(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date r /1 1 20 October 2011 (20.10.2011) V I A (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C12N 15/10 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (21) International Application Number: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, PCT/DK20 11/00003 1 DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, 16 April 201 1 (16.04.201 1) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (25) Filing Language: English NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (26) Publication Language: English SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/325,1 60 16 April 2010 (16.04.2010) US (84) Designated States (unless otherwise indicated, for every PA 2010 70149 16 April 2010 (16.04.2010) DK kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, (71) Applicant (for all designated States except US): ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, NUEVOLUTION A S [DK/DK]; R0nnegade 8, 5, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, DK-2100 Copenhagen (DK). EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (72) Inventors; and SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (75) Inventors/ Applicants (for US only): GOULIAEV, Alex, GW, ML, MR, NE, SN, TD, TG). Haahr [DK/DK]; Brandsted 223, DK-3670 Veks0 Sjsel- land (DK). FRANCH, Thomas [DK/DK]; Tj0rnevej 26, Published: DK-3070 Snekkersten (DK). Godskesen, Michael, An¬ — with international search report (Art. 21(3)) ders [DK/DK]; Plantagekrogen 8, DK-2950 Vedbsk (DK). JENSEN, Kim, Birkevaek [DK/DK]; Voldumvej — before the expiration of the time limit for amending the 30C, DK-2610 R0dovre (DK). claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) (74) Agent: HJERRILD & LEVIN APS; Tuborg Boulevard 12, DK-2900 Hellerup (DK). (54) Title: BI-FUNCTIONAL COMPLEXES AND METHODS FOR MAKING AND USING SUCH COMPLEXES (57) Abstract: The present invention is directed to a method for the synthesis of a bi-functional complex comprising a molecule part and an identifier oligonucleotide part identifying the molecule part. A part of the synthesis method according to the present invention is preferably conducted in one or more organic solvents when a nascent bi-functional complex comprising an optionally protected tag or oligonucleotide identifier is linked to a solid support, and another part of the synthesis method is preferably con ducted under conditions suitable for enzymatic addition of an oligonucleotide tag to a nascent bi-functional complex in solution. Bi-functional complexes and methods for making and using such complexes This application claims the benefit of US 61/325,160 filed on April 16, 2010, the contents of which are hereby incorporated by reference in their entirety. All patent and non-patent references cited in US 61/325,160 or in this application are hereby also incorporated by reference in their entirety. Field of invention The present invention is directed to methods for organic synthesis of molecules and to molecules having been synthesised by the disclosed methods, as well as to methods for using such molecules. Background of invention Libraries of bi-functional complexes can be produced by methods commonly known as split-and-mix methods, or by parallel, but separate synthesis of individual bi-functional complexes followed by mixing of such individually synthesized bi-functional complexes. In a split-and-mix method, different synthesis reactions are performed in a plurality of different reaction compartments. The contents of the various reaction compartments are collected (mixed) and subsequently split into a number of different compartments for a new round of synthesis reactions. The sequential synthesis steps of a split-and- mix method are continued until the desired molecules have been synthesised. It is often desirable to perform an encoded synthesis in order to be able to readily identify desirable molecules, for example after a selection step involving targeting a library of different bi-functional complexes to a molecular target. Encoded synthesis of biochemical molecules is disclosed by Lerner e.g. in US 5,573,905, US 5,723,598 and US 6,060,596. One part of the bi-functional complexes is in the form of a molecule part and the other part is in the form of an identifier oligonucleotide comprising a plurality of oligonucleotide tags which encodes and identifies the building block residues which participated in the formation of the molecule and optionally the chemistries used for reacting the building block residues in the formation of the molecule. The oligonucleotide tags described by Lerner are added to each other exclusively by chemical ligation methods employing nucleotide-phosphoramidite chemistry. The above-cited library synthesis principles require standard organic synthesis steps for both the sequential, chemical ligation of oligonucleotide tags and for the synthesis of the small molecule that is encoded by the resulting oligonucleotide identifier. It is an essential requirement, in the method described by Lemer, that the synthesis of the identifier oligonucleotide is completely orthogonal to the synthesis of the small molecule. Facile organic synthesis of oligonucleotide tags used for the above-mentioned library synthesis principles employs nucleotide-phosphoramidite chemistry. This requires an efficient coupling of a trivalent phosphoramidite with the nucleophilic 5' OH-group of the growing nucleotide chain. Thus, any unprotected nucleophile present in the molecule part of the bi-functional complex may also react with tag phosphoramidite reactive groups in subsequent tag synthesis step and electrophilic groups present in the molecule part may also in some cases react with the nucleophlic 5' OH-group, which was intended to react with the phosphoramidite functional group of the incoming oligonucleotide tag. Also, any protection groups used for protection of either the molecule, in its intermediate form, where such are used for controlling and directing its synthesis into the molecule or into a further intermediate of the molecule, and all protection groups used by the oligonucleotide tag must be compatible with the conditions applied, when the tag oligonucleotide is attached by use of chemical reaction based methods. Furthermore, each round of nucleotide addition by phosphoramidite chemistry requires many steps, such as oxidation, capping of unreacted 5'-OH-groups, and DMT- deprotection using acidic conditions, all of which may challenge the integrity or reactivity of the small molecule part of the bi-functional complex. As will be clear from the above, many prior art split-and-mix methods for performing an encoded synthesis are constrained in their application because of a lack of compatible chemistries between alternating synthesis procedures for adding to an intermediate bi- functional complex i) a reactive compound building block and ii) an oligonucleotide tag identifying said reactive compound building block and optionally the chemistry for said reaction, respectively. It is a general problem that the reaction conditions and chemistries available for reacting reactive compound building blocks are far from always compatible with the phosphoramidite reaction conditions and chemistries required for performing the chemical ligation methods needed for adding an oligonucleotide tag to the identifier oligonucleotide of an intermediate bi-functional complex. Also, chemical synthesis methods exclusively employing on-bead combinatorial chemistry in the absence of any possibility for performing "in solution" reaction steps are constrained with respect to certain types of chemical reaction conditions typically used only in solution. For several prior art split-and-mix methods, the problem of how to increase the sequential synthesis compatibility has been solved by including or even increasing the number of protection groups present on both the reactive compound building blocks and on the oligonucleotide tags identifying said reactive compound building block. The protection groups are added in a step-wise fashion as the alternating synthesis steps are performed. However, step-wise protection and deprotection reactions are cumbersome and have limited applicability when synthesising large libraries. This is due to a lack of available and compatible chemistries as well as the need to include a large number of different protection groups. This is being further complicated in split- and-mix synthesis methods, where many different molecules are in the process of being formed as a mixture, and all of these molecules in their intermediate form must be compatible with the conditions used for attaching the oligonucleotide tag. Accordingly, many different protections groups will have to be employed in order to protect equally many different kinds of reactive groups in the molecules. In many cases, a library synthesis step can only be performed after several different protection reactions have taken place. Consequently, it is often regarded as undesirable, but necessary, to perform the number of protection and deprotection steps required for obtaining the needed degree of protection (and deprotection) of both reactive compound building blocks and oligonucleotide tags. One cannot achieve sequential protection and deprotection of both reactive compound building blocks and oligonucleotide tag reactive groups without carrying out a certain number of protection group reactions.