A method for the preparation of a modified nucleic acid molecule comprising a nucleic acid moiety and a non-nucleic acid moiety by reacting a first reactant and a second reactant, wherein the first reactant comprises the non-nucleic acid moiety and a carboxyl group, and wherein the second reactant is an amino-modified nucleic acid molecule comprising the nucleic acid moiety and an amino modification comprising an amino group which is attached to the nucleic acid moiety, wherein the method comprises the following steps: a) activating the carboxyl group of the first reactant by a condensation reagent and a non-nucleophilic base in a water miscible organic solvent, and b) reacting the activated carboxyl group of the first reactant of step a) and the amino group of the amino modification of the amino-modified nucleic acid molecule which has been dissolved in water or a mixture of a water miscible organic solvent and water, whereby the modified nucleic acid molecule is formed, wherein the first reactant and/or the non-nucleic acid moiety is a polyalkoxy compound, the condensation agent is selected from the group consisting of a) a phosphonium salt selected from the group consisting of BOP, PyBOP, PyBrop, AOP, PyAOP, BrOP and PyClOP, b) a uronium salt selected from the group consisting of HCTU, TCTU, TBTU, HBTU, HATU, TOTU and COMU, and c) a carbodiimide selected from the group consisting of DCC (N,N'-dicyclohexylcarbodiimide), EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimid) and DIC (N,N'-diisopropylcarbodiimide), and the water miscible organic solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, dimethyl sulfoxide, diethyl sulfoxide, methyl ethyl sulfoxide, formamide, methyl formamide, dimethyl formamide, ethyl formamide, ethyl methyl formamide, diethyl formamide, 2-pyrrolidone, N-methyl pyrrolidone, N-ethylpyrrolidone, acetonitrile, acetone, ethyl methyl ketone, methyl propyl ketone, diethyl ketone, methyl isopropyl ketone, methyl formate, ethyl formate, propyl formate, isopropyl formate, methyl acetate, ethyl acetate, methyl propanoate, tetrahydrofuran and dioxan, preferably dimethyl formamide, acetonitrile and dimethyl sulfoxide. a) activating the carboxyl group of the first reactant by a condensation reagent and a non-nucleophilic base in a water miscible organic solvent, and b) reacting the activated carboxyl group of the first reactant of step a) and the amino group of the amino modification of the amino-modified nucleic acid molecule which has been dissolved in water or a mixture of a water miscible organic solvent and water, whereby the modified nucleic acid molecule is formed, the first reactant and/or the non-nucleic acid moiety is a polyalkoxy compound, the condensation agent is selected from the group consisting of a) a phosphonium salt selected from the group consisting of BOP, PyBOP, PyBrop, AOP, PyAOP, BrOP and PyClOP, b) a uronium salt selected from the group consisting of HCTU, TCTU, TBTU, HBTU, HATU, TOTU and COMU, and c) a carbodiimide selected from the group consisting of DCC (N,N'-dicyclohexylcarbodiimide), EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimid) and DIC (N,N'-diisopropylcarbodiimide), and a) a phosphonium salt selected from the group consisting of BOP, PyBOP, PyBrop, AOP, PyAOP, BrOP and PyClOP, b) a uronium salt selected from the group consisting of HCTU, TCTU, TBTU, HBTU, HATU, TOTU and COMU, and c) a carbodiimide selected from the group consisting of DCC (N,N'-dicyclohexylcarbodiimide), EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimid) and DIC (N,N'-diisopropylcarbodiimide), and the water miscible organic solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, dimethyl sulfoxide, diethyl sulfoxide, methyl ethyl sulfoxide, formamide, methyl formamide, dimethyl formamide, ethyl formamide, ethyl methyl formamide, diethyl formamide, 2-pyrrolidone, N-methyl pyrrolidone, N-ethylpyrrolidone, acetonitrile, acetone, ethyl methyl ketone, methyl propyl ketone, diethyl ketone, methyl isopropyl ketone, methyl formate, ethyl formate, propyl formate, isopropyl formate, methyl acetate, ethyl acetate, methyl propanoate, tetrahydrofuran and dioxan, preferably dimethyl formamide, acetonitrile and dimethyl sulfoxide.