; based on TD406). ESI-MS (LC-MS): 563.4 [M+H]+ (theor. <semantics>[C27H47N8O5]+=563.4<annotatio...

Claims

<pat:ClaimStatement>206 CLAIMS< / pat:ClaimStatement> <pat:Claims com:id="claims"> <pat:Claim com:id="CLM-00001"> <pat:ClaimNumber>1< / pat:ClaimNumber> <pat:ClaimText>1. A compound of general formula (I): [Image disponible dans le document PDF, Image available in the PDF document] (I), wherein Y is selected from the group consisting of nitrogen, and N-oxide; <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is selected from the group consisting of H; halogen; <semantics>−OH<annotation encoding="application / x-tex">-OH< / annotation>< / semantics>; <semantics>−N3<annotation encoding="application / x-tex">-N_3< / annotation>< / semantics>; <semantics>−(CH2)nN3<annotation encoding="application / x-tex">-(CH_2)_nN_3< / annotation>< / semantics>, wherein n is an integer in the range of from 1 to 3; –NR2, wherein R is independently selected from H or C1 to C6 alkyl, which may be branched or linear; <semantics>−(CH2)nNR2<annotation encoding="application / x-tex">-(CH_2)_nNR_2< / annotation>< / semantics>, wherein <semantics>n<annotation encoding="application / x-tex">n< / annotation>< / semantics> and <semantics>R<annotation encoding="application / x-tex">R< / annotation>< / semantics> are as defined above; <semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics> to <semantics>C10<annotation encoding="application / x-tex">C_{10}< / annotation>< / semantics> aryl, which can optionally be substituted with -NH2, -NO2, -N3, COOH, -CH2Cl and / or -CH2COOH; C7 to C10 arylalkyl, which can optionally be substituted with <semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>, <semantics>−NO2<annotation encoding="application / x-tex">-NO_2< / annotation>< / semantics>, <semantics>−N3<annotation encoding="application / x-tex">-N_3< / annotation>< / semantics>, <Formule mathématique disponible dans le document PDF, Math available in the PDF document>\begin{tabular}{|c|c|c|c|c|c|c|c|c|c|c|c|c|c|c|c|c|c|c <semantics>−CH2COOH<annotation encoding="application / x-tex">-CH_2COOH< / annotation>< / semantics>; <semantics>−CF3<annotation encoding="application / x-tex">-CF_3< / annotation>< / semantics>; <semantics>−COOR<annotation encoding="application / x-tex">-COOR< / annotation>< / semantics>, wherein R is as defined above; <semantics>−(CH2)nCOOR<annotation encoding="application / x-tex">-(CH_2)_nCOOR< / annotation>< / semantics>, wherein n and R are as defined [Image disponible dans le document PDF, Image available in the PDF document] above; ; -CH2CH(OMe)2; \( \frac{\text{CH}}{\text{CH}}; -SH; -SO3H; -SO2Ar, wherein Ar is phenyl; and NO2; <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is selected from the group consisting of <semantics>{N3, and }<annotation encoding="application / x-tex">\{N_3, \text{ and } \}< / annotation>< / semantics>, wherein <semantics>n<annotation encoding="application / x-tex">n< / annotation>< / semantics> is an integer in the range of from 1 to 3; A are independently selected from the group consisting of H; <semantics>−(CH2)nCOOH<annotation encoding="application / x-tex">-(CH_2)_nCOOH< / annotation>< / semantics>, wherein n is an integer from 1 to 3; <semantics>−CH(CH3)COOH<annotation encoding="application / x-tex">-CH(CH_3)COOH< / annotation>< / semantics>; <semantics>−CH((CH2)nCH3)COOH<annotation encoding="application / x-tex">-CH((CH_2)_nCH_3)COOH< / annotation>< / semantics>, wherein n is as defined above; <semantics>−CH2P(=O)(OR)2<annotation encoding="application / x-tex">-CH_2P(=O)(OR)_2< / annotation>< / semantics>, wherein R is as defined above; -CH((CH2)nCOOH)COOH, wherein n is an integer from 1 to 3; -CH((CH2)nNH2)COOH, wherein n is an integer from 1 to 3; <semantics>−CH2C(=O)(NH2)<annotation encoding="application / x-tex">-CH_2C(=O)(NH_2)< / annotation>< / semantics>; <semantics>−CH2C(=O)(NH)−CH2COOH<annotation encoding="application / x-tex">-CH_2C(=O)(NH)-CH_2COOH< / annotation>< / semantics>; and <semantics>−CH2P(=O)(OH)(Ar)<annotation encoding="application / x-tex">-CH_2P(=O)(OH)(Ar)< / annotation>< / semantics>, wherein Ar is phenyl, which can optionally be substituted with <semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics> to <semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics> alkyl; Z is selected from the group consisting of [Image disponible dans le document PDF, Image available in the PDF document] and wherein [Image disponible dans le document PDF, Image available in the PDF document] R4 is selected from the group consisting of H; halogen; piperidinyl; trimethylsilyl; triisopropylsilyl; phenyl; <semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics> to <semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics> alkyl, which may be branched or linear; <semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics> to <semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics> cycloalkyl; <semantics>−CF3<annotation encoding="application / x-tex">-CF_3< / annotation>< / semantics>; <semantics>−(CH2)nNHR6<annotation encoding="application / x-tex">-(CH_2)_nNHR^6< / annotation>< / semantics>, wherein <semantics>n<annotation encoding="application / x-tex">n< / annotation>< / semantics> is an integer in the range of from 1 to 3 and R6 is selected from H, fluorenylmethyloxycarbonyl, tert- butyloxycarbonyl, and benzyloxycarbonyl; –C(CH3)2(NHR6), wherein R6 is as defined above; adamantyl; <semantics>E→CH<annotation encoding="application / x-tex">E \to CH< / annotation>< / semantics>; –(CH2)nCOOH, wherein n is as defined above; and C6 to C10 aryl, which can optionally be substituted with -NH2, -NO2, -N3, COOH, -CH2Cl and / or -CH2COOH; <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics> is <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> or <semantics>12<annotation encoding="application / x-tex">\frac{1}{2}< / annotation>< / semantics> <semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>, wherein <semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics> is as defined above: [Image disponible dans le document PDF, Image available in the PDF document] and / or R2 and R3 together form a 1,2,3-triazole group of formula R4 is defined above; with the proviso that at most one A is H. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00002"> <pat:ClaimNumber>2< / pat:ClaimNumber> <pat:ClaimText>2. The compound of general formula (I) according to claim 1, wherein: Y is nitrogen; <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is selected from the group consisting of H; Cl; <semantics>−N(CH3)2<annotation encoding="application / x-tex">-N(CH_3)_2< / annotation>< / semantics>; phenyl, which can optionally be substituted with -COOH or -CH2COOH; benzyl, which can optionally be substituted with -COOH or -CH2COOH; -CF3; - [Image disponible dans le document PDF, Image available in the PDF document] COOCH3; -COOCH(CH3)2; -COOtBu; and A are independently selected from the group consisting of H; <semantics>−(CH2)nCOOH<annotation encoding="application / x-tex">-(CH_2)_nCOOH< / annotation>< / semantics>, wherein n is 1 or 2; <semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics> <semantics>CH2P(=O)(OH)2;<annotation encoding="application / x-tex">CH_2P(=O)(OH)_2;< / annotation>< / semantics> <semantics>−CH2P(=O)(OH)(OEt);<annotation encoding="application / x-tex">-CH_2P(=O)(OH)(OEt);< / annotation>< / semantics> <semantics>−CH2P(=O)(OEt)2;<annotation encoding="application / x-tex">-CH_2P(=O)(OEt)_2;< / annotation>< / semantics> <semantics>−CH2C(=O)(NH2);<annotation encoding="application / x-tex">-CH_2C(=O)(NH_2);< / annotation>< / semantics> <semantics>−CH2C(=O)(NH)2<annotation encoding="application / x-tex">-CH_2C(=O)(NH)_2< / annotation>< / semantics> <semantics>CH2COOH<annotation encoding="application / x-tex">CH_2COOH< / annotation>< / semantics>; and <semantics>−CH2P(=O)(OH)(Ph)<annotation encoding="application / x-tex">-CH_2P(=O)(OH)(Ph)< / annotation>< / semantics>; Z is selected from the group consisting of [Image disponible dans le document PDF, Image available in the PDF document] wherein <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> is <semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>: R4 is selected from the group consisting of H; halogen; piperidinyl; trimethylsilyl; triisopropylsilyl; phenyl; cyclopropyl, terc-butyl; <semantics>−CF3<annotation encoding="application / x-tex">-CF_3< / annotation>< / semantics>; <semantics>−CH2NH2<annotation encoding="application / x-tex">-CH_2NH_2< / annotation>< / semantics>; <semantics>−CH2N(H)(Fmoc)<annotation encoding="application / x-tex">-CH_2N(H)(Fmoc)< / annotation>< / semantics>; <semantics>−C(CH3)2(NH2)<annotation encoding="application / x-tex">-C(CH_3)_2(NH_2)< / annotation>< / semantics>; <semantics>−C(CH3)2(NHBoc)<annotation encoding="application / x-tex">-C(CH_3)_2(NHBoc)< / annotation>< / semantics>, and adamantyl; <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics> is H or <semantics>12<annotation encoding="application / x-tex">\frac{1}{2}< / annotation>< / semantics> R4, wherein <semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics> is as defined above; with the proviso that at most one A is H. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00003"> <pat:ClaimNumber>3< / pat:ClaimNumber> <pat:ClaimText>3. The compound according to claim 1 or 2, [Image disponible dans le document PDF, Image available in the PDF document] wherein Z is <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> is <Formule mathématique disponible dans le document PDF, Math available in the PDF document>$\S$ <semantics>−R4<annotation encoding="application / x-tex">-R^4< / annotation>< / semantics> . R4 and R5 are as defined above. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00004"> <pat:ClaimNumber>4< / pat:ClaimNumber> <pat:ClaimText>4. The compound of general formula (I) according to claim 1, wherein R2 and R3 together form a 1,2,3- [Image disponible dans le document PDF, Image available in the PDF document] triazole group of formula such that the bridge between two opposite nitrogen atoms of the cyclen moiety is an entity of general formula (IIa) or (IIb) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (IIa) (IIb); wherein L is selected from the group consisting of [Image disponible dans le document PDF, Image available in the PDF document] and and R1, R4 and R5 are as defined in claim 1. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00005"> <pat:ClaimNumber>5< / pat:ClaimNumber> <pat:ClaimText>5. The compound of general formula (I) according to any one of claims 1 to 4, which is selected from the [Image disponible dans le document PDF, Image available in the PDF document] group consisting of compounds, wherein Y is nitrogen, Z is and the remaining substituents are present in the following combinations: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 212 [Image disponible dans le document PDF, Image available in the PDF document] ٠ < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00006"> <pat:ClaimNumber>6< / pat:ClaimNumber> <pat:ClaimText>6. A method of preparation of the compound of the general formula (I) as defined in any one of claims 1 to 5, comprising the following steps: i) providing an alkyne intermediate of general formula Z-Cl, wherein Z is as defined in claim 1; ii) providing an azide intermediate of general formula (III) [Image disponible dans le document PDF, Image available in the PDF document] (III); wherein Y, <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> are as defined in claim 1; iii) providing a cyclen derivative of general formula (IV) [Image disponible dans le document PDF, Image available in the PDF document] (IV), wherein pA is selected from the group consisting of <semantics>−(CH2)nCOOtBu<annotation encoding="application / x-tex">-(CH_2)_nCOO^tBu< / annotation>< / semantics>, wherein n is an integer from 1 to 3; benzyloxycarbonyl; -CH(CH3)COOR, wherein R is tert-butyl, methyl or ethyl; -CH((CH2)nCH3)COOR, wherein n is an integer from 1 to 3 and R is tert-butyl, methyl or ethyl; -CH((CH2)nCOOR)COOR, wherein n is an integer from 1 to 3 and R are independently selected from tert-butyl, methyl or ethyl; <semantics>−CH2P(=O)(OR)2<annotation encoding="application / x-tex">-CH_2P(=O)(OR)_2< / annotation>< / semantics>, wherein R is <semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics> to <semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics> alkyl, which may be branched or linear; <semantics>−CH2C(=O)(NH2)<annotation encoding="application / x-tex">-CH_2C(=O)(NH_2)< / annotation>< / semantics>; <semantics>−CH2C(=O)(NH)−CH2COOH<annotation encoding="application / x-tex">-CH_2C(=O)(NH)-CH_2COOH< / annotation>< / semantics>; and <semantics>−CH2P(=O)(OH)(Ar)<annotation encoding="application / x-tex">-CH_2P(=O)(OH)(Ar)< / annotation>< / semantics>, wherein Ar is phenyl, which can optionally be substituted with <semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics> to <semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics> alkyl; iv-A) reacting the cyclen derivative of general formula (IV) with alkyne intermediate Z-Cl to obtain an intermediate of general formula (V) [Image disponible dans le document PDF, Image available in the PDF document] (V), wherein Z is as defined in claim 1, and pA is as defined above; or iv-B) reacting the cyclen derivative of general formula (IV) with the azide intermediate of general formula (III) to obtain an intermediate of general formula (VI) [Image disponible dans le document PDF, Image available in the PDF document] (VI), wherein Y, <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>, <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> and pA are as defined above; v-A) reacting the intermediate of general formula (V) with the azide intermediate of general formula (III) to obtain an intermediate of general formula (VII) [Image disponible dans le document PDF, Image available in the PDF document] (VII) wherein Y, <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>, <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>, pA and Z are as defined above; or v-B) reacting the intermediate of general formula (VI) with the alkyne intermediate Z-Cl to obtain the intermediate of general formula (VII); vi) optionally, hydrolysis of protecting groups, resulting in the compound of general formula (I). < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00007"> <pat:ClaimNumber>7< / pat:ClaimNumber> <pat:ClaimText>7. A coordination compound of the compound of the general formula (I) as defined in any one of claims 1 to 5, with a metal cation, selected from the group consisting of lanthanide(III) cations, Na+, Ba2+, Pb2+, Sr2+, Ca2+, Cd2+, Zn2+, Mn2+, Pt2+, Cu2+, Ni2+, Sc3+, Y3+, Bi3+, In3+, Ru3+, Ir3+, Ga3+, Tl3+, and Pd2+. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00008"> <pat:ClaimNumber>8< / pat:ClaimNumber> <pat:ClaimText>8. A method of preparation of the coordination compound as defined in claim 7, comprising the following steps: i) synthesis of the compound of the general formula (I) according to the method as defined in claim 6; ii) providing a salt of an inorganic acid and a metal cation, selected from the group consisting of lanthanide(III) cations, Na+, Ba2+, Pb2+, Sr2+, Ca2+, Cd2+, Zn2+, Mn2+, Pt2+, Cu2+, Ni2+, Sc3+, Y3+, Bi3+, In3+, Ru3+, Ir3+, Ga3+, Tl3+, and <semantics>Pd2+<annotation encoding="application / x-tex">Pd^{2+}< / annotation>< / semantics>; iii) mixing the compound of the general formula (I) from step i) with the metal salt from step ii) in aqueous solution, resulting in chelation of the metal cation by the compound of general formula (I) and formation of the coordination compound as defined in claim 7; iv) optionally, transformation of the coordination compound from step iii), wherein the transformation is selected from at least one of the following reactions: - substitution reaction of halogen group present in R1 and / or R4 and / or R5, with a phenylboronic acid, thus transforming the halogen substituent into –COOH; - substitution reaction of halogen group present in R1 and / or R4 and / or R5, with -N3 group by reaction with NaN3; - hydrolysis of TIPS protecting group present in R1 and / or R4 and / or R5 substituent, wherein R1 and / or R3 and / or [Image disponible dans le document PDF, Image available in the PDF document] resulting in <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and / or <semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics> and / or <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics> being <semantics>ECH<annotation encoding="application / x-tex">E^{CH}< / annotation>< / semantics>; - addition reaction of methanol to R1 and / or R4 and / or R5, wherein R1 and / or R3 and / or R5 is [Image disponible dans le document PDF, Image available in the PDF document] thus transforming the triple bond to dimethyl acetal; - deuteration of CH2 groups of the pendant arms in D2O in presence of DBU, transforming them into CD2 groups; [Image disponible dans le document PDF, Image available in the PDF document] - selective reduction of pyridyl cycle of Z substituent, wherein Z is and R3 and R5 are as defined in claim 1, using NaBH4 or NaBD4 as the reducing agent, thus transforming the Z group into [Image disponible dans le document PDF, Image available in the PDF document] - reaction of NH2 group of R1 and / or R4 and / or R5 and / or A, wherein R1 and / or R4 and / or R5 and / or A contains -NH₂ or -(CH₂)nNH₂, with FmocCl, resulting in transformation of -NH₂ group into -NHFmoc group; - reaction of -COOH group present in R1 and / or R4 and / or R5 and / or A, with an amino group of an aminoacid or peptide, thus forming a peptide bond; - S-alkylation reaction of a halogen of R1, R4 and / or R5 substituent with a thiol, resulting in trasforming the halogen into sulfide; - reaction of \( \frac{\}{} = \frac{}{} CH \) group of R1, R3 and / or R5, wherein R1, R3 and / or R5 contains \( \frac{}{} = \frac{}{} CH \), with an azide, thereby forming a triazole bridge connecting the alkyl- or aryl- to R1, R3 and / or R5 group; - reaction of <semantics>−N3<annotation encoding="application / x-tex">-N_3< / annotation>< / semantics> group of <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and / or <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>, wherein <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> and / or <semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics> contains <semantics>−N3<annotation encoding="application / x-tex">-N_3< / annotation>< / semantics> group, with a substituent comprising a carbon-carbon triple bond, thereby forming a triazole bridge connecting the substituent with the coordination compound; - reaction of -SH group of R1 and / or R5, with a substituent comprising maleimide, thereby forming thiosuccinimide linkage connecting the substituent with the coordination compound; - reaction of –SH group of R1 and / or R5, with a substituent comprising another –SH group, thereby forming a disulfide bridge connecting the substituent with the coordination compound; - reaction of –SH group of R1 and / or R5, with alkyl- or arylhalogenide, thereby forming a thioether linkage connecting the alkyl- or aryl- to the coordination compound; - reaction of –NO2 group of R1 and / or R5, with a substituent comprising –SH group, thereby forming a thioether linkage connecting the substituent with the coordination compound. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00009"> <pat:ClaimNumber>9< / pat:ClaimNumber> <pat:ClaimText>9. A coordination compound chain containing at least two coordination compounds as defined in claim 7, bound via a triazole bridge formed between R1 or R5 group of the first coordination compound and R1 or R5 group of the following coordination compound and / or via amide bond formed between a substituent R1 or R4 or R5 or A of one coordination compound containing an amine group and a substituent R1 or R4 or R5 or A of another coordination compound containing a carboxyl group and / or via disulfide bonds formed between a substituent R1 or R5 of one coordination compound containing –SH group, and a substituent R1 or R5 of another coordination compound containing –SH group. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00010"> <pat:ClaimNumber>10< / pat:ClaimNumber> <pat:ClaimText>10. A coordination compound dimer of general formula (X) [Image disponible dans le document PDF, Image available in the PDF document] (X), wherein M1 and M2 are independently metal cations as defined in claim 7, and R1, R4 and R5 are as defined in claim 1. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00011"> <pat:ClaimNumber>11< / pat:ClaimNumber> <pat:ClaimText>11. A conjugate for drug tracing, which contains the coordination compound as defined inclaim 7 or the coordination compound chain as defined in claim 9, conjugated to a peptide or to a protein; wherein the coordination compound as defined in claim 7 or the coordination compound chain as defined in claim 9 contain R1 and / or R4 and / or R5 group comprising –NH2 or –COOH group; which is conjugated to the peptide or the protein via an amide bond formed between –COOH group present in R1 and / or R4 and / or R5 and amino group of the peptide or the protein or via an amide bond formed between -NH2 group present in R1 and / or R4 and / or R5 and carboxyl group of the peptide or the protein; and wherein the peptide is selected from the group consisting of oligopeptides of 3 to 20 aminoacids; and wherein the protein is selected from the group consisting of antibodies. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00012"> <pat:ClaimNumber>12< / pat:ClaimNumber> <pat:ClaimText>12. A method of in vitro drug tracing, comprising the following steps: i) providing a cell culture or a tissue to be analyzed, containing at least one conjugate as defined in claim 11, wherein the peptide or the protein is of the peptide-based or protein-based drug to be traced; ii) hydrolyzing the cell culture or tissue from step i) using a strong acid, obtaining a hydrolyzate; iii) qualitative and / or quantitative analysis of the hydrolyzate of step ii) for the presence of the coordination compound as defined in claim 7 or of the coordination compound chain as defined in claim 9. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00013"> <pat:ClaimNumber>13< / pat:ClaimNumber> <pat:ClaimText>13. Use in vitro of the coordination compound as defined in claim 7 or of the coordination compound chain as defined in claim 9 or of the coordination compound dimer as defined in claim 10 or of the conjugate as defined in claim 11 in pharmacy. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00014"> <pat:ClaimNumber>14< / pat:ClaimNumber> <pat:ClaimText>14. The coordination compound according to claim 7 or the coordination compound chain according to claim 9 or the coordination compound dimer according to claim 10 for use in medical diagnostics. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00015"> <pat:ClaimNumber>15< / pat:ClaimNumber> <pat:ClaimText>15. The coordination compound according to claim 7 or the coordination compound chain according to claim 9 or the coordination compound dimer according to claim 10, wherein M is selected from the group consisting of 44Sc, 47Sc, 64Cu, 67Cu, 86Y, 90Y, 140Nd, 149Pm, 151Pm, 153Sm, 159Gd, 149Tb, 161Tb, 165Dy, 161Ho, 166Ho, 169Er, 167Tm, 175Yb, and 177Lu, and / or R1, R4 and / or R5 contains a radioactive halogen, for use in medicine as radiodiagnostic and / or radiopharmaceutic agents. < / pat:ClaimText> < / pat:Claim> < / pat:Claims>