TAKEDA KAZUTAKA (JP)
OKADA YOHEI (JP)
LUTHER ANATOL (CH)
Bachem Holding AG October 16, 2023 BAC74641PC Claims 1. A method for the synthesis of a target oligonucleotide OT, said method comprising a step of subjecting a solution comprising a component C selected from the group consisting of a nucleoside and an oligonucleotide to one or more aqueous extractions, wherein the organic phase comprises the component C, and wherein - said component C is covalently bonded to a pseudo solid-phase protecting group PG-s, and - each of said one or more aqueous extractions is carried out in the presence of one or more amide solvents SA, wherein each amide solvent SA is an amide solvent comprising one or more alkyl groups, wherein these one or more alkyl groups together comprise in total 6−24 carbon atoms. 2. The method according to claim 1, wherein the target oligonucleotide OT comprises a first cycle oligonucleotide O-1, and the method comprises the following step (a-1), and a first coupling cycle comprising the following steps: (a-1) providing a component C-0 selected from the group consisting of a nucleoside and an oligonucleotide, wherein the component C-0 is covalently bonded to a pseudo solid-phase protecting group PG-s and comprises a backbone hydroxyl moiety protected by a protecting group PG-0 removable under acidic conditions; (b-1) incubating the component C-0 of step (a-1) with a deprotection mixture M-(b-1), thereby cleaving the protecting group PG-0 from the component C-0, so as to obtain a component (C-0)# having a free backbone hydroxyl group; (c-1) subjecting a solution comprising the component (C-0)# to one or more aqueous extractions, wherein the organic phase comprises the component (C-0)#; (d-1) optionally, reducing the water content of the organic phase comprising the component (C-0)#; (e-1) reacting the component (C-0)# with a building block B-1, wherein said building block B-1 is selected from the group consisting of a nucleoside and an oligonucleotide and comprises - a backbone hydroxyl moiety protected by a protecting group PG-1 removable under acidic conditions, and - a phosphorus moiety covalently bonded via its phosphorus atom to an oxygen atom of the backbone of the building block B-1, under conditions suitable to form a covalent bond between said free backbone hydroxyl group of the component (C-0)# and the phosphorus atom of said phosphorus moiety of the building block B-1, thereby obtaining a first cycle oligonucleotide O-1; (f-1) optionally, incubating the first cycle oligonucleotide O-1 with an oxidizing or sulfurizing agent, thereby converting any P (III) atoms within said first cycle oligonucleotide O-1 to P (V) atoms; (g-1) optionally, subjecting a solution comprising the first cycle oligonucleotide O-1 to one or more aqueous extractions, wherein the organic phase comprises the first cycle oligonucleotide O-1; (h-1) if step (g-1) has been carried out, optionally reducing the water content of the organic phase comprising the first cycle oligonucleotide O-1; wherein during and in between steps (b-1) to (h-1), no solid-liquid separation is performed and steps (c-1) and (g-1) are carried out in the presence of one or more amide solvents SA, wherein each amide solvent SA is defined as in claim 1. 3. The method according to claim 2, wherein the target oligonucleotide OT comprises a second cycle oligonucleotide O-2, and the method further comprises performing a second coupling cycle comprising the following steps: (b-2) incubating the first cycle oligonucleotide O-1 obtained in the first coupling cycle with a deprotection mixture M-(b-2), thereby cleaving the protecting group PG-1 from the first cycle oligonucleotide O-1, so as to obtain a first cycle oligonucleotide (O-1)# having a free backbone hydroxyl group; (c-2) subjecting a solution comprising the first cycle oligonucleotide (O-1)# to one or more aqueous extractions, wherein the organic phase comprises the first cycle oligonucleotide (O-1)#; (d-2) optionally, reducing the water content of the organic phase comprising the first cycle oligonucleotide (O-1)#; (e-2) reacting the first cycle oligonucleotide (O-1)# with a building block B-2, wherein said building block B-2 is selected from the group consisting of a nucleoside and an oligonucleotide and comprises - a backbone hydroxyl moiety protected by a protecting group PG-2 removable under acidic conditions, and - a phosphorus moiety covalently bonded via its phosphorus atom to an oxygen atom of the backbone of the building block B-2, under conditions suitable to form a covalent bond between said free backbone hydroxyl group of the first cycle oligonucleotide (O-1)# and the phosphorus atom of said phosphorus moiety of the building block B-2, thereby obtaining a second cycle oligonucleotide O-2; (f-2) optionally, incubating the second cycle oligonucleotide O-2 with an oxidizing or sulfurizing agent, thereby converting any P (III) atoms within said second cycle oligonucleotide O-2 to P (V) atoms; (g-2) optionally, subjecting a solution comprising the second cycle oligonucleotide O-2 to one or more aqueous extractions, wherein the organic phase comprises the second cycle oligonucleotide O-2; (h-2) if step (g-2) has been carried out, optionally reducing the water content of the organic phase comprising the second cycle oligonucleotide O-2; wherein during and in between steps (b-1) to (h-2), no solid-liquid separation is performed and steps (c-1), (g-1), (c-2), and (g-2) are carried out in the presence of one or more amide solvents SA, wherein each amide solvent SA is defined as in claim 1. 4. The method according to claim 3, wherein the target oligonucleotide OT comprises a n-th cycle oligonucleotide O-n, and the method further comprises performing (n−2) iterations of a coupling cycle comprising the following steps (b-x) to (h-x), wherein n is an integer in the range of 3 to 99, which denotes the total number of coupling cycles performed to obtain the n-th cycle oligonucleotide O-n, and each individual coupling cycle comprising the following steps (b-x) to (h-x) is identified by a serial number x, which runs in steps of 1 from 3 to n: (b-x) incubating the (x−1)-th cycle oligonucleotide O-(x−1) obtained in the previous coupling cycle with a deprotection mixture M-(b-x), thereby cleaving the protecting group PG-(x−1) from the (x−1)-th cycle oligonucleotide O-(x−1), so as to obtain a (x−1)-th cycle oligonucleotide (O-(x−1))# having a free backbone hydroxyl group; (c-x) subjecting a solution comprising the (x−1)-th cycle oligonucleotide (O-(x−1))# to one or more aqueous extractions, wherein the organic phase comprises the (x−1)-th cycle oligonucleotide (O-(x−1))#; (d-x) optionally, reducing the water content of the organic phase comprising the (x−1)-th cycle oligonucleotide (O-(x−1))#; (e-x) reacting the (x−1)-th cycle oligonucleotide (O-(x−1))# with a building block B-x, wherein said building block B-x is selected from the group consisting of a nucleoside and an oligonucleotide and comprises - a backbone hydroxyl moiety protected by a protecting group PG-x removable under acidic conditions, and - a phosphorus moiety covalently bonded via its phosphorus atom to an oxygen atom of the backbone of the building block B-x, under conditions suitable to form a covalent bond between said free backbone hydroxyl group of the (x−1)-th cycle oligonucleotide (O-(x−1))# and the phosphorus atom of said phosphorus moiety of the building block B-x, thereby obtaining a x-th cycle oligonucleotide O-x; (f-x) optionally, incubating the x-th cycle oligonucleotide O-x with an oxidizing or sulfurizing agent, thereby converting any P (III) atoms within said x-th cycle oligonucleotide O-x to P (V) atoms; (g-x) optionally, subjecting a solution comprising the x-th cycle oligonucleotide O-x to one or more aqueous extractions, wherein the organic phase comprises the x-th cycle oligonucleotide O-x; (h-x) if step (g-x) has been carried out, optionally reducing the water content of the organic phase comprising the x-th cycle oligonucleotide O-x; wherein during and in between steps (b-1) to (h-n), no solid-liquid separation is performed, and steps (c-1), (g-1), (c-2), and (g-2), as well as each iteration of steps (c-x) and (g-x) are carried out in the presence of one or more amide solvents SA, wherein each amide solvent SA is defined as in claim 1. 5. The method according to any one of claims 2 to 4, wherein - the phosphorus moiety of the building blocks B-1, B-2, and each building block B-x is independently selected from the group consisting of a phosphoramidite moiety and a H-phosphonate monoester moiety; - in each coupling cycle, in which said phosphorus moiety of the building block B-1, B-2 or B-x is a phosphoramidite moiety, step (f-1) or (f-2) or (f-x) is carried out; and - at least in the final coupling cycle, step (f-1) or (f-2) or (f-x) is carried out. 6. The method according to any one of claims 2 to 4, wherein the component C-0 is a compound of the following Formula I: (Formula I), wherein in in Formula I: each oxygen atom (O) depicted within each nucleoside subunit x-0 to x-m represents the oxygen atom of a hydroxyl moiety of the respective nucleoside subunit; each of the nucleoside subunits x-0 to x-m may be the same or different; m is an integer equal to or larger than 0; PG-0 is a protecting group removable under acidic conditions; Y1 is selected independently for each repetitive unit m from the group consisting of O and S; Z1 is selected independently for each repetitive unit m from the group consisting of O-Rz-1, S-Rz-1, and H; Rz-1 is a protecting group, which may be the same or different for each repetitive unit m; and PG-s is a pseudo solid-phase protecting group. 7. The method according to any one of claims 2 to 6, wherein each of the building blocks B-1, B-2, and B-x is a compound of the following Formula II-1: (Formula II-1), wherein in Formula II-1: each oxygen atom (O) depicted within each nucleoside subunit y-0 to y-q represents the oxygen atom of a hydroxyl moiety of the respective nucleoside subunit; each nucleoside subunit y-0 to y-q may be the same or different; PG is the protecting group PG-1 or PG-2 or PG-x and is a protecting group removable under acidic conditions; q is an integer equal to or larger than 0; Y2 is selected independently for each repetitive unit q from the group consisting of O and S; Z2 is selected independently for each repetitive unit q from the group consisting of O-Rz-2 and S-Rz-2; Rz-2 is a protecting group, which may be the same or different for each repetitive unit q; Z3 is selected from the group consisting of O and S; and Rz-3 is a protecting group; each of Ra and Rb is a C1−C6-alkyl group, wherein Ra and Rb may be the same or different and may also bond to each other to form a 5-membered or 6-membered aliphatic cyclic amine moiety together with the nitrogen atom to which Ra and Rb are bonded; and wherein step (f-1) or (f-2) or (f-x) is carried out in each coupling cycle. 8. The method according to any one of claims 2 to 7, wherein - the first coupling cycle further comprises a step (i-1) of reacting free hydroxyl groups with a blocking agent, wherein step (i-1) is carried out after step (e-1) or after step (f-1); and/or - the second coupling cycle further comprises a step (i-2) of reacting free hydroxyl groups with a blocking agent, wherein step (i-2) is carried out after step (e-2) or after step (f-2); and/or - at least one coupling cycle comprising steps (b-x) to (h-x) further comprises a step (i-x) of reacting free hydroxyl groups with a blocking agent, wherein step (i-x) is carried out after step (e-x) or after step (f-x). 9. The method according to any one of claims 2 and 5 to 8, wherein the method further comprises - a step (k-1) of incubating the first cycle oligonucleotide O-1 with a deprotection mixture M-(k-1), thereby cleaving the protecting group PG-1 from the first cycle oligonucleotide O-1, so as to obtain a first cycle oligonucleotide (O-1)# having a free backbone hydroxyl group; and/or - a step (m-1) of incubating the first cycle oligonucleotide O-1 or (O-1)# with a base, thereby cleaving the pseudo solid-phase protecting group PG-s and, optionally, one or more further protecting groups from the first cycle oligonucleotide O-1 or (O-1)#; and/or - a step (p-1) of modifying the first cycle oligonucleotide O-1 or (O-1)#; wherein, if more than one of steps (k-1), (m-1), and (p-1) are performed, they may be performed in any order. 10. The method according to any one of claims 3 and 5 to 8, wherein the method further comprises - a step (k-2) of incubating the second cycle oligonucleotide O-2 with a deprotection mixture M-(k-2), thereby cleaving the protecting group PG-2 from the second cycle oligonucleotide O-2, so as to obtain a second cycle oligonucleotide (O-2)# having a free backbone hydroxyl group; and/or - a step (m-2) of incubating the second cycle oligonucleotide O-2 or (O-2)# with a base, thereby cleaving the pseudo solid-phase protecting group PG-s and, optionally, one or more further protecting groups from the second cycle oligonucleotide O-2 or (O-2)#; and/or - a step (p-2) of modifying the second cycle oligonucleotide O-2 or (O-2)#; wherein, if more than one of steps (k-2), (m-2), and (p-2) are performed, they may be performed in any order. 11. The method according to any one of claims 4 to 8, wherein the method further comprises - a step (k-n) of incubating the n-th cycle oligonucleotide O-n with a deprotection mixture M-(k-n), thereby cleaving the protecting group PG-n from the n-th cycle oligonucleotide O-n, so as to obtain a n-th cycle oligonucleotide (O-n)# having a free backbone hydroxyl group; and/or - a step (m-n) of incubating the n-th cycle oligonucleotide O-n or (O-n)# with a base, thereby cleaving the pseudo solid-phase protecting group PG-s and, optionally, one or more further protecting groups from the n-th cycle oligonucleotide O-n or (O-n)#; and/or - a step (p-n) of modifying the n-th cycle oligonucleotide O-n or (O-n)#; wherein, if more than one of steps (k-n), (m-n), and (p-n) are performed, they may be performed in any order. 12. The method according to any one of claims 9 to 11, wherein the method comprises exactly one step selected from the group consisting of step (m-1), step (m-2), and step (m-n), and wherein - step (m-1) is carried out by incubating the first cycle oligonucleotide O-1 or (O-1)# with an aqueous solution of a (C1−C6-alkyl)NH2 monoalkylamine, in particular tert-butylamine, and an aliphatic alcohol comprising 1−6 carbon atoms, in particular methanol; - step (m-2) is carried out by incubating the second cycle oligonucleotide O-2 or (O-2)# with an aqueous solution of a (C1−C6-alkyl)NH2 monoalkylamine, in particular tert-butylamine, and an aliphatic alcohol comprising 1−6 carbon atoms, in particular methanol; and - step (m-n) is carried out by incubating the n-th cycle oligonucleotide O-n or (O-n)# with an aqueous solution of a (C1−C6-alkyl)NH2 monoalkylamine, in particular tert-butylamine, and an aliphatic alcohol comprising 1−6 carbon atoms, in particular methanol. 13. The method according to any one of claims 2 to 12, wherein steps (b-1) to (h-1), are carried out in the presence of one or more amide solvents SA and, preferably, one or more ether solvents SE, and further wherein: - if the second coupling cycle comprising steps (b-2) to (h-2), is performed, steps (b-1) to (h-2), are carried out in the presence of one or more amide solvents SA and, preferably, one or more ether solvents SE; and - if (n−2) iterations of the coupling cycle comprising steps (b-x) to (h-x) are performed, all of steps (b-1) to (h-n) are carried out in the presence of one or more amide solvents SA and, preferably, one or more ether solvents SE. 14. The method according to any one of claims 2 to 13, wherein steps (b-1) to (h-1) are carried out in essentially halogen-free solvents, and further wherein: - if a second coupling cycle comprising steps (b-2) to (h-2) is performed, steps (b-1) to (h-2) are carried out in essentially halogen-free solvents; and - if (n−2) iterations of the coupling cycle comprising steps (b-x) to (h-x) are performed, any steps (b-1) to (h-n) are carried out in essentially halogen-free solvents. 15. The method according to any one of claims 2 to 14, wherein in each of the one or more aqueous extractions of step (c-1), the aqueous phase has a pH-value equal to or smaller than 7, preferably in the range of 4−7, and further wherein: - if a second coupling cycle comprising steps (b-2) to (h-2) is performed, in each of the one or more aqueous extractions of step (c-2), the aqueous phase has a pH-value equal to or smaller than 7, preferably in the range of 4−7; and - if (n−2) iterations of the coupling cycle comprising steps (b-x) to (h-x) are performed, in each of the one or more aqueous extractions of each step (c-x), the aqueous phase has a pH-value equal to or smaller than 7, preferably in the range of 4−7. 16. The method according to any one of claims 1 to 15, wherein each amide solvent SA is at each occurrence selected independently from the group consisting of the following Formulae SA-1, SA-2, and SA-3: (Formula SA-1), (Formula SA-2), (Formula SA-3), wherein in Formula SA-1: RA-1 is selected from the group consisting of H and a C1−C22-alkyl group, in which exactly one hydrogen residue may optionally be substituted by a C(O)O(C1−C5-alkyl) group; and each of RA-2 and RA-3 is independently a C1−C23-alkyl group; with the proviso that RA-1, RA-2 and RA-3 together comprise in total 6−24 carbon atoms; wherein in Formula SA-2: o is an integer of 1 or 2; and RA-4 is a C6–C24-alkyl group; and wherein in Formula SA-3: p is an integer of 1 or 2; XA is selected from the group consisting of CH2, O, and NC(O)RA-6, with the proviso that, if p is 1, XA is CH2; RA-5 is a C1–C24-alkyl group; and RA-6 is a C1–C23-alkyl group; with the proviso that RA-5 and RA-6 together comprise in total 6–24 carbon atoms. 17. The method according to any one of claims 13 to 16, wherein each ether solvent SE is at each occurrence selected independently from the group consisting of the following Formulae SE-1 and SE-2: (Formula SE-2), wherein in Formula SE-1: s is an integer of 0 or 1; and each of RE-1, RE-2, RE-3, RE-4, RE-5, RE-6, RE-7, RE-8, RE-9, and RE-10 is independently selected from the group consisting of H and a C1–C5-alkyl group, with the proviso that at least one of RE-1, RE-2, RE-3, RE-4, RE-5, RE-6, RE-7, RE-8, RE-9, and RE-10 is a C1–C5-alkyl group; and wherein in Formula SE-2: each of RE-11 and RE-12 is independently a C1–C6-alkyl group, with the proviso that RE-11 and RE-12 together comprise in total 5–12 carbon atoms. 18. The method according to any one of claims 1 to 17, wherein each pseudo solid-phase protecting group is a protecting group of the following Formula P-1: (Formula P-1), wherein in Formula P-1: the asterisk indicates the oxygen atom of a hydroxyl moiety or the nitrogen atom of an amine moiety protected by the respective pseudo solid-phase protecting group; a is an integer of 0 or 1; b is an integer of 0 or 1; LP is a linker moiety; i is an integer of 1 to 5; and RP-1 is at each occurrence independently selected from the group consisting of O(C1–C40-alkyl), O(C2–C40-alkenyl), O(C2–C40-alkynyl), a C1–C40-alkyl group, a C2–C40-alkenyl group, a C2–C40-alkynyl group, C(O)(C1–C40-alkyl), C(O)(C2–C40-alkenyl), and C(O)(C2–C40-alkynyl); and wherein all present residues RP-1 together comprise in total 18–200 carbon atoms. 19. A composition comprising: - an oligonucleotide which is covalently bonded to at least one pseudo solid-phase protecting group, and - a mixed solvent which is essentially halogen-free and comprises one or more amide solvents SA and, preferably, one or more ether solvents SE, wherein each amide solvent SA is an amide solvent comprising one or more alkyl groups, wherein these one or more alkyl groups together comprise in total 6–24 carbon atoms, preferably wherein the composition and/or one or more components are defined as in one or more of the preceding claims, in particular wherein said one or more amide solvents SA are defined as in claim 16, said one or more ether solvents SE are defined as in claim 17, and/or each pseudo solid-phase protecting group is defined as in claim 18. |
(Formula II-1), wherein in Formula II-1: each oxygen atom (O) depicted within each nucleoside subunit y-0 to y-q represents the oxygen atom of a hydroxyl moiety of the respective nucleoside subunit; each nucleoside subunit y-0 to y-q may be the same or different; PG is the protecting group PG-1 (for the building block B-1) or PG-2 (for the building block B-2) or PG-x (for a building block B-x) and is a protecting group removable under acidic conditions; q is an integer equal to or larger than 0; Y 2 is selected independently for each repetitive unit q from the group consisting of O and S; Z 2 is selected independently for each repetitive unit q from the group consisting of O-R z-2 and S-R z-2 ; R z-2 is a protecting group, which may be the same or different for each repetitive unit q; Z 3 is selected from the group consisting of O and S; and R z-3 is a protecting group; each of R a and R b is a C 1 −C 6 -alkyl group, wherein R a and R b may be the same or different and may also bond to each other to form a 5-membered or 6-membered aliphatic cyclic amine moiety together with the nitrogen atom to which R a and R b are bonded; and wherein step (f-1) or (f-2) or (f-x) is carried out in each coupling cycle. In some embodiments of the method of the invention, each of the building blocks B-1, B-2, and B-x is a compound of the following Formula II-1-a: (Formula II-1-a), wherein in Formula II-1-a: q, PG, Y 2 , Z 2 , R z-2 , Z 3 , R z-3 , R a , and R b are defined as for Formula II-1; and B N , R XI , R XII , R XIII , R XIV , and R XV are defined as for Formula II-a, and wherein step (f-1) or (f-2) or (f-x) is carried out in each coupling cycle. In some embodiments of the method of the invention, each of the building blocks B-1, B-2, and B-x is a compound of the following Formula II-1-b:
(Formula II-1-b), wherein in Formula II-1-b: q, PG, Y 2 , Z 2 , R z-2 , Z 3 , R z-3 , R a , and R b are defined as for Formula II-1, B N , R XI , R XII , R XIII , R XIV , and R XV are defined as for Formula II-b, and wherein step (f-1) or (f-2) or (f-x) is carried out in each coupling cycle. In some embodiments of the method of the invention, each of the building blocks B-1, B-2, and B-x is a compound of the following Formula II-2:
(Formula II-2), wherein in Formula II-2: each oxygen atom (O) depicted within each nucleoside subunit y-0 to y-q represents the oxygen atom of a hydroxyl moiety of the respective nucleoside subunit; each nucleoside subunit y-0 to y-q may be the same or different (i.e. have the same or a different chemical structure); PG is the protecting group PG-1 (for building block B-1) or PG-2 (for building block B-2) or PG-x (for a building block B-x) and is a protecting group removable under acidic conditions; q is an integer equal to or larger than 0; Y 2 is selected independently for each repetitive unit q from the group consisting of O and S; Z 2 is selected independently for each repetitive unit q from the group consisting of H, O-R z-2 , and S-R z-2 ; and R z-2 is a protecting group, which may be the same or different for each repetitive unit q; and wherein at least in the final coupling cycle, step (f-1) or (f-2) or (f-x) is carried out. In some embodiments of the method of the invention, each of the building blocks B-1, B-2, and B-x is a compound of the following Formula II-2-a: (Formula II-2-a), wherein in Formula II-2-a: q, PG, Y 2 , Z 2 , and R z-2 are defined as for Formula II-2; B N , R XI , R XII , R XIII , R XIV , and R XV are defined as for Formula II-a; and wherein at least in the final coupling cycle, step (f-1) or (f-2) or (f-x) is carried out. In some embodiments of the method of the invention, each of the building blocks B-1, B-2, and B-x is a compound of the following Formula II-2-b:
(Formula II-2-b), wherein in Formula II-2-b: q, PG, Y 2 , Z 2 , and R z-2 are defined as for Formula II-2; B N , R XI , R XII , R XIII , R XIV , and R XV are defined as for Formula II-b, and wherein at least in the final coupling cycle, step (f-1) or (f-2) or (f-x) is carried out. In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, II-b, II-1, II-1-a, II-1-b, II-2, II-2-a, and II-2-b, the integer q is an integer in the range of 0−50, 0−35, 0−30, 0−25, 0−20, 0−15, 0−10, 0−5, 0−3, 0−2, 0−1 or q is 0. In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, II-b, II-1, II-1-a, II-1-b, II-2, II-2-a, and II-2-b, the integer q is 0. It will be understood that, if the integer q in any one of Formulae II, II-a, II-b, II-1, II-1-a, II-1-b, II-2, II-2-a, and II-2-b is 0, the protecting group PG is bonded to the respective hydroxyl moiety of the then remaining nucleoside subunit carrying the phosphorus moiety (e.g. nucleoside subunit y-0 in Formulae II, II-1 or II-2). In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, II-b, II-1, II-1-a, II-1-b, II-2, II-2-a, and II-2-b, the protecting group PG is a protecting group comprising an optionally substituted triarylmethyl residue. In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, II-b, II-1, II-1-a, II-1-b, II-2, II-2-a, and II-2-b, the protecting group PG is selected from the group consisting of the triphenylmethyl group (i.e. the trityl group), the (p-methylphenyl)diphenylmethyl group (i.e. the 4-methyltrityl group), the di(p-methylphenyl)phenylmethyl group (i.e. the 4,4'-dimethyltrityl group), the tri(p-methylphenyl)methyl group (i.e. the 4,4',4"-trimethyltrityl group), the (p-methoxyphenyl)diphenylmethyl group (i.e. the MMT group), and the di(p-methoxyphenyl)phenylmethyl group (i.e. the DMT group). In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, II-b, II-1, II-1-a, II-1-b, II-2, II-2-a, and II-2-b, the protecting group PG is selected from the group consisting of the triphenylmethyl group, the (p-methoxyphenyl)diphenylmethyl group, and the di(p-methoxyphenyl)phenylmethyl group. In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, II-b, II-1, II-1-a, II-1-b, II-2, II- 2-a, and II-2-b, the protecting group PG is the di(p-methoxyphenyl)phenylmethyl group. In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, II-b, II-1, II-1-a, II-1-b, II-2, II-2-a, and II-2-b, Y 2 is at each occurrence O. In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, II-b, II-1, II-1-a, II-1-b, II-2, II-2-a, and II-2-b, Y 2 is at each occurrence S. In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, II-b, II-1, II-1-a, II-1-b, II-2, II-2-a, and II-2-b, R z-2 is a protecting group removable under alkaline conditions, wherein R z-2 may be the same or different at each occurrence. The term “removable under alkaline conditions” has been explained above. In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, II-b, II-1, II-1-a, II-1-b, II-2, II-2-a, and II-2-b, R z-2 is for each repetitive unit q independently a protecting group of the chemical structure CH2-CH2-EWG, where EWG is an electron withdrawing group, preferably a cyano group. The electron withdrawing group may for example be selected from the group consisting of a cyano group, a halogen atom such as a chlorine, fluorine, or bromine atom, a formyl group, a keto group, a carboxyester group, or a carboxamide group. In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, II-b, II-1, II-1-a, II-1-b, II-2, II-2-a, and II-2-b, R z-2 is for each repetitive unit q a 2-cyanoethyl group (i.e. CH2-CH2-CN). In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, II-b, II-1, II-1-a, II-1-b, II-2, II-2-a, and II-2-b, Z 2 is selected independently for each repetitive unit q from the group consisting of O-R z-2 and S-R z-2 . In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, II-b, II-1, II-1-a, II-1-b, II-2, II-2-a, and II-2-b, Z 2 is selected independently for each repetitive unit q from the group consisting of O-R z-2 and S-R z-2 , where R z-2 is for each repetitive unit q a 2-cyanoethyl group (i.e. CH-CH -CN). In such embodiments 2 2 2 , Z is selected independently for each repetitive unit q from the group consisting of O-CH2-CH2-CN and S-CH2-CH2-CN. In some embodiments, in the building block B- 1 or B-2 or B-x of any one of Formulae II, II-a, II-b, II-1, II-1-a, II-1-b, II-2, II-2-a, and II-2-b, Z 2 is for each repetitive unit q O-R z-2 , where R z-2 is for each repetitive unit q a 2-cyanoethyl group (i.e. CH 2 -CH 2 -CN). In such embodiments, Z 2 is for each repetitive unit q O-CH 2 -CH 2 -CN. In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, II-b, II-2, II-2-a, and II-2-b, Z 2 is for each repetitive unit q H. In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II, II-a, II-b, II-2, II-2-a, and II-2-b, Y 2 is for each repetitive unit q O and Z 2 is for each repetitive unit q H. The skilled person will understand that any kind of nucleobase B N may be present in a building block B-1 or B-2 or B-x of any one of Formulae II-a, II-b, II-1-a, II-1-b, II-2-a, and II-2-b. In some embodiments, in the building block B-1 or B-2 or B-x of any one of Formulae II-a, II-b, II-1-a, II-1-b, II-2-a, and II-2-b, B N is a nucleobase and at each occurrence independently selected from the group consisting of adenine, guanine, cytosine, 5-methylcytosine, thymine, and uracil. It will be understood by those skilled in the art, that any nucleobase B N in any one of Formulae II-a, II-b, II-1- a, II-1-b, II-2-a, and II-2-b may optionally be protected, i.e. carry one or more protecting groups, without this being indicated specifically. Thus, when, for example, stating that B N is adenine, guanine, 5-methylcytosine, cytosine, thymine, or uracil, this embraces the aforementioned nucleobases in protected form and in free form (i.e. with and without any protecting groups). Nucleobase protecting groups are known to those skilled in the art and have also been explained above, including, for example, the preferred nucleobase protecting groups compiled in Table T-1. In some embodiments, each nucleobase of each building block B-1, B-2 and B-x, in particular each nucleobase B N of each building block B-1, B-2 and B-x of any one of Formulae II-a, II-b, II-1-a, II-1-b, II-2-a, and II-2-b, is independently selected from the group consisting of - adenine, in which the exocyclic amino group is protected; - guanine, in which the exocyclic amino group is protected; - cytosine, in which the exocyclic amino group is protected; - 5-methylcytosine, in which the exocyclic amino group is protected; - thymine; and - uracil. In some embodiments, each nucleobase of each building block B-1, B-2 and B-x, in particular each nucleobase B N of each building block B-1, B-2 and B-x of any one of Formulae II-a, II-b, II-1-a, II-1-b, II-2-a, and II-2-b, is independently selected from the group consisting of - adenine, in which the exocyclic amino group is protected by a benzoyl group, an isobutyryl group or a phenoxyacetyl group; - guanine, in which the exocyclic amino group is protected by an isobutyryl group, a 4-isopropylphenoxyacetyl group or a dimethylformamidino group; - cytosine, in which the exocyclic amino group is protected by an acetyl group or a benzoyl group; - 5-methylcytosine, in which the exocyclic amino group is protected by an acetyl group or a benzoyl group; - thymine; and - uracil. In some embodiments, in each building block B-1, B-2, and B-x of any one of Formulae II-a, II-b, II-1-a, II-1-b, II-2-a, and II-2-b: R XI is at each occurrence independently selected from the group consisting of H, F, O-(C1−C5-alkyl), O-(C1−C5-alkyl)-O-(C1−C5-alkyl), O-Si(C1−C5-alkyl)3, and O-CH2-O-Si(C1−C5-alkyl)3; R XIII is independently at each occurrence H or R XIII and R XI of the same nucleoside subunit (i.e. bonded to the 4´- and 2´-C atom of the same carbohydrate moiety) together form a structure +–CH 2 -O−++, +–CH(CH 3 )-O−++, or +–CH 2 -CH 2 -O−++, where + is the point of attachment to the 4´-carbon atom (i.e. the carbon atom to which R XIII is bonded) and ++ is the point of attachment to the 2´-carbon (i.e. the carbon atom to which R XI is bonded); and for each nucleoside subunit independently, R XII , R XIV , and R XV are either all H or they are bonded together so that the respective nucleoside subunit has a structure of the aforementioned Formula II-a-tc (in a building block B-1 or B-2 or B-x of any one of Formulae II-a, II-1-a, and II-2-a) or Formula II-b-tc (in a building block B-1 or B-2 or B-x of any one of Formula II-b, II-1-b, and II-2-b). In some embodiments, in each building block B-1, B-2, and B-x of any one of Formulae II-a, II-b, II-1-a, II-1-b, II-2-a, and II-2-b: R XI is at each occurrence independently selected from the group consisting of H, F, O-CH3 (i.e. methoxy), O-CH2-CH2-O-CH3 (i.e. 2-methoxyethyl-1-oxy), O-Si(CH3)3 (i.e. trimethylsilyloxy), O-Si(CH3)2(C(CH3)3) (i.e. tert- butyl(dimethyl)silyloxy), and O-CH2-O-Si(C(CH3)3)3 (i.e. ((triisopropylsilyl)oxy)- methyloxy); R XIII is independently at each occurrence H or R XIII and R XI of the same nucleoside subunit (i.e. bonded to the 4´- and 2´-C atom of the same carbohydrate moiety) together form a structure +–CH 2 -O−++, +–CH(CH 3 )-O−++, or +–CH 2 -CH 2 -O−++, where + is the point of attachment to the 4´-carbon atom (i.e. the carbon atom to which R XIII is bonded) and ++ is the point of attachment to the 2´-carbon (i.e. the carbon atom to which R XI is bonded); and for each nucleoside subunit independently, R XII , R XIV , and R XV are either all H or they are bonded together so that the respective nucleoside subunit has a structure of the aforementioned Formula II-a-tc (in a building block B-1 or B-2 or B-x of any one of Formulae II-a, II-1-a, and II-2-a) or Formula II-b-tc (in a building block B-1 or B-2 or B-x of any one of Formula II-b, II-1-b, and II-2-b). In some embodiments, in each building block B-1, B-2, and B-x of any one of Formulae II-a, II-b, II-1-a, II-1-b, II-2-a, and II-2-b: R XI is selected independently at each occurrence from the group consisting of H, F, O-CH3 (i.e. methoxy), and O-CH2-CH2-O-CH3 (i.e.2-methoxyethyl-1-oxy); and each of R XII , R XIII , R XIV , and R XV is H at each occurrence. In some embodiments, in each building block B-1, B-2, and B-x of any one of Formulae II-1, II-1-a, and II-1-b, Z 3 is O. In some embodiments, in each building block B-1, B-2, and B-x of any one of Formulae II-1, II-1-a, and II-1-b, Z 3 is S. In some embodiments, in each building block B-1, B-2, and B-x of any one of Formulae II-1, II-1-a, and II-1-b, R z-3 is a protecting group removable under alkaline conditions. The term “removable under alkaline conditions” has been explained above. In some embodiments, in each building block B-1, B-2, and B-x of any one of Formulae II-1, II-1-a, and II-1-b, R z-3 is a protecting group of the chemical structure CH 2 -CH 2 -EWG, where EWG is an electron withdrawing group, preferably a cyano group. The electron withdrawing group may for example be selected from the group consisting of a cyano group, a halogen atom such as a chlorine, fluorine, or bromine atom, a formyl group, a keto group, a carboxyester group, or a carboxamide group. In some preferred embodiments, in each building block B-1, B-2, and B-x of any one of Formulae II-1, II-1-a, and II-1-b, R z-3 is a 2-cyanoethyl group (i.e. CH2-CH2-CN). In some embodiments, in each building block B-1, B-2, and B-x of any one of Formulae II-1, II-1-a, and II-1-b, each of R a and R b is a C1–C6-alkyl group, wherein R a and R b may be the same or different, and wherein R a and R b may not bond to each other. In some embodiments, in each building block B-1, B-2, and B-x of any one of Formulae II-1, II-1-a, and II-1-b, each of R a and R b is an isopropyl group (i.e. CH(CH 3 ) 2 ). In some embodiments, in each building block B-1, B-2, and B-x of Formula II: PM is a phosphorus moiety, preferably a phosphorus moiety selected from the group consisting of a phosphoramidite moiety and a H-phosphonate monoester moiety; PG is the protecting group PG-1 (for building block B-1) or PG-2 (for building block B-2) or PG-x (for a building block B-x) and is a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; q is an integer in the range of 0−50, 0−35, 0−30, 0−25, 0−20, 0−15, 0−10, or 0−5, or q is 0; Y 2 is selected independently for each repetitive unit q from the group consisting of O and S; Z 2 is selected independently for each repetitive unit q from the group consisting of O-R z-2 , S-R z-2 , and H; and R z-2 is at each occurrence a 2-cyanoethyl group. In some embodiments, in each building block B-1, B-2, and B-x of Formula II: PM is a phosphoramidite moiety; PG is the protecting group PG-1 (for building block B-1) or PG-2 (for building block B-2) or PG-x (for a building block B-x) and is a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; q is an integer in the range of 0−50, 0−35, 0−30, 0−25, 0−20, 0−15, 0−10, or 0−5, or q is 0; Y 2 is selected independently for each repetitive unit q from the group consisting of O and S; Z 2 is selected independently for each repetitive unit q from the group consisting of O-R z-2 and S-R z-2 ; and R z-2 is at each occurrence a 2-cyanoethyl group. In some embodiments, in each building block B-1, B-2, and B-x of Formula II: PM is a phosphoramidite moiety; PG is the protecting group PG-1 (for building block B-1) or PG-2 (for building block B-2) or PG-x (for a building block B-x) and is a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; q is an integer in the range of 0−50, 0−35, 0−30, 0−25, 0−20, 0−15, 0−10, or 0−5, or q is 0; Y 2 is selected independently for each repetitive unit q from the group consisting of O and S; Z 2 is for each repetitive unit q O-R z-2 ; and R z-2 is at each occurrence a 2-cyanoethyl group. In some embodiments, in each building block B-1, B-2, and B-x of Formula II: PM is a H-phosphonate monoester moiety; PG is the protecting group PG-1 (for building block B-1) or PG-2 (for building block B-2) or PG-x (for a building block B-x) and is a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; q is an integer in the range of 0−50, 0−35, 0−30, 0−25, 0−20, 0−15, 0−10, or 0−5, or q is 0; Y 2 is selected independently for each repetitive unit q from the group consisting of O and S, and preferably is O; and Z 2 is for each repetitive unit q H. In some embodiments, in each building block B-1, B-2, and B-x of any one of Formulae II-a and II-b: PM is a phosphorus moiety, preferably a phosphorus moiety selected from the group consisting of a phosphoramidite moiety and a H-phosphonate monoester moiety; PG is the protecting group PG-1 (for building block B-1) or PG-2 (for building block B-2) or PG-x (for a building block B-x) and is a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; q is an integer in the range of 0−50, 0−35, 0−30, 0−25, 0−20, 0−15, 0−10, or 0−5, or q is 0; Y 2 is selected independently for each repetitive unit q from the group consisting of O and S; Z 2 is selected independently for each repetitive unit q from the group consisting of O-R z-2 , S-R z-2 , and H; R z-2 is at each occurrence a 2-cyanoethyl group; R XI is at each occurrence independently selected from the group consisting of H, F, O-(C1−C5-alkyl), O-(C1−C5-alkyl)-O-(C1-C5-alkyl), O-Si(C1−C5-alkyl)3, and O-CH2-O-Si(C1−C5-alkyl)3; R XIII is independently at each occurrence H or R XIII and R XI of the same nucleoside subunit (i.e. bonded to the 4´- and 2´-C atom of the same carbohydrate moiety) together form a structure +–CH 2 -O−++, +–CH(CH 3 )-O−++, or +–CH 2 -CH 2 -O−++, where + is the point of attachment to the 4´-carbon atom (i.e. the carbon atom to which R XIII is bonded) and ++ is the point of attachment to the 2´-carbon (i.e. the carbon atom to which R XI is bonded); and for each nucleoside subunit independently, R XII , R XIV , and R XV are either all H or they are bonded together so that the respective nucleoside subunit has a structure of the aforementioned Formula II-a-tc (in a building block B-1, B-2 or B-x of Formula II-a) or Formula II-b-tc (in a building block B-1, B-2 or B-x of Formula II-b). In some embodiments, in each building block B-1, B-2, and B-x of any one of Formulae II-a and II-b: PM is a phosphorus moiety, preferably a phosphorus moiety selected from the group consisting of a phosphoramidite moiety and a H-phosphonate monoester moiety; PG is the protecting group PG-1 (for building block B-1) or PG-2 (for building block B-2) or PG-x (for a building block B-x) and is a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; q is an integer in the range of 0−50, 0−35, 0−30, 0−25, 0−20, 0−15, 0−10, or 0−5, or q is 0; Y 2 is selected independently for each repetitive unit q from the group consisting of O and S; Z 2 is selected independently for each repetitive unit q from the group consisting of O-R z-2 , S-R z-2 , and H; R z-2 is at each occurrence a 2-cyanoethyl group; R XI is at each occurrence independently selected from the group consisting of H, F, O-CH3 (i.e. methoxy), O-CH2-CH2-O-CH3 (i.e. 2-methoxyethyl-1-oxy), O-Si(CH3)3 (i.e. trimethylsilyloxy) , O-Si(CH 3 ) 2 (C(CH 3 ) 3 ) (i.e. tert-butyl(dimethyl)silyloxy), and O- CH 2 -O-Si(C(CH 3 ) 3 ) 3 (i.e. ((triisopropylsilyl)oxy)-methyloxy); R XIII is independently at each occurrence H or R XIII and R XI of the same nucleoside subunit (i.e. bonded to the 4´- and 2´-C atom of the same carbohydrate moiety) together form a structure +–CH2-O−++, +–CH(CH3)-O−++, or +–CH2-CH2-O−++, where + is the point of attachment to the 4´-carbon atom (i.e. the carbon atom to which R XIII is bonded) and ++ is the point of attachment to the 2´-carbon (i.e. the carbon atom to which R XI is bonded); and for each nucleoside subunit independently, R XII , R XIV , and R XV are either all H or they are bonded together so that the respective nucleoside subunit has a structure of the aforementioned Formula II-a-tc (in a building block B-1, B-2 or B-x of Formula II-a) or Formula II-b-tc (in a building block B-1, B-2 or B-x of Formula II-b). In some embodiments, in each building block B-1, B-2, and B-x of any one of Formulae II-a and II-b: PM is a phosphoramidite moiety; PG is the protecting group PG-1 (for building block B-1) or PG-2 (for building block B-2) or PG-x (for a building block B-x) and is a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; q is an integer in the range of 0−50, 0−35, 0−30, 0−25, 0−20, 0−15, 0−10, or 0−5, or q is 0; Y 2 is selected independently for each repetitive unit q from the group consisting of O and S; Z 2 is for each repetitive unit q O-R z-2 ; R z-2 is at each occurrence a 2-cyanoethyl group; R XI is selected independently at each occurrence from the group consisting of H, F, O-CH3 (i.e. methoxy), and O-CH2-CH2-O-CH3 (i.e.2-methoxyethyl-1-oxy); and each of R XII , R XIII , R XIV , and R XV is H at each occurrence. In some embodiments, in each building block B-1, B-2, and B-x of Formula II-1: PG is the protecting group PG-1 (for building block B-1) or PG-2 (for building block B-2) or PG-x (for a building block B-x) and is a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; q is an integer in the range of 0−50, 0−35, 0−30, 0−25, 0−20, 0−15, 0−10, or 0−5, or q is 0; Y 2 is selected independently for each repetitive unit q from the group consisting of O and S; Z 2 is selected independently for each repetitive unit q from the group consisting of O-R z-2 and S-R z-2 , and Z 2 preferably is for each repetitive unit q O-R z-2 ; R z-2 is at each occurrence a 2-cyanoethyl group; Z 3 is selected from the group consisting of O and S, and preferably is O; R z-3 is a 2-cyanoethyl group; and each of R a and R b is a C1−C6-alkyl group, preferably an isopropyl group. In some embodiments, in each building block B-1, B-2, and B-x of Formula II-1: PG is the protecting group PG-1 (for building block B-1) or PG-2 (for building block B-2) or PG-x (for a building block B-x) and is a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; q is an integer in the range of 0−50, 0−35, 0−30, 0−25, 0−20, 0−15, 0−10, or 0−5, or q is 0; Y 2 is selected independently for each repetitive unit q from the group consisting of O and S; Z 2 is for each repetitive unit q O-R z-2 ; R z-2 is at each occurrence a 2-cyanoethyl group; Z 3 is O; R z-3 is a 2-cyanoethyl group; and each of R a and R b is an isopropyl group. In some embodiments, in each building block B-1, B-2, and B-x of any one of Formula II-1-a and II-1-b: PG is the protecting group PG-1 (for building block B-1) or PG-2 (for building block B-2) or PG-x (for a building block B-x) and is a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; q is an integer in the range of 0−50, 0−35, 0−30, 0−25, 0−20, 0−15, 0−10, or 0−5, or q is 0; Y 2 is selected independently for each repetitive unit q from the group consisting of O and S; Z 2 is selected independently for each repetitive unit q from the group consisting of O-R z-2 and S-R z-2 , and Z 2 preferably is for each repetitive unit q O-R z-2 ; R z-2 is at each occurrence a 2-cyanoethyl group; Z 3 is selected from the group consisting of O and S, and preferably is O; R z-3 is a 2-cyanoethyl group; each of R a and R b is a C1−C6-alkyl group, preferably an isopropyl group; R XI is at each occurrence independently selected from the group consisting of H, F, O-(C 1 −C 5 -alkyl), O-(C 1 −C 5 -alkyl)-O-(C 1 −C 5 -alkyl), O-Si(C 1 −C 5 -alkyl) 3 , and O-CH2-O-Si(C1−C5-alkyl)3; R XIII is independently at each occurrence H or R XIII and R XI of the same nucleoside subunit (i.e. bonded to the 4´- and 2´-C atom of the same carbohydrate moiety) together form a structure +–CH2-O−++, +–CH(CH3)-O−++, or +–CH2-CH2-O−++, where + is the point of attachment to the 4´-carbon atom (i.e. the carbon atom to which R XIII is bonded) and ++ is the point of attachment to the 2´-carbon (i.e. the carbon atom to which R XI is bonded); and for each nucleoside subunit independently, R XII , R XIV , and R XV are either all H or they are bonded together so that the respective nucleoside subunit has a structure of the aforementioned Formula II-a-tc (in a building block B-1, B-2 or B-x of Formula II-1-a) or Formula II-b-tc (in a building block B-1, B-2 or B-x of Formula II-1-b). In some embodiments, in each building block B-1, B-2, and B-x of any one of Formula II-1-a and II-1-b: PG is the protecting group PG-1 (for building block B-1) or PG-2 (for building block B-2) or PG-x (for a building block B-x) and is a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; q is an integer in the range of 0−50, 0−35, 0−30, 0−25, 0−20, 0−15, 0−10, or 0−5, or q is 0; Y 2 is selected independently for each repetitive unit q from the group consisting of O and S; Z 2 is selected independently for each repetitive unit q from the group consisting of O-R z-2 and S-R z-2 , and Z 2 preferably is for each repetitive unit q O-R z-2 ; R z-2 is at each occurrence a 2-cyanoethyl group; Z 3 is selected from the group consisting of O and S and preferably is O; R z-3 is a 2-cyanoethyl group; each of R a and R b is a C1−C6-alkyl group, preferably an isopropyl group; R XI is at each occurrence independently selected from the group consisting of H, F, O-CH 3 (i.e. methoxy), O-CH 2 -CH 2 -O-CH 3 (i.e. 2-methoxyethyl-1-oxy), O-Si(CH 3 ) 3 (i.e. trimethylsilyloxy) , O-Si(CH 3 ) 2 (C(CH 3 ) 3 ) (i.e. tert-butyl(dimethyl)silyloxy), and O- CH 2 -O-Si(C(CH 3 ) 3 ) 3 (i.e. ((triisopropylsilyl)oxy)-methyloxy); R XIII is independently at each occurrence H or R XIII and R XI of the same nucleoside subunit (i.e. bonded to the 4´- and 2´-C atom of the same carbohydrate moiety) together form a structure +–CH2-O−++, +–CH(CH3)-O−++, or +–CH2-CH2-O−++, where + is the point of attachment to the 4´-carbon atom (i.e. the carbon atom to which R XIII is bonded) and ++ is the point of attachment to the 2´-carbon (i.e. the carbon atom to which R XI is bonded); and for each nucleoside subunit independently, R XII , R XIV , and R XV are either all H or they are bonded together so that the respective nucleoside subunit has a structure of the aforementioned Formula II-a-tc (in a block B-1, B-2 or B-x of Formula II-1-a) or Formula II-b-tc (in a B-1, B-2 or B-x of Formula II-1-b). In some embodiments, in each building block B-1, B-2, and B-x of any one of Formula II-1-a and II-1-b: PG is the protecting group PG-1 (for building block B-1) or PG-2 (for building block B-2) or PG-x (for a building block B-x) and is a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; q is an integer in the range of 0−50, 0−35, 0−30, 0−25, 0−20, 0−15, 0−10, or 0−5, or q is 0; B N is a nucleobase, which may be the same or different at each occurrence; Y 2 is selected independently for each repetitive unit q from the group consisting of O and S; Z 2 is selected independently for each repetitive unit q from the group consisting of O-R z-2 and S-R z-2 , and Z 2 preferably is for each repetitive unit q O-R z-2 ; R z-2 is at each occurrence a 2-cyanoethyl group; Z 3 is selected from the group consisting of O and S and preferably is O; R z-3 is a 2-cyanoethyl group; each of R a and R b is a C1−C6-alkyl group, preferably an isopropyl group; R XI is selected independently at each occurrence from the group consisting of H, F, O-CH3 (i.e. methoxy), and O-CH2-CH2-O-CH3 (i.e.2-methoxyethyl-1-oxy); and each of R XII , R XIII , R XIV , and R XV is H at each occurrence. In some embodiments, in each building block B-1, B-2, and B-x of Formula II-2: PG is the protecting group PG-1 (for building block B-1) or PG-2 (for building block B-2) or PG-x (for a building block B-x) and is a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; q is an integer in the range of 0−50, 0−35, 0−30, 0−25, 0−20, 0−15, 0−10, or 0−5, or q is 0; Y 2 is selected independently for each repetitive unit q from the group consisting of O and S, and preferably is O; and Z 2 is for each repetitive unit q H. In some embodiments, in each building block B-1, B-2, and B-x of any one of Formulae II-2-a and II-2-b: PG is the protecting group PG-1 (for building block B-1) or PG-2 (for building block B-2) or PG-x (for a building block B-x) and is a di(p-methoxyphenyl)phenylmethyl (DMT) protecting group; q is an integer in the range of 0−50, 0−35, 0−30, 0−25, 0−20, 0−15, 0−10, or 0−5, or q is 0; Y 2 is selected independently for each repetitive unit q from the group consisting of O and S, and preferably is O; Z 2 is for each repetitive unit q H; R XI is at each occurrence independently selected from the group consisting of H, F, O-CH 3 (i.e. methoxy), O-CH 2 -CH 2 -O-CH 3 (i.e. 2-methoxyethyl-1-oxy), O-Si(CH 3 ) 3 (i.e. trimethylsilyloxy) , O-Si(CH 3 ) 2 (C(CH 3 ) 3 ) (i.e. tert-butyl(dimethyl)silyloxy), and O- CH 2 -O-Si(C(CH 3 ) 3 ) 3 (i.e. ((triisopropylsilyl)oxy)-methyloxy); R XIII is independently at each occurrence H or R XIII and R XI of the same nucleoside subunit (i.e. bonded to the 4´- and 2´-C atom of the same carbohydrate moiety) together form a structure +–CH 2 -O−++, +–CH(CH 3 )-O−++, or +–CH 2 -CH 2 -O−++, where + is the point of attachment to the 4´-carbon atom (i.e. the carbon atom to which R XIII is bonded) and ++ is the point of attachment to the 2´-carbon (i.e. the carbon atom to which R XI is bonded); and for each nucleoside subunit independently, R XII , R XIV , and R XV are either all H or they are bonded together so that the respective nucleoside subunit has a structure of the aforementioned Formula II-a-tc (in a building block B-1, B-2 or B-x of Formula II-2- a) or Formula II-b-tc (in a building block B-1, B-2 or B-x of Formula II-2-b). In the method of the invention, the building block B-x may be the same or different (i.e. have the same or a different chemical structure) for each coupling cycle comprising steps (b-x) to (h-x) (as far as present), unless indicated differently in the context of specific embodiments. A building block B-1, B-2 or B-x for use in the method of the invention may, for example, be obtained commercially, in particular, if said phosphorus moiety is a phosphoramidite moiety or a H-phosphonate monoester moiety. Alternatively, a building block B-1, B-2 or B-x for use in the method of the invention may be obtained by means of chemical synthesis. The person skilled in the art is aware of methods of synthesizing such compounds, wherein the synthesis route will obviously depend on the chemical structure of said phosphorus moiety. Building blocks B-1, B-2 or B-x, e.g. of any one of Formulae II, II-a, and II-b, in which said phosphorus moiety, e.g. said phosphorus moiety PM, is a phosphoramidite moiety, in particular building blocks B-1, B-2 or B-x of any one of Formulae II-1, II-1-a, and II-1-b, may, for example, be synthesized as disclosed in, in K.V. Gothelf et al., Nature Communications 2021, 12, 2760, and in X. Wei et al., Tetrahedron 2013, 69, 3615−3637. Building blocks B-1, B-2 or B-x, e.g. of any one of Formulae II, II-a, and II-b, in which said phosphorus moiety, e.g. said phosphorus moiety PM, is a H-phosphonate monoester moiety, in particular building blocks B-1, B-2 or B-x of any one of Formulae II-2, II-2-a, and II-2-b, may, for example, be synthesized as disclosed in J. Stawinski and R. Strömberg (2005), Di- and Oligonucleotide Synthesis Using H-Phosphonate Chemistry, in Methods in Molecular Biology, vol. 288: Oligonucleotide Synthesis: Methods and Applications, edited by P. Herdewijn, Humana Press Inc., Totowa NJ, https://doi.org/10.1385/1-59259-823-4:081. Building blocks B-1, B-2 or B-x, e.g. of any one of Formulae II, II-a, and II-b, in which said phosphorus moiety, e.g. said phosphorus moiety PM, is a P (V) moiety suitable for chiral phosphorothioate synthesis may, for example, be synthesized as disclosed in P.S. Baran et al., Science 2018, 361, 1234−1238 (also see Supplementary Materials for this reference). The term “reacting” in step (e-1) may be understood in the broadest sense as any operation during which the component (C-0) # and the building block B-1 are present in the same reaction vessel or reactor and engage in the bond forming reaction of step (e-1). The term “reacting” in step (e-2) may be understood in the broadest sense as any operation during which the first cycle oligonucleotide (O-1) # and the building block B-2 are present in the same reaction vessel or reactor and engage in the bond forming reaction of step (e-2). The term “reacting” in step (e-x) may be understood in the broadest sense as any operation during which the (x−1)-th cycle oligonucleotide (O-(x−1)) # and the building block B-x are present in the same reaction vessel or reactor and engage in the bond forming reaction of step (e-x). Typically, the component (C-0) # , the first cycle oligonucleotide (O-1) # or the (x−1)-th cycle oligonucleotide (O-(x−1)) # may already be contained in a reaction vessel or reactor, to which the building block B-1, B-2 or B-x is then added. Alternatively, the building block B-1, B-2 or B-x or a solution thereof may already be contained in a reaction vessel or reactor, to which the component (C-0) # , the first cycle oligonucleotide (O-1) # or the (x−1)-th cycle oligonucleotide (O-(x−1)) # is then added. During each of steps (e-1), (e-2), and (e-x), a covalent (chemical) bond is formed between said free backbone hydroxyl group of the component (C-0) # , the first cycle oligonucleotide (O-1) # or the (x−1)-th cycle oligonucleotide (O-(x−1)) # and the phosphorus atom of said phosphorus moiety of the building block B-1, B-2 or B-x. The bond forming reaction of steps (e-1), (e-2), and (e-x) is herein also referred to as coupling or coupling reaction or condensation or condensation reaction, and steps (e-1), (e-2), and (e-x) are also referred to as coupling steps or condensation steps. The product obtained from the bond forming reaction of step (e-1) is the first cycle oligonucleotide O-1, which comprises the nucleoside sequence of the component (C-0) # and of the building block B-1, wherein these two are now interconnected by an internucleosidic linkage group derived from the phosphorus moiety of the building block B-1. The product obtained from the bond forming reaction of step (e-2) is the second cycle oligonucleotide O-2, which comprises the nucleoside sequence of the first cycle oligonucleotide (O-1) # and of the building block B-2, wherein these two are now interconnected by an internucleosidic linkage group derived from the phosphorus moiety of the building block B-2. The product obtained from the bond forming reaction of step (e-x) is the x-th cycle oligonucleotide O-x, which comprises the nucleoside sequence of the (x−1)-th cycle oligonucleotide (O-(x−1)) # and of the building block B-x, wherein these two are now interconnected by an internucleosidic linkage group derived from the phosphorus moiety of the building block B-x. The “conditions suitable” to form a covalent bond between said free backbone hydroxyl group of the component (C-0) # , the first cycle oligonucleotide (O-1) # or the (x−1)-th cycle oligonucleotide (O-(x−1)) # and the phosphorus atom of said phosphorus moiety of the building block B-1, B-2 or B-x form part of the common knowledge of those skilled in the art. These conditions may, for example, depend on the chemical structure of said phosphorus moiety which is to engage in the bond forming reaction. A bond forming reaction of step (e-1), (e-2) or (e-x), in which the phosphorus moiety engaging in said reaction is a phosphoramidite moiety, as e.g. present in building blocks B-1, B-2 or B-x of any one of Formulae II-1, II-1-a, and II-1-b, is herein also referred to as phosphoramidite coupling (reaction). Such phosphoramidite couplings may preferably be performed in the presence of an activator. Any activator used in oligonucleotide synthesis by the so-called phosphoramidite method may be used in the method of the invention. The activator may, for example, be selected from the group consisting of: - a tetrazole type activator such as 1H-tetrazole, 5-ethylthio-1H-tetrazole (ETT), 5-benzylthio-1H-tetrazole (BTT), 5-methylthio-1H-tetrazole (MTT), 1-methyl-5-mercaptotetrazole, 1-phenyl-5-mercaptotetrazole, and 5-(4-nitrophenyl)-1H-tetrazole, - an imidazole type activator such as 4,5-dicyanoimidazole (DCI) and 2-bromo- 4,5-dicyanoimidacole (2-Br-DCI), - a 1-hydroxybenzotriazole type activator such as 1-hydroxybenzotriazole, 1-hydroxy-6-trifluorobenzotriazole, and 1-hydroxy-6-trifluoro-4- nitrobenzotriazole, - a pyridinium salt type activator such as pyridinium hydrochloride, pyridinium p-toluenesulfonate, and pyridinium trifluoroacetate, and - a saccharin type activator, i.e. salts obtained from reacting saccharin with an organic base such as pyridine, collidine, lutidine, picoline, N-methylimidazole, and triethylamine. 5-Benzylthio-1H-tetrazole (BTT), 5-ethylthio-1H-tetrazole (ETT), 1H-tetrazole, and 4,5-dicyanoimidacole (DCI) may be preferred. N-methylimidazole (NMI) or pyridine may be added alongside the activator, which may help to adjust the acidity of the solution. For example, 1.0−100.0 mol, 1.0−50.0 mol, 1.0−40.0 mol, 1.0−30.0 mol, 1.0−20.0 mol, 1.0−15.0 mol, 1.0−10.0 mol, or 2.5−10.0 mol of the activator may be used per 1 mol of the building block B-1, B-2 or B-x engaging in the respective coupling reaction with its phosphoramidite moiety. As another example, NMI may be used alongside a protic acid, for example a carboxylic acid such as trifluoroacetic acid, without an additional activator. Acetonitrile may also be added. For example, a mixture of acetonitrile, NMI, and TFA (e.g. 7.5:2:2 v/v) may be added for the coupling reaction. In some preferred embodiments of the method of the invention, steps (e-1), (e-2), and (e-x) are carried out using a tetrazole-type activator, preferably ETT, most preferably in combination with a base, in particular pyridine. It will be understood that this does not imply that a step (e-2) and/or (e-x) must be performed. A bond forming reaction of step (e-1), (e-2) or (e-x), in which the phosphorus moiety engaging in said reaction is a H-phosphonate monoester moiety, as e.g. present in building blocks B-1, B-2 or B-x of any one of Formulae II-2, II-2-a, and II-2-b, is herein also referred to as H-phosphonate coupling (reaction). Such H-phosphonate couplings may typically be performed using a condensing agent. Any condensing agent used in oligonucleotide synthesis by the so-called H-phosphonate method may be used in the method of the invention. The condensing agent may, for example, be selected from the group consisting of pivaloyl chloride (PvCl), 1-adamantanecarbonyl chloride (AdCl), 2,2-dimethylbutyryl chloride, isobutyryl chloride, diphenyl chlorophosphate, 2,4,6-triisopropylbenzenesulfonyl chloride, bis(pentafluorophenyl) carbonate, 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinane 2-oxide (also referred to as 5,5-dimethyl-2-oxo-2-chloro-1,3,2-dioxaphosphinane, DMOCP), and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (OXP or BOP-Cl). The building block B-1, B-2 or B-x comprising said H-phosphonate monoester moiety may be pre-activated with (i.e. incubated with) said condensing agent, and then be combined with the component (C-0) # , the first cycle oligonucleotide (O-1) # or the (x−1)-th cycle oligonucleotide (O-(x−1)) # . Besides the condensing agent, a nucleophile such as pyridine may be added. For example, EP3378869A1 discloses suitable reaction conditions. A bond forming reaction of step (e-1), (e-2) or (e-x), in which the phosphorus moiety engaging in said reaction is an arylphosphate diester moiety, is herein also referred to as phosphotriester coupling (reaction). Briefly, the arylphosphate diester moieties may typically be activated with an arylsulfonyl chloride activator, such as mesitylene- 2-sulfonyl chloride (MsCl), usually in the presence of an auxiliary nucleophile such as 1-methylimidazole. Alternatively, pre-formed or in-situ generated 1-hydroxybenzotriazole-phosphotriesters may, for example, be used as phosphorus moiety instead of an aryl phosphate diester moiety in a phosphotriester coupling, again in the presence of an auxiliary nucleophile such as 1-methylimidazole. A bond forming reaction of step (e-1), (e-2) or (e-x), in which the phosphorus moiety engaging in said reaction is a P (V) moiety allowing for chiral phosphorothioate synthesis may, for example, be performed as disclosed in Baran et al.,Science 2018, 361, 1234−1238 (see also the Supplementary Materials of said publication) and ACS Central Science 2021, 7, 1473−1485), or in a similar fashion. Preferably, the solutions in which steps (e-1), (e-2), and (e-x) are carried out are substantially anhydrous, which may mean that they preferably comprise equal to or less than 2000 ppm, 1900 ppm, 1800 ppm, 1700 ppm, 1600 ppm, 1500 ppm, 1400 ppm, 1300 ppm, 1200 ppm, 1100 ppm, 1000 ppm, 900 ppm, 800 ppm, 700 ppm, 600 ppm, 500 ppm, 400 ppm, 300 ppm, 250 ppm, 200 ppm, 150 ppm, or 100 ppm of water. The water content may be determined by means of standard Karl Fischer titration at 25 °C, as known to those skilled in the art. The set up may, for example, be as follows: The titration cell may be filled with HYDRANAL TM -Coulomat Oil for anolyte reagent, and the inner burette may be filled with HYDRANAL TM - Coulomat CG for catholyte reagent. After pretitration for dehydration, sample (100 µL) may be added to the titration sell and the measurement may be started. In line with common practice, the water content of solutions is herein reported in parts per million (ppm). For example, 1.0−20.0 mol, 1.0−10.0 mol, 1.0−5.0 mol, 2.0−5.0 mol, or 2.0−4.0 mol of the building block B-1, B-2 or B-x may be used per mol of the component (C-0) # , the first cycle oligonucleotide (O-1) # or the (x−1)-th cycle oligonucleotide (O-(x−1)) # . Steps (e-1), (e-2), and (e-x) may, for example, be performed at a temperature in the range of 0−90 °C, 10−70 °C, 15−60 °C, 15−50 °C, or 20−50 °C. For convenience, steps (e-1), (e-2), and (e-x) may simply be performed at room temperature. Increased temperatures may result in shorter reaction times. The reaction time may also depend on the chemical structure of the reactants and will routinely be selected by a skilled person, for example based on reaction monitoring using, e.g., thin-layer chromatography and/or high performance liquid chromatography (HPLC), optionally coupled to mass spectrometry. If the internucleosidic linkage group formed in a bond forming reaction of a step (e-1), (e-2) or (e-x) is a P(III) linkage group as defined herein, e.g. a phosphite triester linkage group (as e.g. obtained from a phosphoramidite coupling), and supposed to be sulfurized (by incubation with a sulfurizing agent) to a P (V) linkage group, e.g. a phosphorothioate linkage group, in the subsequent step (f-1), (f-2) or (f-x), the respective step (e-1), (e-2) or (e-x) may be carried out in the presence of an antioxidant . Said antioxidant may suppress unwanted oxidation of a formed P(III) linkage group to a P (V) linkage group, which may not be amenable to sulfurization in the subsequent step. Examples of suitable antioxidants are, e.g., disclosed in EP3950698A1 and include inter alia triphenylphosphine, methyldiphenylphosphine, triethyl phosphite, ethoxydiphenylphosphine, diethoxyphenylphosphine, 9,10-dihydro-9-oxa-10-phosphaphenanthrene 10-oxide, and isobutylene sulfide. Alternatively, the solvents used may be controlled so that they contain no or a low level of oxidizing species. After the bond-forming reaction of step (e-1), (e-2) or (e-x) has been carried out, a quencher may optionally be added, wherein said quencher may be used to consume (i.e. react with) the phosphorus moiety of unreacted (excess) molecules of the building block B-1, B-2 or B-x employed. The quencher will typically be a nucleophilic compound capable of reacting with the phosphorus moiety. Water may, for example, be used as a quencher. Step (f-1) of the methods of the invention is: optionally, incubating the first cycle oligonucleotide O-1 with an oxidizing or sulfurizing agent, thereby converting any P (III) atoms within said first cycle oligonucleotide O-1 to P (V) atoms. Step (f-2) of some of the methods of the invention is: optionally, incubating the second cycle oligonucleotide O-2 with an oxidizing or sulfurizing agent, thereby converting any P (III) atoms within said second cycle oligonucleotide O-2 to P (V) atoms. Step (f-x) of some of the methods of the invention is: optionally, incubating the x-th cycle oligonucleotide O-x with an oxidizing or sulfurizing agent, thereby converting any P (III) atoms within said x-th cycle oligonucleotide O-x to P (V) atoms. The terms “P (III) atom” and “P (V) atom” have been defined above. As used throughout this text, the “oxidation state” may be “the charge of an atom after its homonuclear bonds have been divided equally and heteronuclear bonds assigned to the bond partners according to Allen electronegativity, except when the electronegative atom is bonded reversibly as a Lewis-acid ligand, in which case it does not obtain that bonds electrons”, as described in the IUPAC Recommendations 2016 (P. Karen et al., Pure and Applied Chemistry 2016, 88(8), 831−839). The Allen electronegativities given in said reference may be used and the P−H bond electron pair is assigned to H. As an example, the phosphorus atom of the H-phosphonate monoester moiety in any one of Formulae II-2, II-2-a, and II-2-b has the oxidation state III. As another example, the phosphorus atom of the phosphoramidite moiety in any one of Formulae II-1, II-1-a, and II-1-b has the oxidation state III. As a third example, the phosphorus atoms in the phosphodiester linkage groups of DNA and RNA have the oxidation state V. The term “optionally” in step (f-1), (f-2), and (f-x) denotes that the respective step may or may not be carried out in a given coupling cycle, unless indicated differently in the context of specific embodiments. As known to those skilled in the art, most or even all phosphorus atoms of an oligonucleotide may typically be comprised in the backbone of said oligonucleotide, usually in the internucleosidic linkage group(s). The terms “P (III) linkage group” and “P (V) linkage group” have been defined above. As also known to those skilled in the art, oligonucleotides comprising one or more P (III) linkage groups are typically less stable than related oligonucleotides comprising only P (V) linkage groups (as e.g. present in DNA and RNA). In some embodiments of the method of the invention, the target oligonucleotide O T comprises only P (V) linkage groups. If the first cycle oligonucleotide O-1 obtained in step (e-1) does not comprise any P (III) atoms, in particular not any P (III) linkage groups, it may not be necessary to carry out step (f-1). If the second cycle oligonucleotide O-2 obtained in step (e-2) does not comprise any P (III) atoms, in particular not any P (III) linkage groups, it may not be necessary to carry out step (f-2). If the x-th cycle oligonucleotide O-x obtained in step (e-x) of a coupling cycle does not comprise any P (III) atoms, in particular not any P (III) linkage groups, it may not be necessary to carry out step (f-x) in said coupling cycle. It is understood by those skilled in the art, that the oxidation state of the phosphorus atom within an internucleosidic linkage group formed in the bond forming reaction of a step (e-1), (e-2) or (e-x) will typically depend on the chemical structure of said phosphorus moiety of said building block B-1, B-2 or B-x, which engaged in the respective bond forming reaction. Typically, the oxidation state of the phosphorus atom within such a phosphorus moiety will be preserved in the course of the bond forming reaction of step (e-1), (e-2) or (e-x). For example, if a phosphotriester coupling as defined herein is carried out in a step (e-1), (e-2) or (e-x), the phosphorus atom of the resulting phosphotriester internucleosidic linkage group will typically be present as P (V) atom, i.e. the phosphotriester linkage group is a P (V) linkage group. The same principle applies, e.g., to the P (V) chemistry utilized by Baran et al. (Science 2018, 361, 1234−1238 and ACS Central Science 2021, 7, 1473−1485). On the other hand, if the phosphorus moiety of a component C-x engaging in a bond forming reaction of a step (e-1), (e-2) or (e-x) comprises a P (III) atom, the resulting internucleosidic linkage group will typically also comprise a P (III) atom, i.e. be a P (III) linkage group. For example, the bond forming reaction of a step (e-1), (e-2) or (e-x) may typically afford a phophite triester product (comprising a phosphite triester internucleosidic linkage group, i.e. a P (III) linkage group), if said phosphorus moiety covalently bonded via its phosphorus atom to an oxygen atom of the backbone of the building block B-1, B-2 or B-x, e.g. the phosphorus moiety PM of any one of Formulae II, II-a, and II-b, is a phosphoramidite moiety such as, e.g., present in any one of Formulae II-1, II-1-a, and II-1-b, while a H-phosphonate diester product (comprising a H-phosphonate diester internucleosidic linkage group, i.e. a P (III) linkage group) may typically be obtained, if said phosphorus moiety covalently bonded via its phosphorus atom to an oxygen atom of the backbone of the building block B-1, B-2 or B-x, e.g. the phosphorus moiety PM of any one of Formulae II, II-a, and II-b, is a H-phosphonate monoester moiety such as, e.g., present in any one of Formulae II-2, II-2-a, and II-2-b. H-phosphonate diester linkage groups may be more stable, e.g. under the conditions of steps (b-1), (b-2) or (b-x), than phosphite triester linkage groups, so that a step (f-1) or (f-2) or (f-x) may not need to be performed in each coupling cycle, in which said phosphorus moiety covalently bonded via its phosphorus atom to an oxygen atom of the backbone of the building block B-1, B-2 or B-x, e.g. the phosphorus moiety PM of any one of Formulae II, II-a, and II-b, is a H-phosphonate monoester moiety such as, e.g., present in any one of Formulae II-2, II-2-a, and II-2-b. However, at least in the final coupling cycle, step (f-1) or (f-2) or (f-x) may be carried out, so that any P (III) atoms are converted to P (V) atoms. In some embodiments of the method of the invention: - the phosphorus moiety of the building blocks B-1, B-2, and each building block B-x, e.g. the phosphorus moiety PM of any one of Formulae II, II, II-a, and II-b, is independently selected from the group consisting of a phosphoramidite moiety and a H-phosphonate monoester moiety; - in each coupling cycle, in which said phosphorus moiety of the building block B-1, B-2 or B-x is a phosphoramidite moiety, step (f-1) or (f-2) or (f-x) is carried out; and - at least in the final coupling cycle, step (f-1) or (f-2) or (f-x) is carried out. In some embodiments of the method of the invention: - the phosphorus moiety of the building blocks B-1, B-2, and each building block B-x, e.g. the phosphorus moiety PM of any one of Formulae II, II-a, and II-b, is a phosphoramidite moiety; and - in each coupling cycle, step (f-1) or (f-2) or (f-x) is carried out. In some embodiments of the method of the invention: - the phosphorus moiety of the building blocks B-1, B-2, and each building block B-x, e.g. the phosphorus moiety PM of any one of Formulae II, II-a, and II-b, is a H-phosphonate monoester moiety; and - at least in the final coupling cycle, step (f-1) or (f-2) or (f-x) is carried out. In some embodiments of the method of the invention: - each building block B-1, B-2, and B-x is independently a compound of any one of Formulae II-1 and II-2, preferably a compound of any one of Formulae II-1-a and II-2-a, in particular a compound of any one of Formulae II-1-b and II-2-b; - in each coupling cycle, in which the building block B-1, B-2 or B-x is a compound of any one of Formulae II-1, II-1-a, and II-1-b, step (f-1) or (f-2) or (f-x) is carried out; and - at least in the final coupling cycle, step (f-1) or (f-2) or (f-x) is carried out. In some embodiments of the method of the invention: - each building block B-1, B-2, and B-x is independently a compound of Formula II-1, preferably of Formula II-1-a, in particular of Formula II-1-b; and - in each coupling cycle, step (f-1) or (f-2) or (f-x) is carried out. In some embodiments of the method of the invention: - each building block B-1, B-2, and B-x is a compound of Formula II-2, preferably of Formula II-2-a, in particular of Formula II-2-b; and - at least in the final coupling cycle, step (f-1) or (f-2) or (f-x) is carried out. The “oxidizing agent” or the “sulfurizing agent” to be used in any one of steps (f-1), (f-2), and (f-x) are not particularly limited in terms of their chemical structure as long as the respective agent is capable of converting any P (III) atoms within said first cycle oligonucleotide O-1, said second cycle oligonucleotide O-2, and said x-th cycle oligonucleotide O-x to P (V) atoms. An “oxidizing agent” and a “sulfurizing agent” may differ in the means of how P (III) atoms are converted to P (V) atoms. An “oxidizing agent” may introduce one or more covalent bonds between the P (III) atom to be oxidized and an oxygen atom. A “sulfurizing agent” may introduce one or more covalent bonds between the P (III) atom to be sulfurized and a sulfur atom. As used herein, the term “oxidizing agent” preferably refers to any agent capable of converting a phosphite triester linkage group to a phosphate triester linkage group and a H-phosphonate diester linkage group to a phosphate diester (i.e. a phosphodiester) linkage group. As used herein, the term “sulfurizing agent” preferably refers to any agent capable of converting a phosphite triester linkage group to a thiophosphate triester linkage group and a H-phosphonate diester linkage group to a thiophosphate diester linkage group (i.e. a phosphorothioate) linkage group. Iodine may be a preferred oxidizing agent. For example, an aqueous solution of iodine may be used, preferably in combination with a co-solvent such as an ether solvent, e.g. an ether solvent S E (vide infra), a nitrile solvent such as acetonitrile, a (hetero)aromatic solvent such as pyridine, or a mixture thereof. As one example, a solution of iodine (e.g. 1 mol/L) in a mixed solvent of 4-methyltetrahydropyran (MTHP), water, and, optionally, acetonitrile may be used. Alternatively, peroxides such as tert-butyl hydroperoxide, cumene hydroperoxides, bis-trimethylsilyl peroxide, 2-butanone peroxide, and hydrogen peroxide, or peroxy acids such as m-chloroperbenzoic acid (mCPBA) may, for example, be used as oxidizing agents. As one example, a solution of tert-butyl hydroperoxide in a non-polar solvent may be used. For example, a solution (e.g. 5−6 mol/L) of tert-butyl hydroperoxide in nonane may be used. As another example, an aqueous solution of hydrogen peroxide may be used. For example, an aqueous solution of hydrogen peroxide and, optionally, potassium iodide may be mixed with an aqueous phosphoric acid buffer (e.g. pH 6.8) to obtain an oxidizing agent. As another alternative, (1S)-(+)-(10- camphorsulfonyl)-oxaziridine (CSO) may, for example, be used as oxidizing agent, e.g. as a 0.5 M (i.e.0.5 mol/L) solution in, e.g., acetonitrile. In general, the oxidizing agent may, for example, be applied in form of a 0.005−10.0 M (i.e. mol/L) solution, preferably a 0.01−5.0 M solution in a suitable solvent. Alternatively, neat oxidizing agent may, for example, be added (i.e. the oxidizing agent need not be dissolved in a suitable solvent). Xanthane hydride (5-amino-3H-1,2,4-dithiazole-3-thione), 3H-1,2-benzodithiol-3- one, and 3-(N,N-dimethylamino-methylidene)amino)-3H-1,2,4-dithiazole- 5-thione (CAS RN: 1192027-04-5, DDTT) may be preferred sulfurizing agents. Alternatively, 1,4-dithiothreitol (DTT), phenylacetyl disulfide (PADS) or 3H-1,2-benzodithiol-3-one 1,1-dioxide (Beaucage Reagent) may be used as sulfurizing agents. For example, neat sulfurizing agent (i.e. not in solution) may be added. As one example, neat DDTT may be added. As another example, neat xanthane hydride may be added. Alternatively, a solution of the sulfurizing agent in a suitable solvent may be added. The sulfurizing agent may, for example, be applied in form of a 0.005−5.0 M solution, preferably a 0.01−1.0 M solution in a suitable solvent, for example, selected from the group consisting of pyridine, acetonitrile, water, tetrahydrofuran, and mixtures thereof. As one example, a solution of xanthane hydride in pyridine may be used, optionally in combination with a co-solvent such as acetonitrile. As another example, a solution of xanthane hydride (e.g. 0.2 M) in pyridine may be used. As another example, a solution of xanthane hydride (e.g.0.1 M) in a mixture of pyridine and acetonitrile (e.g.1:1, v/v) may be used. Steps (f-1), (f-2), and (f-x) may, for example, be performed at a temperature in the range of 0−90 °C, 10−70 °C, 15−60 °C, or 15−50 °C. For convenience, steps (f-1), (f-2), and (f-x) may simply be performed at room temperature. Increased temperatures may result in shorter reaction times. The reaction time may also depend on the chemical structure of the reactants and will routinely be selected by a skilled person, for example, based on reaction monitoring using, e.g., thin-layer chromatography and/or high performance liquid chromatography (HPLC), optionally coupled to mass spectrometry. The term “incubating” in steps (f-1), (f-2), and (f-x) may be understood in the broadest sense to refer to any process of contacting the first cycle oligonucleotide O-1, the second cycle oligonucleotide O-2 or the x-th cycle oligonucleotide O-x, respectively, and the respective oxidizing or sulfurizing agent, preferably inside the same reaction vessel or reactor. Typically, the first cycle oligonucleotide O-1, the second cycle oligonucleotide O-2 or the x-th cycle oligonucleotide O-x may already be contained in a reaction vessel or reactor, to which the respective oxidizing or sulfurizing agent is then added. Alternatively, the first cycle oligonucleotide O-1, the second cycle oligonucleotide O-2 or the x-th cycle oligonucleotide O-x may be added to the reaction vessel or reactor containing the respective oxidizing or sulfurizing agent. After said conversion of any P (III) atoms to P (V) atoms of any one of steps (f-1), (f-2), and (f-x), excess oxidizing or sulfurizing agent may typically be quenched (i.e. reduced), e.g., by treatment with a reducing agent. For example, a reducing agent such as triethylphosphite or a solution thereof may be added directly into the reaction mixture of the respective step (f-1) or (f-2) or (f-x). Alternatively, if step (g-1) or (g-2) or (g-x) is carried out, a reducing agent may also be comprised in one or more of the one or more aqueous solutions used for the one or more aqueous extractions. Examples of such water-soluble reducing agents comprise thiosulfate salts such as sodium thiosulfate. Step (g-1) of the methods of the invention is: optionally, subjecting a solution comprising the first cycle oligonucleotide O-1 to one or more aqueous extractions, wherein the organic phase comprises the first cycle oligonucleotide O-1. Step (g-2) of some of the methods of the invention is: optionally, subjecting a solution comprising the second cycle oligonucleotide O-2 to one or more aqueous extractions, wherein the organic phase comprises the second cycle oligonucleotide O-2. Step (g-x) of some of the methods of the invention is: optionally, subjecting a solution comprising the x-th cycle oligonucleotide O-x to one or more aqueous extractions, wherein the organic phase comprises the x-th cycle oligonucleotide O-x. The term “optionally” in steps (g-1), (g-2), and (g-x) denotes that the respective step may or may not be carried out in a given coupling cycle, unless indicated differently in the context of specific embodiments. Steps (g-1), (g-2), and (g-x) may, for example, be carried out to (at least partly) remove one or more side products and/or by-products and/or excess reagents and/or water-miscible solvents. In some embodiments of the method of the invention, step (g-1) is carried out (i.e. is not optional). In some embodiments of the method of the invention, in the second coupling cycle, step (g-2) is carried out (i.e. is not optional). In some embodiments of the method of the invention, in at least one, or each, coupling cycle comprising steps (b-x) to (h-x) (as far as present), step (g-x) is carried out (i.e. is not optional). The skilled artisan will understand that said solution comprising the first cycle oligonucleotide O-1 in step (g-1) may refer to the reaction mixture obtained from carrying out step (e-1), if step (f-1) is not performed, or may refer to the reaction mixture obtained from carrying out step (f-1) (wherein one or more quenchers or reducing agents may, for example, have been added beforehand as explained above). The skilled artisan will also understand that said solution comprising the second cycle oligonucleotide O-2 in step (g-2) may refer to the reaction mixture obtained from carrying out step (e-2), if step (f-2) is not performed, or may refer to the reaction mixture obtained from carrying out step (f-2) (wherein one or more quenchers or reducing agents may, for example, have been added beforehand as explained above). The skilled artisan will also understand that said solution comprising the x-th cycle oligonucleotide O-x in step (g-x) may refer to the reaction mixture obtained from carrying out step (e-x), if step (f-x) is not performed, or may refer to the reaction mixture obtained from carrying out step (f-x) (wherein one or more quenchers or reducing agents may, for example, have been added beforehand as explained above). Optionally, said solutions comprising the first cycle oligonucleotide O-1, the second cycle oligonucleotide O-2 or the x-th cycle oligonucleotide O-x may be obtained from the respective reaction mixture by addition of one or more non-polar solvents, for example, in order to facilitate the phase separation. Alternatively, or additionally, such non-polar solvents may also be added during or in between the one or more aqueous extractions of any one of steps (g-1), (g-2), and (g-x). Non-limiting examples of non-polar solvents comprise those listed above in the context of steps (c-1), (c-2), and (c-x). 4-Methyltetrahydropyran (MTHP) may be a preferred non-polar ether solvent which may be added prior to or during or in between the aqueous extraction(s) of any one of steps (g-1), (g-2), and (g-x). Additionally, or alternatively, one or more amide solvents S A may be added prior to or during or in between the aqueous extraction(s) of any one of steps (g-1), (g-2), and (g-x). The term “aqueous extraction” in steps (g-1), (g-2), and (g-x) of the method of the invention may be understood in the broadest sense as any liquid-liquid extraction operation during which the respective solution comprising the first cycle oligonucleotide O-1, the second cycle oligonucleotide O-2 or the x-th cycle oligonucleotide O-x is extracted with water or an aqueous solution. The term “aqueous solution” has been defined above. As one example, an aqueous solution of acetic acid (e.g.10 vol-%) may be used as aqueous solution for the aqueous extraction(s) of steps (g-1), (g-2), and (g-x). As another example, an aqueous solution of sodium thiosulfate (e.g.0.5 mol/L) may be used as aqueous solution for the aqueous extraction(s) of steps (g-1), (g-2), and (g-x). As another example, a mixture of an aqueous solution of sodium thiosulfate (e.g.0.5 mol/L) and an aqueous solution of N-methylmorpholine (e.g.1 mol/L) (e.g. 5:1 or 4:1 or 7:3 or 2:1 or 5:3 or 4:3, v:v) may be used as aqueous solution for the aqueous extraction(s) of steps (g-1), (g-2), and (g-x). As another example, a mixture of an aqueous solution of sodium thiosulfate (e.g.0.5 mol/L) and acetone (e.g.2:1 or 7:5, v:v) may be used as aqueous solution for the aqueous extraction(s) of steps (g-1), (g-2), and (g-x). As another example, a mixture of an aqueous solution of sodium thiosulfate (e.g. 0.5 mol/L), an aqueous solution of sodium chloride (i.e. brine, e.g. 10 wt-%), and acetone (e.g. 2:1:1, v:v:v) may be used as aqueous solution for the aqueous extraction(s) of steps (g-1), (g-2), and (g-x). As another example, an aqueous solution of ammonium chloride (e.g.20 wt-%) may be used as aqueous solution for the aqueous extraction(s) of steps (g-1), (g-2), and (g-x). As another example, an aqueous solution of sodium chloride (i.e. brine, e.g.20 wt-%) may be used as aqueous solution for the aqueous extraction(s) of steps (g-1), (g- 2), and (g-x). The term “v:v” is herein used to denote volume ratios. For example a mixture obtained from mixing 10 mL of water and 10 mL of acetone would be denoted as 1:1, v:v. It will be understood that for each of the one or more aqueous extractions of a step (g-1) or (g-2) or (g-x), the aqueous solution may be the same or different (i.e. comprise the same or different components in the same or different ratios). It will also be understood that the aqueous solutions may be the same or different for different steps (g-x) of different coupling cycles. In case of more than one organic phases (either from a single aqueous extraction or from back-extraction of one or more aqueous phase), these more than one organic phases may be combined to obtain “the organic phase” mentioned in steps (g-1), (g-2), and (g-x). In general, the means of performing aqueous extractions are well-known to the skilled person. The expression “the organic phase comprises the first cycle oligonucleotide O-1” in step (g-1) may be understood in the broadest sense to mean that some of the molecules of said first cycle oligonucleotide O-1 are dissolved in the organic phase. The expression “the organic phase comprises the second cycle oligonucleotide O-2” in step (g-2) may be understood in the broadest sense to mean that some of the molecules of said second cycle oligonucleotide O-2 are dissolved in the organic phase. The expression “the organic phase comprises the x-th cycle oligonucleotide O-x” in step (g-x) may be understood in the broadest sense to mean that some of the molecules of said x-th cycle oligonucleotide O-x are dissolved in the organic phase. It is preferred that most molecules (e.g. more than 50 %, 60 %, 70 %, 80 %, or 90 % of the molecules) of the said first cycle oligonucleotide O-1 or said second cycle oligonucleotide O-2 or said x-th cycle oligonucleotide O-x are comprised in the organic phase (and thus not in the aqueous phase). Step (h-1) of the methods of the invention is: if step (g-1) has been carried out, optionally reducing the water content of the organic phase comprising the first cycle oligonucleotide O-1. Step (h-2) of some of the methods of the invention is: if step (g-2) has been carried out, optionally reducing the water content of the organic phase comprising the second cycle oligonucleotide O-2. Step (h-x) of some of the methods of the invention is: if step (g-x) has been carried out, optionally reducing the water content of the organic phase comprising the x-th cycle oligonucleotide O-x. The expression “if step (g-1) has been carried out” in step (h-1) means that in the first coupling cycle, step (h-1) may only be carried out, if step (g-1) has been carried out. The expression “if step (g-2) has been carried out” in step (h-2) means that in the second coupling cycle, step (h-2) may only be carried out, if step (g-2) has been carried out. The expression “if step (g-x) has been carried out” in step (h-x) means that in a given coupling cycle comprising steps (b-x) to (h-x) (as far as present), step (h-x) may only be carried out, if step (g-x) has been carried out (in the same coupling cycle). The term “optionally” in steps (h-1), (h-2), and (h-x) denotes that, even if the respective step (g-1), (g-2) or (g-x) has been carried out, the respective step (h-1), (h-2) or (h-x) may or may not be carried, unless indicated differently in the context of specific embodiments. In some embodiments of the method of the invention, step (h-1) is carried out (i.e. is not optional), if step (g-1) has been carried out. In some embodiments of the method of the invention, in the second coupling cycle, step (h- 2) is carried out (i.e. is not optional), if step (g-2) has been carried out. In some embodiments of the method of the invention, in at least one, or each, coupling cycle comprising steps (b-x) to (h-x) (as far as present), step (h-x) is carried out (i.e. is not optional), if step (g-x) has been carried out in the same coupling cycle. The term “the organic phase” in steps (h-1), (h-2), and (h-x) refers to “the organic phase” of the respective step (g-1) or (g-2) or (g-x) of the same coupling cycle. The term “reducing the water content” has been defined above. In some embodiments of the method of the invention, step (h-1) is: if step (g-1) has been carried out, optionally reducing the water content of the organic phase comprising the first cycle oligonucleotide O-1, wherein the water content is adjusted to be equal to or less than 2000 ppm, 1900 ppm, 1800 ppm, 1700 ppm, 1600 ppm, 1500 ppm, 1400 ppm, 1300 ppm, 1200 ppm, 1100 ppm, 1000 ppm, 900 ppm, 800 ppm, 700 ppm, 600 ppm, 500 ppm, 400 ppm, 300 ppm, 250 ppm, 200 ppm, 150 ppm, or 100 ppm. In some embodiments of the method of the invention, step (h-2) is: if step (g-2) has been carried out, optionally reducing the water content of the organic phase comprising the second cycle oligonucleotide O-2, wherein the water content is adjusted to be equal to or less than 2000 ppm, 1900 ppm, 1800 ppm, 1700 ppm, 1600 ppm, 1500 ppm, 1400 ppm, 1300 ppm, 1200 ppm, 1100 ppm, 1000 ppm, 900 ppm, 800 ppm, 700 ppm, 600 ppm, 500 ppm, 400 ppm, 300 ppm, 250 ppm, 200 ppm, 150 ppm, or 100 ppm. In some embodiments of the method of the invention, step (h-x) is: if step (g-x) has been carried out, optionally reducing the water content of the organic phase comprising the x-th cycle oligonucleotide O-x, wherein the water content is adjusted to be equal to or less than 2000 ppm, 1900 ppm, 1800 ppm, 1700 ppm, 1600 ppm, 1500 ppm, 1400 ppm, 1300 ppm, 1200 ppm, 1100 ppm, 1000 ppm, 900 ppm, 800 ppm, 700 ppm, 600 ppm, 500 ppm, 400 ppm, 300 ppm, 250 ppm, 200 ppm, 150 ppm, or 100 ppm. In some embodiments of the method of the invention: - step (h-1) is carried out (i.e. is not optional), if the organic phase comprising the first cycle oligonucleotide O-1 of step (g-1) comprises more than 2000 ppm, 1900 ppm, 1800 ppm, 1700 ppm, 1600 ppm, 1500 ppm, 1400 ppm, 1300 ppm, 1200 ppm, 1100 ppm, 1000 ppm, 900 ppm, 800 ppm, 700 ppm, 600 ppm, 500 ppm, 400 ppm, 300 ppm, 250 ppm, 200 ppm, 150 ppm, or 100 ppm of water; - step (h-2) is carried out (i.e. is not optional), if the organic phase comprising the second cycle oligonucleotide O-2 of step (g-2) comprises more than 2000 ppm, 1900 ppm, 1800 ppm, 1700 ppm, 1600 ppm, 1500 ppm, 1400 ppm, 1300 ppm, 1200 ppm, 1100 ppm, 1000 ppm, 900 ppm, 800 ppm, 700 ppm, 600 ppm, 500 ppm, 400 ppm, 300 ppm, 250 ppm, 200 ppm, 150 ppm, or 100 ppm of water; and - step (h-x) is carried out (i.e. is not optional), if the organic phase comprising the x-th cycle oligonucleotide O-x of step (g-x) of the same coupling cycle comprises more than 2000 ppm, 1900 ppm, 1800 ppm, 1700 ppm, 1600 ppm, 1500 ppm, 1400 ppm, 1300 ppm, 1200 ppm, 1100 ppm, 1000 ppm, 900 ppm, 800 ppm, 700 ppm, 600 ppm, 500 ppm, 400 ppm, 300 ppm, 250 ppm, 200 ppm, 150 ppm, or 100 ppm of water. Any means of reducing the water content may be employed, preferred examples of which comprise azeotropic distillation and the use of a drying agent, both of which have been explained above. In some embodiments of the method of the invention, in at least one or each of steps (h-1), (h-2), and (h-x), reducing the water content is achieved by means of azeotropic distillation and/or by contacting said organic phase comprising the first cycle oligonucleotide O-1, the second cycle oligonucleotide O-2 or the x-th cycle oligonucleotide O-x with a drying agent. In some embodiments of the method of the invention, in at least one or each of steps (h-1), (h-2), and (h-x), reducing the water content is achieved by means of azeotropic distillation. In some embodiments of the method of the invention, in at least one or each of steps (h-1), (h-2), and (h-x), reducing the water content is achieved by means of contacting said organic phase comprising the first cycle oligonucleotide O-1, the second cycle oligonucleotide O-2 or the x-th cycle oligonucleotide O-x with a drying agent. It will be understood that in any one of steps (h-1), (h-2), and (h-x), one or more solvents and/or further components may be added to said organic phase comprising the first cycle oligonucleotide O-1, the second cycle oligonucleotide O-2 or the x-th cycle oligonucleotide O-x prior to, during, and/or after reduction of the water content. In some embodiments of the method of the invention, in at least one or each of steps (d-1), (d-2), (d-x), (h-1), (h-2), and (h-x), reducing the water content is achieved by means of azeotropic distillation. In some embodiments of the method of the invention: - the first coupling cycle further comprises a step (i-1) of reacting free hydroxyl groups with a blocking agent, wherein step (i-1) is carried out after step (e-1) or after step (f-1); and/or - the second coupling cycle further comprises a step (i-2) of reacting free hydroxyl groups with a blocking agent, wherein step (i-2) is carried out after step (e-2) or after step (f-2); and/or - at least one coupling cycle comprising steps (b-x) to (h-x) (as far as present) further comprises a step (i-x) of reacting free hydroxyl groups with a blocking agent, wherein step (i-x) is carried out after step (e-x) or after step (f-x). The free backbone hydroxyl group present in the component (C-0) # , the first cycle oligonucleotide (O-1) # , and the (x−1)-th cycle oligonucleotide (O-(x−1)) # is supposed to engage in the bond forming reaction of step (e-1), (e-2) or (e-x) (of the same coupling cycle), which consumes said free backbone hydroxyl group in the sense of incorporating it into a newly-formed internucleosidic linkage group. However, a (typically very small, e.g. < 1 %, < 0.5 % or < 0.1 %) fraction of the free backbone hydroxyl groups may not engage in the bond forming reaction at the first occasion, i.e. in the same coupling cycle, in which the respective free hydroxyl group has been generated by cleaving a protecting group. Such free hydroxyl groups are herein also referred to as unreacted free hydroxyl groups. These groups would be available to participate in the bond forming reactions of the coupling steps of following coupling cycles. This may not be desirable, since it would afford an oligonucleotide product lacking one nucleoside subunit. Such oligonucleotide products may be difficult to remove from the target oligonucleotide O T later on. As used herein, the terms “blocking agent” and “capping agent” are used interchangeably to denote any chemical reagent capable of acylating, preferably acetylating, a free hydroxyl group. Capping agents for oligonucleotide synthesis form part of the common knowledge of those skilled in the art. Any blocking (i.e. capping) agents known from oligonucleotide synthesis may be used in the method of the invention. Preferred examples of such blocking agents comprise anhydrides of carboxylic acids, in particular acetic anhydride. It is known to those skilled in the art that free carboxylic acids may also be used in combination with activating agents such as carbodiimides (e.g. dicyclohexylcarbdiimide or diisopropylcarbodiimide) and additives such as, e.g., 4-dimethylaminopyridine (DMAP). For example, acetylation may be achieved by treating the growing oligonucleotide chains with neat acetic anhydride or a solution thereof. An organic base such as pyridine, lutidine (e.g.2,6-lutidine), collidine, N-methylimidazole, or a mixture thereof may be added. For example, acetic anhydride (e.g.4 moles of acetic anhydride per 1 mol of employed component (C-0) # ) may be used, preferably in combination with a base such as pyridine (e.g.5 moles of base per 1 mol of employed component (C-0) # ). The blocking agents may be added directly into the reaction vessel or reactor, in which step (e-1), (e-2), (e-x), (f-1), (f-2) or (f-x) was carried out. The term “reacting” in step (i-1), (i-2), and (i-x) may be understood in the broadest sense as any operation during which the growing oligonucleotide chains and the blocking agent are present in the same reaction vessel or reactor and engage in the blocking reaction. In some embodiments of the method of the invention, the method further comprises - a step (k-1) of incubating the first cycle oligonucleotide O-1 with a deprotection mixture M-(k-1), thereby cleaving the protecting group PG-1 from the first cycle oligonucleotide O-1, so as to obtain a first cycle oligonucleotide (O-1) # having a free backbone hydroxyl group; and/or - a step (m-1) of incubating the first cycle oligonucleotide O-1 or (O-1) # with a base, thereby cleaving the pseudo solid-phase protecting group PG-s and, optionally, one or more further protecting groups from the first cycle oligonucleotide O-1 or (O-1) # ; and/or - a step (p-1) of modifying the first cycle oligonucleotide O-1 or (O-1) # ; wherein, if more than one of steps (k-1), (m-1), and (p-1) are performed, they may be performed in any order. It will be understood that any one of steps (k-1), (m-1), and (p-1) may only be carried out after all steps of the first coupling cycle (optionally excluding steps indicated as optional) have been performed. It will also be understood that, if any one of steps (k-1), (m-1), and (p-1) is carried out, the second coupling cycle comprising steps (b-2) to (h-2) and thus any further coupling cycles comprising steps (b-x) to (h-x) (as far as present) may not be carried out. In some embodiments of the method of the invention, the method further comprises - a step (k-2) of incubating the second cycle oligonucleotide O-2 with a deprotection mixture M-(k-2), thereby cleaving the protecting group PG-2 from the second cycle oligonucleotide O-2, so as to obtain a second cycle oligonucleotide (O-2) # having a free backbone hydroxyl group; and/or - a step (m-2) of incubating the second cycle oligonucleotide O-2 or (O-2) # with a base, thereby cleaving the pseudo solid-phase protecting group PG-s and, optionally, one or more further protecting groups from the second cycle oligonucleotide O-2 or (O-2) # ; and/or - a step (p-2) of modifying the second cycle oligonucleotide O-2 or (O-2) # ; wherein, if more than one of steps (k-2), (m-2), and (p-2) are performed, they may be performed in any order. It will be understood that any one of steps (k-2), (m-2), and (p-2) may only be carried out after all steps of the second coupling cycle (optionally excluding steps indicated as optional) have been performed. It will also be understood that, if any one of steps (k-2), (m-2), and (p-2) is carried out, further coupling cycles comprising steps (b-x) to (h-x) (as far as present) may not be carried out. In some embodiments of the method of the invention, the method further comprises - a step (k-n) of incubating the n-th cycle oligonucleotide O-n with a deprotection mixture M-(k-n), thereby cleaving the protecting group PG-n from the n-th cycle oligonucleotide O-n, so as to obtain a n-th cycle oligonucleotide (O-n) # having a free backbone hydroxyl group; and/or - a step (m-n) of incubating the n-th cycle oligonucleotide O-n or (O-n) # with a base, thereby cleaving the pseudo solid-phase protecting group PG-s and, optionally, one or more further protecting groups from the n-th cycle oligonucleotide O-n or (O-n) # ; and/or - a step (p-n) of modifying the n-th cycle oligonucleotide O-n or (O-n) # ; wherein, if more than one of steps (k-n), (m-n), and (p-n) are performed, they may be performed in any order. It will be understood that any one of steps (k-n), (m-n), and (p-n) may only be carried out after all steps of the (n−2)-th iteration of the coupling cycle comprising steps (b- x) to (h-x) (optionally excluding steps indicated as optional) have been performed. The term "deprotection mixture M-(k-1)" refers to any mixture which may be used to effect cleavage of the protecting group PG-1 from the first cycle oligonucleotide O-1. Any definitions and embodiments pertaining to the deprotection mixture M-(b-2) may also apply to the deprotection mixture M-(k-1). The term "deprotection mixture M-(k-2)" refers to any mixture which may be used to effect cleavage of the protecting group PG-2 from the second cycle oligonucleotide O-2. Any definitions and embodiments pertaining to the deprotection mixture M-(b-3) (i.e. a deprotection mixture M-(b-x) with x=3) may also apply to the deprotection mixture M-(k-2). The term "deprotection mixture M-(k-n)" refers to any mixture which may be used to effect cleavage of the protecting group PG-n from the n-th cycle oligonucleotide O-n. Any definitions and embodiments pertaining to the deprotection mixture M-(b-x) may also apply to the deprotection mixture M-(k-n). The term “base” in steps (m-1), (m-2), and (m-n) may be understood in the broadest sense to refer to any base (a proton acceptor in the sense of the Br Ø nsted-Lowry theory), unless indicated differently in the context of specific embodiments. Non- limiting examples of such a base comprise ammonia, a (C 1 −C 6 -alkyl)NH 2 monoalkylamine, in particular methylamine, ethylamine or tert-butylamine, a (C 1 −C 6 -alkyl) 2 NH dialkylamine, in particular dimethylamine or diethylamine, a source of hydroxide ions, and mixtures thereof. As known to the skilled artisan, such bases will typically not be employed as such in a step (m-1), (m-2) or (m-n), but rather in form of a solution of the base in a suitable solvent, in particular water, i.e. as an aqueous solution of the respective base. Such an aqueous solution may further comprise one or more water-miscible organic solvents such as, e.g., acetonitrile, tetrahydrofuran, methanol, ethanol, and the like. As used herein, the term “a source of hydroxide ions” may refer to a salt which comprises hydroxide ions, wherein sodium hydroxide, potassium hydroxide, and ammonium hydroxide may be preferred examples. The person skilled in the art knows that an aqueous solution of ammonia may also be referred to as an ammonium hydroxide solution, since it comprises ammonium ions and hydroxide ions. The skilled artisan understands that a solution comprising a source of hydroxide anions may comprise said source of hydroxide ions in solvated form. In some embodiments, said base of any one of steps (m-1), (m-2), and (m-n) is an aqueous solution of one or more compounds selected from the group consisting of ammonia, a (C1−C6-alkyl)NH2 monoalkylamine, a (C1−C6-alkyl)2NH dialkylamine, sodium hydroxide, potassium hydroxide, and mixtures thereof. In some embodiments, said base of any one of steps (m-1), (m-2), and (m-n) is an aqueous solution of one or more compounds selected from the group consisting of ammonia, methylamine, ethylamine, tert-butylamine, sodium hydroxide, potassium hydroxide, and mixtures thereof. For example, said base of any one of steps (m-1), (m-2), and (m-n) may be an aqueous solution of ammonia, e.g.25−30 wt-% aqueous ammonia. As another example, said base of any one of steps (m-1), (m-2), and (m-n) may be an aqueous solution of tert-butylamine, e.g. a 1:1 (v:v) mixture of water and tert-butylamine. As another example, said base of any one of steps (m-1), (m-2), and (m-n) may be an aqueous solution of methylamine, e.g. a 1:1 (v:v) mixture of water and methylamine. As another example, said base of any one of steps (m-1), (m-2), and (m-n) may be a solution of sodium hydroxide (e.g.1 mol/L) in a mixture of water and tetrahydrofuran (e.g. 1:3, v:v). Alternatively, hydrazine (e.g. used in form of its hydrate) may, for example, be used as nucleophilic base. In some embodiments of the method of the invention, the method comprises exactly one step selected from the group consisting of step (m-1), step (m-2), and step (m-n), and wherein - step (m-1) is carried out by incubating the first cycle oligonucleotide O-1 or (O-1) # with an aqueous solution of an organic amine, preferably an aliphatic amine, more preferably a primary or secondary aliphatic amine, in particular a primary aliphatic amine such as tert-butylamine, and an aliphatic alcohol, preferably an aliphatic alcohol comprising 1−6 carbon atoms, in particular methanol; - step (m-2) is carried out by incubating the second cycle oligonucleotide O-2 or (O-2) # with an aqueous solution of an organic amine, preferably an aliphatic amine, more preferably a primary or secondary aliphatic amine, in particular a primary aliphatic amine such as tert-butylamine, and an aliphatic alcohol, preferably an aliphatic alcohol comprising 1−6 carbon atoms, in particular methanol; and - step (m-n) is carried out by incubating the n-th cycle oligonucleotide O-n or (O-n) # with an aqueous solution of an organic amine, preferably an aliphatic amine, more preferably a primary or secondary aliphatic amine, in particular a primary aliphatic amine such as tert-butylamine, and an aliphatic alcohol, preferably an aliphatic alcohol comprising 1−6 carbon atoms, in particular methanol. In such embodiments, the respective oligonucleotide, i.e., the first cycle oligonucleotide O-1 or (O-1) # in a step (m-1) and the second cycle oligonucleotide O-2 or (O-2) # in a step (m-2) and the n-th cycle oligonucleotide O-n or (O-n) # in a step (m-n) preferably comprises at least one internucleosidic linkage group selected from the group consisting of a thiophosphate triester group and a thiophosphate diester group, preferably a linkage group of Formula B, where X 1 is S and X 2 is either OH or O-CH2-CH2-CN. In some embodiments of the method of the invention, the method comprises exactly one step selected from the group consisting of step (m-1), step (m-2), and step (m-n), and wherein - step (m-1) is carried out by incubating the first cycle oligonucleotide O-1 or (O-1) # with an aqueous solution of a (C1−C6-alkyl)NH2 monoalkylamine, in particular tert-butylamine, and an aliphatic alcohol comprising 1−6 carbon atoms, in particular methanol; - step (m-2) is carried out by incubating the second cycle oligonucleotide O-2 or (O-2) # with an aqueous solution of a (C1−C6-alkyl)NH2 monoalkylamine, in particular tert-butylamine, and an aliphatic alcohol comprising 1−6 carbon atoms, in particular methanol; and - step (m-n) is carried out by incubating the n-th cycle oligonucleotide O-n or (O-n) # with an aqueous solution of a (C 1 −C 6 -alkyl)NH 2 monoalkylamine, in particular tert-butylamine, and an aliphatic alcohol comprising 1−6 carbon atoms, in particular methanol. In such embodiments, the respective oligonucleotide, i.e., the first cycle oligonucleotide O-1 or (O-1) # in a step (m-1) and the second cycle oligonucleotide O-2 or (O-2) # in a step (m-2) and the n-th cycle oligonucleotide O-n or (O-n) # in a step (m-n) preferably comprises at least one internucleosidic linkage group selected from the group consisting of a thiophosphate triester group and a thiophosphate diester group, preferably a linkage group of Formula B, where X 1 is S and X 2 is either OH or O-CH2-CH2-CN. In some embodiments of the method of the invention, the method comprises exactly one step selected from the group consisting of step (m-1), step (m-2), and step (m-n), and wherein - step (m-1) is carried out by incubating the first cycle oligonucleotide O-1 or (O-1) # with an aqueous solution of a (C1−C6-alkyl)NH2 monoalkylamine, in particular tert-butylamine, and an aliphatic alcohol comprising 1−6 carbon atoms, in particular methanol, wherein the volume-ratio of monoalkylamine to aliphatic alcohol to water is 1:1:2 (v:v:v); - step (m-2) is carried out by incubating the second cycle oligonucleotide O-2 or (O-2) # with an aqueous solution of a (C 1 −C 6 -alkyl)NH 2 monoalkylamine, in particular tert-butylamine, and an aliphatic alcohol comprising 1−6 carbon atoms, in particular methanol, wherein the volume-ratio of monoalkylamine to aliphatic alcohol to water is 1:1:2 (v:v:v); and - step (m-n) is carried out by incubating the n-th cycle oligonucleotide O-n or (O-n) # with an aqueous solution of a (C 1 −C 6 -alkyl)NH 2 monoalkylamine, in particular tert-butylamine, and an aliphatic alcohol comprising 1−6 carbon atoms, in particular methanol, wherein the volume-ratio of monoalkylamine to aliphatic alcohol to water is 1:1:2 (v:v:v). In such embodiments, the respective oligonucleotide, i.e., the first cycle oligonucleotide O-1 or (O-1) # in a step (m-1) and the second cycle oligonucleotide O-2 or (O-2) # in a step (m-2) and the n-th cycle oligonucleotide O-n or (O-n) # in a step (m-n) preferably comprises at least one internucleosidic linkage group selected from the group consisting of a thiophosphate triester group and a thiophosphate diester group, preferably a linkage group of Formula B, where X 1 is S and X 2 is either OH or O-CH 2 -CH 2 -CN. The use of an aqueous solution of a (C 1 −C 6 -alkyl)NH 2 monoalkylamine, in particular tert-butylamine, and an aliphatic alcohol comprising 1−6 carbon atoms, in particular methanol is particularly preferred, if the pseudo solid-phase protecting group PG-s is a protecting group of Formula P-1-a below, in particular, with the integer a being 1. Steps (m-1), (m-2), and (m-n) may, for example, be performed at a temperature in the range of 5−95 °C, 10−95 °C, 15−95 °C, 20−95 °C, 25−95 °C, 30−95 °C, 35−95 °C, 50−90 °C, 55−90 °C, 60−85 °C, or 60−80 °C. Lower temperatures, e.g., in the range of 45–70 °C or 50–60 °C, in particular 55 °C, may be preferred when using an aqueous solution of a (C1−C6-alkyl)NH2 monoalkylamine, in particular tert-butylamine, and an aliphatic alcohol comprising 1−6 carbon atoms, in particular methanol. It will be understood that steps (m-1), (m-2), and (m-n) may preferably be performed in a sealed reaction vessel or reactor, e.g. in an autoclave, when operating at elevated temperatures. Under the alkaline conditions of steps (m-1), (m-2), and (m-n), “one or more further protecting groups” (i.e. other than said pseudo solid-phase PG-s) may optionally be cleaved from the respective oligonucleotide. In fact, as will be understood by the skilled artisan, any common protecting groups removable under alkaline conditions will typically be removed during the incubation with said base in steps (m-1), (m-2), and (m-n). Such protecting groups removable under alkaline conditions, e.g. under the conditions of steps (m-1), (m-2), and (m-n), may, for example, be the typical nucleobase protecting groups, non-limiting examples of which comprise the protecting groups listed in Table T-1 above. Additionally, protecting groups at the internucleosidic linkage groups, e.g. any protecting groups R Z-1 and R Z-2 , in particular any 2-cyanoethyl protecting groups, may typically be removed under the conditions of steps (m-1), (m-2), and (m-n). In the context of steps (p-1), (p-2), and (p-n) of the method of the invention, the term “modifying” may be understood in the broadest sense to embrace “chemically modifying” and/or “biotechnologically modifying” the respective oligonucleotides. In the context of steps (p-1), (p-2), and (p-n), “chemically modifying” is defined as subjecting the respective oligonucleotide (which is to be chemically modified) to one or more chemical reactions. Non-limiting examples of such chemical reactions are - the removal of one or more protecting groups (including any pseudo solid-phase protecting groups); - conjugation with one or more compounds selected from the group consisting of a nucleoside, an oligonucleotide, a carbohydrate such as a monosaccharide or a polysaccharide, an amino acid, a peptide, a lipid, an active pharmaceutical ingredient, or the like; and - an intramolecular bond forming reaction resulting in cyclization. It will be understood that more than one such chemical reactions may be performed in the course of said chemical modification. In the context of steps (p-1), (p-2), and (p-n), “biotechnologically modifying” is defined as subjecting the respective oligonucleotide (which is to be biotechnologically modified) to one or more enzymatic reactions. As used herein, the term “enzymatic reaction” refers to any reaction which is enabled by and/or catalyzed by one or more enzymes. A preferred example is enzymatic ligation. In some embodiments, the method of the invention further comprises a step (z) of isolating the target oligonucleotide O T . The means of isolating oligonucleotides upon oligonucleotide synthesis form part of the common knowledge of those skilled in the art. Typically, such a step of isolating an oligonucleotide comprises one or more purification steps and one or more steps aiming at obtaining the oligonucleotide in solid form. For oligonucleotide purification, chromatographic methods may typically be used, in particular ion exchange (especially anion exchange) chromatography and reversed phase (RP) HPLC, e.g. in form of hydrophobic interaction HPLC. These techniques are known to those skilled in the art. Additionally, a step of isolating an oligonucleotide may comprise ultrafiltration and/or desalting steps. Typically, the target oligonucleotide to be isolated may be dissolved in a reaction mixture. It may then be preferable to first obtain a crude product either by precipitating the target oligonucleotide to be purified from the respective reaction mixture or by evaporation to dryness (e.g. in vacuo). Precipitation may for example be achieved by (partly) removing one or more solvents and/or by addition of one or more antisolvents (in which the target oligonucleotide is not soluble or poorly soluble) and/or by cooling the reaction mixture from which the target oligonucleotide to be isolated. The so-obtained crude product may, for example be washed with one or more solvents and/or aqueous solutions. The crude product may then be dissolved, so as to obtain a solution, preferably an aqueous solution of the target oligonucleotide to be isolated. Alternatively, the reaction mixture containing the target oligonucleotide as such may be used without precipitation or evaporation to dryness. For example, a solution, preferably an aqueous solution, containing the target oligonucleotide O T to be isolated may be submitted to ultrafiltration and/or desalting, ion exchange chromatography, and another round of ultrafiltration and/or desalting. Alternatively, a crude product containing the target oligonucleotide O T to be isolated may be submitted to reversed phase (RP) HPLC, e.g. in form of hydrophobic interaction HPLC. The latter method may preferably be performed, if the oligonucleotides still carry the 5´-terminal hydroxyl protecting group, e.g. the DMT group. Said 5´-protecting group may even be removed on the RP-HPLC column by passing an acidic solution through the column. If the 5´-terminal protecting group has been removed prior to purification, ion exchange chromatography may be preferred. Purification is typically followed by one or more steps aiming at obtaining the oligonucleotide in solid form. Lyophilization or spray drying may, for example, be used. In some cases, it may be desirable to obtain the oligonucleotide in form of a salt with certain counter ions. In such cases, salt exchange may be performed, typically prior to lyophilization or spray drying. In the method of the invention, during and in between steps (b-1) to (h-1) (as far as present), no solid-liquid separation is performed and steps (c-1) and (g-1) are carried out in the presence of one or more amide solvents S A , wherein each amide solvent S A is an amide solvent comprising one or more alkyl groups, wherein these one or more alkyl groups together comprise in total 6−48 carbon atoms. It will be understood that the expression “steps (c-1) and (g-1) are carried out in the presence of one or more amide solvents S A ” does not imply that step (g-1) must be carried out, i.e., is not optional. However, if step (g-1) is carried out, it is carried out in the presence of one or more amide solvents S A . If the method of the invention comprises performing a second coupling cycle comprising steps (b-2) to (h-2) (as far as present) , during and in between steps (b- 1) to (h-2) (as far as present), no solid-liquid separation is performed and steps (c- 1), (g-1), (c-2), and (g-2) are carried out in the presence of one or more amide solvents S A , wherein each amide solvent S A is an amide solvent comprising one or more alkyl groups, wherein these one or more alkyl groups together comprise in total 6−48 carbon atoms. It will be understood that the expression “steps (c-1), (g-1), (c-2), and (g-2) are carried out in the presence of one or more amide solvents S A ” does not imply that steps (g-1) and (g-2) must be carried out, i.e., are not optional. However, if one or both of steps (g-1) and (g-2) are carried out, they are carried out in the presence of one or more amide solvents S A . If the method of the invention comprises performing (n−2) iterations of a coupling cycle comprising the following steps (b-x) to (h-x) (as far as present), wherein n is an integer in the range of 3 to 99, which denotes the total number of coupling cycles performed to obtain to obtain the n-th cycle oligonucleotide O-n, during and in between steps (b-1) to (h-n) (as far as present), no solid-liquid separation is performed, and steps (c-1), (g-1), (c-2), and (g-2), as well as each iteration of steps (c-x) and (g-x) is carried out in the presence of one or more amide solvents S A , wherein each amide solvent S A is an amide solvent comprising one or more alkyl groups, wherein these one or more alkyl groups together comprise in total 6−48 carbon atoms. It will be understood that the expression “steps (c-1), (g-1), (c-2), and (g-2), as well as each iteration of steps (c-x) and (g-x) are carried out in the presence of one or more amide solvents S A ” does not imply that steps (g-1), (g-2), and (g-x) must be carried out, i.e., are not optional. However, if one or more of steps (g-1), (g-2) and (g-x) are carried out, they are carried out in the presence of one or more amide solvents S A . As used herein, the term “amide solvent” may be understood in the broadest sense to refer to any solvent characterized in that in its chemical structure, at least one carbonyl carbon atom (C=O) is covalently bonded directly to a nitrogen atom which may be further substituted or protected. An amide solvent S A is herein further defined by comprising one or more alkyl groups, wherein these one or more alkyl groups together comprise in total 6−48 carbon atoms or 8−48 carbon atoms. Examples and further embodiments pertaining to an amide solvent S A will be laid out in a later section of this text. To state that a certain step, e.g. any one of steps (c-1), (g-1), (c-2), (g-2), (c-x), and (g-x), is carried out “in the presence of one or more amide solvents S A ” may be understood in the broadest sense to mean that the solvent or mixed solvent, in which or with which the respective step is carried out, comprises at least one amide solvent S A . In the case of the extraction steps (c-1), (g-1), (c-2), (g-2), (c-x), and (g-x) this may mean that each of the one or more aqueous extractions is carried out in the presence of at least one amide solvent S A , wherein the latter is preferably (at least partly or mostly) comprised in the organic phase. As used herein, the term “solid-liquid separation” refers to any operation during which a solid is separated from a liquid. Most commonly, solid-liquid separation will be filtration or centrifugation, preferably filtration. It will be understood that such solid-liquid separation may typically not be complete, meaning that some residual liquid may typically be attached to the solid after solid-liquid separation, as known to those skilled in the art. It will be understood that the term “solid-liquid separation” does not embrace evaporation of the liquid. Hence, as used herein, a step of, e.g., evaporating a solution to dryness is not considered a “solid-liquid separation”. In some embodiments of the present invention, the process does not comprise any solid-liquid separation during or in between at least at least 3, 4, 5, 6, 7, 8, 9 consecutive coupling cycles. In some embodiments of the present invention, the process does not comprise any solid-liquid separation of the n-th cycle oligonucleotide O-n or of any oligonucleotidic educts or intermediates involved in the synthesis of the n-th cycle oligonucleotide O-n during or in between at least at least 3, 4, 5, 6, 7, 8, 9 consecutive coupling cycles. The term “during and in between steps (b-1) to (h-1)” means that - none of the steps (b-1), (c-1), (d-1), (e-1), (f-1), (g-1), and (h-1) comprises a solid-liquid separation (each of steps (d-1), (f-1), (g-1), and (h-1) may or may not be carried out as explained above), - if carried out, step (i-1) does not comprise a solid-liquid separation, and - no solid-liquid separation is performed in between any two of these steps. The term “during and in between steps (b-1) to (h-2)” means that - none of the steps (b-1), (c-1), (d-1), (e-1), (f-1), (g-1), (h-1), (b-2), (c-2), (d-2), (e-2), (f-2), (g-2), and (h-2) (as far as present, each of steps (d-1), (f-1), (g-1), (h-1), (d-2), (f-2), (g-2), (h-2) may or may not be carried out as explained above), comprises a solid-liquid separation, - if carried out, step (i-1) does not comprise a solid-liquid separation, - if carried out, step (i-2) does not comprise a solid-liquid separation, and - no solid-liquid separation is performed in between any two of these steps. The term “during and in between steps (b-1) to (h-n)” means that - none of the steps (b-1), (c-1), (d-1), (e-1), (f-1), (g-1), (h-1), (b-2), (c-2), (d-2), (e-2), (f-2), (g-2), and (h-2)(each of steps (d-1), (f-1), (g-1), (h-1), (d-2), (f-2), (g- 2), (h-2) may or may not be carried out as explained above) comprises a solid-liquid separation, - no iteration of step (b-x), no iteration of step (c-x), no iteration of step (d-x), no iteration of step (e-x), no iteration of step (f-x), no iteration of step (g-x), and no iteration of step (h-x) (each of steps (d-x), (f-x) (g-x) and (h-x) may or may not be carried out in a given coupling cycle) comprises a solid-liquid separation, - if carried out, step (i-1) does not comprise a solid-liquid separation, - if carried out, step (i-2) does not comprise a solid-liquid separation, - if carried out, no iteration of step (i-x) comprises a solid-liquid separation, and - no solid-liquid separation is performed in between any two of these steps. In some embodiments of the method of the invention, steps (b-1) to (h-1) (i.e. any one of steps (b-1), (c-1), (d-1), (e-1), (f-1), (g-1), and (h-1) as far as present) are carried out in the presence of one or more amide solvents S A and, preferably, one or more ether solvent S E . It will be understood that this does not imply that any optional step must be carried out. In some embodiments of the method of the invention, if the second coupling cycle comprising steps (b-2) to (h-2) is performed, steps (b-1) to (h-2) (i.e. any one of steps (b-1), (c-1), (d-1), (e-1), (f-1), (g-1), (h-1), (b-2), (c-2), (d-2), (e-2), (f-2), (g-2), and (h-2) as far as present) are carried out in the presence of one or more amide solvents S A and, preferably, one or more ether solvent S E . It will be understood that this does not imply that any optional step must be carried out. In some embodiments of the method of the invention, if (n−2) iterations of the coupling cycle comprising steps (b-x) to (h-x) (as far as present) are performed, all of steps (b-1) to (h-n) (as far as present) (i.e. any one of steps (b-1), (c-1), (d-1), (e- 1), (f-1), (g-1), (h-1), (b-2), (c-2), (d-2), (e-2), (f-2), (g-2), and (h-2), as far as present, as well as each iteration of any one of steps (b-x), (c-x), (d-x), (e-x), (f-x), (g-x), and (h-x)) are carried out in the presence of one or more amide solvents S A and, preferably, one or more ether solvent S E . It will be understood that this does not imply that any optional step must be carried out. In some embodiments of the method of the invention, steps (b-1) to (h-1) (as far as present) are carried out in the presence of one or more amide solvents S A and, preferably, one or more ether solvents S E , and further wherein: - if the second coupling cycle comprising steps (b-2) to (h-2) (as far as present) is performed, steps (b-1) to (h-2) (as far as present) are carried out in the presence of one or more amide solvents S A and, preferably, one or more ether solvents S E ; and - if (n−2) iterations of the coupling cycle comprising steps (b-x) to (h-x) (as far as present) are performed, all of steps (b-1) to (h-n) (as far as present) are carried out in the presence of one or more amide solvents S A and, preferably, one or more ether solvents S E . The term “in the presence of one or more amide solvents S A ” has been defined above, in particular with a focus on the extraction steps. In the case of steps pertaining to a chemical reaction such as the deprotection steps (b-1), (b-2), and (b-x), the coupling steps (e-1), (e-2), and (e-x) as well as the oxidation or sulfurization steps (f-1), (f-2), and (f-x), the term “in the presence of one or more amide solvents S A ” may mean that the reaction mixture of the respective step(s) (i.e. the solution in which the respective reaction occurs) comprises at least one amide solvent S A . In the case steps (d-1), (d-2), (d-x), (h-1), (h-2), and (h-x), the term “in the presence of one or more amide solvents S A ” may mean that said organic phase, whose water content is to be reduced, comprises at least one amide solvent S A . It will be understood that any explanations pertaining to the term “in the presence of one or more amide solvents S A ” also apply to the term “in the presence of one or more ether solvents S E ”. As used herein, the term “ether solvent” may be understood in the broadest sense to refer to any solvent characterized in that its chemical structure comprises at least one oxygen atom covalently bonded to exactly two residues independently selected from the group consisting of an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group, a heteroalkynyl group, an aryl group, and a heteroaryl group, wherein each of these two residues engages in a covalent chemical bond to said oxygen atom via a carbon atom (C), and wherein these two residues may optionally bond to each other to form a cyclic structure. Unless indicated differently in the context of specific embodiments, an ether solvent S E may be any ether solvent. Examples and further embodiments pertaining to an ether solvent S E will be laid out in a later section of this text. In some embodiments of the method of the invention: - each of steps (b-1), (e-1) and (f-1) is carried out in a mixed solvent comprising in total 10−90 vol-% of one or more amide solvents S A and 10−90 vol-% of one or more ether solvents S E ; - if the second coupling cycle comprising steps (b-2) to (h-2) (as far as present) is performed, each of steps (b-1), (e-1), (f-1), (b-2), (e-2), and (f-2) is carried out in a mixed solvent comprising in total 10−90 vol-% of one or more amide solvents S A and 10−90 vol-% of one or more ether solvents S E ; and - if (n−2) iterations of the coupling cycle comprising steps (b-x) to (h-x) (as far as present) are performed, each of steps (b-1), (e-1), (f-1), (b-2), (e-2), and (f-2) as well as each iteration of steps (b-x), (e-x), and (f-x) is carried out in a mixed solvent comprising in total 10−90 vol-% of one or more amide solvents S A and 10−90 vol-% of one or more ether solvents S E . It will be understood that this does not imply that the optional step (f-1) or (f-2) or (f-x) is performed in each coupling cycle. The term solvent in the term “carried out in a solvent” will be understood to refer to the reaction solvent, i.e. to the solvent or mixed solvent, in which the respective chemical reaction (deprotection or coupling or oxidation/sulfurization) takes place. In some embodiments of the method of the invention: - each of steps (b-1), (e-1) and (f-1) is carried out in a mixed solvent comprising in total 20−80 vol-% of one or more amide solvents S A and 20−80 vol-% of one or more ether solvents S E ; - if the second coupling cycle comprising steps (b-2) to (h-2) (as far as present) is performed, each of steps (b-1), (e-1), (f-1), (b-2), (e-2), and (f-2) is carried out in a mixed solvent comprising in total 20−80 vol-% of one or more amide solvents S A and 20−80 vol-% of one or more ether solvents S E ; and - if (n−2) iterations of the coupling cycle comprising steps (b-x) to (h-x) (as far as present) are performed, each of steps (b-1), (e-1), (f-1), (b-2), (e-2), and (f-2) as well as each iteration of steps (b-x), (e-x), and (f-x) is carried out in a mixed solvent comprising in total 20−80 vol-% of one or more amide solvents S A and 20−80 vol-% of one or more ether solvents S E . In some embodiments of the method of the invention: - each of steps (b-1), (e-1) and (f-1) is carried out in a mixed solvent comprising in total 30−70 vol-% of one or more amide solvents S A and 30−70 vol-% of one or more ether solvents S E ; - if the second coupling cycle comprising steps (b-2) to (h-2) (as far as present) is performed, each of steps (b-1), (e-1), (f-1), (b-2), (e-2), and (f-2) is carried out in a mixed solvent comprising in total 30−70 vol-% of one or more amide solvents S A and 30−70 vol-% of one or more ether solvents S E ; and - if (n−2) iterations of the coupling cycle comprising steps (b-x) to (h-x) (as far as present) are performed, each of steps (b-1), (e-1), (f-1), (b-2), (e-2), and (f-2) as well as each iteration of steps (b-x), (e-x), and (f-x) is carried out in a mixed solvent comprising in total 30−70 vol-% of one or more amide solvents S A and 30−70 vol-% of one or more ether solvents S E . In some embodiments of the method of the invention: - each of steps (b-1), (e-1) and (f-1) is carried out in a mixed solvent comprising in total 10−50 vol-% of one or more amide solvents S A and 50−90 vol-% of one or more ether solvents S E ; - if the second coupling cycle comprising steps (b-2) to (h-2) (as far as present) is performed, each of steps (b-1), (e-1), (f-1), (b-2), (e-2), and (f-2) is carried out in a mixed solvent comprising in total 10−50 vol-% of one or more amide solvents S A and 50−90 vol-% of one or more ether solvents S E ; and - if (n−2) iterations of the coupling cycle comprising steps (b-x) to (h-x) (as far as present) are performed, each of steps (b-1), (e-1), (f-1), (b-2), (e-2), and (f-2) as well as each iteration of steps (b-x), (e-x), and (f-x) is carried out in a mixed solvent comprising in total 10−50 vol-% of one or more amide solvents S A and 50−90 vol-% of one or more ether solvents S E . In some embodiments of the method of the invention: - each of steps (b-1), (e-1) and (f-1) is carried out in a mixed solvent comprising in total 20−50 vol-% of one or more amide solvents S A and 50−80 vol-% of one or more ether solvents S E ; - if the second coupling cycle comprising steps (b-2) to (h-2) (as far as present) is performed, each of steps (b-1), (e-1), (f-1), (b-2), (e-2), and (f-2) is carried out in a mixed solvent comprising in total 20−50 vol-% of one or more amide solvents S A and 50−80 vol-% of one or more ether solvents S E ; and - if (n−2) iterations of the coupling cycle comprising steps (b-x) to (h-x) (as far as present) are performed, each of steps (b-1), (e-1), (f-1), (b-2), (e-2), and (f-2) as well as each iteration of steps (b-x), (e-x), and (f-x) is carried out in a mixed solvent comprising in total 20−50 vol-% of one or more amide solvents S A and 50−80 vol-% of one or more ether solvents S E . The composition of the solvents in which any one of steps (b-1), (e-1), (f-1), (b-2), (e-2), (f-2), (b-x), (e-x), and (f-x) is carried out, may, for example, be analyzed by means of gas chromatography. For example, the following setup may be used: Column: SH-Rxi-624Sil MS (30 m × 0.32 mmID, 1.8 µm), Injection volume: 1 µL, Inlet: Split (5/1), Injection temperature: 230 °C, Column flow: 35 cm/s Helium, Column temperature program: 40 °C (2 min)-10 °C/min-240 °C (20 min) total 42 min, Detector: FDI at 250 °C. The content of the respective solvents may be calculated by using a calibration curve. Instead of direct injection as laid out above, headspace injection may also be used, e.g., with sample thermostatting at 160 °C for 30 min, with a head space pressure of 70.0 kPa, with a sample and transfer line temperature of 165 °C, and with an injection volume of 1.0 mL. It will be understood that one or more amide solvents S A and/or one or more ether solvents S E may be added to the reaction mixtures or organic phases at any time throughout the method of the invention. In some embodiments of the method of the invention, steps (b-1) to (h-1) (i.e. any one of steps (b-1), (c-1), (d-1), (e-1), (f-1), (g-1), and (h-1) as far as present) are carried out in essentially halogen-free solvents. It will be understood that this does not imply that any optional step must be carried out. In some embodiments of the method of the invention, if the second coupling cycle comprising steps (b-2) to (h-2) (as far as present) is performed, steps (b-1) to (h-2) (i.e. any one of steps (b-1), (c-1), (d-1), (e-1), (f-1), (g-1), (h-1), (b-2), (c-2), (d-2), (e-2), (f-2), (g-2), and (h-2) as far as present) are carried out in essentially halogen- free solvents. It will be understood that this does not imply that any optional step must be carried out. In some embodiments of the method of the invention, if (n−2) iterations of the coupling cycle comprising steps (b-x) to (h-x) (as far as present) are performed, all of steps (b-1) to (h-n) (i.e. any one of steps (b-1), (c-1), (d-1), (e-1), (f-1), (g-1), (h- 1), (b-2), (c-2), (d-2), (e-2), (f-2), (g-2), and (h-2), as far as present, as well as each iteration of any one of steps (b-x), (c-x), (d-x), (e-x), (f-x), (g-x), and (h-x)) are carried out in essentially halogen-free solvents. It will be understood that this does not imply that any optional step must be carried out. In some embodiments of the method of the invention, steps (b-1) to (h-1) (as far as present) are carried out in essentially halogen-free solvents, and further wherein: - if a second coupling cycle comprising steps (b-2) to (h-2) (as far as present) is performed, steps (b-1) to (h-2) (as far as present) are carried out in essentially halogen-free solvents; and - if (n−2) iterations of the coupling cycle comprising steps (b-x) to (h-x) (as far as present) are performed, any steps (b-1) to (h-n) (as far as present) are carried out in essentially halogen-free solvents. As used herein, the term “essentially halogen-free solvent” refers to a solvent which contains in total equal to or less than 3.0 vol-%, 2.0 vol-%, 1.0 vol-%, 0.1 vol-%, 0.01 vol-%, or 0.001 vol-% of halogenated solvents. As used, the term “halogenated solvent” refers to any solvent comprising in its chemical structure at least one halogen atom. Examples of halogenated solvents comprise dichloromethane, chloroform, and 1,1-dichloroethane, and 1,2-dichloroethane. To state that a step “is carried out in essentially halogen-free solvents” means that only essentially halogen-free solvents are used in the respective step. In some embodiments of the method of the invention: - said component C-0 comprises exactly one pseudo solid-phase protecting group, which is the pseudo solid-phase protecting group PG-s; and - the building block B-1 does not comprise any pseudo solid-phase protecting groups. In some embodiments of the method of the invention: - said component C-0 comprises exactly one pseudo solid-phase protecting group, which is the pseudo solid-phase protecting group PG-s; and - none of the building block B-1 and B-2 comprise any pseudo solid-phase protecting groups. In some embodiments of the method of the invention: - said component C-0 comprises exactly one pseudo solid-phase protecting group, which is the pseudo solid-phase protecting group PG-s; and - none of the building block B-1, B-2, and B-x comprise any pseudo solid-phase protecting groups. In some embodiments of the method of the invention, the sum of nucleoside subunits comprised in the component C-0 and all building blocks B-1, B-2, and B-x together is in the range of 5−100, 5−90, 5−80, 5−70, 5−60, 5−50, 5−40, 5−30, 5−20, 6−20 or 6−18. It will be understood that in the component C-0 of any one of Formulae I, I-a, I-b, the amount of nucleoside subunits is determined as 1 + m, where m is the integer m. It will be understood that in each building block B-1, B-2, and B-x of any one of Formulae II, II-a, II-b, II-1, II-1-a, II-1-b, II-2, II-2-a, and II-2-b, the amount of nucleoside subunits is determined as 1 + q, where q is the integer q. In some embodiments of the method of the invention: - said component C-0 comprises exactly one pseudo solid-phase protecting group, which is the pseudo solid-phase protecting group PG-s; - none of the building blocks B-1, B-2, and B-x comprises any pseudo solid-phase protecting groups; and - the sum of nucleoside subunits comprised in the component C-0 and all building blocks B-1, B-2, and B-x together is in the range of 5−100, 5−90, 5−80, 5−70, 5−60, 5−50, 5−40, 5−30, 5−20, 6−20 or 6−18. In some embodiments of the method of the invention; - the first cycle oligonucleotide O-1 comprises exactly one pseudo solid-phase protecting group, which is the pseudo solid-phase protecting group PG-s, and - the first cycle oligonucleotide comprises in total 5−100, 5−90, 5−80, 5−70, 5−60, 5−50, 5−40, 5−30, 5−20, 6−20 or 6−18 nucleoside subunits. In some embodiments of the method of the invention; - the second cycle oligonucleotide O-2 comprises exactly one pseudo solid-phase protecting group, which is the pseudo solid-phase protecting group PG-s, and - the second cycle oligonucleotide O-2 comprises in total 5−100, 5−90, 5−80, 5−70, 5−60, 5−50, 5−40, 5−30, 5−20, 6−20 or 6−18 nucleoside subunits. In some embodiments of the method of the invention; - the n-th cycle oligonucleotide O-n comprises exactly one pseudo solid-phase protecting group, which is the pseudo solid-phase protecting group PG-s, and - the n-th cycle oligonucleotide O-n comprises in total 5−100, 5−90, 5−80, 5−70, 5−60, 5−50, 5−40, 5−30, 5−20, 6−20 or 6−18 nucleoside subunits. Another aspect of the present invention pertains to a composition comprising - an oligonucleotide which is covalently bonded to at least one pseudo solid-phase protecting group, and - a mixed solvent which is essentially halogen-free and comprises one or more amide solvents S A and, preferably, one or more ether solvents S E , wherein each amide solvent S A is an amide solvent comprising one or more alkyl groups, wherein these one or more alkyl groups together comprise in total 6–48 carbon atoms or 8−48 carbon atoms. Another aspect of the present invention pertains to a composition comprising - an oligonucleotide which is covalently bonded to at least one pseudo solid-phase protecting group, and - a mixed solvent which is essentially halogen-free and comprises one or more amide solvents S A and, preferably, one or more ether solvents S E , wherein each amide solvent S A is an amide solvent comprising one or more alkyl groups, wherein these one or more alkyl groups together comprise in total 6–24 carbon atoms. Another aspect of the present invention pertains to a composition comprising - an oligonucleotide which is covalently bonded to at least one pseudo solid-phase protecting group, and - a mixed solvent which is essentially halogen-free and comprises one or more amide solvents S A and, preferably, one or more ether solvents S E , wherein each amide solvent S A is an amide solvent comprising one or more alkyl groups, wherein these one or more alkyl groups together comprise in total 6–16 or 6–15 carbon atoms. In some embodiments of the composition of the invention, said oligonucleotide is covalently bonded to exactly one pseudo solid-phase protecting group and comprises in total 5−100, 5−90, 5−80, 5−70, 5−60, 5−50, 5−40, 5−30, 5−20, 6−20 or 6−18 or 5–18 nucleoside subunits. In some preferred embodiments of the composition of the invention, said oligonucleotide is covalently bonded to exactly one pseudo solid-phase protecting group and comprises equal to or more than 5 nucleoside subunits, in particular 5–18 nucleoside subunits. In some embodiments of the composition of the invention, said oligonucleotide, which is covalently bonded to a pseudo solid-phase protecting group, has a structure of any one of the above- mentioned Formulae I, I-a, and I-b. In some embodiments of the composition of the invention, said oligonucleotide, which is covalently bonded to a pseudo solid-phase protecting group, is the component C-0 as defined above. In such embodiments, any definitions and embodiments pertaining to the component C-0 in the context of the method of the invention may likewise apply to the component C-0 in the context of the composition of the invention. In some embodiments of the composition of the invention, said oligonucleotide, which is covalently bonded to a pseudo solid-phase protecting group, is the component (C-0) # as defined above. In such embodiments, any definitions and embodiments pertaining to the component (C-0) # in the context of the method of the invention may likewise apply to the component (C-0) # in the context of the composition of the invention. The term “essentially halogen-free” has been defined in the context of the method of the invention. This definition likewise applies to the composition of the invention, in particular to said mixed solvent. In some embodiments of the composition of the invention, said mixed solvent comprises 10−90 vol-% of one or more amide solvents S A and 10−90 vol-% of one or more ether solvents S E . In some embodiments of the composition of the invention, said mixed solvent comprises 20−80 vol-% of one or more amide solvents S A and 20−80 vol-% of one or more ether solvents S E . In some embodiments of the composition of the invention, said mixed solvent comprises 30−70 vol-% of one or more amide solvents S A and 30−70 vol-% of one or more ether solvents S E . In some embodiments of the composition of the invention, said mixed solvent comprises 10−50 vol-% of one or more amide solvents S A and 50−90 vol-% of one or more ether solvents S E . In some embodiments of the composition of the invention, said mixed solvent comprises 20−50 vol-% of one or more amide solvents S A and 50−80 vol-% of one or more ether solvents S E . The composition of said mixed solvent may, for example, be analyzed by means of gas chromatography. For example, the following setup may be used: Column: SH-Rxi- 624Sil MS (30 m × 0.32 mmID, 1.8 µm), Injection volume: 1 µL, Inlet: Split (5/1), Injection temperature: 230 °C, Column flow: 35 cm/s Helium, Column temperature program: 40 °C (2 min)-10 °C/min-240 °C (20 min) total 42 min, Detector: FDI at 250 °C. The content of the respective solvents may be calculated by using a calibration curve. In some embodiments of the method and the composition of the invention, each amide solvent S A is an amide solvent comprising one or more alkyl groups, wherein these one or more alkyl groups together comprise in total 6−48, 8−48, 6−47, 8−47, 6−46, 8−46, 6−45, 8−45, 6−44, 8−44, 6−43, 8−43, 6−42, 8−42, 6−41, 8−41, 6−40, 8−40, 6−39, 8−39, 6−38, 8−38, 6−37, 8−37, 6−36, 8−36, 6−35, 8−35, 6−34, 8−34, 6−33, 8−33, 6−32, 8−32, 6−31, 8−31, 6−30, 8−30, 6−29, 8−29, 6−28, 8−28, 6−27, 8−27, 6−26, 8−26, 6−25, 8−25, 6−24, 8−24, 6–23, 8–23, 6–22, 8–22, 6–21, 8–21, 6–20, 8–20, 6–19, 8–19, 6–18, 8–18, 6–17, 8–17, 6−16, 8−16, 6–15, 8–15, 6–14, 8–14, 6–13, 8–13, 6−12, or 8−12, 6−48 carbon atoms. In some embodiments of the method and the composition of the invention, each amide solvent S A is at each occurrence selected independently from the group consisting of the following Formulae S A -1, S A -2, and S A -3: wherein in Formula S A -1: R A-1 is selected from the group consisting of H and a C1−C24-alkyl group, in which exactly one hydrogen residue may optionally be substituted by a C(O)O(C1−C5-alkyl) group; and each of R A-2 and R A-3 is independently a C1−C24-alkyl group; with the proviso that R A-1 , R A-2 and R A-3 together comprise in total 6−48 carbon atoms; wherein in Formula S A -2: o is an integer of 1 or 2; and R A-4 is a C 6 –C 24 -alkyl group; and wherein in Formula S A -3: p is an integer of 1 or 2; X A is selected from the group consisting of CH 2 , O, and NC(O)R A-6 , with the proviso that, if p is 1, X A is CH 2 ; R A-5 is a C1–C24-alkyl group; and R A-6 is a C1–C24-alkyl group; with the proviso that R A-5 and R A-6 together comprise in total 6–48 carbon atoms. Herein, when denoting residues comprising heteroatoms, brackets are occasionally used for illustrative purposes, as, e.g., exemplified in the following residue: C(O)O(C1C5-alkyl). Such brackets are not to be construed to indicate that the group in brackets is only optionally comprised in the respective residue. If an oxygen atom of a chemical residue is depicted in brackets, this indicates that said oxygen atom is covalently bonded only to the carbon atom depicted to the left in the chemical formula of the respective residue. If a hydrocarbon group such as, e.g., a C 1 –C 5 -alkyl group forms part of a residue comprising further atoms, said hydrocarbon group may be presented in brackets to highlight the fact that it is a separate group within said residue. This will easily be understood based on the common general knowledge. For example, a C(O)O(C 1 –C 5 -alkyl) residue is an ester residue, bonded via the carboxyl carbon atom to the respective parent structure, wherein the C1–C5-alkyl moiety is bonded to the oxygen atom not depicted in brackets. As another example, a O(C1–C40-alkyl) residue denotes an alkoxy residue in which the alkyl moiety comprises at least one and not more than 40 carbon atoms. As another example, a C(O)(C1–C40-alkyl) residue denotes an alkanoyl residue bonded to the respective parent structure via a carbonyl carbon atom, wherein the C1–C40-alkyl moiety is bonded directly to the carbonyl carbon atom and not to the oxygen atom depicted in brackets. In some embodiments of the method and the composition of the invention, each amide solvent S A is independently of each other a solvent of any one of the aforementioned Formulae S A -1, S A -2, and S A -3, wherein in Formula S A -1: R A-1 is selected from the group consisting of H and a C 1 –C 24 -alkyl group, in which exactly one hydrogen atom may optionally be substituted by a C(O)O(C 1 −C 5 -alkyl) group; and each of R A-2 and R A-3 is independently a C1–C24-alkyl group, with the proviso that R A-1 , R A-2 and R A-3 together comprise in total 8–48 carbon atoms; wherein in formula A-2: o is an integer of 1 or 2; and R A-4 is a C 8 –C 24 -alkyl group; and wherein in formula A-3: p is an integer of 1 or 2; X A is selected from the group consisting of CH2 (i.e. a methylene group), O, and NC(O)R A-6 , with the proviso that, if p is 1, X A is CH2; R A-5 is a C1–C24-alkyl group; and R A-6 is a C1–C24-alkyl group; with the proviso that R A-5 and R A-6 together comprise in total 8–48 carbon atoms. In some embodiments of the method and the composition of the invention, each amide solvent S A is independently of each other a solvent of any one of the aforementioned Formulae S A -1, S A -2, and S A -3, wherein in Formula S A -1: R A-1 is selected from the group consisting of H and a C 1 –C 24 -alkyl group, in which exactly one hydrogen residue may optionally be substituted by a C(O)O(C 1 −C 5 -alkyl) group; and each of R A-2 and R A-3 is independently a C 1 –C 24 -alkyl group, with the proviso that R A-1 , R A-2 and R A-3 together comprise in total 6–36 carbon atoms; wherein in formula A-2: o is an integer of 1 or 2; and R A-4 is a C6–C24-alkyl group; and wherein in formula A-3: p is an integer of 1 or 2; X A is selected from the group consisting of CH2 (i.e. a methylene group), O, and NC(O)R A-6 , with the proviso that, if p is 1, X A is CH2; R A-5 is a C1–C24-alkyl group; and R A-6 is a C1–C24-alkyl group; with the proviso that R A-5 and R A-6 together comprise in total 6–36 carbon atoms. In some embodiments of the method and the composition of the invention, each amide solvent S A is independently of each other a solvent of any one of the aforementioned Formulae S A -1, S A -2, and S A -3, wherein in Formula S A -1: R A-1 is selected from the group consisting of H and a C 1 –C 22 -alkyl group, in which exactly one hydrogen residue may optionally be substituted by a C(O)O(C1−C5-alkyl) group; and each of R A-2 and R A-3 is independently a C1–C23-alkyl group, with the proviso that R A-1 , R A-2 and R A-3 together comprise in total 6–24 carbon atoms; wherein in formula A-2: o is an integer of 1 or 2; and R A-4 is a C6–C24-alkyl group; and wherein in formula A-3: p is an integer of 1 or 2; X A is selected from the group consisting of CH 2 (i.e. a methylene group), O, and NC(O)R A-6 , with the proviso that, if p is 1, X A is CH 2 ; R A-5 is a C 1 –C 24 -alkyl group; and R A-6 is a C 1 –C 23 -alkyl group; with the proviso that R A-5 and R A-6 together comprise in total 6–24 carbon atoms. In some embodiments of the method and the composition of the invention, each amide solvent S A is independently of each other a solvent of any one of the aforementioned Formulae S A -1, S A -2, and S A -3, wherein in Formula S A -1: R A-1 is selected from the group consisting of H and a C1–C14-alkyl group, in which exactly one hydrogen residue may optionally be substituted by a C(O)O(C1−C5-alkyl) group; and each of R A-2 and R A-3 is independently a C1–C15-alkyl group, with the proviso that R A-1 , R A-2 and R A-3 together comprise in total 6–16 carbon atoms; wherein in formula A-2: o is an integer of 1 or 2; and R A-4 is a C6–C16-alkyl group; and wherein in formula A-3: p is an integer of 1 or 2; X A is selected from the group consisting of CH 2 (i.e. a methylene group), O, and NC(O)R A-6 , with the proviso that, if p is 1, X A is CH 2 ; R A-5 is a C1–C16-alkyl group; and R A-6 is a C1–C15-alkyl group; with the proviso that R A-5 and R A-6 together comprise in total 6–16 carbon atoms. In some embodiments of the method and the composition of the invention, each amide solvent S A is independently of each other a solvent of any one of the aforementioned Formulae S A -1, S A -2, and S A -3, wherein in Formula S A -1: R A-1 is selected from the group consisting of H and a C1–C13-alkyl group, in which exactly one hydrogen residue may optionally be substituted by a C(O)O(C1−C5-alkyl) group; and each of R A-2 and R A-3 is independently a C1–C14-alkyl group, with the proviso that R A-1 , R A-2 and R A-3 together comprise in total 6–15 carbon atoms; wherein in formula A-2: o is an integer of 1 or 2; and R A-4 is a C 6 –C 15 -alkyl group; and wherein in formula A-3: p is an integer of 1 or 2; X A is selected from the group consisting of CH 2 (i.e. a methylene group), O, and NC(O)R A-6 , with the proviso that, if p is 1, X A is CH 2 ; R A-5 is a C 1 –C 15 -alkyl group; and R A-6 is a C1–C14-alkyl group; with the proviso that R A-5 and R A-6 together comprise in total 6–15 carbon atoms. In some embodiments of the method and the composition of the invention, each amide solvent S A is independently of each other a solvent of any one of the aforementioned Formulae S A -1, S A -2, and S A -3, wherein in Formula S A -1: R A-1 is selected from the group consisting of H and a C1–C24-alkyl group, and each of R A-2 and R A-3 is independently a C1–C24-alkyl group; with the proviso that R A-1 , R A-2 and R A-3 together comprise in total 8–48 carbon atoms; wherein in formula A-2: o is an integer of 1 or 2; and R A-4 is a C 8 –C 24 -alkyl group; and wherein in formula A-3: p is an integer of 1 or 2; X A is selected from the group consisting of CH2 (i.e. a methylene group) and O, with the proviso that, if p is 1, X A is CH2; and R A-5 is a C8–C24-alkyl group. In some embodiments of the method and the composition of the invention, each amide solvent S A is independently of each other a solvent of any one of the aforementioned Formulae S A -1, S A -2, and S A -3, wherein in Formula S A -1: R A-1 is H; and each of R A-2 and R A-3 is independently a C1–C24-alkyl group; with the proviso that R A-1 , R A-2 and R A-3 together comprise in total 8–48 carbon atoms; wherein in formula A-2: o is an integer of 1 or 2; and R A-4 is a C 8 –C 24 -alkyl group; and wherein in formula A-3: p is an integer of 1 or 2; X A is selected from the group consisting of CH 2 (i.e. a methylene group) and O, with the proviso that, if p is 1, X A is CH 2 ; and R A-5 is a C 8 –C 24 -alkyl group. In some embodiments of the method and the composition of the invention, each amide solvent S A is independently of each other a solvent of any one of the aforementioned Formulae S A -1, S A -2, and S A -3, wherein in Formula S A -1: R A-1 is H; and each of R A-2 and R A-3 is independently a C4–C12-alkyl group; wherein in formula A-2: o is an integer of 1 or 2; and R A-4 is a C8–C12-alkyl group; and wherein in formula A-3: p is an integer of 1 or 2; X A is selected from the group consisting of CH 2 (i.e. a methylene group) and O, with the proviso that, if p is 1, X A is CH 2 ; and R A-5 is a C 8 –C 12 -alkyl group. In some embodiments of the method and the composition of the invention, each amide solvent S A is independently of each other a solvent of any one of the aforementioned Formulae S A -1, S A -2, and S A -3, wherein in Formula S A -1: R A-1 is H; and each of R A-2 and R A-3 is independently a C 4 –C 12 -alkyl group; wherein in formula A-2: o is an integer of 1 or 2; and R A-4 is a C8–C12-alkyl group; and wherein in formula A-3: p is an integer of 1 or 2; X A is CH2; and R A-5 is a C8–C12-alkyl group. In some embodiments of the method and the composition of the invention, each amide solvent S A is independently of each other a solvent of any one of the aforementioned Formulae S A -1, S A -2, and S A -3, wherein in Formula S A -1: R A-1 is selected from the group consisting of H and a C 1 –C 12 -alkyl group; and each of R A-2 and R A-3 is independently a C 1 –C 12 -alkyl group, with the proviso that R A-1 , R A-2 and R A-3 together comprise in total 6–16 carbon atoms; wherein in formula A-2: o is an integer of 1 or 2; and R A-4 is a C6–C16-alkyl group; and wherein in formula A-3: p is an integer of 1 or 2; X A is CH2; and R A-5 is a C6–C16-alkyl group In some embodiments of the method and the composition of the invention, each amide solvent S A is independently of each other a solvent of any one of the aforementioned Formulae S A -1, and S A -2, wherein in Formula S A -1: R A-1 is selected from the group consisting of H and a C 1 –C 12 -alkyl group; and each of R A-2 and R A-3 is independently a C 1 –C 12 -alkyl group, with the proviso that R A-1 , R A-2 and R A-3 together comprise in total 6–16 carbon atoms; wherein in formula A-2: o is an integer of 1 or 2; and R A-4 is a C6–C16-alkyl group. In some embodiments of the method and the composition of the invention, each amide solvent S A is independently of each other a solvent of any one of the aforementioned Formulae S A -1, and S A -2. In some embodiments of the method and the composition of the invention, each amide solvent S A is independently of each other a solvent of the aforementioned Formulae S A -1. In some embodiments of the method and the composition of the invention, each amide solvent S A is independently of each other a solvent of the aforementioned Formulae S A -2. The skilled artisan is capable of identifying and obtaining amide solvents S A fulfilling the aforementioned structural requirements and such amide solvents may also be commercially available. Examples of amide solvents S A of Formula S A -1 comprise N,N-dibutylformamide (DBF), N,N-dibutylacetamide, methyl 5-(dimethylamino)-2- methyl-5-oxopentanoate (CAS-RN 1174627-68-9), N,N-dimethyloctanamide, N,N-dimethyldecanamide, N,N-diethyldodecanamide, and N,N-bis(1- methylpropyl)acetamide. Examples of amide solvents S A of Formula S A -2 comprise N-octyl-2-pyrrolidone (NOP), N-octyl-2-piperidone, and 1-cyclohexyl-2-pyrrolidone (CAS RN: 6837-24-7). Examples of amide solvents S A of Formula S A -3 comprise N-nonanoylpyrrolidine (CAS-RN 20308-70-7), N-nonanoylpiperidine (CAS-RN 20368-13-2), N-nonanoylmorpholine (CAS-RN 5299-64-9), and 1,4-dipentanoylpiperazine (CAS RN 18903-08-7). In some embodiments of the method and the composition of the invention, each amide solvent S A independently of each other is selected from the group consisting of N,N-dibutylformamide (DBF) and N-octyl-2-pyrrolidone (NOP). In some embodiments of the method and the composition of the invention, each amide solvent S A is independently of each other selected from the group consisting of, N-octyl-2-pyrrolidone (NOP), N,N-dibutylformamide (DBF), N,N-diethyldodecanamide, and 1-cyclohexyl-2- pyrrolidone. In some embodiments of the method and the composition of the invention, each ether solvent S E is at each occurrence selected independently from the group consisting of the following Formulae S E -1 and S E -2: (Formula S E -2), wherein in Formula S E -1: s is an integer of 0 or 1, and each of R E-1 , R E-2 , R E-3 , R E-4 , R E-5 , R E-6 , R E-7 , R E-8 , R E-9 , and R E-10 is independently selected from the group consisting of H and a C1−C5-alkyl group, with the proviso that at least one of R E-1 , R E-2 , R E-3 , R E-4 , R E-5 , R E-6 , R E-7 , R E-8 , R E-9 , and R E-10 is a C1−C5-alkyl group; and wherein in Formula S E -2: each of R E-11 and R E-12 is independently a C1−C6-alkyl group, with the proviso that R E-11 and R E-12 together comprise in total 5−12 carbon atoms (i.e. not less than 5 and not more than 12 carbon atoms). In some embodiments of the method and the composition of the invention, each ether solvent S E is independently of each other a solvent of any one of the aforementioned Formulae S E -1 and S E -2, wherein in Formula S E -1: s is an integer of 0 or 1, and each of R E-1 , R E-2 , R E-3 , R E-4 , R E-5 , R E-6 , R E-7 , R E-8 , R E-9 , and R E-10 is independently selected from the group consisting of H and a C 1 −C 5 -alkyl group, with the proviso that exactly one, exactly two or exactly three of R E-1 , R E-2 , R E-3 , R E-4 , R E-5 , R E-6 , R E-7 , R E-8 , R E-9 , and R E-10 are a C1−C5-alkyl group; and wherein in Formula S E -2: each of R E-11 and R E-12 is independently a C1−C6-alkyl group, with the proviso that R E-11 and R E-12 together comprise in total 6−12 carbon atoms. In some embodiments of the method and the composition of the invention, each ether solvent S E is independently of each other a solvent of any one of the aforementioned Formulae S E -1 and S E -2, wherein in Formula S E -1: s is an integer of 0 or 1, and each of R E-1 , R E-2 , R E-3 , R E-4 , R E-5 , R E-6 , R E-7 , R E-8 , R E-9 , and R E-10 is independently selected from the group consisting of H and CH 3 (i.e. a methyl group, Me), with the proviso that exactly one or exactly two of R E-1 , R E-2 , R E-3 , R E-4 , R E-5 , R E-6 , R E-7 , R E-8 , R E-9 , and R E-10 are CH 3 ; and wherein in Formula S E -2: each of R E-11 and R E-12 is independently a C1−C6-alkyl group, with the proviso that R E-11 and R E-12 together comprise in total 6−12 carbon atoms. In some embodiments of the method and the composition of the invention, each ether solvent S E is independently of each other a solvent of any one of the aforementioned Formulae S E -1 and S E -2, wherein in Formula S E -1: s is an integer of 0 or 1, and each of R E-1 , R E-2 , R E-3 , R E-4 , R E-5 , R E-6 , R E-7 , R E-8 , R E-9 , and R E-10 is independently selected from the group consisting of H and CH3 (i.e. a methyl group, Me), with the proviso that exactly one of R E-1 , R E-2 , R E-3 , R E-4 , R E-5 , R E-6 , R E-7 , R E-8 , R E-9 , and R E-10 is CH3; and wherein in Formula S E -2: each of R E-11 and R E-12 is independently a C 1 −C 6 -alkyl group, with the proviso that R E-11 and R E-12 together comprise in total 6−12 carbon atoms. In some embodiments of the method and the composition of the invention, each ether solvent S E is independently of each other a solvent of the aforementioned Formula S E -1, wherein in Formula S E -1: s is an integer of 0 or 1, and each of R E-1 , R E-2 , R E-3 , R E-4 , R E-5 , R E-6 , R E-7 , R E-8 , R E-9 , and R E-10 is independently selected from the group consisting of H and CH3 (i.e. a methyl group, Me), with the proviso that exactly one of R E-1 , R E-2 , R E-3 , R E-4 , R E-5 , R E-6 , R E-7 , R E-8 , R E-9 , and R E-10 is CH3. The skilled artisan is capable of identifying and obtaining ether solvents S E fulfilling the aforementioned structural requirements and such ether solvents may also be commercially available. Examples of ether solvents S E of Formula S E-1 comprise 4-methyltetrahydropyran (MTHP), 3-methyltetrahydropyran, 2-methyltetrahydropyran, 2-methyltetrahydrofuran, 3-methyltetrahydrofuran, 2,5-dimethyltetrahydrofuran, 2,2-dimethyltetrahydrofuran, 2,2,5,5-tetramethyltetrahydrofuran, and the like. Examples of ether solvents S E of Formula S E -2 comprise cyclopentyl methyl ether (CPME), cyclohexyl methyl ether, dibutyl ether, isoamyl ether, methyl tert-butyl ether (MTBE), diisopropyl ether, and the like. In some embodiments of the method and the composition of the invention each ether solvent S E is independently selected from the group consisting of 4-methyltetrahydropyran (MTHP) and cyclopentyl methyl ether (CPME). In some embodiments of the method and the composition of the invention each ether solvent S E is 4-methyltetrahydropyran (MTHP). In some embodiments of the method and the composition of the invention, each pseudo solid-phase protecting group, e.g. the pseudo solid-phase protecting group PG-s, is a protecting group of the following Formula P-1: (Formula P-1), wherein in Formula P-1: the asterisk indicates the point of attachment of the pseudo solid-phase protecting group to a hydroxyl or amine moiety of the respective nucleoside moiety (in other words: the asterisk represents the oxygen atom of the protected hydroxyl moiety or the nitrogen atom of the protected amine moiety); a is an integer of 0 or 1; b is an integer of 0 or 1; L P is a linker moiety; i is an integer of 1 to 5, preferably 1 to 3, in particular 2 to 3; and R P-1 is at each occurrence independently selected from the group consisting of O(C1−C40-alkyl), O(C2−C40-alkenyl), O(C2−C40-alkynyl), a C1−C40-alkyl group, a C2−C40-alkenyl group, a C2−C40-alkynyl group, C(O)(C1−C40-alkyl), C(O)(C2−C40-alkenyl), and C(O)(C2−C40-alkynyl); wherein all present residues R P-1 together comprise in total 18−200 or 30−200 or 36−120 carbon atoms. Unless indicated differently in the context of specific embodiments, a pseudo solid-phase protecting group of Formula P-1 may be bonded to any position of a nucleoside or oligonucleotide, with the proviso that said point of attachment indicated by the asterisk in Formula P-1 (i.e. the atom of the nucleoside or oligonucleotide to which said pseudo solid-phase protecting group is covalently bonded) must be the oxygen atom of a hydroxyl moiety or the nitrogen atom of an amine moiety. Preferred examples of hydroxyl moieties to which a pseudo solid-phase protecting group of Formula P-1 may be covalently bonded are hydroxyl moieties of the backbone of a nucleoside or oligonucleotide, e.g. any hydroxyl moieties available in the carbohydrate (preferably ribose or 2´-deoxyribose) moiety of a nucleoside moiety as well as any hydroxyl moieties present in an internucleosidic linkage group. Preferred examples of amine moieties to which a pseudo solid-phase protecting group of Formula P-1 may be covalently bonded are amine moieties of nucleobases, in particular the exocyclic amine moieties of adenine, guanine, cytosine, and 5-methylcytosine. The component C-0 of any one of Formulae I, I-a, and I-b comprises a pseudo solid-phase protecting group PG-s which is bonded to a hydroxyl moiety. If said protecting group PG-s in the component C-0 of any one of Formulae I, I-a, and I-b is a protecting group of the aforementioned Formula P-1, the asterisk of Formula P-1 indicates the oxygen atom in the respective Formula I, I-a, and I-b, to which the protecting group PG-s is bonded and the covalent bond between the protecting group PG-s and said oxygen atom in any one of Formulae I, I-a, and I-b is the covalent bond interconnecting the carbonyl carbon atom and the asterisk in Formula P-1 (in other words: only one and not two covalent chemical bonds interconnect the carbonyl carbon atom shown in Formula P-1 and the respective oxygen atom of the respective Formula I, I-a, and I-b). It will be understood that, if the integer a in Formula P-1 is 0, the oxygen atom in brackets will be absent and the carbonyl carbon atom depicted to its right will be covalently bonded directly to the linker moiety L P , if the integer b is 1, or to the phenyl moiety, if the integer b is 0. It will also be understood that if the integer b in Formula P-1 is 0, the linker moiety L P will be absent and the phenyl moiety depicted to its left will be covalently bonded directly to the oxygen atom, if the integer a is 1, or to the carbonyl carbon atom, if the integer a is 0. This rationale is applicable to any atoms, atom groups or residues depicted in brackets having an integer which may be 0. In some embodiments of the invention, the integer a in Formula P-1 is 0. In some embodiments of the invention, the integer a in Formula P-1 is 1. In some embodiments of the invention, the integer b in Formula P-1 is 1. In some embodiments of the invention, the integer a in Formula P-1 is 0. In some embodiments of the invention, the integer b in Formula P-1 is 0. In some embodiments of the invention, the integer a in Formula P-1 is 0 and the integer b in Formula P-1 is 1. In some embodiments of the invention, the integer a in Formula P-1 is 1 and the integer b in Formula P-1 is 1. In some embodiments of the invention, the integer a in Formula P-1 is 1 and the integer b in Formula P-1 is 0. In some embodiments of the invention, the integer a in Formula P-1 is 0 and the integer b in Formula P-1 is 0. The linker moiety L P in a pseudo solid-phase protecting group of Formula P-1 may be any chemical residue which interconnects the oxygen atom, if the integer a is 1, or the carbonyl carbon atom, if the integer a is 0, with the phenyl residue to which R P-1 is bonded. For example, said linker moiety may be a C 1 −C 40 -alkylene moiety, in which alkylene moiety one or more carbon atoms and/or one or more hydrogen residues may optionally be substituted for a heteroatom selected from the group consisting of O and N. As used herein, the term “alkylene group (or moiety or residue)” may be understood in the broadest sense to be similar to an alkyl residue, with the sole difference, that an alkylene residue mandatorily comprises two or more, preferably exactly two, chemical bonds (for the avoidance of doubt: a double bond is not the same as two chemical bonds) to the parent structure comprising said alkylene group. In other words: An alkylene group may preferably be an alkanediyl residue. This will be understood by the skilled person and may be exemplified as follows: A methyl group (i.e. –CH 3 ) is a classical alkyl group, which bonds to the respective parent structure via exactly one covalent chemical bond (indicated via the hyphen). The corresponding alkylene group would be a methylene group (i.e. –CH 2 −) and differs from the alkyl group in that is bonds to the parent structure via exactly two covalent chemical bonds (indicated by the hyphens; both bonds originate from the methylene carbon atom). Unless indicated differently in the context of specific embodiments, an alkylene group may be branched, unbranched (i.e. linear) or cyclic. In some embodiments of the invention, the linker moiety L P in Formula P-1 is a residue of the following Formula P-1-L: (Formula P-1-L), wherein in Formula P-1-L: the two asterisks represent the oxygen atom to which L P is bonded in Formula P-1, if the integer a is 1, or the carbonyl carbon atom to which L P is bonded in Formula P-1, if the integer a is 0; the three asterisks represent the carbon atom of the substituted phenyl moiety to which L P is bonded in Formula P-1; c is an integer of 0 or 1; L 1 is a C 1 −C 12 -alkylene group; d is an integer of 0 or 1; X P-1 is selected from the group consisting of +C(O)++, +C(O)N(R P-B )++, +C(O)O++, and +C(O)S++, where R P-B is selected from the group consisting of H and a C1−C6-alkyl group, and where + is the point of attachment to L 1 or ** and ++ is the point of attachment to L 2 or X P-2 or L 3 or X P-3 or ***; e is an integer of 0 or 1; L 2 is a C1−C12-alkylene group; f is an integer of 0 or 1; X P-2 is selected from the group consisting of ++C(O)+, ++C(O)N(R P-C )+, ++C(O)O+, and ++C(O)S+, where R P-C is selected from the group consisting of H and a C1−C6-alkyl group, and where + is the point of attachment to L 2 or X P-1 or L 1 or ** and ++ is the point of attachment to L 3 or X P-3 or ***; X P-1 , L 2 , and X P-2 may optionally together represent a structure of the following Formula P-1-L*: (Formula P-1-L*), wherein in Formula P-1-L*: the dashed line represents the covalent bond to L 1 or **; the wavy line represents the covalent bond to L 3 or X P-3 or ***; and k is an integer of 0 or 1 and preferably is 0; g is an integer of 0 or 1; L 3 is a C 1 −C 12 -alkylene group; h is an integer of 0 or 1; X P-3 is selected from the group consisting of ++CH(R P-D )+, ++C(O)N(R P-E )+, and ++C(O)O+ where + denotes the point of attachment to L 3 or X P-2 or L 2 or X P-1 or L 1 or ** and ++ denotes ***, and where R P-E is selected from the group consisting of H and a C1C6-alkyl group, and where R P-D is selected from the group consisting of H and a residue of the following Formula P-1-L**: (Formula P-1-L**), wherein in Formula P-1-L**: the hashtag (#) represents the carbon atom to which R P-D is bonded in ++CH(R P-D )+, k is an integer of 0 to 4; R P-3 is defined as R P-1 (i.e. the same definitions apply to R P-3 of Formula P-1-L** and R P-1 of Formula P-1); and R P-2 is H or R P-2 and a residue R P-1 of Formula P-1 may optionally together represent a covalent chemical bond or O so as to form a fluoreny or xanthenyl moiety comprising the two phenyl residues of Formulae P-1 and P-1-L**; wherein: - all residues R P-1 and R P-3 present in a pseudo solid-phase protecting group of Formula P-1 with the linker moiety L P being a liker moiety of Formula P-1-L together comprise in total 18−200 or 30−200 or 36−120 carbon atoms; and - if present, any residues L 1 , L 2 , and L 3 together comprise in total 1−24, preferably 1−12 carbon atoms. In some embodiments of the invention, in the linker moiety L P of Formula P-1-L: - the sum of integers c and e and g is 1 or 2 (i.e. c + e + g = 1 or 2); - the sum of integers d and f and h is 0 or 1 or 2 (i.e. d + f + h = 0 or 1 or 2); and - any residues L 1 , L 2 , and L 3 together comprise in total 1−8 carbon atoms. In some embodiments of the method and the composition of the invention, each pseudo solid-phase protecting group, e.g. the pseudo solid-phase protecting group PG-s, is a protecting group of any one of the following Formulae P-1-a, P-1-b, P-1-c, (Formula P-1-a), wherein in Formula P-1-a: the integers a and i, the asterisk, and R P-1 are defined as for Formula P-1; and L 1 is a C 1 −C 12 -alkylene group, preferably a C 1 −C 3 -alkylene group; (Formula P-1-b), wherein in Formula P-1-b: the integers a and i, the asterisk, and R P-1 are defined as for Formula P-1; L 1 is a C 1 −C 12 -alkylene group, preferably a C 1 −C 4 -alkylene group, in particular a C 1 −C 2 -alkylene group; and X P-2 is selected from the group consisting of ++C(O)+, ++C(O)N(R P-C )+, ++C(O)O+, and ++C(O)S+, where R P-C is selected from the group consisting of H and a C1−C6-alkyl group, and where + is the point of attachment to L 1 and ++ is the point of attachment to the phenyl moiety substituted with R P-1 ; (Formula P-1-c), wherein in Formula P-1-c: the integers a and i, the asterisk, and R P-1 are defined as for Formula P-1; c is an integer of 0 or 1 and preferably is 1; L 1 is a C1−C12-alkylene group, preferably a C1−C4-alkylene group, in particular a C2-alkylene group (i.e. an ethylene group, CH2-CH2); X P-1 is selected from the group consisting of +C(O)N(R P-B )++, +C(O)O++, and +C(O)S++, where R P-B is selected from the group consisting of H and a C1−C6-alkyl group, and where + is the point of attachment to L 1 or O or the carbonyl carbon atom and ++ is the point of attachment to L 2 ; L 2 is a C1−C12-alkylene group, preferably a C1−C4-alkylene group; X P-2 is selected from the group consisting of ++C(O)N(R P-C )+, ++C(O)O+, and ++C(O)S+, where R P-C is selected from the group consisting of H and a C1−C6-alkyl group, and where + is the point of attachment to L 2 and ++ is the point of attachment to the phenyl moiety substituted with R P-1 ; and may optionally together represent the following structure which the dashed line represents the covalent bond to L 1 or O or the carbonyl carbon, and the wavy line represents the covalent bond to the phenyl moiety substituted with R P-1 ; wherein in Formula P-1-d: the integers a and i, the asterisk, and R P-1 are defined as for Formula P-1; L 1 is a C1−C12-alkylene group, preferably a C1−C4-alkylene group, in particular a C2-alkylene group (i.e. an ethylene group, CH2-CH2); X P-1 is selected from the group consisting of +C(O)N(R P-B )++, +C(O)O++, and +C(O)S++, where R P-B is selected from the group consisting of H and a C 1 −C 6 -alkyl group, and where + is the point of attachment to L 1 and ++ is represents the carbon atom to which R P-D is bonded in CHR P-D ; and R P-D is selected from the group consisting of H and a residue of the following Formula P-1-L**: (Formula P-1-L**), wherein in Formula P-1-L**: the hashtag (#) represents the carbon atom to which R P-D is bonded in CHR P-D , k is an integer of 0 to 4; R P-3 is defined as R P-1 (i.e. the same definitions apply to R P-3 of Formula P-1-L** and R P-1 of Formula P-1); and R P-2 is H or R P-2 and a residue R P-1 may optionally together represent a covalent chemical bond or O so as to form a fluoreny or xanthenyl moiety comprising the phenyl residue to which R P-2 is bonded and the phenyl residue to which R P-1 is bonded; (Formula P-1-e), wherein in Formula P-1-e: the integers a and i, the asterisk, and R P-1 are defined as for Formula P-1; L 1 is a C1−C12-alkylene group, preferably a C1−C4-alkylene group, in particular a C2-alkylene group (i.e. an ethylene group, CH2-CH2); X P-1 is selected from the group consisting of +C(O)++, +C(O)N(R P-B )++, +C(O)O++, and +C(O)S++, where R P-B is selected from the group consisting of H and a C1−C6-alkyl group, and where + is the point of attachment to L 1 and ++ is the point of attachment to L 2 ; L 2 is a C1−C12-alkylene group, preferably a C1−C4-alkylene group, in particular a C 1 −C 4 -alkylene group; and X P-3 is selected from the group consisting of ++C(O)N(R P-E )+, and ++C(O)O+ where + denotes the point of attachment to L 2 and ++ is the point of attachment to the phenyl moiety substituted with R P-1 , and where R P-E is selected from the group consisting of H and a C 1 C 6 -alkyl group; and wherein in any one of Formulae P-1-a, P-1-b, P-1-c and P-1-e, all present residues R P-1 together comprise in total 18−200 or 30−200 or 36−120 carbon atoms; and wherein in Formula P-1-d, all present residues R P-1 and R P-3 together comprise in total 18−200 or 30−200 or 36−120 carbon atoms. In some embodiments of the method and the composition of the invention, each pseudo solid-phase protecting group, e.g. the pseudo solid-phase protecting group PG-s, is a protecting group of any one of the aforementioned Formulae P-1-a, P-1-b, P-1-c, P-1-d, and P-1-e, wherein in Formula P-1-a: the asterisk and R P-1 are defined as for Formula P-1; a is an integer of 0 or 1; i is an integer of 1 to 3, preferably 2 to 3; and L 1 is a C 1 −C 3 -alkylene group (i.e. selected from the group consisting of CH 2 , CH 2 -CH 2 , and CH 2 -CH 2 -CH 2 ); wherein in Formula P-1-b: the asterisk and R P-1 are defined as for Formula P-1; the integer a is 0 (i.e. the oxygen atom is absent and L 1 bonds directly to the carbonyl carbon atom); i is an integer of 1 to 3, preferably 2 to 3; L 1 is a C1−C4-alkylene group, in particular a C1−C2-alkylene group; and X P-2 is selected from the group consisting of ++C(O)N(R P-C )+ and ++C(O)O+, where R P-C is selected from the group consisting of H and a C1−C6-alkyl group, and where + is the point of attachment to L 1 and ++ is the point of attachment to the phenyl moiety substituted with R P-1 ; wherein in Formula P-1-c: the asterisk and R P-1 are defined as for Formula P-1; the integer a is 0; i is an integer of 1 to 3, preferably 2 to 3; c is an integer of 0 or 1 and preferably is 1; L 1 is a C 1 −C 4 -alkylene group, in particular a C 2 -alkylene group (i.e. an ethylene group, CH2-CH2); X P-1 is selected from the group consisting of +C(O)N(R P-B )++ and +C(O)O++, where R P-B is selected from the group consisting of H and a C1−C6-alkyl group, and where + is the point of attachment to L 1 or the carbonyl carbon atom and ++ is the point of attachment to L 2 ; L 2 is a C1−C4-alkylene group; X P-2 is selected from the group consisting of ++C(O)N(R P-C )+ and ++C(O)O+, where R P-C is selected from the group consisting of H and a C1−C6-alkyl group, and where + is the point of attachment to L 2 and ++ is the point of attachment to the phenyl moiety substituted with R P-1 ; and may optionally together represent the following structure which the dashed line represents the covalent bond to L 1 or the carbonyl carbon atom, and the wavy line represents the covalent bond to the phenyl moiety substituted with R P-1 ; wherein in Formula P-1-d: the asterisk and R P-1 are defined as for Formula P-1; the integer a is 0; i is an integer of 1 to 3, preferably 2 to 3; L 1 is a C1−C4-alkylene group, in particular a C2-alkylene group; X P-1 is selected from the group consisting of +C(O)N(R P-B )++ and +C(O)O++, where R P-B is selected from the group consisting of H and a C1−C6-alkyl group, and where + is the point of attachment to L 1 or the carbonyl carbon atom and ++ represents the carbon atom to which R P-D is bonded in CHR P-D ; and R P-D is selected from the group consisting of H and a residue of the aforementioned Formula P-1-L**, wherein in Formula P-1-L**: the hashtag (#) represents the carbon atom to which R P-D is bonded in CHR P-D , k is an integer of 0 to 3; R P-3 is defined as R P-1 (i.e. the same definitions apply to R P-3 of Formula P-1-L** and R P-1 of Formula P-1); and R P-2 is H; and wherein in Formula P-1-e: the integer a is 0; i is an integer of 1 to 3, preferably 2 to 3; L 1 is a C1−C4-alkylene group, in particular a C2-alkylene group; X P-1 is selected from the group consisting of +C(O)++, +C(O)N(R P-B )++, and +C(O)O++, where R P-B is selected from the group consisting of H and a C1−C6-alkyl group, and where + is the point of attachment to L 1 and ++ is the point of attachment to L 2 ; L 2 is a C1−C4-alkylene group, in particular a C1−C2-alkylene group; and X P-3 is selected from the group consisting of ++C(O)N(R P-E )+, and ++C(O)O+, where R P-E is selected from the group consisting of H and a C1−C6-alkyl group, and where + denotes the point of attachment to L 2 and ++ is the point of attachment to the phenyl moiety substituted with R P-1 ; and wherein in any one of Formulae P-1-a, P-1-b, P-1-c, and P-1-e, all present residues R P-1 together comprise in total 18−200 or 30−200 or 36−120 carbon atoms; and wherein in Formula P-1-d, all present residues R P-1 and R P-3 together comprise in total 18−200 or 30−200 or 36−120 carbon atoms. In some embodiments of the method and the composition of the invention, each pseudo solid-phase protecting group, e.g. the pseudo solid-phase protecting group PG-s, is a protecting group of any one of the aforementioned Formulae P-1-a, P-1- b, P-1-c, P-1-d, and P-1-e, wherein in Formula P-1-a: the asterisk and R P-1 are defined as for Formula P-1; a is an integer of 0 or 1; i is an integer of 1 to 3, preferably 2 to 3; and L 1 is C1−C3-alkylene group; wherein in Formula P-1-b: the asterisk and R P-1 are defined as for Formula P-1; the integer a is 0; i is an integer of 1 to 3, preferably 2 to 3; L 1 is a C1−C4-alkylene group, in particular a C1−C2-alkylene group; and X P-2 is selected from the group consisting of ++C(O)N(R P-C )+ and ++C(O)O+, where R P-C is selected from the group consisting of H and CH3, and where + is the point of attachment to L 1 and ++ is the point of attachment to the phenyl moiety substituted with R P-1 ; wherein in Formula P-1-c: the asterisk and R P-1 are defined as for Formula P-1; the integer a is 0; i is an integer of 1 to 3, preferably 2 to 3; the integer c is 1; L 1 is a C 1 −C 4 -alkylene group, in particular a C 2 -alkylene group (i.e. an ethylene group, CH 2 -CH 2 ); X P-2 together represent the following structure which the dashed line represents the covalent bond to L 1 and the wavy line represents the covalent bond to the phenyl moiety substituted with R P-1 ; and wherein in Formula P-1-d: the asterisk and R P-1 are defined as for Formula P-1; the integer a is 0; i is an integer of 1 to 3, preferably 2 to 3; L 1 is a C 1 −C 4 -alkylene group, in particular a C 2 -alkylene group; X P-1 is selected from the group consisting of +C(O)N(R P-B )++ and +C(O)O++, where R P-B is selected from the group consisting of H and a CH3, and where + is the point of attachment to L 1 and ++ represents the carbon atom to which R P-D is bonded in CHR P-D ; and R P-D is selected from the group consisting of H and a residue of the aforementioned Formula P-1-L**, wherein in Formula P-1-L**: the hashtag (#) represents the carbon atom to which R P-D is bonded in CHR P-D , k is an integer of 0 to 3; R P-3 is defined as R P-1 (i.e. the same definitions apply to R P-3 of Formula P-1-L** and R P-1 of Formula P-1); and R P-2 is H; and wherein in Formula P-1-e: the integer a is 0; i is an integer of 1 to 3, preferably 2 to 3; L 1 is a C 1 −C 4 -alkylene group, in particular a C 2 -alkylene group; X P-1 is selected from the group consisting of +C(O)++, +C(O)N(R P-B )++, and +C(O)O++, where R P-B is selected from the group consisting of H and CH3, and where + is the point of attachment to L 1 and ++ is the point of attachment to L 2 ; L 2 is a C1−C4-alkylene group, in particular a C1−C2-alkylene group; and X P-3 is selected from the group consisting of ++C(O)N(R P-E )+, and ++C(O)O+, where R P-E is selected from the group consisting of H and a CH3, and where + denotes the point of attachment to L 2 and ++ is the point of attachment to the phenyl moiety substituted with R P-1 ; and wherein in any one of Formulae P-1-a, P-1-b, P-1-c, and P-1-e all present residues R P-1 together comprise in total 36−120 carbon atoms; and wherein in Formula P-1-d, all present residues R P-1 and R P-3 together comprise in total 36−120 carbon atoms. In some embodiments of the invention, R P-1 in any one of Formulae P-1, P-1-a, P-1-b, P-1-c, P-1-d, and P-1-e as well as R P-3 in any one of Formulae P-1 and P-1-d is at each occurrence independently selected from the group consisting of O(C 1 −C 40 -alkyl), O(C 2 −C 40 -alkenyl), a C 1 −C 40 -alkyl group, a C 2 −C 40 -alkenyl group, C(O)(C 1 −C 40 -alkyl), and C(O)(C 2 −C 40 -alkenyl). In some embodiments of the invention, R P-1 in any one of Formulae P-1, P-1-a, P-1-b, P-1-c, P-1-d, and P-1-e as well as R P-3 in any one of Formulae P-1 and P-1-d is at each occurrence independently selected from the group consisting of O(C 1 −C 30 -alkyl), O(C 2 −C 30 - alkenyl), a C 1 −C 30 -alkyl group, a C 2 −C 30 -alkenyl group, C(O)(C 1 −C 30 -alkyl), and C(O)(C 2 −C 30 -alkenyl). In some embodiments of the invention, R P-1 in any one of Formulae P-1, P-1-a, P-1-b, P-1-c, P-1-d, and P-1-e as well as R P-3 in any one of Formulae P-1 and P-1-d is at each occurrence independently selected from the group consisting of O(C1−C30-alkyl), O(C2−C30-alkenyl), C(O)(C1−C30-alkyl), and C(O)(C2−C30-alkenyl). In some embodiments of the invention, R P-1 in any one of Formulae P-1, P-1-a, P-1-b, P-1-c, P-1-d, and P-1-e as well as R P-3 in any one of Formulae P-1 and P-1-d is at each occurrence independently selected from the group consisting of O(C1−C30-alkyl) and C(O)(C1−C30-alkyl). In some embodiments of the invention, R P-1 in any one of Formulae P-1, P-1-a, P-1-b, P-1-c, P-1-d, and P- 1-e as well as R P-3 in any one of Formulae P-1 and P-1-d is at each occurrence independently O(C1−C30-alkyl). In some embodiments of the invention, R P-1 in any one of Formulae P-1, P-1-a, P-1-b, P-1-c, P-1-d, and P-1-e as well as R P-3 in any one of Formulae P-1 and P-1-d is at each occurrence independently O(C1−C30- alkyl), wherein said C 1 −C 30 -alkyl in O(C 1 −C 30 -alkyl) is a linear (i.e. unbranched and non-cyclic) alkyl residue. Pseudo solid-phase protecting groups of the aforementioned Formula P-1-a, methods for their preparation, introduction into nucleosides or oligonucleotides as well as cleavage from oligonucleotides are, e.g., disclosed in PCT/EP2022/059528 published as WO 2022/214692 A1, wherein reference is in particular made to Formulae II, II-a, and III to VII of said reference as well as to Examples 1 to 40 of said reference. Examples of pseudo solid-phase protecting groups of Formula P-1- a comprise protecting groups of the following structures: wherein in any one of these structures, the asterisk and R P-1 are defined as for Formula P-1. R P-1 may, e.g., be at each occurrence a C22H45-alkyl group, a C21H43-alkyl group, a C20H41-alkyl group, a C19H39-alkyl group or a C18H37-alkyl group. Pseudo solid-phase protecting groups of the aforementioned Formula P-1-b are, e.g., disclosed in EP3825300A1. Examples of pseudo solid-phase protecting groups of Formula P-1-b comprise protecting groups of the following structures: , wherein in any one of these structures, the asterisk and R P-1 are defined as for Formula P-1. R P-1 may, e.g., be at each occurrence a C 22 H 45 -alkyl group, a C 21 H 43 -alkyl group, a C 20 H 41 -alkyl group, a C 19 H 39 -alkyl group or a C 18 H 37 -alkyl group. Pseudo solid-phase protecting groups of the aforementioned Formula P-1-c are, e.g., disclosed in S. Kim et al., Chemistry – A European Journal 2013, 19, 8615−8620 (DOI: 10.1002/chem.201300655), wherein reference is also made to the Supporting Information belonging to said reference and comprising the experimental protocols. Particularly preferred examples of pseudo solid-phase protecting groups of Formula P-1-c comprise protecting groups of the following structures: , wherein in any one of these structures, the asterisk and R P-1 are defined as for Formula P-1. R P-1 may, e.g., be at each occurrence a C 22 H 45 -alkyl group, a C 21 H 43 -alkyl group, a C 20 H 41 -alkyl group, a C 19 H 39 -alkyl group or a C 18 H 37 -alkyl group. Pseudo solid-phase protecting groups of the aforementioned Formula P-1-d are, e.g., disclosed in US2013267697A1, EP2711370A1, and EP3398955A1. Examples of pseudo solid-phase protecting groups of Formula P-1-d comprise protecting groups of the following structures: , wherein in any one of these structures, the asterisk, R P-1 , and R P-3 are defined as for Formula P-1. R P-1 and R P-3 may, e.g., be at each occurrence a C 22 H 45 -alkyl group, a C21H43-alkyl group, a C20H41-alkyl group, a C19H39-alkyl group or a C18H37-alkyl group. Examples of pseudo solid-phase protecting groups of Formula P-1-d comprise protecting groups of the following structures: , wherein in any one of these structures, the asterisk, R P-1 , and R P-3 are defined as for Formula P-1. R P-1 and R P-3 may, e.g., be at each occurrence a C22H45-alkyl group, a C21H43-alkyl group, a C20H41-alkyl group, a C19H39-alkyl group or a C18H37-alkyl group. In some embodiments of the method and the composition of the invention, each pseudo solid-phase protecting group, e.g. the pseudo solid-phase protecting group PG-s, is a protecting group of the aforementioned Formula P-1-a. The following Figures and Examples, including the experiments conducted and the results achieved, are provided for illustrative purposes only and are not to be construed as limiting the scope of the claims. The present invention, for example, pertains to the following phrases 1 to 16: 1. A method for the synthesis of a target oligonucleotide O T , wherein the target oligonucleotide O T comprises a first cycle oligonucleotide O-1, and the method comprises the following step (a-1), and a first coupling cycle comprising the following steps: (a-1) providing a component C-0 selected from the group consisting of a nucleoside and an oligonucleotide, wherein the component C-0 is covalently bonded to a pseudo solid-phase protecting group PG-s and comprises a backbone hydroxyl moiety protected by a protecting group PG-0 removable under acidic conditions; (b-1) incubating the component C-0 of step (a-1) with a deprotection mixture M-(b-1), thereby cleaving the protecting group PG-0 from the component C-0, so as to obtain a component (C-0) # having a free backbone hydroxyl group; (c-1) subjecting a solution comprising the component (C-0) # to one or more aqueous extractions, wherein the organic phase comprises the component (C-0) # ; (d-1) optionally, reducing the water content of the organic phase comprising the component (C-0) # ; (e-1) reacting the component (C-0) # with a building block B-1, wherein said building block B-1 is selected from the group consisting of a nucleoside and an oligonucleotide and comprises - a backbone hydroxyl moiety protected by a protecting group PG-1 removable under acidic conditions, and - a phosphorus moiety covalently bonded via its phosphorus atom to an oxygen atom of the backbone of the building block B-1, under conditions suitable to form a covalent bond between said free backbone hydroxyl group of the component (C-0) # and the phosphorus atom of said phosphorus moiety of the building block B-1, thereby obtaining a first cycle oligonucleotide O-1; (f-1) optionally, incubating the first cycle oligonucleotide O-1 with an oxidizing or sulfurizing agent, thereby converting any P (III) atoms within said first cycle oligonucleotide O-1 to P (V) atoms; (g-1) optionally, subjecting a solution comprising the first cycle oligonucleotide O-1 to one or more aqueous extractions, wherein the organic phase comprises the first cycle oligonucleotide O-1; (h-1) if step (g-1) has been carried out, optionally reducing the water content of the organic phase comprising the first cycle oligonucleotide O-1; wherein during and in between steps (b-1) to (h-1), no solid-liquid separation is performed and steps (c-1) and (g-1) are carried out in the presence of one or more amide solvents S A , wherein each amide solvent S A is an amide solvent comprising one or more alkyl groups, wherein these one or more alkyl groups together comprise in total 6−48 carbon atoms. The method according to phrase 1, wherein the target oligonucleotide O T comprises a second cycle oligonucleotide O-2, and the method further comprises performing a second coupling cycle comprising the following steps (b-2) to (h-2): (b-2) incubating the first cycle oligonucleotide O-1 obtained in the first coupling cycle with a deprotection mixture M-(b-2), thereby cleaving the protecting group PG-1 from the first cycle oligonucleotide O-1, so as to obtain a first cycle oligonucleotide (O-1) # having a free backbone hydroxyl group; (c-2) subjecting a solution comprising the first cycle oligonucleotide (O-1) # to one or more aqueous extractions, wherein the organic phase comprises the first cycle oligonucleotide (O-1) # ; (d-2) optionally, reducing the water content of the organic phase comprising the first cycle oligonucleotide (O-1) # ; (e-2) reacting the first cycle oligonucleotide (O-1) # with a building block B-2, wherein said building block B-2 is selected from the group consisting of a nucleoside and an oligonucleotide and comprises - a backbone hydroxyl moiety protected by a protecting group PG-2 removable under acidic conditions, and - a phosphorus moiety covalently bonded via its phosphorus atom to an oxygen atom of the backbone of the building block B-2, under conditions suitable to form a covalent bond between said free backbone hydroxyl group of the first cycle oligonucleotide (O-1) # and the phosphorus atom of said phosphorus moiety of the building block B-2, thereby obtaining a second cycle oligonucleotide O-2; (f-2) optionally, incubating the second cycle oligonucleotide O-2 with an oxidizing or sulfurizing agent, thereby converting any P (III) atoms within said second cycle oligonucleotide O-2 to P (V) atoms; (g-2) optionally, subjecting a solution comprising the second cycle oligonucleotide O-2 to one or more aqueous extractions, wherein the organic phase comprises the second cycle oligonucleotide O-2; (h-2) if step (g-2) has been carried out, optionally reducing the water content of the organic phase comprising the second cycle oligonucleotide O-2; wherein during and in between steps (b-1) to (h-2), no solid-liquid separation is performed and steps (c-1), (g-1), (c-2), and (g-2) are carried out in the presence of one or more amide solvents S A , wherein each amide solvent S A is an amide solvent comprising one or more alkyl groups, wherein these one or more alkyl groups together comprise in total 6−48 carbon atoms. The method according to phrase 2, wherein the target oligonucleotide O T comprises a n-th cycle oligonucleotide O-n, and the method further comprises performing (n−2) iterations of a coupling cycle comprising the following steps (b-x) to (h-x), wherein n is an integer in the range of 3 to 99, which denotes the total number of coupling cycles performed to obtain the n-th cycle oligonucleotide O-n, and each individual coupling cycle comprising the following steps (b-x) to (h-x) is identified by a serial number x, which runs in steps of 1 from 3 to n: (b-x) incubating the (x−1)-th cycle oligonucleotide O-(x−1) obtained in the previous coupling cycle with a deprotection mixture M-(b-x), thereby cleaving the protecting group PG-(x−1) from the (x−1)-th cycle oligonucleotide O-(x−1), so as to obtain a (x−1)-th cycle oligonucleotide (O-(x−1)) # having a free backbone hydroxyl group; (c-x) subjecting a solution comprising the (x−1)-th cycle oligonucleotide (O-(x−1)) # to one or more aqueous extractions, wherein the organic phase comprises the (x−1)-th cycle oligonucleotide (O-(x−1)) # ; (d-x) optionally, reducing the water content of the organic phase comprising the (x−1)-th cycle oligonucleotide (O-(x−1)) # ; (e-x) reacting the (x−1)-th cycle oligonucleotide (O-(x−1)) # with a building block B-x, wherein said building block B-x is selected from the group consisting of a nucleoside and an oligonucleotide and comprises - a backbone hydroxyl moiety protected by a protecting group PG-x removable under acidic conditions, and - a phosphorus moiety covalently bonded via its phosphorus atom to an oxygen atom of the backbone of the building block B-x, under conditions suitable to form a covalent bond between said free backbone hydroxyl group of the (x−1)-th cycle oligonucleotide (O-(x−1)) # and the phosphorus atom of said phosphorus moiety of the building block B-x, thereby obtaining a x-th cycle oligonucleotide O-x; (f-x) optionally, incubating the x-th cycle oligonucleotide O-x with an oxidizing or sulfurizing agent, thereby converting any P (III) atoms within said x-th cycle oligonucleotide O-x to P (V) atoms; (g-x) optionally, subjecting a solution comprising the x-th cycle oligonucleotide O-x to one or more aqueous extractions, wherein the organic phase comprises the x-th cycle oligonucleotide O-x; (h-x) if step (g-x) has been carried out, optionally reducing the water content of the organic phase comprising the x-th cycle oligonucleotide O-x; wherein during and in between steps (b-1) to (h-n), no solid-liquid separation is performed, and steps (c-1), (g-1), (c-2), and (g-2), as well as each iteration of steps (c-x) and (g-x) are carried out in the presence of one or more amide solvents S A , wherein each amide solvent S A is an amide solvent comprising one or more alkyl groups, wherein these one or more alkyl groups together comprise in total 6−48 carbon atoms. 4. The method according to any one of phrases 1 to 3, wherein - the phosphorus moiety of the building blocks B-1, B-2, and each building block B-x is independently selected from the group consisting of a phosphoramidite moiety and a H-phosphonate monoester moiety; - in each coupling cycle, in which said phosphorus moiety of the building block B-1, B-2 or B-x is a phosphoramidite moiety, step (f-1) or (f-2) or (f-x) is carried out; and - at least in the final coupling cycle, step (f-1) or (f-2) or (f-x) is carried out. 5. The method according to any one of phrases 1 to 4, wherein the component C-0 is a compound of the following Formula I:
(Formula I), wherein in in Formula I: each oxygen atom (O) depicted within each nucleoside subunit x-0 to x-m represents the oxygen atom of a hydroxyl moiety of the respective nucleoside subunit; each of the nucleoside subunits x-0 to x-m may be the same or different; m is an integer equal to or larger than 0; PG-0 is a protecting group removable under acidic conditions; Y 1 is selected independently for each repetitive unit m from the group consisting of O and S; Z 1 is selected independently for each repetitive unit m from the group consisting of O-R z-1 , S-R z-1 , and H; R z-1 is a protecting group, which may be the same or different for each repetitive unit m; and PG-s is a pseudo solid-phase protecting group. The method according to any one of phrases 1 to 5, wherein each of the building blocks B-1, B-2, and B-x is a compound of the following Formula II-1: (Formula II-1), wherein in Formula II-1: each oxygen atom (O) depicted within each nucleoside subunit y-0 to y-q represents the oxygen atom of a hydroxyl moiety of the respective nucleoside subunit; each nucleoside subunit y-0 to y-q may be the same or different; PG is the protecting group PG-1 or PG-2 or PG-x and is a protecting group removable under acidic conditions; q is an integer equal to or larger than 0; Y 2 is selected independently for each repetitive unit q from the group consisting of O and S; Z 2 is selected independently for each repetitive unit q from the group consisting of O-R z-2 and S-R z-2 ; R z-2 is a protecting group, which may be the same or different for each repetitive unit q; Z 3 is selected from the group consisting of O and S; and R z-3 is a protecting group; each of R a and R b is a C 1 −C 6 -alkyl group, wherein R a and R b may be the same or different and may also bond to each other to form a 5-membered or 6-membered aliphatic cyclic amine moiety together with the nitrogen atom to which R a and R b are bonded; and wherein step (f-1) or (f-2) or (f-x) is carried out in each coupling cycle. The method according to any one of phrases 1 to 6, wherein - the first coupling cycle further comprises a step (i-1) of reacting free hydroxyl groups with a blocking agent, wherein step (i-1) is carried out after step (e-1) or after step (f-1); and/or - the second coupling cycle further comprises a step (i-2) of reacting free hydroxyl groups with a blocking agent, wherein step (i-2) is carried out after step (e-2) or after step (f-2); and/or - at least one coupling cycle comprising steps (b-x) to (h-x), further comprises a step (i-x) of reacting free hydroxyl groups with a blocking agent, wherein step (i-x) is carried out after step (e-x) or after step (f-x). The method according to any one of phrases 1 and 4 to 7, wherein the method further comprises - a step (k-1) of incubating the first cycle oligonucleotide O-1 with a deprotection mixture M-(k-1), thereby cleaving the protecting group PG-1 from the first cycle oligonucleotide O-1, so as to obtain a first cycle oligonucleotide (O-1) # having a free backbone hydroxyl group; and/or - a step (m-1) of incubating the first cycle oligonucleotide O-1 or (O-1) # with a base, thereby cleaving the pseudo solid-phase protecting group PG-s and, optionally, one or more further protecting groups from the first cycle oligonucleotide O-1 or (O-1) # ; and/or - a step (p-1) of modifying the first cycle oligonucleotide O-1 or (O-1) # ; wherein, if more than one of steps (k-1), (m-1), and (p-1) are performed, they may be performed in any order. The method according to any one of phrases 2 and 4 to 7, wherein the method further comprises - a step (k-2) of incubating the second cycle oligonucleotide O-2 with a deprotection mixture M-(k-2), thereby cleaving the protecting group PG-2 from the second cycle oligonucleotide O-2, so as to obtain a second cycle oligonucleotide (O-2) # having a free backbone hydroxyl group; and/or - a step (m-2) of incubating the second cycle oligonucleotide O-2 or (O-2) # with a base, thereby cleaving the pseudo solid-phase protecting group PG-s and, optionally, one or more further protecting groups from the second cycle oligonucleotide O-2 or (O-2) # ; and/or - a step (p-2) of modifying the second cycle oligonucleotide O-2 or (O-2) # ; wherein, if more than one of steps (k-2), (m-2), and (p-2) are performed, they may be performed in any order. The method according to any one of phrases 3 and 4 to 7, wherein the method further comprises - a step (k-n) of incubating the n-th cycle oligonucleotide O-n with a deprotection mixture M-(k-n), thereby cleaving the protecting group PG-n from the n-th cycle oligonucleotide O-n, so as to obtain a n-th cycle oligonucleotide (O-n) # having a free backbone hydroxyl group; and/or - a step (m-n) of incubating the n-th cycle oligonucleotide O-n or (O-n) # with a base, thereby cleaving the pseudo solid-phase protecting group PG-s and, optionally, one or more further protecting groups from the n-th cycle oligonucleotide O-n or (O-n) # ; and/or - a step (p-n) of modifying the n-th cycle oligonucleotide O-n or (O-n) # ; wherein, if more than one of steps (k-n), (m-n), and (p-n) are performed, they may be performed in any order. The method according to any one of phrases 1 to 10, wherein steps (b-1) to (h-1), are carried out in the presence of one or more amide solvents S A and, preferably, one or more ether solvents S E , and further wherein: - if the second coupling cycle comprising steps (b-2) to (h-2), is performed, steps (b-1) to (h-2), are carried out in the presence of one or more amide solvents S A and, preferably, one or more ether solvents S E ; and - if (n−2) iterations of the coupling cycle comprising steps (b-x) to (h-x) are performed, all of steps (b-1) to (h-n) are carried out in the presence of one or more amide solvents S A and, preferably, one or more ether solvent S E . The method according to any one of phrases 1 to 11, wherein steps (b-1) to (h-1) are carried out in essentially halogen-free solvents, and further wherein: - if a second coupling cycle comprising steps (b-2) to (h-2) is performed, steps (b-1) to (h-2) are carried out in essentially halogen-free solvents; and - if (n−2) iterations of the coupling cycle comprising steps (b-x) to (h-x) are performed, any steps (b-1) to (h-n) are carried out in essentially halogen-free solvents. 13. The method according to any one of phrases 1 to 12, wherein each amide solvent S A is at each occurrence selected independently from the group consisting of the following Formulae 3: (Formula S A - (Formula S A -2), (Formula S A -3), wherein in Formula S A -1: R A-1 is selected from the group consisting of H and a C1−C24-alkyl group, in which exactly one hydrogen residue may optionally be substituted by a C(O)O(C1−C5-alkyl) group; and each of R A-2 and R A-3 is independently a C1−C24-alkyl group; with the proviso that R A-1 , R A-2 and R A-3 together comprise in total 6−48 carbon atoms; wherein in Formula S A -2: o is an integer of 1 or 2; and R A-4 is a C 6 –C 24 -alkyl group; and wherein in Formula S A -3: p is an integer of 1 or 2; X A is selected from the group consisting of CH 2 , O, and NC(O)R A-6 , with the proviso that, if p is 1, X A is CH2; R A-5 is a C1–C24-alkyl group; and R A-6 is a C1–C24-alkyl group; with the proviso that R A-5 and R A-6 together comprise in total 6–48 carbon atoms. 14. The method according to any one of phrases 1 to 13, wherein each ether solvent S E is at each occurrence selected independently from the group consisting of the following Formulae S E -1 and S E -2: (Formula S E -1), (Formula S E -2), wherein in Formula S E -1: s is an integer of 0 or 1; and each of R E-1 , R E-2 , R E-3 , R E-4 , R E-5 , R E-6 , R E-7 , R E-8 , R E-9 , and R E-10 is independently selected from the group consisting of H and a C 1 –C 5 -alkyl group, with the proviso that at least one of R E-1 , R E-2 , R E-3 , R E-4 , R E-5 , R E-6 , R E-7 , R E-8 , R E-9 , and R E-10 is a C1–C5-alkyl group; and wherein in Formula S E -2: each of R E-11 and R E-12 is independently a C1–C6-alkyl group, with the proviso that R E-11 and R E-12 together comprise in total 5–12 carbon atoms. The method according to any one of phrases 1 to 14, wherein each pseudo solid-phase protecting group is a protecting group of the following Formula P-1: (Formula P-1), wherein in Formula P-1: the asterisk indicates the oxygen atom of a hydroxyl moiety or the nitrogen atom of an amine moiety protected by the respective pseudo solid-phase protecting group; a is an integer of 0 or 1; b is an integer of 0 or 1; L P is a linker moiety; i is an integer of 1 to 5; and R P-1 is at each occurrence independently selected from the group consisting of O(C1–C40-alkyl), O(C2–C40-alkenyl), O(C2–C40-alkynyl), a C1–C40-alkyl group, a C2–C40-alkenyl group, a C2–C40-alkynyl group, C(O)(C1–C40-alkyl), C(O)(C2–C40-alkenyl), and C(O)(C2–C40-alkynyl); and wherein all present residues R P-1 together comprise in total 18–200 carbon atoms. A composition comprising: - an oligonucleotide which is covalently bonded to at least one pseudo solid- phase protecting group, and - a mixed solvent which is essentially halogen-free and comprises one or more amide solvents S A and, preferably, one or more ether solvents S E , wherein each amide solvent S A is an amide solvent comprising one or more alkyl groups, wherein these one or more alkyl groups together comprise in total 6–48 carbon atoms, preferably wherein the composition and/or one or more components are defined as in one or more of the preceding claims, in particular wherein said one or more amide solvents S A are defined as in claim 13, said one or more ther solvents S E are deinfed as in claim 14, each pseudo solid-phase protecting group is defined as in claim 15, and/or said oligonucleotide is a compound of Formula I as defined in claim 5, with the proviso that the integer m is in the range of 4−19.
Description of the Figure Figure 1 illustrates the one or more coupling cycles which may be performed as part of the method of the invention. The method of the invention may comprise a first coupling cycle comprising steps (b-1) to (h-1) (as far as present), wherein steps (d-1), (f-1), (g-1), and (h-1) are optional, which is indicated in Figure 1 by embracing these steps in brackets. Prior to the first coupling cycle, a component C-0 is provided [step (a-1)]. In the first coupling cycle, the protecting group PG-0 is removed from said component C-0 [step (b-1)] which yields the component (C-0) # . This is followed by one or more aqueous extractions [step (c-1)], optionally followed by reducing the water content of the organic phase which comprises the component (C-0) # [step (d-1)]. The component (C-0) # is reacted with a provided first building block B-1 [step (e-1)] which yields a first cycle oligonucleotide O-1. Optionally, any P (III) atoms within O-1 may be converted to P (V) atoms by incubation with an oxidizing or sulfurizing agent [step (f-1)], optionally followed by one or more aqueous extractions [step (g-1)], optionally followed by reducing the water content of the organic phase which comprises the first cycle oligonucleotide O-1 [step (h-1)]. The method of the invention may further comprise a second coupling cycle comprising steps (b-2) to (h-2), wherein steps (d-2), (f-2), (g-2), and (h-2) are optional, which is indicated in Figure 1 by embracing these steps in brackets. The first cycle oligonucleotide O-1 may serve as the educt of the second coupling cycle. The protecting group PG-1 is removed from the first cycle O-1 [step (b-2)] which yields the first cycle oligonucleotide (O-1) # . This is followed by one or more aqueous extractions [step (c-2)], optionally followed by reducing the water content of the organic phase which comprises the first cycle oligonucleotide (O-1) # [step (d-1)]. The first cycle oligonucleotide (O-1) # is reacted with a provided second building block B-2 [step (e-2)] which yields a second cycle oligonucleotide O-2. Optionally, any P (III) atoms within O-2 may be converted to P (V) atoms by incubation with an oxidizing or sulfurizing agent [step (f-2)], optionally followed by one or more aqueous extractions [step (g-2)], optionally followed by reducing the water content of the organic phase which comprises the second cycle oligonucleotide O-2 [step (h-2)]. The method of the invention may further comprise (n−2) iterations of a coupling cycle comprising steps (b-x) to (h-x) (as far as present), which are referred to as “further coupling cycles” in Figure 1. Steps (d-x), (f-x), (g-x), and (h-x) are optional in each of these further coupling cycles, which is indicated in Figure 1 by embracing these steps in brackets. The second cycle oligonucleotide O-2 will then be used as educt O-(x−1), of the third coupling cycle (x=3). The protecting group PG-(x−1), i.e. PG-2, is removed [step (b-x)] which yields oligonucleotide (O-(x−1)) # , i.e. (O-2) # (x=3). This is followed by one or more aqueous extractions [step (c-x)], optionally followed by reducing the water content of the organic phase which comprises the oligonucleotide (O-(x−1)) # , i.e. (O-2) # (x=3) [step (d-1)]. The oligonucleotide (O-(x−1)) # , i.e. (O-2) # , is reacted with a provided building block B-x, i.e. B-3 (x=3) [step (e-x)] which yields an oligonucleotide O-x, i.e. O-3 (x=3). Optionally, any P (III) atoms within O-3 may be converted to P (V) atoms by incubation with an oxidizing or sulfurizing agent [step (f-x)], optionally followed by one or more aqueous extractions [step (g-x)], optionally followed by reducing the water content of the organic phase which comprises the oligonucleotide O-x, i.e. O-3 (x=3) [step (h-x)]. Up to (n−2) coupling cycles comprising steps (b-x) to (h-x) (as far as present) [“further coupling cycles”] may be performed, in each of which the oligonucleotide O-x of the previous coupling cycle is used as educt O-(x−1). The fact that the first cycle oligonucleotide O-1 need not be subjected to the second coupling cycle, the fact that the second cycle oligonucleotide O-2 need not be subjected to the third coupling cycle, and the fact that each x-th cycle oligonucleotide O-x need not be subjected to another coupling cycle are indicated in Figure 1 by the dashed "exit" arrows.
Examples General information and methods Target oligonucleotides of the syntheses presented herein The following Examples pertain to the synthesis of target oligonucleotides, wherein these target oligonucleotides are summarized in the following Table T-2. Table T-2: Target oligonucleotides of the oligonucleotide syntheses presented herein. a) "(Kc-C1-carbonate)" in the sequence of target oligonucleotides O T -b, O T -c, and O T -d denotes a specific pseudo solid-phase protecting group bonded to the 3´-hydroxyl moiety of the 3´-terminal dT nucleoside subunit. The structure of this pseudo solid-phase protecting group is depicted in compound (1) below. The following notation is herein used to denote oligonucleotide sequences, unless indicated differently: A = adenosine dA = 2´-doexyadenosine G = guanosine dG = 2´-doexyguanosine C = cytidine dC = 2´-doexycytidine MeC or meC = 5-methylcytidine (the nucleobase is 5-methylcytosine) T = thymidine (meaning 2´-deoxythymidine and not ribothymidine) U = uridine MeU or meU = 5-methyluridine (the nucleobase is 5-methyluracil, i.e. thymine) “M” indicates that the nucleoside subunit denoted to the right of said letter “M” comprises a 2´-O-(2-methoxyethyl) residue (2´-O-MOE, i.e. the 2´-carbon atom of the carbohydrate moiety is substituted with O-CH 2 -CH 2 -O-CH 3 ). “f” indicates that the nucleoside subunit denoted to the right of said letter “f” comprises a 2´-F residue (i.e. the 2´-carbon atom of the carbohydrate moiety is substituted with a fluorine residue). “m” indicates that the nucleoside subunit denoted to the right of said letter “m” comprises a 2´-methoxy (Ome, OCH3) residue (i.e. the 2´-carbon atom of the carbohydrate moiety is substituted with OCH3). The presence of protecting groups at the nucleobases is indicated in brackets to the right of the nucleoside symbol: “(bz)” and “(Bz)” interchangeably denote a benzoyl protecting group at the exocyclic amine moiety of the respective nucleobase; “(ac)” and “(Ac)” interchangeably denote an acetyl protecting group at the exocyclic amine moiety of the nucleobase; “(ib)” denotes an isobutyryl protecting group at the exocyclic amine moiety of the nucleobase. Unless indicated differently, all internucleosidic linkage groups are phosphodiester linkage groups. The letter "s" to the right of a nucleoside symbol indicates that the internucleosidic linkage group in 3´-position of the respective nucleoside-subunit is a phosphorothioate linkage group instead of a phosphodiester linkage group. Nucleoside subunits are separated by hyphens to enhance readability. Herein, unless indicated differently, all oligonucleotides are denoted in 5´ to 3´ direction (i.e. the nucleoside subunit denoted to the very left is the 5´-terminal nucleoside subunit). Nonetheless, to enhance readability, the 5´- and the 3´-termnini are herein typically indicated as such. For example, 5´-MmeUs-MmeC-3´ herein denotes a dinucleotide, in which the 3´-hydroxyl moiety of a 2´-O-MOE substituted 5-methyluridine and the 5´-hydroxyl moiety of a 2´-O-MOE substituted 5-methylcytidine are interconnected by a phosphorothioate linkage group. As another example, 5´-dA(bz)-dT-3´ denotes a dinucleotie, in which the 3´-hydroxyl moiety of a benzyol-protected 2´- deoxyadenosine and the 5´-hydroxyl moiety of a (2´-deoxy)thymidine are interconnected by a phosphodiester linkage group. HPLC methods Method A Solid phase: YMC-Triart C18, 12 nm, 3.0 μm, 4.6×150 mm; Mobile phase A: 0.1 % AcOH aq.; Mobile Phase B: THF; Flow rate: 1.0 mL/min; Gradient (mobile phase B %): 0.0-10.0 min; 75 to 90 %, 10.0-15.0 min; 90 %, 15.0-15.1 min; 90 to 75 %, 15.1- 20.0 min; 75 %; Column temperature: 40 °C; Detection wavelength: 220 nm. Method B Solid phase: YMC-Triart C18, 12 nm, 1.9 μm, 2.1×150 mm; Mobile phase A: 10 mM dibutylamine aq. (pH adjusted to 6.0 by AcOH); Mobile phase B: THF, with Stabilizer; Flow rate: 0.3 mL/min; Gradient (mobile phase B %): 0.0-15.0 min; 65 % to 75 %, 15.0-15.1 min; 75 to 90 %, 15.1-20.1 min; 90 %, 20.0-20.1 min; 90 to 65 %, 20.1-30.0 min; 65 %; Column temperature: 60 °C; Detection wavelength: 250 nm. Method C Solid phase: ACQUITY UPLC BEH C18, 1.7 μm, 2.1×100 mm; Mobile phase A: 10 mM dibutylamine aq. (pH adjusted to 6.0 by AcOH); Mobile phase B: MeOH; Flow rate: 0.2 mL/min; Gradient (mobile phase B %): 0-0.5 min; 10 %, 0.5-20.0 min; 10 to 90 %, 20.0- 22.0 min; 90 %, 22.0-22.1 min; 90 to 10 %, 22.1-30.0 min; 10 %; Column temperature: 70 °C; Detection wavelength: 260 nm. Gradient-2 (mobile phase B %): 0-5 min; 10 %, 5-30.0 min; 10 to 60 %, 30.0- 31.0 min; 60 to 90 %, 31.0-37.0 min; 90 %, 37.0-38.0 min; 90 to 10 %, 38.0-43.0 min; 10%. Method D Solid phase: Triart Accura C8, 1.9 μm, 2.1×150 mm; Mobile phase A: 400 mM HFIP- 15mM Triethylamine aq.; Mobile phase B: MeOH; Flow rate: 0.2 mL/min; Gradient (mobile phase B %): 0-11 min; 24 to 34 %, 11.0-13.0 min; 34 to 75 %, 13.0-13.01 min; 75 to 24 %, 13.1-20.0 min; 24 %; Column temperature: 70 °C; Detection wavelength: 260 nm. Method E Solid phase: Triart Accura C8, 1.9 μm, 2.1×150 mm; Mobile phase A: 10 mM dibutylamine aq. (pH adjusted to 7.0 by AcOH); Mobile phase B: MeOH; Flow rate: 0.5 mL/min; Gradient (mobile phase B %): 0-1.0 min; 24 %, 1.0-5.0 min; 24 to 48 %, 5.0-10.0 min; 48 to 50 %, 10.0-12.0 min; 50 to 55 %, 12.0-16.0 min; 55 to 60 %, 16.0-18.0 min; 60 to 70%, 18.0 to 20.0 min; 70 to 75%, 20.0-25.0 min; 75%, 25.0- 25.1 min; 75 to 24%, 25.1-30 min; 24%; Column temperature: 70 °C; Detection wavelength: 260 nm. Method F Solid phase: Triart Accura C8, 1.9 μm, 2.1×150 mm; Mobile phase A: AcOH aq.; Mobile phase B: THF; Flow rate: 1.0 mL/min; Gradient (mobile phase B %): 0-10.0 min; 65 to 90 %, 10.0-15.0 min; 90 %, 15.0-15.1 min; 90 to 65 %, 15.01-20.0 min; 65 %; Column temperature: 40 °C; Detection wavelength: 220 nm. Method G Solid phase: Waters ACQUITY BEH, 1.7 um, 2.1×100 mm; Mobile phase A: 50 mM di-n-buthylamminoum acetate aq.; Mobile phase B: Acetonitril:H2O (90:10 v/v) ; Flow rate: 0.2 mL/min; Gradient (mobile phase B %): 0-30 min; 25 to 45 %, 30-31 min; 45 to 90 %, 31-33 min; 90 %, 33-33.1 min; 90 to 25 %, 33.1-45 min; 25 %; Column temperature: 60 °C; Detection wavelength: 260 nm. Method H Solid phase: YMC-Triart C18, 12 nm, 1.9 μm, 2.1×150 mm; Mobile phase A: 0.1% AcOH aq.; Mobile phase B: THF; Flow rate: 0.3 mL/min; Gradient (mobile phase B %): 0.0-15.0 min; 65% to 75 %, 15.0-15.1 min; 75 to 90 %, 15.1-20.1 min; 90%, 20.0-20.1 min; 90 to 65%, 20.1-30.0 min; 65%; Detected wavelength: 260 nm. HPLC-MS methods Method A Solid phase: YMC-Triart C18, 12 nm, 1.9 μm, 2.1×150 mm; Mobile phase A: 0.1% AcOH aq.; Mobile phase B: THF, with Stabilizer; Flow rate: 0.3 mL/min; Gradient (mobile phase B %): 0.0-15.0 min; 65% to 75 %, 15.0-15.1 min; 75 to 90 %, 15.1- 20.1 min; 90%, 20.0-20.1 min; 90 to 65%, 20.1-30.0 min; 65%; Column temperature: 60°C; Detection wavelength: 250 nm.; Acquisition range: 100-3000 m/z Method B Solid phase: YMC-Triart Bio C18, 30 nm, 1.9 μm, 2.1×100 mm; Mobile phase A: 0.1 % TFA aq.; Mobile phase B: THF; Flow rate: 0.48 mL/min; Gradient (mobile phase B %): 0-0.5 min; 65 %, 0.5-1.0min; 65 to 72 %, 1.0-3.0 min; 72 %, 3.0-5.0 min; 72 to 80 %, 5.0-6.0 min; 80 to 85 %, 6-6.5 min; 80 to 90 %; Column temperature: 40 °C; Detection wavelength: 220 nm; Acquisition range: 500-3000 m/z Method C Solid phase: ACQUITY UPLC BEH C18, 1.7 μm, 2.1×100 mm; Mobile phase A: 200 mM HFIP-7.5 mM triethylamine aq.; Mobile phase B: MeOH; Flow rate: 0.2 mL/min; Gradient (mobile phase B %): 0-0.5 min; 10 %, 0.5-20.0 min; 10 to 90 %, 20.0- 22.0 min; 90 %, 22.0-22.1 min; 90 to 10 %, 22.1-30.0 min; 10 %; Column temperature: 70 °C; Detection wavelength: 260 nm.; Acquisition range: 500-2500 m/z Method D Solid phase: ACQUITY UPLC BEH C18, 1.7 μm, 2.1×100 mm; Mobile phase A: 10mM dibutylamine (pH adjusted to 7.0) aq.; Mobile phase B: MeOH; Flow rate: 0.5 mL/min; Gradient (mobile phase B %): 0-0.5 min; 24 %, 0.5-11.0 min; 24 to 34 %, 11.0- 13.0 min; 34 to 75 %, 13.0-13.1 min; 75 to 24 %, 13.1-20.0 min; 24%; Column temperature: 70 °C; Detection wavelength: 260 nm.; Acquisition range: 500-3000 m/z. Method E Solid phase: ACQUITY UPLC BEH C18, 1.7 μm, 2.1×100 mm; Mobile phase A: 400 mM HFIP-7.5 mM triethylamine aq.; Mobile phase B: MeOH; Flow rate: 0.5 mL/min; Gradient (mobile phase B %): 0-0.5 min; 24 %, 0.5-11.0 min; 24 to 34 %, 11.0- 13.0 min; 34 to 75 %, 13.0-13.1 min; 75 to 24 %, 13.1-20.0 min; 24%; Column temperature: 70 °C; Detection wavelength: 260 nm.; Acquisition range: 500-3000 m/z. Method F Solid phase: YMC-Triart C18, 12 nm, 1.9 μm, 2.1×150 mm; Mobile phase A: 0.1% AcOH aq.; Mobile phase B: THF; Flow rate: 0.3 mL/min; Gradient (mobile phase B %): 0.0-15.0 min; 65% to 75 %, 15.0-15.1 min; 75 to 90 %, 15.1-20.1 min; 90%, 20.0-20.1 min; 90 to 65%, 20.1-30.0 min; 65%; Column temperature: 60°C; Detection wavelength: 260 nm.; Acquisition range: 100-3000 m/z. Method G Solid phase: Waters ACQUITY BEH, 1.7 um, 2.1×100 mm; Mobile phase A: 50 mM di-n-buthylamminoum acetate aq.; Mobile phase B: Acetonitril:H 2 O (90:10 v/v) ; Flow rate: 0.2 mL/min; Gradient (mobile phase B %): 0-30 min; 25 to 45 %, 30-31 min; 45 to 90 %, 31-33 min; 90 %, 33-33.1 min; 90 to 25 %, 33.1-45 min; 25 %; Column temperature: 60 °C; Detection wavelength: 260 nm.; Acquisition range: 500-3000 m/z. MS condition (general) Ion source: Dual ESI; Ionization mode: positive or negative; Vcap: 3500 V, 20; Gas temp: 325 °C; Gas Flow: 8 L/min; Nebulizer: 50 psi. Pre-treatment of N-octyl-2-pyrrolidone N-octyl-2-pyrrolidone (NOP) was obtained commercially. Prior to use, it was treated as follows: L-Ascorbic acid (1 wt-%) and 2,6-di-tert-butyl-p-cresol (1 wt-%) were added, followed by stirring at room temperature (i.e. approximately 25 °C) for 30 min. The so-obtained solution was washed four times: first and second wash with 0.5 M NaHCO 3 aq. (1:1 v/v), third wash with 1 vol-% acetic acid aq. (1:1 v/v), and fourth wash with H 2 O (1:1 v/v). Determination of the water content Throughout the examples presented herein, reference is occasionally made to the water content of solutions. Unless indicated differently, the water content was determined by means of standard Karl Fischer titration at room temperature (i.e. approximately 25 °C). The titration cell was filled with HYDRANAL TM -Coulomat Oil for anolyte reagent, and the inner burette was filled with HYDRANAL TM -Coulomat CG for catholyte reagent. After pretitration for dehydration, sample (100 µL) was added to the titration sell and the measurement started. In line with common practice, the water content of solutions is herein reported in parts per million (ppm). Analysis of solvent compositions after azeotropic distillation Throughout the examples presented herein, reference is occasionally made to the composition of mixed solvents after azeotropic distillation. This content is herein provided in form of volume-% (vol-%) and was, unless indicated differently, determined by gas chromatography. Samples were analyzed by the following method: Column: SH-Rxi-624Sil MS (30 m × 0.32 mmID, 1.8 µm), Injection volume: 1 µL, Inlet: Split (5/1), Injection temperature: 230 °C, Column flow: 35 cm/s Helium, Column temperature program: 40 °C(2 min)-10 °C/min-240 °C (20 min) total 42 min, Detector: FDI at 250 °C. Then, the content of solvent was calculated by using a calibration curve. Room temperature (rt) As used herein, unless indicated differently, the terms room temperature (rt) and ambient temperature are used interchangeably to denote a temperature of approximately 25 °C. Unless indicated differently, all reactions were performed at rt. Reaction setup Unless indicated differently, all oligonucleotide syntheses presented in the following were carried out in an eggplant flask made of glass equipped with a magnetic stir bar. All aqueous extractions were carried out in a common separatory funnel. All azeotropic distillations were carried out using a common rotary evaporator. Base treatment to effect cleavage of the pseudo solid-phase protecting groups and other base-labile protecting groups was carried out in an ACE Pressure Tupe by OSAKA CHEMICAl Co., Ltd., which is a pressure-resistant sealed glass tube. Synthesis and introduction of pseudo solid-phase protecting groups Pseudo solid-phase protecting groups of the above-mentioned Formula P-1-a, wherein the integer a is 1 Pseudo solid-phase protecting groups of the above-mentioned Formula P-1-a, where the integer a is 1, may be introduced into a nucleoside or oligonucleotide having exactly one free hydroxyl or amine group by reacting said free hydroxyl or amine group with an activated carbonic acid derivative, preferably in the presence of a base such as 1-methylimidazole, and reacting the so-obtained compound with an alcohol of the following structure: , where L 1 , R P-1 , and the integer i are defined as for Formula P-1-a. Said activated carbonic acid derivative may, for example, be selected from the group consisting of phosgene, disuccinimidyl carbonate, and 1,1'-carbonyldiimidazole. Exemplary synthesis of DMTr-dT-(Kc-C1-carbonate) (1) To a solution of DMTr-dT (i.e. 5´-DMTr-protected dT,14.41 g, 26.46 mmol) and 1,1'-carbonyldiimidazole (8.55 g, 52.73 mmol) in 2-methyltetrahydrofuran (300 mL) stirred at rt was added 1-methylimidazole (4.2 mL, 52.69 mmol). The resulting reaction mixture was stirred at rt for 2 h (monitored by HPLC, Method A) and subsequently washed twice with saturated NH4Cl aq. (300 mL and 150 mL) and then with saturated NaCl aq. (75 mL). The organic layer was concentrated in vacuo to give DMTr-dT-1H-imidazole-1-carboxyl, which was used directly without further purification. DBU (3.9 mL, 26.13 mmol) and 1-methylimidazole (2.1 mL, 26,35 mmol) were added to a stirred solution of DMTr-dT-1H-imidazole-1-carboxyl (approximately 26 mmol) and 3,5-bis(docosyloxy)benzenemethanol (CAS-RN: 955095-32-6, 10.00 g, 13.20 mmol) in 2-methyltetrahydrofuran (200 mL) at rt. The resulting reaction mixture was stirred at rt for 110 min, followed by addition of DMTr-dT (7.12 g, 13.07 mmol) and stirring at rt for 16 h (monitored by HPLC, Method A). Acetic anhydride (2.0 mL, 21.16 mmol) and pyridine (2.0 mL, 24.78 mmol) were added. After stirring at rt for 45 min, methanol (32 mL, 789 mmol) was added. After stirring 30 min at rt, the reaction mixture was concentrated in vacuo, followed by addition of acetonitrile (500 mL). The resulting precipitate was filtrated and washed twice with acetonitrile (200 mL × 2) to give DMTr-dT-(Kc-C1-carbonate) (19.58 g, quantitative yield) as a white solid. Exemplary synthesis of DMTr-MG(ib)-(Kc-C1-carbonate) (2) (2) 1-Methylimidazole (631 µL, 7.92 mmol) was added to a stirred solution of DMTr- MG(ib) (i.e.5´-DMTr-protected guanosine with 2´-O-(2-methoxyethyl) residue, 2.71 g, 3.80 mmol) and 1,1´-carbonyldiimidazole (1.29 g, 7.56 mmol) in 2-methyltetrahydrofuran (60 mL) at rt. The resulting reaction mixture was stirred at rt for 40 min (monitored by HPLC, method A) and subsequently washed twice with saturated NH 4 Cl aq. (300mL and 150 mL) and then with saturated NaCl aq. (75 mL). The organic phase was concentrated in vacuo to give DMTr-MG(ib)-1H-imidazole- 1-carboxyl, which was used directly without further purification. DBU (591 µL, 3.96 mmol) and 1-methylimidazole (316 µL, 3.91 mmol) were added to a stirred solution of DMT-MG(ib)-1H-imidazole-1-carboxyl (ca. 3.8 mmol) and 3,5-bis(docosyloxy)benzenemethanol (CAS-RN: 955095-32-6, 2.00 g, 2.64 mmol) in 2-methyltetrahydrofuran (40 mL) at rt. The resulting reaction mixture was stirred at rt for 4 h, followed by addition of DMTr-MG(ib) (1.86 g, 2.61 mmol) and stirring the reaction mixture at rt for 17 h (monitored by HPLC with Method A). Acetic anhydride (3.0 mL, 31.69 mmol), pyridine (3.2 mL, 39.61 mmol) and 1-methylimidazole (3.2 mL, 39.61 mmol) were added. After stirring at rt for 10 min, methanol (4.8 mL, 118.84 mmol) was added. After stirring 10 min at rt, the reaction mixture was concentrated in vacuo, followed by addition of acetonitrile (100 mL). The resulting precipitate was filtrated and washed twice with acetonitrile (40 mL × 2) to give DMTr-MG(ib)-(Kc-C1-carbonate) (2, 3.74 g, yield 94.6 %) as a white solid. Pseudo solid-phase protecting groups of the above-mentioned Formula P-1-a, wherein the integer a is 0 Pseudo solid-phase protecting groups of the above-mentioned Formula P-1-a, where the integer a is 0, may be introduced into a nucleoside or oligonucleotide having exactly one free hydroxyl or amine group by reacting said free hydroxyl or amine group with a compound of the following structure: , where L 1 , R P-1 , and the integer i are defined as for Formula P-1-a and R L is selected from the group consisting of a hydroxyl group (OH) and a leaving group (e.g. Cl) capable of being substituted by said hydroxyl or amine moiety of said nucleoside or oligonucleotide. If R L is Cl, the reaction may preferably be conducted in the presence of a base such as pyridine, collidine, triethylamine (TEA) or diisopropylethylamine (DIPEA). If R L is a hydroxyl group, the latter may be activated, e.g. towards ester bond formation, by treatment with a coupling agent such as a carbodiimide (e.g. N,N-diisopropylcarbodiimide) in combination with an additive such as 4-(dimethylamino)pyridine (DMAP), 2-cyano- 2-(hydroxyimino)acetate (Oxyma), 1-hydroxybenzotriazole (HOBt) or 1-hydroxy- 7-azabenzotriazole (HOAt), or by treatment with so-called aminium / uronium salts such as (benzotriazolyl)tetramethyluronium tetrafluoroborate (TBTU), N-[(7-aza-1H- benzotriazol-1-yl)(dimethylamino)-methylene]-N-methylmethana minium tetrafluoroborate N-oxide (TATU), 2-(1H-benzotriazol-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate (HBTU), N-[(7-aza-1H-benzotriazol-1- yl)(dimethylamino)-methylene]-Nmethylmethanaminium hexafluorophosphate N-oxide (HATU) or 1-cyano-2-ethoxy-2- oxoethylidenaminooxy)dimethylamino- morpholino-carbenium-hexafluorophosphate (COMU) in combination with a base such as diisopropylethylamine. To a stirred solution of DMTr-dT (0.30 mmol, 163 mg), DIPEA (0.45 mmol, 78.6 μL), COMU (0.3 mmol, 128.5 mg) and DMAP (0.02 mmol, 2.4 mg) in CH 2 Cl 2 (20 mL) was added 3-(2,4-bis(docosyloxy)phenyl)propanoic acid (0.15 mmol, 120 mg) ) at rt. The resulting reaction mixture was stirred at rt for 16 h and concentrated in vacuo. The precipitate was filtered and washed with MeOH to give DMTr-dT-(Kb-C2-acid) (3, 114 mg, yield 57 %) as white solid. 3-(2,4-bis(docosyloxy)phenyl)propanoic acid used in the synthesis of (3) was prepared as follows: K2CO3 (6 eq) was added to a stirred solution of methyl 3-(2,4- dihydroxyphenyl)propionate (5 mmol) and 1-bromodocosane (3 eq) in DMF/THF (1/1 v/v, 100 mL) at rt. The resulting reaction mixture was stirred at 80 °C for 18 h, diluted with MeCN at 60 °C, and filtered. The collected solid was washed with MeCN (60 °C) and concentrated in vacuo to give methyl 3-(2,4- bis(docosyloxy)phenyl)propanoate quantitatively as white solid. Aq. KOH (1 M, 6 eq) was added to a stirred solution of methyl 3-(2,4- bis(docosyloxy)phenyl)propanoate (5.0 mmol) in EtOH/THF (1/1 v/v, 50 mL) at rt. The resulting reaction mixture was stirred at 90 °C for 5 h, neutralized with 1 M aq. HCl at rt, and filtered. The collected solid was washed with water/acetone and concentrated in vacuo to give 3-(2,4-bis(docosyloxy)phenyl)propanoic acid (1.96 g) in 49 % yield over 2 steps from methyl 3-(2,4-dohydroxyphenyl)propionate (5 mmol) as a white solid. It is noted that such acids may be reduced with LiAlH4 in THF to arrive at the corresponding alcohol. Syntheses of oligonucleotides Example 1: Synthesis A of target oligonucleotide O T -a (see Table T-2) DMTr-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (5) Dichloroacetic acid (DCA, 5.0 mL) was added at rt to a stirred solution of DMTr- MG(ib)-(Kc-C1-carbonate) (2, 987mg, 0.659 mmol) and thiomalic acid (504 mg, 3.36 mmol) in 4-methyltetrahydropyran (MTHP, 15 mL), and the mixture was stirred at rt until reaction monitoring by HPLC (Method B was used throughout Example 1) indicated completion of the DMTr-deprotection. N-Octyl-2-pyrrolidone (NOP, 13 mL), N-methylmorpholine (NMM, 9 mL), acetone (15 mL) and 15 wt-% aqueous (aq.) sodium chloride solution (brine, 40 mL) was added, followed by extraction. The organic phase was separated and extracted twice: first with water/acetone (2:1 v/v, 30 mL), and then with a mixture of water/acetone (3:1 v/v, 20 mL) and acetic acid (150 µL). MTHP (15 mL) was added to the organic phase comprising MG(ib)-(Kc- C1-carbonate) (4), followed by concentration in vacuo (bath temperature 35−55 °C, pressure 100 hPa) to a volume of 20 mL. The MTHP (15 mL) addition and subsequent concentration was repeated three times (final volume: 20 mL, water content: 524 ppm). The so-obtained solution comprising MG(ib)-(Kc-C1-carbonate) (4) was used directly in the subsequent step (without any precipitation, filtration or purification steps in between). NMM (1.0 mL, 12.55 mmol), DMTr-MG(ib) phosphoramidite (CAS-RN: 251647-55-9, 1.93 g, 2.11 mmol) and 5-benzylthio-1H- tetrazole (BTT, 1.30 g, 6.76 mmol) were added to said solution comprising MG(ib)- (Kc-C1-carbonate) (4) and the mixture was stirred at rt until reaction monitoring by HPLC indicated completion of the coupling. 3-(N,N-dimethylamino- methylidene)amino)-3H-1,2,4-dithiazole-5-thione (CAS-RN: 1192027-04-5, DDTT, 548 µg, 2.67 mmol) was added. After stirring for 10 min at rt, triethylphosphite (226 µL, 1.32 mmol) was added. After stirring for 10 min at rt, acetic anhydride (Ac 2 O, 250 µL, 2.64 mmol) and pyridine (266 µL, 3.30 mmol) were added. After stirring for 10 min at rt, the solution was washed (i.e. extracted with aqueous solutions) twice: first with a mixture of 10 vol-% acetic acid (AcOH) aq. (10 mL) and AcOH (1 mL), then with a mixture of 10 vol-% AcOH aq. (10 mL). MTHP (15 mL) was added to the organic phase, followed by concentration in vacuo to a volume of 20 mL (bath temperature 35−55 °C, pressure 100 hPa). This MTHP (15 mL) addition and subsequent concentration was repeated twice (final volume: 20 mL, water content: 1156 ppm). The so-obtained solution comprising DMTr-MG(ib)s-MG(ib)-(Kc-C1- carbonate) (5) was used directly in the subsequent step (without any precipitation, filtration or purification steps in between). Second coupling cycle and further coupling cycles The second coupling cycle and all further coupling cycles were performed according to the following general protocol and as described in detail in the following Tables E-1 and E-2. General protocol for coupling cycle In a typical coupling cycle, the following steps were performed in the presented order. DMTr-deprotection Thiomalic acid and TFA were added to the solution obtained from the preceding azeotropic distillation and the mixture was stirred at rt until reaction monitoring by HPLC indicated complete DMTr-deprotection. Aqueous extraction(s) The reaction mixture obtained from carrying out the DMTr-deprotection was extracted with one or more aqueous solutions as indicated in Table E-2. Azeotropic distillation MTHP was added to the organic phase obtained from the preceding aqueous extractions, followed by concentration in vacuo (bath temperature 35−55 °C, pressure 100 hPa). This MTHP addition and concentration step was typically repeated as indicated in Table E-2. The water content was adjusted to be in the range of 117−524 ppm. The composition of the solution obtained after azeotropic distillation was analyzed as laid out above for the 2 nd to 6 th and for the 8 th to 17 th coupling cycle. The content of NOP was in the range of 21−44 vol-% and the content of MTHP was in the range of 56−79 vol-%. Coupling reaction The respective phosphoramidite building block (obtained commercially) and BTT were added directly to the solution obtained from carrying out the preceding azeotropic distillation and the mixture was stirred at rt until reaction monitoring by HPLC indicated completion of the coupling. Sulfurization (including quenching with triethylphosphite) DDTT was added and the mixture was stirred for 10 min at rt. Triethylphosphite was added and the mixture was stirred for 10 min at rt. Capping Ac2O, pyridine, and 1-methylimidazole were added and the mixture was stirred for 10 min at rt. Aqueous extraction(s) The reaction mixture obtained from carrying out the capping step was extracted with one or more aqueous solutions as indicated in Table E-2. Azeotropic distillation MTHP was added to the organic phase obtained from the preceding aqueous extraction(s), followed by concentration in vacuo (bath temperature 35−55 °C, pressure 100 hPa). This MTHP addition and concentration step was typically repeated as indicated in Table E-2. The water content was adjusted to be in the range of 1006−2340 ppm. The composition of the solution obtained after azeotropic distillation was analyzed as laid out above for the 9 th to 17 th coupling cycle. The content of NOP was in the range of 24−40 vol-% and the content of MTHP was in the range of 60−76 vol-%. The so-obtained solution was used directly in the next coupling cycle (without any precipitation, filtration or purification steps in between). Table E-1: Overview of iterations 2 to 17 of the coupling cycle of Examples 1 and 2 (vide infra) a), b): the terms “starting material” and “product” are not to be construed to indicate any precipitation and/or isolation steps in between the coupling cycles. Table E-2: Experimental detail for the 2 nd to the 17 th coupling cycle of Example 1 as listed in Table E-1 Thiomalic acid (1.46 g, 9.72 mmol) and TFA (5.0 mL) were added directly to the solution comprising compound 21 obtained from the preciding azeotropic distillation, followed by by stirring at rt until reaction monitoring by HPLC (Method B was used throughout Example 1) indicated completion of the DMTr-deprotection. N-Octyl-2- pyrrolidone (NOP, 5 mL), N-methylmorpholine (NMM, 16 mL), acetone (15 mL) and 15 wt-% aqueous (aq.) sodium chloride solution (brine, 20 mL) was added, followed by extraction. The organic phase was separated and extracted as follows: first with a mixture of 10 wt-% brine (20 mL) and acetone (10 mL), second with a mixture of 1 M NMM aq. (20 mL), 10 wt-% brine (5 mL) and NOP (5 mL), third with a mixture of 1 M NMM aq. (20 mL), 10 wt-% brine (5 mL) and acetone (10 mL), fourth with a mixture of 2.5 wt-% brine (20 mL), acetone (5 mL) and ACOH (0.5 mL), fifth with a mixture of 2.5 wt-% brine (20 mL) and acetone (5 mL). The organic phase obtained from the final aqueous extraction was concentrated in vacuo, followed by addition of diisopropylether (IPE, 50 mL). The resulting precipitate was filtered and washed twice with IPE (12.5 mL × 2) to give mMeUs-mMeC(bz)s-MA(bz)s-mMeC(bz)s- mMeUs-mMeUs-mMeUs-mMeC(bz)s-MA(bz)s-mMeUs-MA(bz)s-MA(bz)s-mM eUs- MG(ib)s-mMeC(bz)s-mMeUs-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (22, 2.38 g, crude). Target oligonucleotide O T -a A solution of the crude of compound 22 (104 mg, 5.7 nmol) in a mixture of H2O and tert-butylamine (1:1 v/v, 2 mL) was stirred at 80 °C for 5 h. Additional tert-butylamine (2.0 mL) was added to the mixture. After stirring at 80 °C for additional 5 h, the reaction mixture was cooled to room temperature and analyzed by HPLC-MS (Method C) to find 5-mMeUs-mMeCs-mAs-mMeCs-mMeUs-mMeUs-mMeUs- mMeCs-mAs-mMeUs-mAs-mAs-mMeUs-MGs-mMeCs-mMeUs-MGs-MG-3 (O T -a). MS (Method C) m/z: [M - H] 3- calcd for C234H337N61O128P17S17 3- , 2373.0844, found 2373.0848. Example 2: Synthesis B of target oligonucleotide O T -a (see Table T-2) DMTr-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (5) DCA (5.0 mL) was added under stirring to an ice-cooled solution (5−10 °C) of DMTr- MG(ib)-(Kc-C1-carbonate) (2, 0.984 g, 0.657 mmol) and thiomalic acid (0.496g, 3.30 mmol) in MTHP (15 mL). The mixture was stirred at rt until reaction monitoring by HPLC (Method B was used throughout Example 2) indicated completion of the DMTr-deprotection. NMM (7 mL), 1 M NMM aq. (10 mL), acetone (2.5 mL), MTHP (5 mL) and 10 wt-% brine (5 mL) were added. The organic phase was separated and washed (i.e. extracted) three times: first with water/acetone solution (1:1 v/v, 15 mL), then water/acetone solution (2:1 v/v, 15 mL), and lastly with a mixture of 5 wt-% brine (20 mL), acetone (7.5 mL) and AcOH (0.1 mL). N-Octyl-2-pyrrolidone (NOP, 10 mL) was added to the so-obtained organic phase. The mixture was dehydrated azeotropically (bath temperature 35−55 °C, pressure 100 hPa; final water content: 132 ppm) in vacuo with MTHP to obtain a solution comprising MG(ib)-(Kc-C1- carbonate) (4), which was used directly in the subsequent step (without any precipitation, filtration or purification steps in between).1-Methylimidazole (1.0 mL, 12.55 mmol), DMTr-MG(ib) phosphoramidite (CAS-RN: 251647-55-9, 1.23 g, 1.35 mmol) and BTT (1.26 g, 6.56 mmol) were added to said solution comprising MG(ib)- (Kc-C1-carbonate) (4). The mixture was stirred at rt, and consumption of the starting material was monitored by HPLC. Xanthane hydride (0.299 g, 1.99 mmol) was added. After stirring for 10 min at rt, triethylphosphite (0.171 mL, 1.00 mmol) was added. After stirring for 10 min at rt, Ac2O (250 µL, 2.64 mmol) and pyridine (266 µL, 3.30 mmol) were added, followed by stirring at rt for 10 min. Second coupling cycle and further coupling cycles All further iterations of the coupling cycle were performed according to the following general protocol and as described in detail in the following Table E-3. The starting materials and products of each coupling cycle are identical to those listed in Table E-1 above. Again, the terms “starting material” and “product” are not to be construed to indicate any precipitation and/or isolation steps in between the coupling cycles. General protocol for coupling cycles In a typical coupling cycle, the following steps were performed in the presented order. DMTr-deprotection 2-PrOH, thiomalic acid, AcOH, TMSCl, and, if indicated, Ac 2 O were added under ice-cooling at a temperature in the range of 5−10 °C directly to the solution obtained from the preceding capping step. The mixture was stirred at rt for 45 min. Aqueous extraction(s) The reaction mixture obtained from carrying out the DMTr-deprotection was extracted with one or more aqueous solutions as indicated in Table E-3. Azeotropic distillation MTHP (15–30 mL), and if indicated, BTT and/ or NOP was added to the organic phase obtained from the preceding aqueous extractions, followed by concentration in vacuo (bath temperature 35−55 °C, pressure 100 hPa). This MTHP addition and concentration step was typically repeated. The water content was adjusted to be in the range of 132−424 ppm. The composition of the solution obtained after azeotropic distillation was analyzed as laid out above for the 2 nd to 6 th and for the 8 th to 17 th coupling cycle. The content of NOP was in the range of 36.7−63.5 vol-% and the content of MTHP was in the range of 36.5−63.3 vol-%. Coupling reaction The respective phosphoramidite building block (obtained commercially) and BTT were added and the mixture was stirred at rt until reaction monitoring by HPLC indicated completion of the coupling. Sulfurization (including quenching with triethylphosphite) Xanthane hydride was added and the mixture was stirred for 10 min at rt. Triethylphosphite was added and the mixture was stirred for 10 min at rt. Capping Ac 2 O, pyridine, and 1-methylimidazole were added and the mixture was stirred for 10 min at rt. Table E-3: Experimental detail for the 2 nd to the 17 th coupling cycle as listed in Table E-1 Isoprpyl alcohol (2-PrOH, 0.5 mL), thiomalic acid (2.99 g, 19.9 mmol), AcOH (4.0 mL), Ac2O (0.5 mL) and TMSCl (5 mL) were added directly to the solution obtained from the preceding capping step, under ice-cooling at a temperature in the range of 5−10 °C, followed by stirring at rt for 45 min.2-PrOH (5.0 mL), MTHP (22.5 mL), NMM (24 mL), acetone (7.5 mL) and 10 wt-% brine (30 mL) were added, followed by extraction and separation of the organic phase, and extracting the latter as follows: first with a mixture of 15 wt-% brine (10 mL) and 1 M NMM (10 mL) and acetone (10 mL), next with a mixture of 15 wt-% brine (5 mL), 1 M NMM and (20 mL), acetone (10 mL), next with a mixture of 15 wt-% brine (10 mL), 1 M NMM (10 mL) and acetone (10 mL), and lastly with a mixture of 5 wt-% brine (15 mL), acetone (10 mL) and AcOH (0.5 mL). The organic phase obtained from the final aqueous extraction was concentrated in vacuo, followed by addition of diisopropylether (IPE, 50 mL). The resulting precipitate was filtered and washed twice with IPE (50 mL × 2) and then with 2-PrOH (50 mL) to give mMeUs-mMeC(bz)s-MA(bz)s-mMeC(bz)s- mMeUs-mMeUs-mMeUs-mMeC(bz)s-MA(bz)s-mMeUs-MA(bz)s-MA(bz)s-mM eUs- MG(ib)s-mMeC(bz)s-mMeUs-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (22, 5.39 g, crude). Target oligonucleotide O T -a A solution of the crude of compound 22 (0.249 g, 0.030 mmol) in H2O and tert- butylamine (1:1 v/v, 7.5 mL) was stirred at 60 °C for 8h. Additional tert-butyelamine (0.75 mL) was added to the mixture and the solution was stirred at 80 °C for additional 7 h (monitored by HPLC with Method C, Gradient-1). The reaction mixture was cooled to room temperature and analyzed by HPLC-MS (Method C) to find 5- mMeUs-mMeCs-mAs-mMeCs-mMeUs-mMeUs-mMeUs-mMeCs-mAs-mMeUs- mAs-mAs-mMeUs-MGs-mMeCs-mMeUs-MGs-MG-3 (O T -a). MS (Method C) m/z: [M - H] 3- calcd for C234H337N61O128P17S17 3- , 2373.0848, found 2373.0860. Example 3: Synthesis A of target oligonucleotide O T -b (see Table T-2) DMTr-dG(ib)-dT-(Kc-C1-carbonate) (24) Dichloroacetic acid (100 mL) was added to a stirred solution of DMTr-dT-(Kc-C1- carbonate) (1, 13.20 mmol) and thiomalic acid (9.96 g, 66.33 mmol) in cyclopentyl methyl ether (CPME, 300 mL) at rt and the mixture was stirred until reaction monitoring by HPLC (Method B) indicated completion of the DMTr-deprotection. Acetone (50 mL), 1 M N-methylmorpholine (NMM) aq. (200 mL) and NMM (100 mL) were added, followed by extraction. The organic phase was separated and washed (i.e. extracted) twice with water/acetone solution (1:1 v/v, 300 mL × 2). The organic phase was concentrated in vacuo, followed by addition of acetonitrile (300 mL). The resulting precipitate was filtrated and washed twice with acetonitrile (100 mL × 2) to give dT-(Kc-C-1-carbonate) (23, 12.56 g, purity 94.59 %, yield 92.7 %). A solution of dT-(Kc-C1-carbonate) (23, 677 mg, 0.660 mmol) in CPME/N,N- dibutylformamide (DBF) (6:1 v/v, 35 mL) was concentrated in vacuo (bath temperature 35−55 °C, pressure 100 hPa) to a volume of 20 mL. The so-obtained solution comprising dT-(Kc-C1-carbonate) (23) was used directly in the subsequent step (without any precipitation, filtration or purification steps in between). 1-Methylimidazole (1.0 mL, 12.55 mmol), DMTr-dG(ib) phosphoramidite (CAS-RN: 93183-15-4, 1.11 g, 1.32 mmol) and BTT (637 mg, 3.31 mmol) were added to said solution comprising dT-(Kc-C1-carbonate) (23), and the mixture was stirred at rt until reaction monitoring by HPLC (Method B was used throughout Example 3) indicated completion of the coupling. Ac2O (250 µL, 2.64 mmol) and pyridine (266 µL, 3.30 mmol) were added. After stirring for 10 min at rt, 1 M I2 in CPME (1.45 mL, 1.45 mmol), H 2 O (36 µL), and acetonitrile (MeCN, 1.5 mL) were added. After stirring for 10 min at rt, the reaction mixture was extracted twice: first with 0.5 N Na 2 S 2 O 3 aq. (10 mL), then with a mixture of 0.5 N Na2S2O3 aq. (5 mL) and 1 M NMM aq. (1 mL). The so-obtained solution (organic phase) comprising DMTr-dG(ib)-dT-(Kc-C1- carbonate) (24) was used directly in the next step (without any precipitation, filtration or purification steps in between). DMTr-dA(bz)-dG(ib)-dT-(Kc-C1-carbonate) (26) Thiomalic acid (0.991 g, 6.60 mmol) and dichloroacetic acid (DCA, 5.0 mL) were added to the so-obtained organic phase, followed by stirring at rt until reaction monitoring by HPLC indicated complete DMTr-deprotection. DBF (1.3 mL), 10 wt-% brine (12.5 mL), and NMM (10 mL) were added, followed by extraction. The organic phase was separated and extracted twice with 10 wt-% brine/N,N- dimethylformamide (DMF) solution (7:13 v/v, 25 mL × 2). CPME (15 mL) was added to the so-obtained organic phase comprising dG(ib)-dT-(Kc-C1-carbonate) (25), followed by concentration in vacuo to a volume of 20 mL (bath temperature 35−55 °C, pressure 100 hPa). The CPME (15 mL) addition and subsequent concentration was repeated three times (final volume: 20 mL).1-Methylimidazole (1.0 mL, 12.55 mmol), DMTr-dA(bz) phosphoramidite (CAS-RN: 98796-53-3, 1.15 g, 1.32 mmol) and BTT (635 mg, 3.30 mmol) were added to said solution comprising dG(ib)-dT- (Kc-C1-carbonate) (25), and the mixture was stirred at rt until reaction monitoring by HPLC indicated completion of the coupling. Ac2O (250 µL, 2.64 mmol) and pyridine (266 µL, 3.30 mmol) were added. After stirring for 10 min at rt, 1 M I2 in CPME (1.45 mL, 1.45 mmol), H2O (36 µL), and acetonitrile (MeCN, 1.5 mL) were added. After stirring for 10 min at rt, the reaction mixture was extracted twice: first with 0.5 N Na2S2O3 aq. (10 mL), then with a mixture of 0.5 N Na2S2O3 aq. (5 mL) and 1 M NMM aq. (1.25 mL). The so-obtained solution (organic phase) comprising DMTr-dA(bz)- dG(ib)-dT-(Kc-C1-carbonate) (26) was used directly in the next step (without any precipitation, filtration or purification steps in between). DMTr-dC(bz)-dA(bz)-dG(ib)-dT-(Kc-C1-carbonate) (28) Thiomalic acid (0.992 g, 6.61 mmol) and dichloroacetic acid (DCA, 5.0 mL) were added to the so-obtained organic phase, followed by stirring at rt until reaction monitoring by HPLC indicated complete DMTr-deprotection. DBF (1.3 mL), 10 wt-% brine (12.5 mL), and NMM (11.2 mL) were added, followed by extraction. The organic phase was separated and extracted twice with 10 wt-% brine/DMF solution (7:13 v/v, 25 mL × 2). CPME (15 mL) was added to the so-obtained organic phase comprising dA(bz)-dG(ib)-dT-(Kc-C1-carbonate) (27), followed by concentration in vacuo to a volume of 20 mL (bath temperature 35−55 °C, pressure 100 hPa). The CPME (15 mL) addition and subsequent concentration was repeated three times (final volume: 20 mL). 1-Methylimidazole (1.0 mL, 12.55 mmol), DMTr-dC(bz) phosphoramidite (CAS-RN: 102212-98-6, 1.12 g, 1.32 mmol) and BTT (635 mg, 3.30 mmol) were added to the solution comprising dA(bz)-dG(ib)-dT-(Kc-C1- carbonate) (27), and the mixture was stirred at rt until reaction monitoring by HPLC indicated completion of the coupling. Ac2O (250 µL, 2.64 mmol) and pyridine (266 µL, 3.30 mmol) were added. After stirring for 10 min at rt, 1 M I2 in CPME (1.45 mL, 1.45 mmol), H2O (36 µL), and acetonitrile (MeCN, 1.5 mL) were added. After stirring for 10 min at rt, the reaction mixture was extracted twice: first with 0.5 N Na 2 S 2 O 3 aq. (10 mL), then with a mixture of 0.5 N Na 2 S 2 O 3 aq. (5 mL) and 1 M NMM aq. (1.25 mL). The so-obtained solution (organic phase) comprising DMTr-dC(bz)- dA(bz)-dG(ib)-dT-(Kc-C1-carbonate) (28) was used directly in the next step (without any precipitation, filtration or purification steps in between). dT-dC(bz)-dA(bz)-dG(ib)-dT-(Kc-C1-carbonate) (O T -b) Thiomalic acid (0.992 g, 6.61 mmol) and dichloroacetic acid (DCA, 5.0 mL) were added to the so-obtained organic phase, followed by stirring at rt until reaction monitoring by HPLC indicated complete DMTr-deprotection. DBF (1.3 mL), 10 wt-% brine (12.5 mL), and NMM (11.6 mL) were added, followed by extraction. The organic phase was separated and extracted twice with 10 wt-% brine/DMF solution (7:13 v/v, 25 mL × 2). CPME (15 mL) was added to the so-obtained organic phase comprising dC(bz)-dA(bz)-dG(ib)-dT-(Kc-C1-carbonate) (29), followed by concentration in vacuo to a volume of 20 mL (bath temperature 35−55 °C, pressure 100 hPa). The CPME (15 mL) addition and subsequent concentration was repeated twice (final volume: 20 mL). 1-Methylimidazole (1.0 mL, 12.55 mmol), DMTr-dT phosphoramidite (CAS-RN: 98796-51-1, 1.01 g, 1.33 mmol) and BTT (636 mg, 3.31 mmol) were added to said solution comprising dC(bz)-dA(bz)-dG(ib)-dT-(Kc-C1- carbonate) (29), and the mixture was stirred at rt until reaction monitoring by HPLC indicated completion of the coupling. Ac 2 O (250 µL, 2.64 mmol) and pyridine (266 µL, 3.30 mmol) were added. After stirring for 10 min at rt, 1 M I 2 in CPME (1.45 mL, 1.45 mmol), H 2 O (36 µL), and MeCN (1.5 mL) were added. After stirring for 10 min at rt, the reaction mixture was extracted twice: first with 0.5 N Na2S2O3 aq. (10 mL), then with a mixture of 0.5 N Na2S2O3 aq. (5 mL) and 1 M NMM aq. (1.25 mL). The so-obtained solution (organic phase) comprising DMTr-dT-dC(bz)-dA(bz)-dG(ib)- dT-(Kc-C1-carbonate) (30) was used directly in the next step (without any precipitation, filtration or purification steps in between). Thiomalic acid (0.992 g, 6.61 mmol) and dichloroacetic acid (DCA, 5.0 mL) were added to the so-obtained organic phase, followed by stirring at rt until reaction monitoring by HPLC indicated complete DMTr-deprotection. DBF (1.3 mL), 10 wt-% brine (12.5 mL), and NMM (12.0 mL) were added, followed by extraction. The organic phase was separated and extracted twice with 10 wt-% brine/DMF solution (7:13 v/v, 25 mL × 2). The so-obtained organic phase comprising dT-dC(bz)-dA(bz)- dG(ib)-dT-(Kc-C1-carbonate) (O T -b) was concentrated in vacuo, followed by addition of MeOH (25 mL). The resulting precipitate was filtered and washed twice with MeOH (12.5 mL × 2) to give dT-dC(bz)-dA(bz)-dG(ib)-dT-(Kc-C1-carbonate) (O T -b, 1.06 g, purity 83.152 %, yield 58.6 %) as a white solid. MS (method A) m/z: [M + 2H] 2+ calcd for C 131 H 185 N 21 O 36 P 4 + , 1376.1115; found 1376.1157. Example 4: Synthesis B of target oligonucleotide O T -b (see Table T-2) DMTr-dG(ib)-dT-(Kc-C1-carbonate) (24) dT-(Kc-C1-carbonate) (23) was synthesized as described for Example 3 above. A solution of dT-(Kc-C1-carbonate) (23, 677 mg, 0.660 mmol) in 4-methyltetrahydropyran (MTHP)/N,N-dibutylformamide (DBF) (6:1 v/v, 35 mL) was concentrated in vacuo to a volume of 15 mL (bath temperature 35−55 °C, pressure 100 hPa).1-Methylimidazole (1.0 mL, 12.55 mmol), DMTr-dG(ib) phosphoramidite (CAS-RN: 93183-15-4, 1.11 g, 1.32 mmol) and BTT (637 mg, 3.31 mmol) were added to said solution comprising dT-(Kc-C1-carbonate) (23), and the mixture was stirred at rt until reaction monitoring by HPLC (Method B was used throughout Example 4) indicated completion of the coupling. Ac2O (250 µL, 2.64 mmol) and pyridine (266 µL, 3.30 mmol) were added. After stirring for 10 min at rt, 1 M I2 in MTHP (1.45 mL, 1.45 mmol), H2O (36 µL), and acetonitrile (MeCN, 1.5 mL) were added. After stirring for 10 min at rt, the reaction mixture was extracted twice: first with 0.5 N Na 2 S 2 O 3 aq. (10 mL), then with a mixture of 0.5 N Na 2 S 2 O 3 aq. (5 mL) and 1 M NMM aq. (1.3 mL). The so-obtained solution (organic phase) comprising DMTr-dG(ib)-dT-(Kc-C1-carbonate) (24) was used directly in the next step (without any precipitation, filtration or purification steps in between). DMTr-dA(bz)-dG(ib)-dT-(Kc-C1-carbonate) (26) Thiomalic acid (0.991 g, 6.60 mmol) and dichloroacetic acid (DCA, 5.0 mL) were added to the so-obtained organic phase, followed by stirring at rt until reaction monitoring by HPLC indicated complete DMTr-deprotection. DBF (1.3 mL), 10 wt-% brine (12.5 mL), and NMM (10 mL) were added, followed by extraction. The organic phase was separated and extracted twice with 10 wt-% brine/N,N- dimethylformamide (DMF) solution (2:3 v/v, 22.5 mL × 2). MTHP (15 mL) was added to the so-obtained organic phase comprising dG(ib)-dT-(Kc-C1-carbonate) (25), followed by concentration in vacuo to a volume of 15 mL (bath temperature 35−55 °C, pressure 100 hPa). The MTHP (15 mL) addition and subsequent concentration was repeated three times (final volume: 15 mL).1-Methylimidazole (1.0 mL, 12.55 mmol), DMTr-dA(bz) phosphoramidite (CAS-RN: 98796-53-3, 1.15 g, 1.32 mmol) and BTT (636 mg, 3.30 mmol) were added to said solution comprising dG(ib)-dT- (Kc-C1-carbonate) (25), and the mixture was stirred at rt until reaction monitoring by HPLC indicated completion of the coupling. Ac 2 O (250 µL, 2.64 mmol) and pyridine (266 µL, 3.30 mmol) were added. After stirring for 10 min at rt, 1 M I 2 in MTHP (1.45 mL, 1.45 mmol), H 2 O (36 µL), and acetonitrile (MeCN, 1.5 mL) were added. After stirring for 10 min at rt, the reaction mixture was extracted twice: first with 0.5 N Na 2 S 2 O 3 aq. (10 mL), then with a mixture of 0.5 N Na 2 S 2 O 3 aq. (5 mL) and 1 M NMM aq. (1.25 mL). MTHP (15 mL) was added to the organic phase comprising DMTr- dA(bz)-dG(ib)-dT-(Kc-C1-carbonate) (26), followed by concentration in vacuo to a volume of 15 mL (bath temperature 35−55 °C, pressure 100 hPa). This MTHP (15 mL) addition and subsequent concentration was repeated once (final volume: 15 mL). The so-obtained solution (organic phase) comprising DMTr-dA(bz)-dG(ib)- dT-(Kc-C1-carbonate) (26) was used directly in the next step (without any precipitation, filtration or purification steps in between). DMTr-dC(bz)-dA(bz)-dG(ib)-dT-(Kc-C1-carbonate) (28) Thiomalic acid (0.992 g, 6.61 mmol) and dichloroacetic acid (DCA, 7.5 mL) were added to the so-obtained organic phase, followed by stirring at rt until reaction monitoring by HPLC indicated complete DMTr-deprotection. DBF (1.3 mL), 10 wt-% brine (12.5 mL), and NMM (12 mL) were added, followed by extraction. The organic phase was separated and extracted twice with 10 wt-% brine/DMF solution (2:3 v/v, 22.5 mL × 2). MTHP (15 mL) was added to the so-obtained organic phase comprising dA(bz)-dG(ib)-dT-(Kc-C1-carbonate) (27), followed by concentration in vacuo to a volume of 15 mL (bath temperature 35−55 °C, pressure 100 hPa). The MTHP (15 mL) addition and subsequent concentration was repeated three times (final volume: 15 mL). 1-Methylimidazole (1.0 mL, 12.55 mmol), DMTr-dC(bz) phosphoramidite (CAS-RN: 102212-98-6, 1.12 g, 1.32 mmol) and BTT (636 mg, 3.30 mmol) were added to said solution comprising dA(bz)-dG(ib)-dT-(Kc-C1- carbonate) (27), and the mixture was stirred at rt until reaction monitoring by HPLC indicated completion of the coupling. Ac2O (250 µL, 2.64 mmol) and pyridine (266 µL, 3.30 mmol) were added. After stirring for 10 min at rt, 1 M I2 in MTHP (1.45 mL, 1.45 mmol), H2O (36 µL), and acetonitrile (MeCN, 1.5 mL) were added. After stirring for 10 min at rt, the reaction mixture was extracted twice: first with 0.5 N Na2S2O3 aq. (10 mL), then with a mixture of 0.5 N Na2S2O3 aq. (5 mL) and 1 M NMM aq. (1.25 mL). The so-obtained solution (organic phase) comprising DMTr-dC(bz)- dA(bz)-dG(ib)-dT-(Kc-C1-carbonate) (28) was used directly in the next step (without any precipitation, filtration or purification steps in between). dT-dC(bz)-dA(bz)-dG(ib)-dT-(Kc-C1-carbonate) (O T -b) Thiomalic acid (0.992 g, 6.61 mmol) and dichloroacetic acid (DCA, 7.5 mL) were added to the so-obtained organic phase, followed by stirring at rt until reaction monitoring by HPLC indicated complete DMTr-deprotection. DBF (1.3 mL), 10 wt-% brine (12.5 mL), and NMM (12 mL) were added, followed by extraction. The organic phase was separated and extracted twice with 10 wt-% brine/DMF solution (2:3 v/v, 22.5 mL × 2). MTHP (15 mL) was added to the so-obtained organic phase comprising dC(bz)-dA(bz)-dG(ib)-dT-(Kc-C1-carbonate) (29), followed by concentration in vacuo to a volume of 15 mL (bath temperature 35−55 °C, pressure 100 hPa). The MTHP (15 mL) addition and subsequent concentration was repeated twice (final volume: 15 mL). 1-Methylimidazole (1.0 mL, 12.55 mmol), DMTr-dT phosphoramidite (CAS-RN: 98796-51-1, 1.01 g, 1.33 mmol) and BTT (636 mg, 3.31 mmol) were added to said solution comprising dC(bz)-dA(bz)-dG(ib)-dT-(Kc-C1- carbonate) (29), and the mixture was stirred at rt until reaction monitoring by HPLC indicated completion of the coupling. Ac2O (250 µL, 2.64 mmol) and pyridine (266 µL, 3.30 mmol) were added. After stirring for 10 min at rt, 1 M I2 in MTHP (1.45 mL, 1.45 mmol), H2O (36 µL), and MeCN (1.5 mL) were added. After stirring for 10 min at rt, the reaction mixture was extracted twice: first with 0.5 N Na 2 S 2 O 3 aq. (10 mL), then with a mixture of 0.5 N Na 2 S 2 O 3 aq. (5 mL) and 1 M NMM aq. (1.25 mL). The so-obtained solution (organic phase) comprising DMTr-dT-dC(bz)-dA(bz)-dG(ib)- dT-(Kc-C1-carbonate) (30) was used directly in the next step (without any precipitation, filtration or purification steps in between). Thiomalic acid (0.992 g, 6.61 mmol) and dichloroacetic acid (DCA, 7.5 mL) were added to the so-obtained organic phase, followed by stirring at rt until reaction monitoring by HPLC indicated complete DMTr-deprotection. DBF (1.3 mL), 10 wt-% brine (12.5 mL), and NMM (11.0 mL) were added, followed by extraction. The organic phase was separated and extracted twice with 10 wt-% brine/DMF solution (2:3 v/v, 22.5 mL × 2). The so-obtained organic phase comprising dT-dC(bz)-dA(bz)- dG(ib)-dT-(Kc-C1-carbonate) (O T -b) was concentrated in vacuo, followed by addition of MeOH (25 mL). The resulting precipitate was filtered and washed twice with MeOH (12.5 mL × 2) to give dT-dC(bz)-dA(bz)-dG(ib)-dT-(Kc-C1-carbonate) (O T -b, 989 mg, purity 79.699 %, yield 54.7 %) as a white solid. MS (method A) m/z: [M + 2H] 2+ calcd for C131H185N21O36P4 + , 1376.1115; found 1376.1157. Example 5: Synthesis of target oligonucleotide O T -c (see Table T-2) DMTr-dA(bz)s-dT-(Kc-C1-carbonate) (32) dT-(Kc-C-1-carbonate) (23) was synthesized as described for Example 3 above. A solution of dT-(Kc-C1-carbonate) (23, 676 mg, 0.659 mmol) in 4-methyltetrahydropyran (MTHP)/N-octyl-2-pyrrolidone (NOP) (5:1 v/v, 30 mL) was concentrated in vacuo (bath temperature 35−55 °C, pressure 100 hPa) to a volume of 15 mL.1-Methylimidazole (1.0 mL, 12.55 mmol), DMTr-dA(bz) phosphoramidite (CAS-RN: 98796-53-3, 1.72 g, 1.97 mmol) and BTT (640 mg, 3.33 mmol) were added to the so-obtained solution comprising dT-(Kc-C1-carbonate) (23), and the mixture was stirred at rt until reaction monitoring by HPLC (Method B was used throughout Example 5) indicated completion of the coupling.3-(N,N-dimethylamino- methylidene)amino)-3H-1,2,4-dithiazole-5-thione (CAS-RN: 1192027-04-5, DDTT, 544 mg, 2.65 mmol) was added, followed by stirring at rt for 10 min. Ac2O (250 µL, 2.64 mmol) and pyridine (266 µL, 3.30 mmol) were added. After stirring for 10 min at rt, the reaction mixture was extracted twice with 10 vol-% AcOH aq. (10 mL × 2). The so-obtained solution (organic phase) comprising DMTr-dA(bz)s-dT-(Kc-C1- carbonate) (32) was used directly in the next step (without any precipitation, filtration or purification steps in between). DMTr-dC(bz)s-dA(bz)s-dT-(Kc-C1-carbonate) (34) Thiomalic acid (1.01 g, 6.73 mmol) and dichloroacetic acid (DCA, 5.0 mL) were added to the so-obtained organic phase, followed by stirring at rt until reaction monitoring by HPLC indicated complete DMTr-deprotection. NOP (1.3 mL), 10 wt- % brine (12.5 mL), and NMM (10 mL) were added, followed by extraction. The organic phase was separated and extracted twice with a solution of acetone and water (1:1 v/v, 20 mL × 2). MTHP (15 mL) was added to the so-obtained organic phase comprising dA(bz)s-dT-(Kc-C1-carbonate) (33), followed by concentration in vacuo to a volume of 15 mL (bath temperature 35−55 °C, pressure 100 hPa). The MTHP (15 mL) addition and subsequent concentration was repeated once (final volume: 15 mL). 1-Methylimidazole (1.0 mL, 12.55 mmol), DMTr-dC(bz) phosphoramidite (CAS-RN: 102212-98-6, 1.62 g, 1.91 mmol) and BTT (632 mg, 3.29 mmol) were added to said solution comprising dA(bz)-dT-(Kc-C1-carbonate) (33), and the mixture was stirred at rt until reaction monitoring by HPLC indicated completion of the coupling. DDTT (544 mg, 2.65 mmol) was added, followed by stirring at rt for 10 min. Ac2O (250 µL, 2.64 mmol) and pyridine (266 µL, 3.30 mmol) were added. After stirring for 10 min at rt, the reaction mixture was extracted twice: first with 10 vol-% AcOH aq, then with a mixture of 10 vol-% AcOH aq. (10 mL) and acetone (10 mL). The so-obtained solution (organic phase) comprising DMTr- dC(bz)s-dA(bz)s-dT-(Kc-C1-carbonate) (34) was used directly in the next step (without any precipitation, filtration or purification steps in between). DMTr-dG(ib)s-dC(bz)s-dA(bz)s-dT-(Kc-C1-carbonate) (36) Thiomalic acid (1.01 g, 6.73 mmol) and dichloroacetic acid (DCA, 5.0 mL) were added to the so-obtained organic phase, followed by stirring at rt until reaction monitoring by HPLC indicated complete DMTr-deprotection. NOP (1.3 mL), 10 wt- % brine (12.5 mL), and NMM (10 mL) were added, followed by extraction. The organic phase was separated and extracted eight times: twice with a solution of acetone and water (1:1 v/v, 20 mL × 2), then with a mixture of 0.5 N NaHCO3 (5 mL), H2O (5 mL) and acetone (10 mL), then with a mixture of 0.5 N NaHCO3 (5 mL) 10 wt-% NaCl aq. (10 mL), and DMF (5 mL), then with a mixture of 50 vol-% aq. acetone (20mL) and acetic acid (0.5 mL), then with a mixture of 50 vol-% aq. acetone (20 mL) and NMM (1 mL), and lastly twice with 50 vol-% aq. acetone (20 mL × 2). MTHP (15 mL) was added to the so-obtained organic phase comprising dC(bz)s-dA(bz)s-dT-(Kc-C1-carbonate) (35), followed by concentration in vacuo to a volume of 15 mL (bath temperature 35−55 °C, pressure 100 hPa). The MTHP (15 mL) addition and subsequent concentration was repeated once (final volume: 15 mL).1-Methylimidazole (1.0 mL, 12.55 mmol), DMTr-dG(ib) phosphoramidite (CAS- RN: 93183-15-4, 1.68 g, 2.00 mmol) and BTT (646 mg, 3.36 mmol) were added to said solution comprising dC(bz)s-dA(bz)s-dT-(Kc-C1-carbonate) (35), and the mixture was stirred at rt until reaction monitoring by HPLC indicated completion of the coupling. DDTT (544 mg, 2.65 mmol) was added, followed by stirring at rt for 10 min. Ac2O (250 µL, 2.64 mmol) and pyridine (266 µL, 3.30 mmol) were added. After stirring for 10 min at rt, the reaction mixture was extracted twice: first with 10 vol-% AcOH aq, then with a mixture of 10 vol-% AcOH aq. (10 mL) and acetone (10 mL). The so-obtained solution (organic phase) comprising DMTr-dG(ib)s-dC(bz)s- dA(bz)s-dT-(Kc-C1-carbonate) (36) was used directly in the next step (without any precipitation, filtration or purification steps in between). dTs-dG(ib)s-dC(bz)s-dA(bz)s-dT-(Kc-C1-carbonate) (O T -c) Thiomalic acid (1.01 g, 6.73 mmol) and dichloroacetic acid (DCA, 5.0 mL) were added to the so-obtained organic phase, followed by stirring at rt until reaction monitoring by HPLC indicated complete DMTr-deprotection. NOP (1.3 mL), 10 wt- % brine (12.5 mL), and NMM (10 mL) were added, followed by extraction. The organic phase was separated and extracted eight times: twice with a solution of acetone and water (1:1 v/v, 20 mL × 2), then with a mixture of 0.5 N NaHCO 3 (5 mL), H 2 O (5 mL) and acetone (10 mL), then with a mixture of 0.5 N NaHCO 3 (5 mL) 10 wt-% NaCl aq. (10mL), and DMF (5 mL), then with a mixture of 50 vol-% aq. acetone (20mL) and acetic acid (0.5 mL), then with a mixture of 50 vol-% aq. acetone (20 mL) and NMM (1 mL), and lastly twice with 50 vol-% aq. acetone (20 mL × 2). MTHP (15 mL) was added to the so-obtained organic phase comprising dG(ib)s-dC(bz)s-dA(bz)s-dT-(Kc-C1-carbonate) (37), followed by concentration in vacuo to a volume of 15 mL (bath temperature 35−55 °C, pressure 100 hPa). The MTHP (15 mL) addition and subsequent concentration was repeated once (final volume: 15 mL). 1-Methylimidazole (1.0 mL, 12.55 mmol), DMTr-dT phosphoramidite (CAS-RN: 98796-51-1, 1.50 g, 1.97 mmol) and BTT (635 mg, 3.30 mmol) were added to said solution comprising comprising dG(ib)s-dC(bz)s-dA(bz)s- dT-(Kc-C1-carbonate) (37), and the mixture was stirred at rt until reaction monitoring by HPLC indicated completion of the coupling. DDTT (542 mg, 2.63 mmol) was added, followed by stirring at rt for 10 min. Ac2O (250 µL, 2.64 mmol) and pyridine (266 µL, 3.30 mmol) were added. After stirring for 10 min at rt, the reaction mixture was extracted twice: first with a mixture of 10wt% aq. NaCl (19 mL) and acetic acid (1 mL), then with a mixture of 10wt% aq. NaCl (20 mL), NOP (2.5 mL), and acetone (10 mL). The so-obtained solution (organic phase) comprising DMTr-dTs-dG(ib)s- dC(bz)s-dA(bz)s-dT-(Kc-C1-carbonate) (38) was used directly in the next step (without any precipitation, filtration or purification steps in between). Thiomalic acid (1.0 g, 6.66 mmol) and dichloroacetic acid (DCA, 5.0 mL) were added to the so-obtained organic phase, followed by stirring at rt until reaction monitoring by HPLC indicated complete DMTr-deprotection. NOP (1.3 mL), 10 wt-% brine (25 mL), and NMM (11 mL) were added, followed by extraction. The organic phase was separated and extracted twice with 50 vol-% aq. acetone. The so-obtained organic phase comprising dTs-dG(ib)s-dC(bz)s-dA(bz)s-dT-(Kc-C1-carbonate) (O T -c) was concentrated in vacuo, followed by addition of MeOH (40 mL). The resulting precipitate was filtered and washed twice, fist with MeCN (20 mL), then with MeOH (20 mL), to give dTs-dG(ib)s-dC(bz)s-dA(bz)s-dT-Kc (O T -c, 1.02 g, purity 79.945%, yield 55.1%) as a white solid. MS (method A) m/z: [M + 2H] 2+ calcd. for C131H185N21O32P4S4 2+ , 1408.0659; found 1408.0706. Example 6: Comparative Example – attempted synthesis of target oligonucleotide O T -d (see Table T-2) using DMF as amide solvent In this comparative example, elongation of an exemplary 4mer oligonucleotide to a 5mer oligonucleotide was attempted, wherein the amide solvent S A as defined herein was replaced by N,N-dimethylformamide (DMF). A solution of dT-dC(bz)-dA(bz)-dT-(Kc-C1-carbonate) (39, 3.04 g, 1.32 mmol) in cyclopentyl methyl ether (CPME)/DMF (16:3 v/v, 95 mL) was concentrated in vacuo to a volume of 35 mL. DMTr-dA(Bz) phosphoramidite (CAS-RN: 98796-53-3, 2.31 g, 2.64 mmol) and BTT (2.54 g, 13.21 mmol) were added, and the mixture was stirred at rt until reaction monitoring by HPLC indicated completion of the coupling. Ac2O (449 μL, 5.28 mmol), pyridine (533 μL, 6.60 mmol) and 1-methylimidazole (526 μL, 6.60 mmol) were added. After stirring for 10 min at rt, 1 M I2 in CPME (2.91 mL, 2.91 mmol), H2O (71 μL) and MeCN (3 mL) were added. After stirring for 10 min at rt, 0.5 N Na2S2O3 and 1 N NMM solution (2:1 v/v, 15 mL) was added to the reaction mixture. An emulsion formed and the phase separation was not completed. The subsequent aqueous extraction and DMTr-deprotection could not to be carried out. Thus, when replacing the amide solvent S A as defined herein by the common amide solvent DMF, even a 5mer synthesis could not be completed. Example 7: Synthesis A of target oligonucleotide O T -e (see Table T-2) DMTr-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (5) Dichloroacetic acid (DCA, 6.0 mL) and thiomalic acid (TMA, 0.919 mL, 5.0 eq) were added at rt to a stirred solution of DMTr-MG(ib)-(Kc-C1-carbonate) (2, 0.80 g, 537 μmol, 1.0 eq) in 4-methyltetrahydropyran (MTHP, 12 mL). The mixture was stirred at rt until reaction monitoring by HPLC (Method B was used throughout Example 7) indicated completion of the DMTr-deprotection. N-Octyl-2-pyrrolidone (NOP, 7 mL), N-methylmorpholine (NMM, 8 mL), Acetone (12 mL), and 15 wt-% aqueous (aq.) sodium chloride solution (brine, 30 mL) were added, followed by extraction. The organic phase was separated and extracted as follows: - with a mixture of NMM (2 mL), 5 wt-% aqueous sodium chloride solution (brine, 9 mL), and acetone (9 mL), next - with a mixture of 5 wt-% aqueous sodium chloride solution (brine, 12.5 mL) and acetone (12.5 mL), next - with a mixture of water (8 mL), acetone (4 mL), and acetic acid (0.1 mL), and lastly - with a mixture of water (15 mL), acetone (8 mL), and MTHP (6 mL). Following this extraction procedure, the organic phase was subjected to 3 rounds of azeotropic distillation, during each of which MTHP (16-24 mL) was added, followed by concentration in vacuo to a volume of 12 mL (bath temperature 45−55 °C, pressure 40−100 hPa). The so-obtained solution (water content: 396.8 ppm; GC- analysis: combined content of MeCN, hexane, acetone and NMM was below 0.2 vol-%, NOP: 37 vol-%, MTHP: 63 vol-%) comprising MG(ib)-(Kc-C1-carbonate) (4) was used directly in the subsequent step (without any precipitation, filtration or purification steps in between). DMTr-MG(ib) phosphoramidite (CAS-RN: 251647- 55-9, 1.23 g, 1.34 mmol, 2.5 eq) and a mixture of TFA, N-methylimidazole (NMI), and acetonitrile (MeCN) (9:11:30 v/v/v, 5 mL in total) was added to said solution comprising MG(ib)-(Kc-C1-carbonate) (4), and the mixture was stirred at rt until reaction monitoring by HPLC indicated completion of the coupling. NMI (0.6 mL), and 3-(N,N-dimethylaminomethylidene)amino)-3H-1,2,4-dithiazole-5 -thione (CAS- RN: 1192027-04-5, DDTT, 0.81 g, 7.5 eq) were added. After stirring for 10 min at rt, triethylphosphite (0.685 mL, 7.5 eq) was added. After stirring for 10 min at rt, pyridine (0.213 mL, 5.0 eq) and acetic anhydride (Ac2O, 0.20 mL, 4.0 eq) was added, followed by stirring at rt for 10 min, addition of propan-2-ol (0.80 mL), and stirring for 10 min at rt. The so-obtained solution comprising DMTr-MG(ib)s-MG(ib)- (Kc-C1-carbonate) (5) was used directly in the subsequent step (without any precipitation, filtration or purification steps in between). Second coupling cycle and further coupling cycles The second coupling cycle and all further coupling cycles were performed according to the following general protocol, unless indicated differently. The starting materials and products of each coupling cycle are identical to those listed in Table E-1 above, wherein, except for the above-mentioned first coupling cycle, only the 2 nd , 3 rd , and 4 th coupling cycles were performed in the present Example 7. Again, the terms “starting material” and “product” are not to be construed to indicate any precipitation and/or isolation steps in between the coupling cycles. General protocol for coupling cycles In a typical coupling cycle, the following steps were performed in the presented order, unless indicated differently. DMTr-deprotection At 0°C, trifluoroacetic acid (TFA, 6.0 mL) and 3-mercaptopropionic acid (MPA, 0.919 mL) were added directly to the solution obtained from the preceding capping step. The mixture was stirred at rt for 45 min. Aqueous extractions N-methylmorpholine (NMM, 14 mL), n-hexane (2 nd and 4 th coupling cycle: 6 mL; 3 rd coupling cycle: 12 mL), MTHP (3 mL), 15 wt-% aqueous (aq.) sodium chloride solution (brine, 9 mL), and acetone (9 mL) were added, followed by extraction. The organic phase was separated and extracted as follows: - with a mixture of NMM (2 mL), 5 wt-% aqueous sodium chloride solution (brine, 9 mL), and acetone (9 mL), next - with a mixture of 5 wt-% aqueous sodium chloride solution (brine, 9 mL) and acetone (9 mL), next - with a mixture of 5 wt-% aqueous sodium chloride solution (brine, 9 mL), acetone (9 mL), and acetic acid (0.15 mL), and lastly - with a mixture of 5 wt-% aqueous sodium chloride solution (brine, 9 mL) and acetone (9 mL). Azeotropic distillation MTHP (12-24 mL) and NOP (2 nd cycle; 3.6 mL, 3 rd ; 4 mL) were added to the organic phase obtained from the preceding aqueous extractions, followed by concentration in vacuo (bath temperature 35−55 °C, pressure 100 hPa) to a volume of 12 mL. This MTHP addition and concentration step was typically repeated once or twice. The water content was adjusted to be in the range of 178.3−321.5 ppm. The composition of the solution obtained after azeotropic distillation was analyzed as laid out above. The content of NOP was in the range of 52−57 vol-% and the content of MTHP was in the range of 43−48 vol-%. The combined content of MeCN, hexane, acetone and NMM was below 0.2 vol-% in all coupling cycles. Coupling reaction The respective 5´-DMTr-protected phosphoramidite (2 nd coupling cycle: 2.0 eq; 3 rd and 4 th coupling cycle: 3.0 eq) and a mixture of TFA, NMI, and acetonitrile (9:11:30 v/v/v, 4−5 mL in total) were added to the solution obtained from azeotropic distillation, followed by stirring at rt until reaction monitoring by HPLC indicated completion of the coupling. Sulfurization (including quenching with triethylphosphite) NMI (0.6 mL), and DDTT (2 nd coupling cycle: 0.66 g, 6.0 eq; 3 rd coupling cycle: 0.82 g, 7.5 eq; 4 th coupling cycle: 0.98 g, 9.0 eq) were added, and the mixture was stirred at rt for 10 min. Triethylphosphite (2 nd coupling cycle: 0.549 mL, 6.0 eq; 3 rd coupling cycle: 0.687 mL, 7.5 eq; 4 th coupling cycle: 0.824 mL, 9.0 eq) was added, followed by stirring for 10 min at rt. Capping Pyridine (0.213 mL, 5.0 eq) and Ac 2 O (0.2 mL, 4.0 eq) were added, followed by stirring at rt for 10 min. Propan-2-ol (0.8 mL) was added, followed by stirring at rt for 10 min. After completion of the 4 th coupling cycle, one more DMTr-deprotection, followed by aqueous extractions as laid out above in the general protocol were performed. The organic phase obtained from the final aqueous extraction was concentrated in vacuo, followed by addition of methanol (20 mL). The resulting precipitate was filtered and washed with MeOH (20mL, twice) to give DMTr-MG(ib)s-mMeC(bz)s- mMeUs-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (8, 1.46 g, 66.3% crude yield). Target oligonucleotide O T -e (see Table T-2) A solution of the crude compound 8 (302.4 mg, 0.09 nmol) in a mixture of H2O and tert-butylamine (1:1 v/v, 9 mL) was stirred at 80 °C for 10 h. The reaction mixture was cooled to rt and analyzed by HPLC-MS to find 5´-MGs-MMeCs-MmeUs-MGs- MG-3´ (O T -e). MS (Method D) m/z: [M–2H] 2- calcd for C65H91N20O35P4S4 2- , 982.1939, found 982.1931. Purity (Method C, Gradient-2): 78.7% Example 8: Synthesis A of target oligonucleotide O T -f (see Table T-2) DMTr-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (5) A solution of MG(ib)-(Kc-C1-carbonate) (4, 0.633 g, 0.528 mmol) in N-Octyl-2- pyrrolidone (NOP, 6 mL) was subjected to 3 rounds of azeotropic distillation, during each of which MTHP (12 mL) was added, followed by concentration in vacuo to a volume of 9 mL (bath temperature 45−55 °C, pressure 40−100 hPa). The so- obtained solution (water content: 241.1 ppm) comprising MG(ib)-(Kc-C1-carbonate) (4) was used directly in the subsequent step (without any precipitation, filtration or purification steps in between). DMTr-MG(ib) phosphoramidite (CAS-RN: 251647- 55-9, 1.21 g, 1.36 mmol, 2.6 eq) and a mixture of TFA, N-methylimidazole (NMI), and acetonitrile (MeCN) (9:11:30 v/v/v, 4 mL in total) was added to said solution comprising MG(ib)-(Kc-C1-carbonate) (4), and the mixture was stirred at rt until reaction monitoring by HPLC indicated completion of the coupling. Pyridine (0.213 mL, 5.0 eq), NMI (1.8.6 mL), and 3-(N,N-dimethylaminomethylidene)amino)-3H- 1,2,4-dithiazole-5-thione (CAS-RN: 1192027-04-5, DDTT, 0.54 g, 5.0 eq) were added. After stirring for 10 min at rt, triethylphosphite (0.453 mL, 5.0 eq) was added. After stirring for 10 min at rt, acetic anhydride (Ac 2 O, 0.20 mL, 4.0 eq) was added, followed by stirring at rt for 10 min, addition of propan-2-ol (0.80 mL), and stirring for 10 min at rt. The so-obtained solution comprising DMTr-MG(ib)s-MG(ib)-(Kc-C1- carbonate) (5) was used directly in the subsequent step (without any precipitation, filtration or purification steps in between). Second coupling cycle and further coupling cycles The second coupling cycle and all further coupling cycles were performed according to the following general protocol, unless indicated differently. The starting materials and products of each coupling cycle are identical to those listed in Table E-1 above, wherein, except for the above-mentioned first coupling cycle, only the 2 nd to 9 th coupling cycles were performed in the present Example 8. Again, the terms “starting material” and “product” are not to be construed to indicate any precipitation and/or isolation steps in between the coupling cycles. General protocol for coupling cycles In a typical coupling cycle, the following steps were performed in the presented order, unless indicated differently. DMTr-deprotection At 0°C, trifluoroacetic acid (TFA, 6.0 mL) and 3-mercaptopropionic acid (MPA, 0.919 mL), were added directly to the solution obtained from the preceding capping step. The mixture was stirred at rt for 45 min. Aqueous extractions N-methylmorpholine (NMM, 14 mL), alkane (2 nd coupling cycle: cyclohexane; 3 rd coupling cycle: n-hexane; 4 th to 9 th coupling cycles: n-heptane; 6.0 mL in all cases), MTHP (3 mL), and 15 wt-% aqueous (aq.) sodium chloride solution (brine, 22.5 mL) were added, followed by extraction. The organic phase was separated and extracted as follows: - with a mixture of NMM (1 mL), 5 wt-% aqueous sodium chloride solution (brine, 9−12 mL), and acetone (9−12 mL), next - with a mixture of 5 wt-% aqueous sodium chloride solution (brine, 22.5 mL) and acetone (22.5 mL), next - with a mixture of 5 wt-% aqueous sodium chloride solution (brine, 22.5 mL), acetone (22.5 mL), and acetic acid (0.1 mL), and lastly - with a mixture of 5 wt-% aqueous sodium chloride solution (brine, 9-10 mL) and acetone (9-10 mL), wherein in the 4 th to 8 th coupling cycle, 2.5 wt-% brine was used instead of 5 wt-% brine and water (18 mL) was added. Azeotropic distillation MTHP (12-24 mL) and NOP (2 nd , 8 th and 9 th coupling cycle: 2 mL; 3 rd and 5 th to 7 th coupling cycle: 3 mL) were added to the organic phase obtained from the preceding aqueous extractions, followed by concentration in vacuo (bath temperature 35−55 °C, pressure 100 hPa) to a volume of 9 mL. This MTHP addition and concentration step was typically repeated once or twice. The water content was adjusted to be in the range of 185.6−412.3 ppm. The composition of the solution obtained after azeotropic distillation was analyzed as laid out above. The content of NOP was in the range of 27−67 vol-% and the content of MTHP was in the range of 73−33 vol- %. The combined content of MeCN, the respective alkane, acetone and NMM was below 0.2 vol-% in all coupling cycles, wherein no analysis has been conducted in the 6 th coupling cycle. Coupling reaction The respective 5´-DMTr-protected phosphoramidite (2 nd to 6 th coupling cycle: 2.0 eq; 7 th to 9 th coupling cycle: 3.0 eq) and a mixture of TFA, NMI, and acetonitrile (9:11:30 v/v/v, 4−5 mL in total) were added to the solution obtained from azeotropic distillation, followed by stirring at rt until reaction monitoring by HPLC indicated completion of the coupling. Sulfurization (including quenching with triethylphosphite) Pyridine (0.213 mL, 5.0 eq), NMI (0.6 mL), and DDTT (2 nd to 6 th coupling cycle: 0.44−0.47 g, 3.0 eq; 7 th to 9 th coupling cycle: 0.66 g, 5.0 eq) were added, and the mixture was stirred at rt for 10 min. Triethylphosphite (2 nd to 6 th coupling cycle: 0.366 mL, 3.0 eq; 7 th to 9 th coupling cycle: 0.550 mL, 5.0 eq) was added, followed by stirring for 10 min at rt. Capping Ac2O (0.2 mL, 4.0 eq) was added, followed by stirring at rt for 10 min. Propan-2-ol (0.8 mL) was added, followed by stirring at rt for 10 min. After completion of the 9 th coupling cycle, one more DMTr-deprotection, followed by aqueous extractions as laid out above in the general protocol were performed. The organic phase obtained from the final aqueous extraction was concentrated in vacuo, followed by addition of methanol (20 mL). The resulting precipitate was filtered and washed with methanol (20 mL, twice) to give DMTr-MA(bz)s-mMeUs-MA(bz)s- MA(bz)s-mMeUs-MG(ib)s-mMeC(bz)s-mMeUs-MG(ib)s-MG(ib)-(Kc-C1- carbonate) (13, 1.61 g, 51.8% crude yield) Target oligonucleotide O T -f (see Table T-2) A solution of the crude of compound 13 (305.1 mg, 0.05 mmol) in a mixture of H2O and tert-butylamine (1:1 v/v, 9 mL) was stirred at 80 °C for 10 h. The reaction mixture was cooled to room temperature and analyzed by HPLC-MS to find 5´-MAs-MMeUs- MAs-MAs-MMeUs-MGs-MMeCs-MMeUs-MGs-MG-3´ (O T -f). MS (Method E) m/z: [M-2H] 2- calcd for C130H184N39O69P9S9 2- , 1980.861, found 1980.8608. Purity (Method D): 66.6% Example 9: Synthesis B of target oligonucleotide O T -e (see Table T-2) DMTr-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (5) A solution of MG(ib-(Kc-C1-carbonate) (4, 1.58 g, 1.32 mmol) was subjected to 2 rounds of azeotropic distillation, during each of which MTHP (15 mL) was added, followed by concentration in vacuo to a volume of 15 mL (bath temperature 45−55 °C, pressure 40−100 hPa). The so-obtained solution (water content: 100.2 ppm; GC-analysis: combined content of MeCN, heptane, acetone and NMM was below 0.2 vol-%, NOP: 31 vol-%, MTHP: 69 vol-%) comprising MG(ib)-(Kc-C1-carbonate) (4) was used directly in the subsequent step (without any precipitation, filtration or purification steps in between). DMTr-MG(ib) phosphoramidite (CAS-RN: 251647- 55-9, 2.41 g, 2.64 mmol, 2.0) and a mixture of TFA, N-methylimidazole (NMI), and acetonitrile (MeCN) (9:11:30 v/v/v, 10 mL in total) were added to said solution comprising MG(ib)-(Kc-C1-carbonate) (4), and the mixture was stirred at rt until reaction monitoring by HPLC indicated completion of the coupling. Pyridine (0.533 mL, 5.0 eq), NMI (1.5 mL), and 3-(N,N-dimethylaminomethylidene)amino)-3H-1,2,4- dithiazole-5-thione (CAS-RN: 1192027-04-5, DDTT, 0.81 g, 3.0 eq) were added. After stirring for 10 min at rt, triethylphosphite (0.686 mL, 3.0 eq) was added. After stirring for 10 min at rt, acetic anhydride (Ac2O, 0.5 mL, 4.0 eq) was added, followed by stirring at rt for 10 min, addition of propan-2-ol (2.0 mL), and stirring for 10 min at rt. The so-obtained solution comprising DMTr-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (5) was used directly in the subsequent step (without any precipitation, filtration or purification steps in between). Second coupling cycle and further coupling cycles The second coupling cycle and all further coupling cycles were performed according to the following general protocol, unless indicated differently. The starting materials and products of each coupling cycle are identical to those listed in Table E-1 above, wherein, except for the above-mentioned first coupling cycle, only the 2 nd , 3 rd , and 4 th coupling cycles were performed in the present Example 9. Again, the terms “starting material” and “product” are not to be construed to indicate any precipitation and/or isolation steps in between the coupling cycles. General protocol for coupling cycles In a typical coupling cycle, the following steps were performed in the presented order, unless indicated differently. DMTr-deprotection Methanesulfonic acid (MSA, 12.5 mL) and glutathione (2 nd and 3 rd coupling cycle: 2.03 g; 4 th coupling cycle: 3.02 g), were added at rt directly to the solution obtained from the preceding capping step. The mixture was stirred at rt for 45 min. Aqueous extractions N-methylmorpholine (NMM, 35 mL), n-heptane (15 mL), MTHP (7.5 mL), and 15 wt- % aqueous (aq.) sodium chloride solution (brine, 45 mL) were added, followed by extraction. The organic phase was separated and extracted as follows: - with a mixture of 5 wt-% aqueous sodium chloride solution (brine, 22.5 mL) and acetone (22.5 mL), and then - with a mixture of 5 wt-% aqueous sodium chloride solution (brine, 22.5 mL), acetone (22.5 mL), and acetic acid (0.7−1.3 mL). Azeotropic distillation MTHP (30 mL) and NOP (only added in the 4 th coupling cycle: 2mL) was added to the organic phase obtained from the preceding aqueous extractions, followed by concentration in vacuo (bath temperature 35−55 °C, pressure 100 hPa) to a volume of 22.5 mL. This MTHP addition and concentration step was typically repeated once or twice. The water content was adjusted to be in the range of 86.9−347.0 ppm. The composition of the solution obtained after azeotropic distillation was analyzed as laid out above. The content of NOP was in the range of 33−57 vol-% and the content of MTHP was in the range of 67−43 vol-%. The combined content of MeCN, heptane, acetone and NMM was below 0.2 vol-% in all coupling cycles. Coupling reaction The respective 5´-DMTr-protected phosphoramidite (2 nd and 3 rd coupling cycle: 2.0 eq; 4 th coupling cycle: 3.0 eq) and a mixture of TFA, NMI, and acetonitrile (9:11:30 v/v/v, 10 mL in total) were added to the solution obtained from azeotropic distillation, followed by stirring at rt until reaction monitoring by HPLC indicated completion of the coupling. Sulfurization (including quenching with triethylphosphite) Pyridine (0.533 mL, 5.0 eq), NMI (1.5 mL), and DDTT (2 nd and 3 rd coupling cycle: 0.81 g, 3.0 eq; 4 th coupling cycle: 1.22 g, 4.5 eq) were added, and the mixture was stirred at rt for 10 min. Triethylphosphite (0.686 mL, 3.0 eq) was added, followed by stirring for 10 min at rt. Capping Ac2O (0.5 mL, 4.0 eq) was added, followed by stirring at rt for 10 min. Propan-2-ol (2.0 mL) was added, followed by stirring at rt for 10 min. After completion of the 4 th coupling cycle, the batch was divided into two equal halves by volume. A first half of the batch was treated as described in the present Example 9 below, while the other half of the batch was used in Example 10 below. One half of the batch was subjected to one more DMTr-deprotection, followed by aqueous extractions as laid out above in the general protocol. The organic phase obtained from the final aqueous extraction was concentrated in vacuo, followed by addition of methanol (50 mL). The resulting precipitate was filtered and washed by MeOH (25 mL, twice) to give DMTr-MG(ib)s-mMeC(bz)s-mMeUs-MG(ib)s-MG(ib)- (Kc-C1-carbonate) (8, 1.21 g, 56% crude yield). Target oligonucleotide O T -e (see Table T-2) A solution of the crude of compound 8 (303.1 mg, 0.09 mmol) in a mixture of H2O and tert-butylamine (1:1 v/v, 9 mL) was stirred at 80 °C for 10 h. The reaction mixture was cooled to room temperature and analyzed by HPLC-MS to find 5´-MGs- MMeCs-MMeUs-MGs-MG-3´ (O T -e). MS (Method D) m/z: [M–2H] 2- calcd for C65H92N20O35P4S4 2- , 982.1939, found 982.1930. Purity (Method C, Gradient-2): 81.7% Example 10: Synthesis B of target oligonucleotide O T -f (see Table T-2) The second half of the batch as divided in Example 9 was subjected to the 5 th to 9 th coupling cycle, the staring materials and products of which were identical to those listed in Table E-1 above. Again, the terms “starting material” and “product” are not to be construed to indicate any precipitation and/or isolation steps in between the coupling cycles. The 5 th to 9 th coupling cycle were performed according to the following general protocol. General protocol for coupling cycles In a typical coupling cycle, the following steps were performed in the presented order, unless indicated differently. DMTr-deprotection Methanesulfonic acid (MSA, 6.25 mL) and glutathione (5 th coupling cycle: 1.22 g, 5.0 eq; 6 th and 7 th coupling cycle: 1.52 g, 7.5 eq; 8 th and 9 th coupling cycle: 2.02 g, 10.0 eq), were added at rt directly to the solution obtained from the preceding capping step. The mixture was stirred at rt for 45 min. Aqueous extractions N-methylmorpholine (NMM, 17.5 mL), n-heptane (7.5 mL), MTHP (3.75 mL), and 15 wt-% aqueous (aq.) sodium chloride solution (brine, 22.5 mL) were added, followed by extraction. The organic phase was separated and extracted as follows: - with a mixture of 5 wt-% aqueous sodium chloride solution (brine, 11.25 mL) and acetone (11.25 mL), and then - with a mixture of 5 wt-% aqueous sodium chloride solution (brine, 22.5 mL), acetone (22.5 mL), and acetic acid (0.7−0.8 mL). Azeotropic distillation MTHP (15 mL) and NOP (only added in the 6 th coupling cycle: 1.5 mL) was added to the organic phase obtained from the preceding aqueous extractions, followed by concentration in vacuo (bath temperature 35−55 °C, pressure 100 hPa) to a volume of 22.5 mL. This MTHP addition and concentration step was typically repeated once or twice. The water content was adjusted to be in the range of 59.0−154.3 ppm. The composition of the solution obtained after azeotropic distillation was analyzed as laid out above for the 5 th to 8 th coupling cycle. The content of NOP was in the range of 41−66 vol-% and the content of MTHP was in the range of 59−34 vol-%. The combined content of MeCN, heptane, acetone and NMM was below 0.2 vol-% in all coupling cycles. Coupling reaction The respective 5´-DMTr-protected phosphoramidite (5 th coupling cycle: 2.5 eq; 6 th coupling cycle: 3.0 eq; 7 th and 9 th coupling cycle: 4.0 eq; 8 th coupling cycle: 5.0 eq) and a mixture of TFA, NMI, and acetonitrile (9:11:30 v/v/v, 5 mL in total) were added to the solution obtained from azeotropic distillation, followed by stirring at rt until reaction monitoring by HPLC indicated completion of the coupling. Sulfurization (including quenching with triethylphosphite) Pyridine (0.266 mL, 5.0 eq), NMI (0.75 mL), and DDTT (5 th and 6 th coupling cycle: 0.54 g, 4.0 eq; 7 th and 9 th coupling cycle: 0.68 g, 5.0 eq; 8 th coupling cycle: 0.81 g, 6.0) were added, and the mixture was stirred at rt for 10 min. Triethylphosphite (0.343 mL, 3.0 eq) was added, followed by stirring for 10 min at rt. Capping Ac2O (0.25 mL, 4.0 eq) was added, followed by stirring at rt for 10 min. Propan-2-ol (1.0 mL) was added, followed by stirring at rt for 10 min. After completion of the 9 th coupling cycle, one more DMTr-deprotection, followed by aqueous extractions as laid out above in the general protocol were performed. The organic phase obtained from the final aqueous extraction was concentrated in vacuo. Methanol (100 mL) was added, and the resulting precipitate was collected. Ethanol (100 mL) was added, and the resulting precipitate was collected. The combined precipitate was washed by Ethanol (50 mL, twice) to give DMTr-MA(bz)s- mMeUs-MA(bz)s-MA(bz)s-mMeUs-MG(ib)s-mMeC(bz)s-mMeUs-MG(ib)s- MG(ib)- (Kc-C1-carbonate) (13, 2.04 g, 52.6% crude yield starting from DMTr-MG(ib)-(Kc- C1-carbonate) (2)). Target oligonucleotide O T -f (see Table T-2) A solution of the crude of compound 13 (294.9 mg, 0.05 mmol) in a mixture of H2O and tert-butylamine (1:1 v/v, 9 mL) was stirred at 80 °C for 10 h. The reaction mixture was cooled to rt and analyzed by HPLC-MS to find 5´-MAs-MMeUs-MAs-MAs- MMeUs-MGs-MMeCs-MMeUs-MGs-MG-3´ (O T -f). MS (Method E) m/z: [M-2H] 2- calcd for C130H184N39O69P9S9 2- , 1980.861 found 1980.8593. Purity (Method D): 67.0% Example 11: Synthesis C of target oligonucleotide O T -a and synthesis of target oligonucleotide O T -g (see Table T-2) DMTr-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (5) A solution of MG(ib)-(Kc-C1-carbonate) (4, 1.58 g, 1.32 mmol) in NOP (15 mL) was subjected to two rounds of azeotropic distillation, during each of which MTHP (30 mL) was added, followed by concentration in vacuo to a volume of 22.5 mL (bath temperature 45−55 °C, pressure 40−100 hPa). The so-obtained solution (water content: 135,0 ppm; GC-analysis: combined content of MeCN, Heptane, acetone and NMM was below 0.2 vol-%, NOP: 41 vol-%, MTHP: 59 vol-%) comprising MG(ib)-(Kc-C1-carbonate) (4) was used directly in the subsequent step (without any precipitation, filtration or purification steps in between). DMTr-MG(ib) phosphoramidite (CAS-RN: 251647-55-9, 2.41 g, 2.64 mmol, 2.0 eq) and a mixture of TFA, N-methylimidazole (NMI), and acetonitrile (MeCN) (11:9:30 v/v/v, 10 mL in total) was added to said solution comprising MG(ib)-(Kc-C1-carbonate) (4) and the mixture was stirred at rt until reaction monitoring by HPLC indicated completion of the coupling. Pyridine (0.533 mL, 5.0 eq), NMI (1.5 mL), and 3-(N,N- dimethylaminomethylidene)amino)-3H-1,2,4-dithiazole-5-thione (CAS-RN: 1192027-04-5, DDTT, 0.81 g, 3.0 eq) were added. After stirring for 10 min at rt, triethylphosphite (686 µL, 3.0 eq) was added. After stirring for 10 min at rt, acetic anhydride (Ac2O, 499 µL, 4.0 eq) was added, followed by stirring at rt for 10 min, addition of propan-2-ol (2.0 mL), and stirring for 10 min at rt. The so-obtained solution comprising DMTr-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (5) was used directly in the subsequent step (without any precipitation, filtration or purification steps in between). 2 nd to 14 th coupling cycle The 2 nd to 14 th coupling cycle were performed according to the following general protocol, unless indicated differently. The starting materials and products of each coupling cycle are identical to those listed in Table E-1 above. Again, the terms “starting material” and “product” are not to be construed to indicate any precipitation and/or isolation steps in between the coupling cycles. General protocol for coupling cycles In a typical coupling cycle, the following steps were performed in the presented order, unless indicated differently. DMTr-deprotection Trifluoroacetic acid (TFA, 15.0 mL) and 3-mercaptopropionic acid (MPA, 2.298 mL) were added at rt directly to the solution obtained from the preceding capping step. The mixture was stirred at rt for 45 min. Aqueous extractions N-methylmorpholine (NMM, 35 mL), n-heptane (15 mL), MTHP (7.5 mL), and 15 wt-% aqueous (aq.) sodium chloride solution (brine, 45 mL) were added, followed by extraction. The organic phase was separated and extracted as follows: - with a mixture of NMM (5 mL), 5 wt-% aqueous sodium chloride solution (brine, 22.5 mL), and acetone (22.5 mL), next - with a mixture of 5 wt-% aqueous sodium chloride solution (brine, 22.5 mL) and acetone (22.5 mL), next - with a mixture of 5 wt-% aqueous sodium chloride solution (brine, 22.5 mL), acetone (22.5 mL), and acetic acid (0.30−0.88 mL), and lastly - with a mixture of 5 wt-% aqueous sodium chloride solution (brine, 22.5 mL) and acetone (22.5 mL). Azeotropic distillation MTHP (30 mL) and NOP (2 nd and 3 rd coupling cycle: 7.5 mL, 4 th , 5 th , 7 th , 8 th , 13 th , 14 th coupling cycle: 5 mL, 6 th coupling cycle: 14 mL, 9 th coupling cycle: 3 mL, 10 th to 12 th coupling cycle: 4 mL) were added to the organic phase obtained from the preceding aqueous extractions, followed by concentration in vacuo (bath temperature 35−55 °C, pressure 40-100 hPa). This MTHP addition and concentration step was typically repeated once or twice. The water content was adjusted to be in the range of 60.4−312.4 ppm. The composition of the solution obtained after azeotropic distillation was analyzed as laid out above. The content of NOP was in the range of 27−64 vol-% and the content of MTHP was in the range of 36−73 vol-%. The combined content of MeCN, heptane, acetone and NMM was below 0.2 vol-% in all coupling cycles. Coupling reaction The respective 5´-DMTr-protected phosphoramidite (2 nd to 5 th coupling cycle: 2.0 eq; 6 th coupling cycle: 3.0 eq; 7 th coupling cycle: 3.3 eq; 8 th coupling cycle: 3.5 eq; 9 th to 14 th coupling cycle: 3.0 eq) and a mixture of TFA, NMI, and acetonitrile (11:9:30 v/v/v, 10 mL in total) were added to the solution obtained from azeotropic distillation, followed by stirring at rt until reaction monitoring by HPLC indicated completion of the coupling. Sulfurization (including quenching with triethylphosphite) Pyridine (0.533 mL, 5.0 eq), NMI (1.5 mL), and DDTT (2 nd and 3 rd coupling cycle: 0.81 g, 3.0 eq; 4 th to 6 th coupling cycle: 0.81−1.22 g, 3.0−4.5 eq; 7 th to 9 th coupling cycle: 1.09−1.22 g, 4.0−4.5 eq; 10 th to 14 th coupling cycle: 1.08−1.09 g, 4.0 eq) were added, and the mixture was stirred at rt for 10 min. Triethylphosphite (686 µL, 3.0 eq) was added, followed by stirring for 10 min at rt. Capping Ac2O (499 μL, 4.0 eq) was added, followed by stirring at rt for 10 min. Propan-2-ol (2.0 mL) was added, followed by stirring at rt for 10 min. After completion of the 14 th coupling cycle, the batch was divided into two halves of equal volumes. One half batch was used for the preparation of target oligonucleotide O T -g and the other half batch was subjected to the 15 th to 17 th coupling cycle to obtain target oligonucleotide O T -a. Target oligonucleotide O T -g One half of the batch comprising compound 18 (cf. Table E-1) was subjected to one more DMTr-deprotection, followed by aqueous extractions as laid out above in the general protocol. The organic phase obtained from the final aqueous extraction was concentrated in vacuo, followed by addition of methanol (25 mL). The resulting precipitate was filtered and washed with methanol (25 mL, 3 times) to give mMeC(bz)s-mMeUs-mMeUs-mMeUs-mMeC(bz)s-MA(bz)s-mMeUs-MA(bz)s- MA(bz)s-mMeUs-MG(ib)s-mMeC(bz)s-mMeUs-MG(ib)s-MG(ib)-(Kc-C1- carbonate) (23, 1.97 g, crude). A solution of the crude of compound 23 (97.9 mg, 0.01 mmol) in a mixture of H 2 O and tert-butylamine (2:1 v/v, 9 mL) was stirred at 80 °C for 10 h. The reaction mixture was cooled to rt and analyzed by HPLC (Method E) and HPLC-MS (Method E) to find 5´-MMeUs-MMeCs-MAs-MMeCs-MMeUs-MMeUs-MMeUs-MMeCs-MAs- MMeUs-MAs-MAs-MMeUs-MGs-MMeCs-3´ (O T -g). MS(Method E) m/z: [M - 3H] 3- calcd for C 195 H 283 N 51 O 107 P 14 S 14 3- , calcd. 1976.349, found 1976.3451. Purity (Method E): 49.4%. 15 th to 17 th coupling cycle The half batch which was not used for the synthesis of target oligonucleotide O T -g was subjected to the 15 th to 17 th coupling cycle which were performed according to the following general protocol, unless indicated differently. The starting materials and products of each coupling cycle are identical to those listed in Table E-1 above. Again, the terms “starting material” and “product” are not to be construed to indicate any precipitation and/or isolation steps in between the coupling cycles. General protocol for coupling cycles In a typical coupling cycle, the following steps were performed in the presented order, unless indicated differently. DMTr-deprotection Trifluoroacedtic acid (TFA, 7.5 mL) and 3-mercaptopropionic acid (MPA, 1.149 mL) were added at rt directly to the solution obtained from the preceding capping step. The mixture was stirred at rt for 45 min. Aqueous extractions N-methylmorpholine (NMM, 17.5 mL), n-heptane (7.5 mL), MTHP (3.75 mL), and 15 wt-% aqueous (aq.) sodium chloride solution (brine, 22.5 mL) were added, followed by extraction. The organic phase was separated and extracted as follows: - with a mixture of NMM (2.5 mL), 5 wt-% aqueous sodium chloride solution (brine, 11.25 mL), and acetone (11.25 mL), next - with a mixture of 5 wt-% aqueous sodium chloride solution (brine, 11.25 mL) and acetone (11.25 mL), next - with a mixture of 5 wt-% aqueous sodium chloride solution (brine, 11.25 mL), acetone (11.25 mL), and acetic acid (1.1 mL), and lastly - with a mixture of 5 wt-% aqueous sodium chloride solution (brine, 11.25 mL) and acetone (11.25 mL). Azeotropic distillation MTHP (30 mL) and NOP (only added in the 15 th coupling cycle: 5 mL) was added to the organic phase obtained from the preceding aqueous extractions, followed by concentration in vacuo (bath temperature 35−55 °C, pressure 100 hPa). This MTHP addition and concentration step was typically repeated once or twice. The water content was adjusted to be in the range of 261.0−312.3 ppm. The composition of the solution obtained after azeotropic distillation was analyzed as laid out above. The content of NOP was in the range of 19−42 vol-% and the content of MTHP was in the range of 58−81 vol-%. The combined content of MeCN, heptane, acetone and NMM was below 0.2 vol-% in all coupling cycles. Coupling reaction The respective 5´-DMTr-protected phosphoramidite (15 th coupling cycle: 3.0 eq; 16 th coupling cycle: 3.5 eq; 17 th coupling cycle: 3.0 eq) and a mixture of TFA, NMI, and acetonitrile (11:9:30 v/v/v, 5 mL in total) were added to the solution obtained from azeotropic distillation, followed by stirring at rt until reaction monitoring by HPLC indicated completion of the coupling. Sulfurization (including quenching with triethylphosphite) Pyridine (0.267 mL, 5.0 eq), NMI (0.75 mL), and DDTT (0.54−0.61 g, 4.0−4.5 eq) were added, and the mixture was stirred at rt for 10 min. Triethylphosphite (343 µL, 3.0 eq) was added, followed by stirring for 10 min at rt. Capping Ac 2 O (250 μL, 4.0 eq) was added, followed by stirring at rt for 10 min. Propan-2-ol (1.0 mL) was added, followed by stirring at rt for 10 min. After completion of the 17 th coupling cycle, one more DMTr-deprotection, followed by aqueous extractions as laid out above in the general protocol were performed. The organic phase obtained from the final aqueous extraction was concentrated in vacuo, followed by subsequent addition of two portions of methanol (1 st portion: 50 mL, 2 nd portion: 100 mL). The resulting precipitate was filtered and washed with methanol (50 mL, twice) and then propan-2-ol (50 mL) to give mMeUs-mMeC(bz)s- MA(bz)s-mMeC(bz)s-mMeUs-mMeUs-mMeUs-mMeC(bz)s-MA(bz)s-mMeUs- MA(bz)s-MA(bz)s-mMeUs-MG(ib)s-mMeC(bz)s-mMeUs-MG(ib)s-MG(ib) -(Kc-C1- carbonate) (22, 1.75 g, crude). Target oligonucleotide O T -a A solution of the crude of compound 22 (98.3 mg, 0.01 mmol) in a mixture of H 2 O and tert-butylamine (2:1 v/v, 9 mL) was stirred at 80 °C for 14 h. The reaction mixture was cooled to rt and analyzed by HPLC to find 5-mMeUs-mMeCs-mAs-mMeCs- mMeUs-mMeUs-mMeUs-mMeCs-mAs-mMeUs-mAs-mAs-mMeUs-MGs-mMeCs- mMeUs-MGs-MG-3 (O T -a). Purity (Method E): 25.8% Example 12: Synthesis D of target oligonucleotide O T -a (see Table T-2) DMTr-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (5) A solution of MG(ib)-(Kc-C1-carbonate) (4, 1.58 g, 1.32 mmol) in NOP (12 mL) was subjected to 2 rounds of azeotropic distillation, during each of which MTHP (15 mL) was added, followed by concentration in vacuo to a volume of 20 mL (bath temperature 45−55 °C, pressure 40−100 hPa). The so-obtained solution (water content: 104.2 ppm; GC-analysis: combined content of MeCN, Heptane, acetone and NMM was below 0.2 vol-%, NOP: 69 vol-%, MTHP: 31 vol-%) comprising MG(ib)-(Kc-C1-carbonate) (4) was used directly in the subsequent step (without any precipitation, filtration or purification steps in between). DMTr-MG(ib) phosphoramidite (CAS-RN: 251647-55-9, 2.41 g, 2.64 mmol, 2.0 eq), 5-benzylthio- 1H-tetrazole (BTT, 2.54 g, 10.0 eq), N-methylimidazole (NMI, 2.0 mL), and acetonitrile (MeCN, 10 mL) were added to said solution comprising MG(ib)-(Kc-C1- carbonate) (4) and the mixture was stirred at rt until reaction monitoring by HPLC indicated completion of the coupling. Acetic acid (0.378 mL, 5.0 eq) was added, followed by stirring at rt for 20 min. Pyridine (0.533 mL, 5.0 eq) and 3-(N,N- dimethylaminomethylidene)amino)-3H-1,2,4-dithiazole-5-thione (CAS-RN: 1192027-04-5, DDTT, 1.02 g, 4.0 eq) were added. After stirring for 10 min at rt, triethylphosphite (914 µL, 4.0 eq) was added. After stirring for 10 min at rt, acetic anhydride (Ac2O, 250 µL, 2.0 eq) was added, followed by stirring at rt for 10 min, addition of propan-2-ol (2.0 mL), and stirring for 10 min at rt. The so-obtained solution comprising DMTr-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (5) was used directly in the subsequent step (without any precipitation, filtration or purification steps in between). 2 nd to 14 th coupling cycle The 2 nd to 14 th coupling cycle were performed according to the following general protocol, unless indicated differently. The starting materials and products of each coupling cycle are identical to those listed in Table E-1 above. Again, the terms “starting material” and “product” are not to be construed to indicate any precipitation and/or isolation steps in between the coupling cycles. General protocol for coupling cycles In a typical coupling cycle, the following steps were performed in the presented order, unless indicated differently. DMTr-deprotection Trifluoroacetic acid (TFA, 15.0 mL) and 3-mercaptopropionic acid (MPA, 1.15 mL), were added at rt directly to the solution obtained from the preceding capping step. The mixture was stirred at rt for 45 min. Aqueous extractions N-methylmorpholine (NMM, 35 mL), n-heptane (15 mL), MTHP (7.5−10.0 mL), and 15 wt-% aqueous (aq.) sodium chloride solution (brine, 45 mL) were added, followed by extraction. The organic phase was separated and extracted as follows: - with a mixture of NMM (5 mL), 5 wt-% aqueous sodium chloride solution (brine, 22.5 mL), and acetone (22.5 mL), next - with a mixture of 5 wt-% aqueous sodium chloride solution (brine, 22.5 mL) and acetone (22.5 mL), next - with a mixture of 5 wt-% aqueous sodium chloride solution (brine, 22.5 mL), acetone (22.5 mL), and acetic acid (0.6−1.2 mL), and lastly - with a mixture of 5 wt-% aqueous sodium chloride solution (brine, 22.5 mL) and acetone (22.5 mL). Azeotropic distillation MTHP (30 mL) and NOP (2 nd to 4 th , 8 th , 10 th coupling cycle: 3 mL; 5 th and 9 th coupling cycle: 2 mL; 6 th coupling cycle; 5mL; 7 th coupling cycle: 1 mL; 11 th and 12 th coupling cycle: 2.5 mL) were added to the organic phase obtained from the preceding aqueous extractions, followed by concentration in vacuo (bath temperature 35−55 °C, pressure 100 hPa). This MTHP addition and concentration step was typically repeated once or twice. The water content was adjusted to be in the range of 58.0−231.6 ppm. The composition of the solution obtained after azeotropic distillation was analyzed as laid out above. The content of NOP was in the range of 25−58 vol-% and the content of MTHP was in the range of 42−75 vol-%. The combined content of MeCN, heptane, acetone and NMM was below 0.2 vol-% in all coupling cycles. Coupling reaction The respective 5´-DMTr-protected phosphoramidite (2 nd to 6 th coupling cycle: 2.0 eq; 7 th , 8 th , 10 th , and 11 th coupling cycle: 2.5 eq; 9 th and 12 th to 14 th coupling cycle: 3.0 eq) 5-benzylthio-1H-tetrazole (BTT, 2.54 g, 10.0 eq), N-methylimidazole (NMI, 2.0 mL), and acetonitrile (MeCN, 10 mL) were added to the solution obtained from azeotropic distillation, followed by stirring at rt until reaction monitoring by HPLC indicated completion of the coupling. Acetic acid (0.378 mL, 5.0 eq) was added, followed by stirring at rt for 20 min. Sulfurization (including quenching with triethylphosphite) Pyridine (0.533 mL, 5.0 eq) and DDTT (1.02−1.22 g, 4.0−5.0 eq) were added, and the mixture was stirred at rt for 10 min. Triethylphosphite (914 µL, 4.0 eq) was added, followed by stirring for 10 min at rt. Capping Ac2O (2 nd and 3 rd coupling cycle: 0.25 mL, 2.0 eq; 4 th , 5 th , and 10 th to 14 th coupling cycle: 0.013 mL, 0.1 eq; 6 th to 9 th coupling cycle: 0.062 mL, 0.5 eq) was added, followed by stirring at rt for 10 min. Propan-2-ol (2.0 mL) was added, followed by stirring at rt for 10 min. After completion of the 14 th coupling cycle, the batch was divided into two halves of equal volumes, only one of which was subjected to the 15 th to 17 th coupling cycle. 15 th to 17 th coupling cycle The 15 th to 17 th coupling cycle were performed according to the following general protocol, unless indicated differently. The starting materials and products of each coupling cycle are identical to those listed in Table E-1 above. Again, the terms “starting material” and “product” are not to be construed to indicate any precipitation and/or isolation steps in between the coupling cycles. General protocol for coupling cycles In a typical coupling cycle, the following steps were performed in the presented order, unless indicated differently. DMTr-deprotection Trifluoroacetic acid (TFA, 7.5 mL) and 3-mercaptopropionic acid (MPA, 15 th coupling cycle: 0.547 mL, 10.0 eq; 16 th and 17 th coupling cycle: 1.148 mL, 20.0 eq), were added at rt directly to the solution obtained from the preceding capping step. The mixture was stirred at rt for 45 min. Aqueous extractions N-methylmorpholine (NMM, 17.5 mL), n-heptane (7.5 mL), NOP (1.0−2.0 mL), MTHP (3.75−7.0 mL), and 15 wt-% aqueous (aq.) sodium chloride solution (brine, 45 mL) were added, followed by extraction. The organic phase was separated and extracted as follows: - with a mixture of NMM (2.5 mL), 5 wt-% aqueous sodium chloride solution (brine, 11.25 mL), and acetone (11.25 mL), next - with a mixture of 5 wt-% aqueous sodium chloride solution (brine, 11.25 mL) and acetone (11.25 mL), next - with a mixture of 5 wt-% aqueous sodium chloride solution (brine, 11.25 mL), acetone (11.25 mL), and acetic acid (1.2−1.4 mL), and lastly - with a mixture of 5 wt-% aqueous sodium chloride solution (brine, 11.25 mL) and acetone (11.25 mL). Azeotropic distillation MTHP (15 mL) was added to the organic phase obtained from the preceding aqueous extractions, followed by concentration in vacuo (bath temperature 35−55 °C, pressure 100 hPa). This MTHP addition and concentration step was typically repeated once or twice. The water content was adjusted to be in the range of 239.1−296.1 ppm. The composition of the solution obtained after azeotropic distillation was analyzed as laid out above. The content of NOP was in the range of 22−27 vol-% and the content of MTHP was in the range of 78−73 vol-%. The combined content of MeCN, heptane, acetone and NMM was below 0.2 vol-% in all coupling cycles. Coupling reaction The respective 5´-DMTr-protected phosphoramidite (15 th coupling cycle: 4.0 eq; 16 th and 17 th coupling cycle: 5.0 eq), 5-benzylthio-1H-tetrazole (BTT, 1.26 g, 10.0 eq), N-methylimidazole (NMI, 1.0 mL), and acetonitrile (MeCN, 5.0 mL) were added to the solution obtained from azeotropic distillation, followed by stirring at rt until reaction monitoring by HPLC indicated completion of the coupling. Acetic acid (0.189 mL, 5.0 eq) was added, followed by stirring at rt for 20 min. Sulfurization (including quenching with triethylphosphite) Pyridine (0.266 mL, 5.0 eq) and DDTT (0.68−1.36 g, 5.0−10.0 eq) were added, and the mixture was stirred at rt for 10 min. Triethylphosphite (0.457−1.14 mL, 5.0−10.0 eq) was added, followed by stirring for 10 min at rt. Capping Ac2O (15 th coupling cycle: 0.016 mL, 0.25 eq; 16 th coupling cycle: 0.031 mL, 0.5 eq; 17 th coupling cycle: 0.062 mL, 0.5 eq) was added, followed by stirring at rt for 10 min. Propan-2-ol (1.0 mL) was added, followed by stirring at rt for 10 min. After completion of the 17 th coupling cycle, one more DMTr-deprotection, followed by aqueous extractions as laid out above in the general protocol were performed. The organic phase obtained from the final aqueous extraction was concentrated in vacuo, followed by addition of methanol (100 mL). The resulting precipitate was filtered and washed with methanol (50 mL, twice) to give mMeUs-mMeC(bz)s- MA(bz)s-mMeC(bz)s-mMeUs-mMeUs-mMeUs-mMeC(bz)s-MA(bz)s-mMeUs- MA(bz)s-MA(bz)s-mMeUs-MG(ib)s-mMeC(bz)s-mMeUs-MG(ib)s-MG(ib) -(Kc-C1- carbonate) (22, 1.70 g, crude). Target oligonucleotide O T -a A solution of the crude of compound 22 (101 mg, 0.01 mmol) in a mixture of H2O and tert-butylamine (2:1 v/v, 9 mL) was stirred at 80 °C for 11 h. The reaction mixture was cooled to room temperature and analyzed by HPLC-MS to find 5-mMeUs- mMeCs-mAs-mMeCs-mMeUs-mMeUs-mMeUs-mMeCs-mAs-mMeUs-mAs-mAs- mMeUs-MGs-mMeCs-mMeUs-MGs-MG-3 (O T -a). MS (Method E) m/z: [M - 3H] 3- calcd for C 234 H 337 N 61 O 128 P 17 S 17 3- , 2373.0848, found 2373.0798. Purity (Method E): 42.8%. Example 13: Synthesis C of target oligonucleotide O T -b (see Table T-2) DMTr-dG(ib)-dT-(Kc-C1-carbonate) (24) dT-(Kc-C1-carbonate) (23) was synthesized as described for Example 3 above. A solution of dT-(Kc-C1-carbonate) (23, 1.36 g, 1.33 mmol) in 4-methyltetrahydropyran (MTHP)/N-cyclohexyl-2-pyrrolidone (NcHP) (7:1 v/v, 80 mL) was concentrated in vacuo to a volume of 40 mL (bath temperature 35−55 °C, pressure 100 hPa).1-Methylimidazole (NMI, 2.0 mL, 25.1 mmol), DMTr-dG(ib) phosphoramidite (CAS-RN: 93183-15-4, 2.22 g, 2.64 mmol) and BTT (2.54 g, 13.2 mmol) were added to said solution comprising dT-(Kc-C1-carbonate) (23), and the mixture was stirred at rt until reaction monitoring by HPLC (Method F was used throughout Example 13) indicated completion of the coupling. Ac2O (499 µL, 5.28 mmol) and pyridine (533 µL, 6.60 mmol) were added. After stirring for 10 min at rt, 1 M I 2 in cyclopentyl methyl ether (CPME, 2.91 mL, 2.91 mmol), H 2 O (71 µL), and acetonitrile (MeCN, 3.0 mL) were added. After stirring for 10 min at rt, the reaction mixture was extracted twice: first with 0.5 N Na 2 S 2 O 3 aq. (20 mL), then with a mixture of 0.5 N Na 2 S 2 O 3 aq. (10 mL) and 0.5 M N-methylmorpholine (NMM) aq. (5 mL). The so-obtained solution (organic phase) comprising DMTr-dG(ib)-dT-(Kc-C1- carbonate) (24) was used directly in the next step (without any precipitation, filtration or purification steps in between). DMTr-dA(bz)-dG(ib)-dT-(Kc-C1-carbonate) (26) Thiomalic acid (1.99 g, 13.3 mmol) and dichloroacetic acid (DCA, 10.0 mL) were added to the so-obtained organic phase, followed by stirring at rt until reaction monitoring by HPLC indicated complete DMTr-deprotection. NcHP (2.5 mL), 10 wt- % brine (45 mL), NMM (20 mL) and MTHP 20 mL were added, followed by extraction. The organic phase was separated and extracted twice: first with a mixture of 10 wt-% brine/N,N-dimethylformamide (DMF) solution (45:55 v/v, 40 mL) and acetic acid (200 µL), then with 10 wt-% brine/N,N-dimethylformamide (DMF) solution (45:55 v/v, 40 mL). MTHP (15 mL) was added to the so-obtained organic phase comprising dG(ib)-dT-(Kc-C1-carbonate) (25), followed by concentration in vacuo to a volume of 40 mL (bath temperature 35−55 °C, pressure 100 hPa). The MTHP (30 mL) addition and subsequent concentration was repeated three times (final volume: 40 mL). 1-Methylimidazole (2.0 mL, 25.1 mmol), DMTr-dA(bz) phosphoramidite (CAS-RN: 98796-53-3, 2.31 g, 2.64 mmol) and BTT (2.54 g, 13.2 mmol) were added to said solution comprising dG(ib)-dT-(Kc-C1-carbonate) (25), and the mixture was stirred at rt until reaction monitoring by HPLC indicated completion of the coupling. Ac 2 O (499 µL, 5.28 mmol) and pyridine (533 µL, 6.60 mmol) were added. After stirring for 10 min at rt, 1 M I 2 in CPME (2.91 mL, 2.91 mmol), H 2 O (71 µL), and acetonitrile (MeCN, 3.0 mL) were added. After stirring for 10 min at rt, the reaction mixture was extracted twice: first with 0.5 N Na2S2O3 aq. (20 mL), then with a mixture of 0.5 N Na2S2O3 aq. (10 mL) and 0.5 M NMM aq. (5 mL). The so-obtained solution (organic phase) comprising DMTr-dA(bz)-dG(ib)-dT- (Kc-C1-carbonate) (26) was used directly in the next step (without any precipitation, filtration or purification steps in between). DMTr-dC(bz)-dA(bz)-dG(ib)-dT-(Kc-C1-carbonate) (28) Thiomalic acid (1.99 g, 13.3 mmol) and dichloroacetic acid (DCA, 15 mL) were added to the so-obtained organic phase, followed by stirring at rt until reaction monitoring by HPLC indicated complete DMTr-deprotection. NcHP (2.5 mL), 10 wt- % brine (75 mL), and NMM (24 mL) were added, followed by extraction. The organic phase was separated and extracted twice: first with 10 wt-% brine/N,N- dimethylformamide (DMF) solution (45:55 v/v, 40 mL), then with a mixture of 10 wt- % brine/N,N-dimethylformamide (DMF) solution (45:55 v/v, 40 mL) and acetic acid (50 µL). MTHP (30 mL) was added to the so-obtained organic phase comprising dA(bz)-dG(ib)-dT-(Kc-C1-carbonate) (27), followed by concentration in vacuo to a volume of 30 mL (bath temperature 35−55 °C, pressure 100 hPa). The MTHP (30 mL) addition and subsequent concentration was repeated twice (final volume: 40 mL).1-Methylimidazole (2.0 mL, 25.1 mmol), DMTr-dC(bz) phosphoramidite (CAS- RN: 102212-98-6, 2.24 g, 2.64 mmol) and BTT (2.54 mg, 13.2 mmol) were added to said solution comprising dA(bz)-dG(ib)-dT-(Kc-C1-carbonate) (27), and the mixture was stirred at rt until reaction monitoring by HPLC indicated completion of the coupling. Ac2O (499 µL, 5.28 mmol) and pyridine (533 µL, 6.60 mmol) were added. After stirring for 10 min at rt, 1 M I2 in CPME (2.91 mL, 2.91 mmol), H2O (71 µL), and acetonitrile (MeCN, 3.0 mL) were added. After stirring for 10 min at rt, the reaction mixture was extracted twice: first with 0.5 N Na2S2O3 aq. (20 mL), then with a mixture of 0.5 N Na2S2O3 aq. (10 mL) and 0.5 M NMM aq. (5 mL). The so-obtained solution (organic phase) comprising DMTr-dC(bz)-dA(bz)-dG(ib)-dT-(Kc-C1- carbonate) (28) was used directly in the next step (without any precipitation, filtration or purification steps in between). dT-dC(bz)-dA(bz)-dG(ib)-dT-(Kc-C1-carbonate) (O T -b) Thiomalic acid (1.98 g, 13.2 mmol) and dichloroacetic acid (DCA, 10 mL) were added to the so-obtained organic phase, followed by stirring at rt until reaction monitoring by HPLC indicated complete DMTr-deprotection. NcHP (2.5 mL), 10 wt- % brine (75 mL), and NMM (20 mL) were added, followed by extraction. The organic phase was separated and extracted twice with 10 wt-% brine/N,N- dimethylformamide (DMF) solution (45:55 v/v, 40 mL × 2). MTHP (30 mL) was added to the so-obtained organic phase comprising dC(bz)-dA(bz)-dG(ib)-dT-(Kc- C1-carbonate) (29), followed by concentration in vacuo to a volume of 40 mL (bath temperature 35−55 °C, pressure 100 hPa). The MTHP (30 mL) addition and subsequent concentration was repeated twice (final volume: 40 mL). 1- Methylimidazole (2.0 mL, 25.1 mmol), DMTr-dT phosphoramidite (CAS-RN: 98796- 51-1, 2.01 g, 2.64 mmol) and BTT (2.56 g, 13.3 mmol) were added to said solution comprising dC(bz)-dA(bz)-dG(ib)-dT-(Kc-C1-carbonate) (29), and the mixture was stirred at rt until reaction monitoring by HPLC indicated completion of the coupling. Ac2O (499 µL, 5.28 mmol) and pyridine (533 µL, 6.60 mmol) were added. After stirring for 10 min at rt, 1 M I2 in CPME (2.91 mL, 2.91 mmol), H2O (71 µL), and MeCN (3.0 mL) were added. After stirring for 10 min at rt, the reaction mixture was extracted twice: first with 0.5 N Na 2 S 2 O 3 aq. (20 mL), then with a mixture of 0.5 N Na 2 S 2 O 3 aq. (10 mL) and 0.5 M NMM aq. (5 mL). The so-obtained solution (organic phase) comprising DMTr-dT-dC(bz)-dA(bz)-dG(ib)-dT-(Kc-C1-carbonate) (30) was used directly in the next step (without any precipitation, filtration or purification steps in between). Thiomalic acid (1.99 g, 13.3 mmol) and dichloroacetic acid (DCA, 10 mL) were added to the so-obtained organic phase, followed by stirring at rt until reaction monitoring by HPLC indicated complete DMTr-deprotection. NcHP (2.5 mL), 10 wt- % brine (25 mL), and NMM (20 mL) were added, followed by extraction. The organic phase was separated and extracted twice: first with 10 wt-% brine/DMF solution (45:55 v/v, 40 mL), then with MTHP (90 mL), NcHP (5 mL) and brine/DMF solution (65:35 v/v, 65 mL). The so-obtained organic phase comprising dT-dC(bz)-dA(bz)- dG(ib)-dT-(Kc-C1-carbonate) (O T -b) was concentrated in vacuo, followed by addition of MeOH (120 mL). The resulting precipitate was filtered and washed twice with MeOH (30 mL × 2) to give dT-dC(bz)-dA(bz)-dG(ib)-dT-(Kc-C1-carbonate) (O T - b, 1.94 g, purity 71.647 %, yield 53.7 %) as a white solid. MS (method F) m/z: [M + 2H] 2+ calcd for C131H185N21O36P4 + , 1376.1115; found 1376.1138. Example 14: Synthesis D of target oligonucleotide O T -b (see Table T-2) DMTr-dG(ib)-dT-(Kc-C1-carbonate) (24) dT-(Kc-C1-carbonate) (23) was synthesized as described for Example 3 above. A solution of dT-(Kc-C1-carbonate) (23, 1.36 g, 1.33 mmol) in 4-methyltetrahydropyran (MTHP)/N,N-diethyldodecanamide (7:1 v/v, 80 mL) was concentrated in vacuo to a volume of 40 mL (bath temperature 35−55 °C, pressure 100 hPa). 1-Methylimidazole (NMI, 2.0 mL, 25.1 mmol), DMTr-dG(ib) phosphoramidite (CAS-RN: 93183-15-4, 2.21 g, 2.63 mmol) and BTT (2.54 g, 13.2 mmol) were added to said solution comprising dT-(Kc-C1-carbonate) (23), and the mixture was stirred at rt until reaction monitoring by HPLC (Method F was used throughout Example 14) indicated completion of the coupling. Ac2O (499 µL, 5.28 mmol) and pyridine (533 µL, 6.60 mmol) were added. After stirring for 10 min at rt, 1 M I2 in cyclopentyl methyl ether (CPME, 2.91 mL, 2.91 mmol), H2O (71 µL), and acetonitrile (MeCN, 3.0 mL) were added. After stirring for 10 min at rt, the reaction mixture was extracted twice: first with 0.5 N Na 2 S 2 O 3 aq. (20 mL), then with a mixture of 0.5 N Na 2 S 2 O 3 aq. (10 mL) and 0.5 M N-methylmorpholine (NMM) aq. (5 mL). The so-obtained solution (organic phase) comprising DMTr-dG(ib)-dT-(Kc-C1- carbonate) (24) was used directly in the next step (without any precipitation, filtration or purification steps in between). DMTr-dA(bz)-dG(ib)-dT-(Kc-C1-carbonate) (26) Thiomalic acid (1.99 g, 13.3 mmol) and dichloroacetic acid (DCA, 10.0 mL) were added to the so-obtained organic phase, followed by stirring at rt until reaction monitoring by HPLC indicated complete DMTr-deprotection. N,N- diethyldodecanamide (2.5 mL), 10 wt-% brine (25 mL) and NMM (20 mL) were added, followed by extraction. The organic phase was separated and extracted twice: first with 10 wt-% brine/N,N-dimethylformamide (DMF) solution (45:55 v/v, 40 mL) and acetic acid (500 µL), then with 10 wt-% brine/N,N-dimethylformamide (DMF) solution (45:55 v/v, 40 mL) and acetic acid (50 µL). MTHP (30 mL) was added to the so-obtained organic phase comprising dG(ib)-dT-(Kc-C1-carbonate) (25), followed by concentration in vacuo to a volume of 40 mL (bath temperature 35−55 °C, pressure 100 hPa). The MTHP (30 mL) addition and subsequent concentration was repeated once (final volume: 40 mL).1-Methylimidazole (2.0 mL, 25.1 mmol), DMTr-dA(bz) phosphoramidite (CAS-RN: 98796-53-3, 2.31 g, 2.64 mmol) and BTT (2.54 g, 13.2 mmol) were added to said solution comprising dG(ib)-dT-(Kc-C1- carbonate) (25), and the mixture was stirred at rt until reaction monitoring by HPLC indicated completion of the coupling. Ac 2 O (499 µL, 5.28 mmol) and pyridine (533 µL, 6.60 mmol) were added. After stirring for 10 min at rt, 1 M I 2 in CPME (2.91 mL, 2.91 mmol), H 2 O (71 µL), and acetonitrile (MeCN, 3.0 mL) were added. After stirring for 10 min at rt, the reaction mixture was extracted twice: first with 0.5 N Na 2 S 2 O 3 aq. (20 mL), then with a mixture of 0.5 N Na 2 S 2 O 3 aq. (10 mL) and 0.5 M NMM aq. (5 mL). The so-obtained solution (organic phase) comprising DMTr-dA(bz)-dG(ib)- dT-(Kc-C1-carbonate) (26) was used directly in the next step (without any precipitation, filtration or purification steps in between). DMTr-dC(bz)-dA(bz)-dG(ib)-dT-(Kc-C1-carbonate) (28) Thiomalic acid (1.98 g, 13.2 mmol) and dichloroacetic acid (DCA, 15 mL) were added to the so-obtained organic phase, followed by stirring at rt until reaction monitoring by HPLC indicated complete DMTr-deprotection. N,N- diethyldodecanamide (2.5 mL), 10 wt-% brine (25 mL), and NMM (25 mL) were added, followed by extraction. The organic phase was separated and extracted twice with 10 wt-% brine/N,N-dimethylformamide (DMF) solution (45:55 v/v, 40 mL × 2). MTHP (30 mL) was added to the so-obtained organic phase comprising dA(bz)- dG(ib)-dT-(Kc-C1-carbonate) (27), followed by concentration in vacuo to a volume of 30 mL (bath temperature 35−55 °C, pressure 100 hPa). The MTHP (30 mL) addition and subsequent concentration was repeated once (final volume: 40 mL).1- Methylimidazole (2.0 mL, 25.1 mmol), DMTr-dC(bz) phosphoramidite (CAS-RN: 102212-98-6, 2.25 g, 2.65 mmol) and BTT (2.54 mg, 13.2 mmol) were added to said solution comprising dA(bz)-dG(ib)-dT-(Kc-C1-carbonate) (27), and the mixture was stirred at rt until reaction monitoring by HPLC indicated completion of the coupling. Ac2O (499 µL, 5.28 mmol) and pyridine (533 µL, 6.60 mmol) were added. After stirring for 10 min at rt, 1 M I 2 in CPME (2.91 mL, 2.91 mmol), H 2 O (71 µL), and acetonitrile (MeCN, 3.0 mL) were added. After stirring for 10 min at rt, the reaction mixture was extracted twice: first with 0.5 N Na2S2O3 aq. (20 mL), then with a mixture of 0.5 N Na2S2O3 aq. (10 mL) and 0.5 M NMM aq. (5 mL). The so-obtained solution (organic phase) comprising DMTr-dC(bz)-dA(bz)-dG(ib)-dT-(Kc-C1- carbonate) (28) was used directly in the next step (without any precipitation, filtration or purification steps in between). dT-dC(bz)-dA(bz)-dG(ib)-dT-(Kc-C1-carbonate) (O T -b) Thiomalic acid (1.98 g, 13.2 mmol) and dichloroacetic acid (DCA, 10 mL) were added to the so-obtained organic phase, followed by stirring at rt until reaction monitoring by HPLC indicated complete DMTr-deprotection. N,N- diethyldodecanamide (2.5 mL), 10 wt-% brine (25 mL), and NMM (20 mL) were added, followed by extraction. The organic phase was separated and extracted twice: first with a mixture of 10 wt-% brine/N,N-dimethylformamide (DMF) solution (45:55 v/v, 40 mL) and acetic acid (650 µL), then with 10 wt-% brine/N,N- dimethylformamide (DMF) solution (45:55 v/v, 40 mL). MTHP (30 mL) was added to the so-obtained organic phase comprising dC(bz)-dA(bz)-dG(ib)-dT-(Kc-C1- carbonate) (29), followed by concentration in vacuo to a volume of 40 mL (bath temperature 35−55 °C, pressure 100 hPa). The MTHP (30 mL) addition and subsequent concentration was repeated once (final volume: 40 mL). 1- Methylimidazole (2.0 mL, 25.1 mmol), DMTr-dT phosphoramidite (CAS-RN: 98796- 51-1, 2.01 g, 2.64 mmol) and BTT (2.54 g, 13.2 mmol) were added to said solution comprising dC(bz)-dA(bz)-dG(ib)-dT-(Kc-C1-carbonate) (29), and the mixture was stirred at rt until reaction monitoring by HPLC indicated completion of the coupling. Ac2O (499 µL, 5.28 mmol) and pyridine (533 µL, 6.60 mmol) were added. After stirring for 10 min at rt, 1 M I2 in CPME (2.91 mL, 2.91 mmol), H2O (71 µL), and MeCN (3.0 mL) were added. After stirring for 10 min at rt, the reaction mixture was extracted twice: first with 0.5 N Na2S2O3 aq. (20 mL), then with a mixture of 0.5 N Na 2 S 2 O 3 aq. (10 mL) and 0.5 M NMM aq. (5 mL). The so-obtained solution (organic phase) comprising DMTr-dT-dC(bz)-dA(bz)-dG(ib)-dT-(Kc-C1-carbonate) (30) was used directly in the next step (without any precipitation, filtration or purification steps in between). Thiomalic acid (1.99 g, 13.3 mmol) and dichloroacetic acid (DCA, 10 mL) were added to the so-obtained organic phase, followed by stirring at rt until reaction monitoring by HPLC indicated complete DMTr-deprotection. N,N- Diethyldodecanamide (2.5 mL), 10 wt-% brine (25 mL), and NMM (20 mL) were added, followed by extraction. The organic phase was separated and extracted twice: first with a mixture of 10 wt-% brine/DMF solution (45:55 v/v, 40 mL) and acetic acid (600 µL), then with brine/DMF solution (45:55 v/v, 40 mL) and acetic acid (100 µL). The so-obtained organic phase comprising dT-dC(bz)-dA(bz)-dG(ib)-dT- (Kc-C1-carbonate) (O T -b) was concentrated in vacuo, followed by addition of MeOH (120 mL). The resulting precipitate was filtered and washed twice with MeOH (30 mL × 2) to give dT-dC(bz)-dA(bz)-dG(ib)-dT-(Kc-C1-carbonate) (O T -b, 2.08 g, purity 71.125 %, yield 57.5 %) as a white solid. MS (method F) m/z: [M + 2H] 2+ calcd for C131H185N21O36P4 + , 1376.1115; found 1376.1111. Example 15: Synthesis C of target oligonucleotide O T -f (see Table T-2) DMTr-MG(ib)s-MG(ib)-(Kc-C1-carbonate) (5) A solution of MG(ib)-(Kc-C1-carbonate) (4, 1.58 g, 1.32 mmol) in N-octyl-2- pyrrolidone (NOP, 7.5 mL) was subjected to 5 rounds of azeotropic distillation, during each of which 4-methyltetrahydropyran (MTHP, 15 mL) was added, followed by concentration in vacuo to a volume of 15 mL (bath temperature 45−55 °C, pressure 40−100 hPa). DMTr-MG(ib) phosphoramidite (CAS-RN: 251647-55-9, 2.43 g, 2.66 mmol, 2.0 eq.) and MTHP (10 mL) were added to the so-obtained solution (water content: 370.8 ppm) comprising MG(ib)-(Kc-C1-carbonate) (4), followed by concentration in vacuo (bath temperature 45 °C, pressure 40 hPa) to a volume of 15 mL. 5-Ethylthio-1H-tetrazole (1.73 g, 13.29 mmol, 10.1 eq.) and pyridine (2.13 mL, 26.39 mmol, 20.0 eq.) were added to said solution comprising MG(ib)-(Kc-C1-carbonate) (4), and the mixture was stirred at rt until reaction monitoring by HPLC (Method H was used throughout Example 15) indicated completion of the coupling. Water (24 µL, 1.32 mmol, 1.0 eq.) was added, followed by stirring for 30 min. 3-(N,N-dimethylaminomethylidene)amino)-3H-1,2,4- dithiazole-5-thione (CAS-RN: 1192027-04-5, DDTT, 0.816 g, 3.97 mmol, 3.0 eq) was added. After stirring for 10 min at rt, triethylphosphite (0.686 mL, 3.0 eq) was added. After stirring for 10 min at rt, propan-2-ol (2.0 mL) was added, followed by stirring for 10 min at rt. The so-obtained solution comprising DMTr-MG(ib)s-MG(ib)- (Kc-C1-carbonate) (5) was used directly in the subsequent step (without any precipitation, filtration or purification steps in between). Second coupling cycle and further coupling cycles The second coupling cycle and all further coupling cycles were performed according to the following general protocol, unless indicated differently. The starting materials and products of each coupling cycle are identical to those listed in Table E-1 above, wherein, except for the above-mentioned first coupling cycle, only the 2 nd to 9 th coupling cycles were performed in the present Example 15. Again, the terms “starting material” and “product” are not to be construed to indicate any precipitation and/or isolation steps in between the coupling cycles. General protocol for coupling cycles In a typical coupling cycle, the following steps were performed in the presented order, unless indicated differently. DMTr-deprotection At rt, glutathione (GSH, 2.03 g) was added directly to the solution obtained from the preceding sulfurization step, then trifluoroacetic acid (TFA, 15.0 mL) was added at 0 °C. The mixture was stirred at rt for 10 min. Aqueous extractions Pyridine (25 mL), n-heptane (15.0 mL), MTHP (15 mL), and 15 wt-% aqueous (aq.) sodium chloride solution (brine, 90 mL) were added, followed by extraction. The organic phase was separated and extracted as follows: - with a mixture of NOP (2 nd to 8 th cycle: 2.0 mL; 9 th cycle: 0 mL), 5 wt-% aqueous sodium chloride solution (brine, 45 mL), and acetone (45 mL), next - with a mixture of 5 wt-% aqueous sodium chloride solution (brine, 45 mL) and acetone (45 mL). Azeotropic distillation MTHP (15 mL) was added to the organic phase obtained from the preceding aqueous extractions, followed by concentration in vacuo (bath temperature 35−55 °C, pressure 40-200 hPa) to a volume of 15 mL. This MTHP addition and concentration step was typically repeated one to three times. The water content was adjusted to be in the range of 305.4−390.3 ppm. Then, the respective 5’-DMTr- protected phosphoramidite ( 2.0 eq.) and MTHP (10 mL) were added to the solution, followed by concentration in vacuo (bath temperature 45 °C, pressure 40-100 hPa) to a volume of 15 mL. The composition of the solution obtained after azeotropic distillation was analyzed as laid out above. The content of NOP was in the range of 53−72 vol-% and the content of MTHP was in the range of 47−28 vol-%. The combined content of n-heptane, acetone and pyridine was below 0.2 vol-% in all coupling cycles. Coupling reaction 5-Ethylthio-1H-tetrazole (10 eq.) and pyridine (20 eq.) were added to the solution obtained from azeotropic distillation, followed by stirring at rt until reaction monitoring by HPLC indicated completion of the coupling. Sulfurization (including quenching with triethylphosphite and propan-2-ol) DDTT (3.0 eq.) was added, and the mixture was stirred at rt for 30 min. Triethylphosphite (3.0 eq) was added, followed by stirring for 10 min at rt. Then, propan-2-ol (2.0 mL) was added, followed by stirring for 10 min at rt. After completion of the 9 th coupling cycle, one more DMTr-deprotection, followed by aqueous extractions as laid out above in the general protocol were performed. The organic phase obtained from the final aqueous extraction was concentrated in vacuo, followed by addition of methanol (240 mL). The resulting precipitate was filtered and washed with methanol (60 mL, twice) to give MA(bz)s-mMeUs-MA(bz)s- MA(bz)s-mMeUs-MG(ib)s-mMeC(bz)s-mMeUs-MG(ib)s-MG(ib)-(Kc-C1- carbonate) (13, 3.64 g, 47.1% crude yield) Target oligonucleotide O T -f (see Table T-2) A solution of the crude compound 13 (502.6 mg, 0.086 mmol) in a mixture of H2O, methanol and tert-butylamine (2:1:1 v/v, 15 mL) was stirred at 55 °C for 17 h. The reaction mixture was cooled to rt and the precipitate was filtrated and the filtrate was concentrated in vacuo (bath temperature 45 °C, pressure 40 hPa) to give 5´-MAs- MMeUs-MAs-MAs-MMeUs-MGs-MMeCs-MMeUs-MGs-MG-3´ (O T -f, 502.0 mg, quantitative) as white solid. The so-obtained O T -f (28.6 mg) was washed with mixture of acetonitrile and H2O (99:1 v/v.1.0 mL), followed by filtration to give 5´- MAs-MMeUs-MAs-MAs-MMeUs-MGs-MMeCs-MMeUs-MGs-MG-3´ (O T -f, 19.0 mg, 95.0 % crude yield from crude compound 13) as white solid, which was analyzed by HPLC-MS to find 5´-MAs-MMeUs-MAs-MAs-MMeUs-MGs-MMeCs-MmeUs-MGs- MG-3´ (O T -f). MS (Method G) m/z: [M–3H] 3- calcd for C130H183N39O69P9S9 3- , 1320.2384, found 1320.2412. Purity (Method C, Gradient-2): 78.7%.