## 2 Materials and Methods
### Synthesis of the Nucleoside Derivatives  
#### Synthesis of 4-amino-6-oxo-1-(3',5'-O-t-butyldimethylsilyl-2',4'-dideoxy-p-ribityl) triazine (4)  
The linker **3** (1.3 g, 3.0 mmol), which was prepared by a modified literature procedure [21], was added to 5-aza cytosine Na salt (1.0 g, 7.5 mmol) in DMSO (30 mL). The mixture was stirred at 60 \({}^{\circ}\)C for 18 h. The resulting mixture was diluted with EtOAc and quenched with NH\({}_{4}\)Cl. The product was extracted with EtOAc and the combined organic layer was washed with brine, dried over Na\({}_{2}\)SO\({}_{4}\), filtered, and evaporated under reduced pressure. The resulting oil was purified by silica gel column chromatography (CH\({}_{3}\)OH/CHCl\({}_{3}\), 1:100, then CH\({}_{3}\)OH/CHCl\({}_{3}\), 1:50) to afford the corresponding N1-alkylation (772 mg, 1.74 mmol, 58%) and N3-alkylation (126 mg, 0.29 mmol, 10%) products. N1-alkylation product: \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) \(\delta\) 7.90 (s, 1H), 6.98 (brs, 1H), 5.65 (brs, 1H), 3.97 (ddd, 2H, J = 12.0, 12.0, 6.0 Hz), 3.90-3.77 (m, 2H), 3.64 (dd, 2H, J = 6.4, 6.4 Hz), 1.99-1.60 (m, 6H), 1.37-1.23 (m, 1 H), 0.89 (s, 9H), 0.87 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H), 0.03 (s, 6H); \({}^{13}\)C-NMR (125 MHz, CDCl3) \(\delta\) 166.7, 158.7, 154.5, 67.4, 59.6, 45.1, 40.2, 36.2, 26.12, 26.09, 18.4, 18.3, \(-\)4.2, \(-\)4.3, \(-\)5.14, \(-\)5.16; HRMS (ESI) calcd. for C\({}_{20}\)H\({}_{43}\)N\({}_{4}\)O\({}_{3}\)Si\({}^{+}\) [M + H]\({}^{+}\)_m/z_ 443.2868, found _m/z_ 443.2879. N3-alkylation product: \({}^{1}\)H-NMR (600 MHz, CDCl3) \(\delta\) 8.34 (s, 1H), 5.90 (brs, 1H), 5.61 (brs, 1H), 4.42-4.35 (m, 1H), 4.05-4.01 (m, 1H), 3.70-3.64 (m, 2H), 1.99-1.95 (m, 1H), 1.89-1.84 (m, 2H), 1.7-1.67 (m, 2H), 0.871 (s, 9H), 0.867 (s, 9H), 0.046 (s, 3H), 0.027 (s, 3H), 0.025 (s, 3H), 0.018 (s, 3H); \({}^{13}\)C-NMR (125 MHz, CDCl3) \(\delta\) 170.4, 167.93, 167.88, 66.3, 64.5, 59.6, 40.3, 35.9, 25.8, 18.2, 18.0, -4.6, -4.8, -5.36, -5.38; HRMS (ESI) calcd. for C\({}_{20}\)H\({}_{43}\)N\({}_{4}\)O\({}_{5}\)Si\({}_{2}\)\({}^{+}\) [M + H]\({}^{+}\) _m/z_ 443.2868, found _m/z_ 443.2879  
2.2 Synthesis of 4-amino-2-(2-octylthioethyl)-6-oxo-1-(3',5'-O-t-butyldimethylsilyl-2', 4'-dideoxy-p-ribityI) triazine (6)  
A 28% aq NH\({}_{4}\)OH (10 mL) solution was added to a solution of the N1-alkylation product **4** (172 mg, 390 \(\upmu\)mol) in dioxane-methanol (10 mL, 1/1, _v/v_), then sealed with a glass stopper. The mixture was stirred at 55 \({}^{\circ}\)C for 24 h. The resulting solution was evaporated under vacuum at 43 \({}^{\circ}\)C. The resulting moist solid was co-evaporated with ethanol \(\times\) 3 to afford guanylurea **5**. This product was directly used for the next step without further purification. The orthoester (597 mg, 1.95 mmol, purity = 91%) was added to a solution of guanylurea (169 mg, 390 \(\upmu\)mol) in DMF (0.2 M, 1.95 mL). The mixture was stirred at 120 \({}^{\circ}\)C for 2 h. The resulting yellow solution was diluted with Et\({}_{2}\)O. The product was extracted with Et\({}_{2}\)O and the combined organic layer was washed with NH\({}_{4}\)Cl aq, NaHCO\({}_{3}\) aq, and brine, dried over Na\({}_{2}\)SO\({}_{4}\), filtered and evaporated. The crude product was purified by silica gel column chromatography (CHCl\({}_{3}\) then, CHCl\({}_{3}\) with 1% Et\({}_{3}\)N, then CH\({}_{3}\)OH/CHCl\({}_{3}\), 1:300 with 1% Et\({}_{3}\)N) to afford **6** (198.3 \(\upmu\)mol, 51%) as a yellow oil: \({}^{1}\)H-NMR (600 MHz, CDCl\({}_{3}\)) \(\delta\) 5.70 (brs, 1H), 5.17 (brs, 1H), 4.02-3.89 (m, 3H), 3.65 (dd, 2H, \(J\) = 6.6, 6.6 Hz), 2.95-2.88 (m, 3H), 2.54 (t, 2H, \(J\) = 7.8 Hz), 1.93-1.88 (m, 1 H), 1.79-1.64 (m, 4H), 1.59 (quin, 2H, \(J\) = 7.2 Hz), 1.39-1.25 (m, 10H), 0.91 (s, 9H), 0.89 (t, 3H, \(J\) = 7.2 Hz), 0.88 (s, 9H), 0.089 (s, 3H), 0.086 (s, 3H), 0.04 (s, 6H); \({}^{13}\)C-NMR (150 MHz, CDCl\({}_{3}\)) \(\delta\) 168.8, 165.3, 155.8, 67.6, 59.6, 41.6, 40.4, 35.8, 34.3, 33.0, 32.1, 29.9, 29.5, 29.2, 28.2, 26.19, 26.18, 22.9, 18.5, 18.3, 14.4, 0.26, -4.18, -4.26, -4.30, -5.1; HRMS (ESI) calcd.