Name: 83-88-5|7,8-Dimethyl-10-((2S,3S,4R)-2,3,4,5-tetrahydroxypentyl)benzo[g]pteridine-2,4(3H,10H)-dione|98%
Brand: Ambeed
SKU: A454767
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1
[ 752-13-6 ]
[ 83-88-5 ]

Yield	Reaction Conditions	Operation in experiment
	With calcium methylate
	With sodium methylate

Reference： [1]Tishler et al. [Journal of the American Chemical Society, vol. 67, p. 2167][Journal of the American Chemical Society, 1947, vol. 69, p. 1487,1491]
[2]Tishler et al. [Journal of the American Chemical Society, vol. 67, p. 2167][Journal of the American Chemical Society, 1947, vol. 69, p. 1487,1491]

2
[ 67-52-7 ]
[ 21037-26-3 ]
[ 83-88-5 ]

Yield	Reaction Conditions	Operation in experiment
74.2%	In acetic acid; butan-1-ol for 4h; Heating;

Reference： [1]Shaps, I. A.; Letunova, A. B.; Sharykina, S. P.; Englinskaya, L. V.; Kramer, L. I. [Pharmaceutical Chemistry Journal, 1986, vol. 20, # 1, p. 61 - 64][Khimiko-Farmatsevticheskii Zhurnal, 1986, vol. 20, # 1, p. 102 - 105]
[2]Tishler et al. [Journal of the American Chemical Society, 1947, vol. 69, p. 1487,1490] Beresowskii et al. [Zhurnal Prikladnoi Khimii, 1949, vol. 22, p. 533,536][Chem.Abstr., 1950, p. 2463]

3
[ 63-42-3 ]
[ 83-88-5 ]
[ 24276-83-3 ]

Reference： [1]Journal of Vitaminology,1959,vol. 5,p. 8,9,10,13
[2],1955,vol. 9,p. 119,120
Chem.Abstr.,1956,p. 15701

4
[ 108-30-5 ]
[ 83-88-5 ]
O^5'-(3-Carboxy-propionyl)-riboflavin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine
	With pyridine In dimethyl sulfoxide at 80℃;
	With pyridine In N,N-dimethyl-formamide at 80℃; for 24h;	1 To Vitamin B in DMF was added Succinic anhydride and pyridine. The reacting mixture was stirred at 80 °C for 24 h. After adding CH2C12, yellow particles were formed and collected through centrifuge. The yellow solid intermediate 7 was used for the next step.

Reference： [1]Furter et al. [Journal of Biological Chemistry, 1945, vol. 160, p. 293,297]
[2]Bareford, Lisa M.; Avaritt, Brittany R.; Ghandehari, Hamidreza; Nan, Anjan; Swaan, Peter W. [Pharmaceutical Research, 2013, vol. 30, # 7, p. 1799 - 1812]
[3]Current Patent Assignee: UNIVERSITY SYSTEM OF OHIO - WO2019/27999, 2019, A1 Location in patent: Page/Page column 74; 75

5
[ 108-24-7 ]
[ 83-88-5 ]
[ 752-13-6 ]

Yield	Reaction Conditions	Operation in experiment
99%	With pyridine at 120℃; for 0.333333h;
95%	With perchloric acid In acetic acid at 40℃; for 0.5h;
95%	With perchloric acid In acetic acid at 40℃; for 1h; Inert atmosphere;

88%	In perchloric acid; acetic acid at 45℃;
86%	With pyridine at 50℃; for 24h; Inert atmosphere;	1 Example 1: Synthesis of 2 ', 3', 4 ', 5'-tetraacetyl-riboflavin (Compound II) Riboflavin (5.0 g, 13 mmol) was added to a three-necked flask,Anhydrous acetic anhydride 40ml and pyridine 10 ml,Heated to 50 ° C,Access to argon protection,After stirring for 24 hours,Adding ammonium chloride saturated solution and ethyl acetate,The aqueous phase was extracted with ethyl acetate (3 x 60 ml)The organic phase was collected, dried over anhydrous magnesium sulfate,The residue was purified by distillation under reduced pressure. Column chromatography (mobile phase: ethyl acetate: petroleum ether = 5: 1 (V: V))To obtain 6.10 g of a yellow powdery solid (Compound II)Yield 86%.
85%	With perchloric acid; acetic acid at 45℃; for 0.5h; Inert atmosphere;
83%	With perchloric acid In acetic acid at 80℃; for 1.5h; Inert atmosphere;	S2 Synthesis and characterization of RFT Riboflavin (2.0 g, 5.3mmol) was suspended in the mixture of acetic acid (5 mL) and aceticanhydride (15 mL), perchloric acid (0.2 mL) was added dropwise and the mixture was mechanically stirred approximately 1.5 h at 80 °C under an argon atmosphere. The reaction mixture was cooled and added dropwise to a beaker containing 100 mL of saturated sodium bicarbonate solution (0.8 M) to neutralize the remaining acetic acid. The crude product was extracted with EtOAc and washed several times with saturated sodium chloride. The EtOAc layer was then dried over anhydroussodium sulfate, decanted, and evaporated under reduced pressure. The resulting product was recrystallized from 19:5 (v/v) MeOH/H2O to yield bright orange crystals (83%). The progress of the reaction was followed with thin-layer chromatography (TLC) using silica gel plates and a 9:1 (v/v) EtOAc/EtOH mobile phase (product Rf = 0.5).
80%	With perchloric acid; acetic acid at 40℃; for 0.5h;
76%	With perchloric acid; acetic acid at 20℃; for 0.0833333h;
75%	With dmap at 40℃; for 24h; Inert atmosphere;	4.2.1 Tetra-O-acetyl riboflavin (TARF) In a two-necked round-bottomed flask, riboflavin (2.0 g, 5.3 mmol), acetic anhydride (20 mL), and 4-dimethylaminopyridine (2.6 g, 21.3 mmol) were mixed and stirred under argon for 24 h at 40 °C. After this period, the solution was left to cool to room temperature, diluted in chloroform (60 mL) and followed by addition of saturated aqueous NH4Cl solution (40 mL). After phase separation, the aqueous layer was extracted with chloroform (2×60 mL). The combined organic layers were dried over MgSO4, filtered off and the solvent removed under vacuum. The residue was purified by column chromatography on silica gel, using ethyl acetate as eluent to afford tetra-O-acetyl riboflavin. Yield: 75%. 1H NMR (500 MHz, CDCl3) δ: 9.12 (br s, 1H), 7.92 (s, 1H), 7.51 (s, 1H), 5.59 (br d, J=9 Hz, 1H), 5.40-5.39 (m, 1H), 5.35-5.32 (m, 1H), 4.85 (br s, 2H), 4.36 (dd, J1=12; J2=3 Hz, 1H), 4.18 (dd, J1=12; J2=6 Hz, 1H), 2.50 (s, 3H), 2.37 (s, 3H), 2.21 (s, 3H), 2.15 (s, 3H), 2.01 (s, 3H), 1.68 (br s, 3H). 13C NMR (125 MHz, CDCl3) δ: 170.6, 170.3, 169.8, 169.7, 159.3, 154.9, 150.6, 148.1, 137.0, 135.9, 134.6, 132.8, 131.1, 115.6, 70.4, 69.4, 68.9, 61.8, 21.4, 21.0, 20.8, 20.6, 20.3, 18.4. IR (KBr) cm-1: 3036, 1749, 1662, 1538, 1212. HRMS [ESI(+)]: Calculated for (C25H28N4O10+H)+, 545.1884; measured: 545.1881.
71.1%	With pyridine for 0.25h; Heating;
50%	With pyridine for 16h;	1 Example 1: Synthesis of a compound of formula II In a three-necked flask, riboflavin (1 g, 2.66 mmol) was dissolved in pyridine (10 mL).Acetic anhydride (1.356 g, 13.3 mmol) was added and stirred for 16 hours. The reaction was complete by TLC.The reaction solution was dissolved in 30 mL of water and the aqueous phase was extracted with dichloromethane (10 mL×3).The combined organic layers were washed with brine (20 mL×1)The solvent was distilled off under reduced pressure, and the obtained crude product was purified by column chromatography.(ethyl acetate: petroleum ether (v/v) = 20:1) was purified to give 721 mg as a yellow powder.The yield was 50%.
	With pyridine

Reference： [1]Metternich, Jan B.; Sagebiel, Sven; Lückener, Anne; Lamping, Sebastian; Ravoo, Bart Jan; Gilmour, Ryan [Chemistry - A European Journal, 2018, vol. 24, # 17, p. 4228 - 4233]
[2]Caelen, Isabelle; Kalman, Andras; Wahlstroem, Lennart [Analytical Chemistry, 2004, vol. 76, # 1, p. 137 - 143]
[3]Jhulki, Isita; Chanani, Prem K.; Abdelwahed, Sameh H.; Begley, Tadhg P. [Journal of the American Chemical Society, 2016, vol. 138, # 27, p. 8324 - 8327]
[4]Neveselý, Tomáš; Svobodová, Eva; Chudoba, Josef; Sikorski, Marek; Cibulka, Radek [Advanced Synthesis and Catalysis, 2016, vol. 358, # 10, p. 1654 - 1663]
[5]Current Patent Assignee: SHENZHEN FUSHAN BIOTECHNOLOGY - CN106565718, 2017, A Location in patent: Paragraph 0030; 0031
[6]Zhang, Wen; Carpenter, Keith L.; Lin, Song [Angewandte Chemie - International Edition, 2020, vol. 59, # 1, p. 409 - 417][Angew. Chem., 2020, vol. 132, # 59, p. 417 - 425,9]
[7]Tang, Guo; Gong, Zhiyu; Han, Wenjun; Sun, Xiaoling [Tetrahedron Letters, 2018, p. 658 - 662]
[8]Location in patent: experimental part Barthel, Alexander; Trieschmann, Lothar; Stroehl, Dieter; Kluge, Ralph; Boehm, Gerald; Csuk, Rene [Archiv der Pharmazie, 2009, vol. 342, # 8, p. 445 - 452]
[9]Lesieur, Mathieu; Genicot, Christophe; Pasau, Patrick [Organic Letters, 2018, vol. 20, # 7, p. 1987 - 1990]
[10]Silva, Alexandre Vieira; López-Sánchez, Almudena; Junqueira, Helena Couto; Rivas, Luis; Baptista, Mauricio S.; Orellana, Guillermo [Tetrahedron, 2015, vol. 71, # 3, p. 457 - 462]
[11]Banekovich, Christian; Ott, Ingo; Koch, Thao; Matuszczak, Barbara; Gust, Ronald [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 3, p. 683 - 687]
[12]Current Patent Assignee: SHENZHEN FUSHAN BIOTECHNOLOGY - CN109134470, 2019, A Location in patent: Paragraph 0033
[13]Tishler et al. [Journal of the American Chemical Society, 1945, vol. 67, p. 2165,2167] Kuhn; Wagner-Jauregg [Chemische Berichte, 1933, vol. 66, p. 1577,1582] v.Euler et al. [Helvetica Chimica Acta, 1935, vol. 18, p. 522,530] Yasuda, Masahide; Nishinaka, Yoshimasa; Nakazono, Takumi; Hamasaki, Takeshi; Nakamura, Nobuya; Shiragami, Tsutomu; Pac, Chyongjin; Shima, Kensuke [Photochemistry and Photobiology, 1998, vol. 67, # 2, p. 192 - 197] Fukuzumi, Shunichi; Yasui, Kiyomi; Suenobu, Tomoyoshi; Ohkubo, Kei; Fujitsuka, Mamoru; Ito, Osamu [Journal of Physical Chemistry A, 2001, vol. 105, # 46, p. 10501 - 10510]

6
[ 76-83-5 ]
[ 83-88-5 ]
[ 136738-76-6 ]

Yield	Reaction Conditions	Operation in experiment
64%	With pyridine at 110℃; for 1h;
63.4%	In pyridine at 110℃; for 4h;
	With pyridine

Reference： [1]Isobe, Minoru; Takahashi, Hiroyuki; Goto, Toshio [Tetrahedron Letters, 1990, vol. 31, # 5, p. 717 - 718]
[2]Takahashi, Hiroyuki; Isobe, Minoru; Goto, Toshio [Tetrahedron, 1991, vol. 47, # 32, p. 6215 - 6222]
[3]Kuhn. et al. [Chemische Berichte, 1936, vol. 69, p. 1543,1546]

7
[ 83-88-5 ]
[ 2474-49-9 ]

Yield	Reaction Conditions	Operation in experiment
	With aerobe bacteria

Reference： [1]Smyrniotis et al. [Journal of the American Chemical Society, 1958, vol. 80, p. 2541,2543]

8
[ 83-88-5 ]
[ 1086-80-2 ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium periodate In water at 50℃; for 24h;
70%	With sodium periodate In water at 50℃; for 24h;
	With methanol; air

	With air; acetic acid
	With 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione In aq. phosphate buffer at 24 - 26℃; Photolysis;	2.1 Photolysis of RF The photolysis of 5×10-5 M RF solutions, containing 2.5×10-4 M CF was carried out at 25±1 °C in the presence and absence of 0.2-1.0 M Na2HPO4 at pH 6.0-8.0. The pH of the solution was adjusted with 1.0-5.0 M HCl/NaOH solution. The solution (100 ml) was irradiated in a dark chamber using a Philips 125 W high pressure mercury vapor fluorescent lamp (emission at 405 and 435 nm), fixed horizontally at a distance of 30 cm from the center of the flask. The 435 nm band of the radiation source overlaps the 445 nm absorption maximum of RF [11] while CF (λmax 273 nm) [32] does not absorb in the visible region. The solution was stirred by bubbling a stream of air into the flask. Samples were withdrawn at appropriate intervals for chromatographic examination and spectrophotometric determination. The photolysis of RF was also carried out under the same conditions in the presence of 1 M phosphate and 0.625-2.50×10-4 M CF at pH 7.0.
	Acidic conditions; Irradiation;	When riboflavin is irradiated with either UVA or blue light, its sugar moiety is cleaved, forming lumichrome in neutral or acidic pH. Lumiflavin is also formed in basic pH. Lumichrome exhibits a peak absorbance at approximately 430 nm while lumiflavin's peak is 450 nm. Both photoproducts are structurally capable of ustilizing π→π* transitions to form ROS.
	In aq. phosphate buffer UV-irradiation;
	In aq. phosphate buffer for 0.333333h; Irradiation;	The Degradation of Peptides and Proteins by RF upon Blue Light Irradiation. RF (50 mM, 3.1 μL) was added to the solution of peptide (1.3 mM, 300 μL) in PBS (10 mM, pH 7.4). The resulting mixture was irradiated for 20 min by LED lamp (13 W, 450-475 nm). The sample was subsequently analyzed by HPLC. For the degradation of insulin, the solution of insulin (30 μM) and RF (12 μM) in PBS (300 μL) was irradiated for 20 min before thesample was analyzed by HPLC. For O2-dependent assay, the solution of AcYQRL (1.3 mM) and RF (0.52 mM, 0.4 eq.) in PBS (300 μL) was flushed with N2 followed by irradiation for 20 min. For the study of RF equivalent and irradiation time, RF (0.1 eq., 0.2 eq., 0.4 eq.) was added to the PBS solution of YSPIYL (1.3 mM, 300 μL), the mixture was exposed to blue light for 0, 5, 10, 20 min, respectively. Then the samples were analyzed by HPLC.

Reference： [1]Ohkado, Ryoma; Ishikawa, Tatsuro; Iida, Hiroki [Green Chemistry, 2018, vol. 20, # 5, p. 984 - 988]
[2]Sakai, Takuya; Kumoi, Takuma; Ishikawa, Tatsuro; Nitta, Takahiro; Iida, Hiroki [Organic and Biomolecular Chemistry, 2018, vol. 16, # 21, p. 3999 - 4007]
[3]Karrer et al. [Helvetica Chimica Acta, 1934, vol. 17, p. 1010][Helvetica Chimica Acta, 1935, vol. 18, p. 266,270]
[4]Kuhn; Rudy [Chemische Berichte, 1934, vol. 67, p. 1936,1939][Chemische Berichte, 1935, vol. 68, p. 169]
[5]Sheraz, Muhammad Ali; Kazi, Sadia Hafeez; Ahmed, Sofia; Mirza, Tania; Ahmad, Iqbal; Evstigneev, Maxim P. [Journal of Photochemistry and Photobiology A: Chemistry, 2014, vol. 273, p. 17 - 22]
[6]Current Patent Assignee: CONVERSION ENERGY ENTPR - US9012406, 2015, B2 Location in patent: Page/Page column 1
[7]Jiang, Wei; Pang, Xin-Yu; Wang, Li-Li; Yang, Liu-Pan; Zhang, Hong [Chemical Communications, 2021, vol. 57, # 100, p. 13724 - 13727]
[8]Wu, Chunlei; Li, Yanyan; Cheng, Zhehong; Wang, Pengxin; Ma, Zhilong; Liu, Ke; Cheng, Yulian; Zhou, Yimin; Lin, Xian; Shao, Ximing; Yang, Yong; Li, Hongchang; Fang, Lijing [Chinese Chemical Letters, 2022, vol. 33, # 9, p. 4339 - 4344]

9
[ 83-88-5 ]
[ 4250-90-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: riboflavin With sulfuric acid; periodic acid In water at 0℃; for 0.5h; Darkness; Stage #2: With sodium carbonate In water at 18 - 25℃;	3.1 Example 3: Preparation of: 3-(SH2-(7,8-Dimethyl-2.4-dioxo-3,4-dihvdro-2H-benzo[glpteridin- lO-vD-ethylaminol- (R)-cycIopentanecarboxylic acid trifluoroaeetic acid salt; Step 1: Preparation of 2-(7,8-Dimethyl-2,4-dioxo-3,4-dihydrobenzo[glpteridin- 10(211 )-γ 1 hicetaldeh vde; [0105] To a suspension of riboflavin (8.5 g, 0.0023 mol) in 2 N aqueous sulfuric acid (225 mL), cooled to 0 °C in a flask covered with tinfoil, is added orthoperiodic acid (18.9 g, 0.0825 mmol) dissolved in water (200 mL). After 30 min., the reaction is allowed to warm to room temperature. Once the reaction mixture becomes clear (a transparent yellow solution), the pH of the reaction solution is adjusted carefully to 3.8-3.9 (using a pH meter) by addition of solid sodium carbonate. [It is extremely important that the pH is monitored carefully, if one goes over a pH of 3.9 the product does not precipitate out of solution.] The precipitate is then filtered off and washed liberally with cold water, ethanol, and diethyl ether to yield 6.04 g of the desired product as an orange solid (Yield: 94%). LC-MS m/z 285.1 [M + H]+, retention time 1.63 min.
49%	Stage #1: riboflavin With sulfuric acid; periodic acid at 20℃; for 1h; Stage #2: In toluene Heating; Further stages.;
	With sulfuric acid; periodic acid unter Liehtausschluss;

	With sulfuric acid; periodic acid at 20℃; for 2h;
	With sodium periodate
	Multi-step reaction with 2 steps 1: sodium periodate / water / 20 °C 2: toluene / 4 h / Reflux
	With sulfuric acid; periodic acid In water at 20℃; for 16h;	4 preparation of 7,8-dimethyl-10-acetaldehyde isoalloxazine Riboflavin (2.28g, 0.6mmol) and the molar concentration of 2mol / L aqueous solution of sulfuric acid (60mL) suspension formed, coated foil into a flask and cooled to 0°C . The periodic acid (5.04g, 22mmol) was dissolved in water (20 mL) after (i.e. periodate aqueous solution) was added to the reaction flask. After stirring for 16h, warmed to room temperature. When the reaction mixture became clear yellow solution (ie became clear) with solid sodium carbonate and the reaction solution was carefully adjusted to pH 3.8 to 3.9. The precipitate was then filtered, washed thoroughly with a lot of cold water until no sulfate detected until the cake was washed with anhydrous ethanol to give an orange solid product, namely 7,8-dimethyl-10-aldehyde group - isoalloxazine.

Reference： [1]Current Patent Assignee: BIORELIX, INC. - WO2011/8247, 2011, A1 Location in patent: Page/Page column 208-209
[2]Svoboda, Jiri; Koenig, Burkhard; Sadeghian, Keyarash; Schuetz, Martin [Zeitschrift fur Naturforschung, B: Chemical Sciences, 2008, vol. 63, # 1, p. 47 - 54]
[3]Fall; Petering [Journal of the American Chemical Society, 1956, vol. 78, p. 377,378, 379]
[4]Matsuo, Takashi; Hayashi, Takashi; Hisaeda, Yoshio [Journal of the American Chemical Society, 2002, vol. 124, # 38, p. 11234 - 11235]
[5]Location in patent: scheme or table Kino, Katsuhito; Kobayashi, Teruhiko; Arima, Eiji; Komori, Rie; Kobayashi, Takanobu; Miyazawa, Hiroshi [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 7, p. 2070 - 2074]
[6]Murahashi, Shun-Ichi; Zhang, Dazhi; Iida, Hiroki; Miyawaki, Toshio; Uenaka, Masaaki; Murano, Kenji; Meguro, Kanji [Chemical Communications, 2014, vol. 50, # 71, p. 10295 - 10298]
[7]Current Patent Assignee: NATIONAL UNIVERSITY OF DEFENSE TECHNOLOGY - CN104496992, 2016, B Location in patent: Paragraph 0059-0061

10
[ 83-88-5 ]
[ 3180-56-1 ]

Yield	Reaction Conditions	Operation in experiment
	durch bakterielle Zersetzung;
	Multi-step reaction with 2 steps 1: sodium periodate 2: sodium tetrahydroborate
	Multi-step reaction with 2 steps 1: sodium periodate / water / 20 °C 2: sodium tetrahydroborate / methanol / 20 °C

	Multi-step reaction with 2 steps 1: sodium periodate / water / 17 h / 25 °C 2: sodium tetrahydroborate / ethanol; isopropyl alcohol; propan-1-ol / 25 °C
	Multi-step reaction with 2 steps 1: sodium periodate / water / 16 h / 20 °C / Darkness 2: sodium tetrahydroborate / ethanol; isopropyl alcohol; propan-1-ol / 16 h / 20 °C / Darkness

Reference： [1]Miles; Stadtman [Journal of the American Chemical Society, 1955, vol. 77, p. 5746]
[2]Choi, Jungkweon; Park, Jongjin; Tanaka, Atsushi; Park, Man Jae; Jang, Yoon Jung; Fujitsuka, Mamoru; Kim, Seog K.; Majima, Tetsuro [Angewandte Chemie - International Edition, 2013, vol. 52, # 4, p. 1134 - 1138][Angew. Chem., 2013, vol. 125, # 4, p. 1172 - 1176,5]
[3]Murahashi, Shun-Ichi; Zhang, Dazhi; Iida, Hiroki; Miyawaki, Toshio; Uenaka, Masaaki; Murano, Kenji; Meguro, Kanji [Chemical Communications, 2014, vol. 50, # 71, p. 10295 - 10298]
[4]Sakai, Takuya; Kumoi, Takuma; Ishikawa, Tatsuro; Nitta, Takahiro; Iida, Hiroki [Organic and Biomolecular Chemistry, 2018, vol. 16, # 21, p. 3999 - 4007]
[5]Pokluda, Adam; Anwar, Zubair; Boguschová, Veronika; Anusiewicz, Iwona; Skurski, Piotr; Sikorski, Marek; Cibulka, Radek [Advanced Synthesis and Catalysis, 2021, vol. 363, # 18, p. 4371 - 4379]

11
[ 83-88-5 ]
[ 146-17-8 ]

Yield	Reaction Conditions	Operation in experiment
	With meta-phosphoric acid Erwaermen des Reaktionsprodukts mit wss.HCl;
	With chlorophosphonic acid Behandeln des Reaktionsprodukts mit H₂O;
	With chloroform; phosphorus pentoxide; phenol Behandeln des Reaktionsprodukts mit wss.HCl;

	With pyruvate kinase; phosphoenolpyruvic acid; ATP In various solvent(s) at 37℃; for 16h;
	With human riboflavin kinase from the yeast Schizosaccharomyces pombe; ATP; magnesium chloride; 2,2'-piperazine-1,4-diyl-bis-ethanesulfonic acid at 25 - 100℃; for 0.1h; Enzymatic reaction;	2.3 \| Steady-state RFK activity The RFK activity of HsRFK was measured at 25°C in 500 μLof 20 mM of PIPES, pH 7.0 and 0.3 mM of MgCl2, containingvariable concentrations of RF (0.2-15 μM) and ATP (2-600 μM), as previously described.30,31 The inhibitory effectof the substrates and products of the reaction was also analyzedby measuring the RFK activity in reaction mixtures atincreasing concentrations of FMN (0-5 μM), varying the ATPconcentration and keeping the RF constant for the determinationof the FMN inhibitory effect; and at increasing concentrationsof ADP (0-120 μM), varying the RF concentrationand keeping ATP fixed. In all cases, reactions were initiatedby addition of 40 nM HsRFK to reaction mixtures preincubatedat 25°C. After 1 minute of incubation at 25°C reactionswere stopped by boiling the samples at 100°C for 5 minutes.The flavin composition of the supernatant was analyzedusing an Alliance HPLC system (Waters) equipped with a2707 autosampler and an HSST3 column (4.6 × 50 mm,3.5 mm; Waters) preceded by a pre-column (4.6 × 20 mm,3.5 mm; Waters) as previously described.31 Flavin concentrationswere quantified using RF or FMN standard curvesacquired under the same conditions, and the observed steadystaterates for FMN production (v0) were determined in unitsof nmoles of flavin transformed per min per nmol of enzyme(v0/[e]). The kinetic data obtained for one substrate at saturatingconcentrations of the second substrate were fitted to the Michaelis-Menten kinetic model, obtaining kcat and Kmvalues. The inhibition mechanism of the products of the RFKreaction -FMN and ADP- was determined by evaluating theireffect on Km and kcat by individual fitting of data sets to theMichaelis-Menten model. Additionally, data sets acquiredat variable concentrations of the product acting as inhibitorwere globally fitted to the Lineweaver-Burk equation forcompetitive inhibition

Reference： [1]Viscontini et al. [Helvetica Chimica Acta, 1952, vol. 35, p. 451,455]
[2]Current Patent Assignee: ROCHE HOLDING AG - US2610179, 1951, A Current Patent Assignee: ROCHE HOLDING AG - DE831549, 1950, C [DRP/DRBP Org.Chem.][DRP/DRBP Org.Chem.]
[3]Current Patent Assignee: ROCHE HOLDING AG - US2677680, 1951, A
[4]Richter, Gerald; Weber, Stefan; Roemisch, Werner; Bacher, Adelbert; Fischer, Markus; Eisenreich, Wolfgang [Journal of the American Chemical Society, 2005, vol. 127, # 49, p. 17245 - 17252]
[5]Anoz-Carbonell, Ernesto; Rivero, Maribel; Polo, Victor; Velázquez-Campoy, Adrián; Medina, Milagros [FASEB Journal, 2020, vol. 34, # 8, p. 10871 - 10886]

12
[ 57392-44-6 ]
[ 83-88-5 ]
[ 20704-80-7 ]

Yield	Reaction Conditions	Operation in experiment
25%	In N,N-dimethyl-formamide at 45℃; for 144h; subtilisin;

Reference： [1]Riva,S.; Choipineau,J.; Kieboom,A.P. [Journal of the American Chemical Society, 1988, vol. 110, p. 584]

13
[ 107-92-6 ]
[ 83-88-5 ]
[ 752-56-7 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; trichlorophosphate at 70 - 75℃; for 5h;
	With pyridine; trichlorophosphate at 70 - 75℃; for 5h;

Reference： [1]Ebitani, Matsue; Kashiwagi, Hiroshi; Inoue, Masami; Nishibe, Keiichi [Bulletin of the Chemical Society of Japan, 1991, vol. 64, # 4, p. 1093 - 1096]
[2]Ebitani, Matsue; Kashiwagi, Hiroshi; Inoue, Masami; Enomoto, Saburo; Ishida, Toshimasa [Chemical and pharmaceutical bulletin, 1989, vol. 37, # 9, p. 2273 - 2275]

14
[ 83-88-5 ]
C₁₇H₂₁N₄O₆*C₁₇H₂₀N₄O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.89 g	With sodium dithionite In water at 60℃; a few minutes;

Reference： [1]Ebitani, Matsue; Kashiwagi, Hiroshi; Inoue, Masami; Nishibe, Keiichi [Bulletin of the Chemical Society of Japan, 1991, vol. 64, # 4, p. 1093 - 1096]

15
C₂₈H₃₆N₁₀O₁₅P₄ [ No CAS ]
[ 83-88-5 ]
[ 740066-94-8 ]

Yield	Reaction Conditions	Operation in experiment
12.5%	In dimethyl sulfoxide at 65℃;

Reference： [1]Pankiewicz, Krzysztof W.; Lesiak, Krystyna; Watanabe, Kyoichi A. [Journal of the American Chemical Society, 1997, vol. 119, # 16, p. 3691 - 3695]

16
[ 699-40-1 ]
[ 83-88-5 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine

Reference： [1]Tishler et al. [Journal of the American Chemical Society, 1945, vol. 67, p. 2165,2167]

17
riboflavin [ No CAS ]
[ 83-88-5 ]

Yield	Reaction Conditions	Operation in experiment
	With Escherichia coli ribonucleotide reductase active-R₂ form In phosphate buffer at 22℃;

Reference： [1]Dobbing, A. Mark; Borman, Christopher D.; Twitchett, Mark B.; Leese, David N.; Salmon, G. Arthur; Sykes, A. Geoffrey [Journal of the American Chemical Society, 2000, vol. 122, # 10, p. 2206 - 2212]

18
[ 1125-88-8 ]
[ 83-88-5 ]
[ 278793-03-6 ]

Yield	Reaction Conditions	Operation in experiment
50%	With camphor-10-sulfonic acid In N,N-dimethyl-formamide
22%	With (1S)-10-camphorsulfonic acid In N,N-dimethyl-formamide at 80℃; Darkness;	4.2.1. Synthesis of 2′,4′-O-benzylidene-riboflavin (2) Riboflavin (1) (2 g, 5.31 mmol) was dissolved in dry DMF (25 mL), (+)-camphor-10- sulfonic acid (CSA) (62 mg, 0.26 mmol) and 796 μL of benzaldehyde dimethyl acetal (5.31 mmol) were added. The reaction was taken at 80 °C in the dark for a night. The reaction was monitorated by TLC (dichloromethane-methanol, 9:1, v:v) and quenched at room temperature by addition of triethylamine until neutrality. After evaporation of solvents, the residue concentrated under reduced pressureand subsequently purified on silica gel with dichloromethane-methanol(95:5 to 90:10) to yield compound 2 (537 mg, 1.16 mmol, 22%). Compound 2: 1H NMR (DMSO-d6, 400 MHz, r.t.) 8.02 ppm (1H, s,aromatic-Rf); 7.82 ppm (1H, s, aromatic-Rf); 5.52 ppm (1H, s, H6′); 5.20and 4.85 ppm (2H, m, H1′); 4.18 ppm (1H, m, H2′); 3.80-3.73 ppm (1H,m, H5′); 3.65 ppm (1H, m, H4′); 3.60-3.41 ppm (2H, overlapped signals,H5′ and H3′); 2.39 ppm (3H, s, CH3-Rf); 2.45 ppm (3H, s, CH3-Rf). 13CNMR (DMSO- d6, 100 MHz, r.t.): δ = 160.3; 155.8; 151.0; 146.0; 138.3;137.5; 136.2; 134.1; 132.4; 130.9; 128.9; 128.1; 126.5; 118.7; 100.0; 82.5; 78.8; 63.8; 61.7; 46.8; 21.0 and 19.2 ppm.
14%	With camphor-10-sulfonic acid In N,N-dimethyl-formamide at 50℃; for 16h;

Reference： [1]Schwoegler, Anja; Carell, Thomas [Organic Letters, 2000, vol. 2, # 10, p. 1415 - 1418]
[2]Romanucci, Valeria; Oliva, Rosario; Petraccone, Luigi; Claes, Sandra; Schols, Dominique; Zarrelli, Armando; Di Fabio, Giovanni [Bioorganic Chemistry, 2020, vol. 104]
[3]Mees, Alexandra; Behrens, Christoph; Schwoegler, Anja; Ober, Matthias; Carell, Thomas [European Journal of Organic Chemistry, 2003, # 14, p. 2670 - 2677]

19
[ 1125-88-8 ]
[ 83-88-5 ]
10-(2,6-diphenyl-tetrahydro-[1,3]dioxino[5,4-d][1,3]dioxin-4-ylmethyl)-7,8-dimethyl-10H-benzo[g]pteridine-2,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With camphor-10-sulfonic acid In N,N-dimethyl-formamide

Reference： [1]Schwoegler, Anja; Carell, Thomas [Organic Letters, 2000, vol. 2, # 10, p. 1415 - 1418]

20
[ 50-00-0 ]
[ 83-88-5 ]
[ 1023271-21-7 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride In water at 60℃; for 48h;
	With hydrogenchloride In water at 60℃; for 48h;
	With hydrogenchloride In water

With hydrogenchloride In water at 60℃; for 48h;

Preparation of 3-Methyl-2’,4’:3’,5’-di-O-methylenedioxyriboflavin A mixture of riboflavin (376 mg, 1.0 mmol), concentrated HCl (600 mL), and 37% aqueous solution of formaldehyde (900 mL) was refluxed in a water bath at 60 C for 48 h. After evaporation under reduced pressure at 80°C, K2CO3 (1.38 g, 10 mmol), dimethylformamide (DMF, 100 mL), and CH3I (0.620mL, 10 mmol) were added successively to the resulting crude O-protected riboflavin, and the mixture was stirred for 25 h at room temperature. The reaction mixture was poured into CHCl3 (100mL) and washed with water (100mL x 5). The combined organic layers were dried over MgSO4 and evaporated under reduced pressure. The crude product was purified by column chromatography (Al2O3, MeOH-CHCl3) to give 3-methyl-20, 40:30,50-di-O-methylenedioxyriboflavin (153 mg, 37%) as a yellow solid: mp>300 °C; IR (KBr) 1712, 1658, 1584, 1547, 1350, 1277, 1237, 1078, 1053, 1014, 990, 980 cm 1; 1H NMR (500 MHz, CDCl3) δ 2.44 (s, 3 H), 2.55 (s, 3 H), 3.52 (s, 3 H), 3.54-3.61 (m, 3 H), 4.17 (dd, J=7.6, 3.0 Hz, 1 H), 4.27 (ddd, J=9.1, 9.1, 3.6 Hz, 1 H), 4.62 (d, J=6.3 Hz, 1 H), 4.69 (d, J=6.3 Hz, 1 H), 4.91 (d, J=6.3 Hz, 1 H), 4.84-4.98 (m, 1 H), 5.05 (d, J=6.3 Hz, 1 H), 5.10 (br, 1 H), 7.56 (s, 1 H), 8.06 (s, 1 H); 13C NMR (125 MHz, CDCl3) δ 19.4, 21.6, 28.7, 45.2, 68.2, 72.8, 75.0, 77.1, 93.5, 94.1, 116.0, 131.8, 132.6, 134.8, 135.6, 136.5, 147.4, 149.2, 155.7, 160.0. HRMS (FAB) calcd. for C20H23O6N4 (M+H+): 415.1618. Found: 415.1629.

Reference： [1]Imada, Yasushi; Iida, Hiroki; Murahashi, Shun-Ichi; Naota, Takeshi [Angewandte Chemie - International Edition, 2005, vol. 44, # 11, p. 1704 - 1706]
[2]Imada, Yasushi; Iida, Hiroki; Kitagawa, Takahiro; Naota, Takeshi [Chemistry - A European Journal, 2011, vol. 17, # 21, p. 5908 - 5920]
[3]Imada, Yasushi; Tonomura, Itoko; Komiya, Naruyoshi; Naota, Takeshi [Synlett, 2013, vol. 24, # 13, p. 1679 - 1682]
[4]Imada, Yasushi; Takagishi, Masamitsu; Komiya, Naruyoshi; Naota, Takeshi [Synthetic Communications, 2013, vol. 43, # 22, p. 3064 - 3071]

21
[ 83-88-5 ]
C₁₇H₂₀N⁽¹⁵⁾N₃O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium ⁽¹⁵⁾N-nitrite; urea-15N₂

Reference： [1]Koder Jr., Ronald L.; Walsh, Joseph D.; Pometun, Maxim S.; Dutton, P. Leslie; Wittebort, Richard J.; Miller, Anne-Frances [Journal of the American Chemical Society, 2006, vol. 128, # 47, p. 15200 - 15208]

22
[ 41864-22-6 ]
[ 83-88-5 ]
N-e-Lys-riboflavin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Riboflavin (Sigma-Aldrich) was dissolved at 37.6 mg/ml in DMSO and heated until in solution. A 2.5 molar excess of Solid l,l'-carbonyl-di(l,2,4-triazole) (150 mg) was added and reacted for 20 minutes. A two-fold weight excess of Lys-Cu-Lys dissolved in DMSO was added plus 300 ul TEA. The reaction was allowed to proceed overnight, and then the reaction was precipitated at pH 4.5. The product was dissolved in EDTA and applied to a Dowex 1x2 resin and the flow-though applied to XAD resin and washed with 0.2M EDTA. The product was eluted with methanol, rotary evaporated and lyophilized

Reference： [1]Patent: WO2007/131286,2007,A1 .Location in patent: Page/Page column 72

23
[ 83-88-5 ]
[ 851591-01-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: HCl / H₂O / 48 h / 60 °C 2: 153 mg / K₂CO₃ / dimethylformamide / 24 h / 20 °C
	Multi-step reaction with 2 steps 1: hydrogenchloride / water / 48 h / 60 °C 2: potassium carbonate / N,N-dimethyl-formamide / 25 h / 20 °C
	Multi-step reaction with 2 steps 1: hydrogenchloride / water 2: potassium carbonate / N,N-dimethyl-formamide

Multi-step reaction with 2 steps 1: hydrogenchloride / water / 48 h / 60 °C 2: potassium carbonate / N,N-dimethyl-formamide / 25 h / 20 °C

Reference： [1]Imada, Yasushi; Iida, Hiroki; Murahashi, Shun-Ichi; Naota, Takeshi [Angewandte Chemie - International Edition, 2005, vol. 44, # 11, p. 1704 - 1706]
[2]Imada, Yasushi; Iida, Hiroki; Kitagawa, Takahiro; Naota, Takeshi [Chemistry - A European Journal, 2011, vol. 17, # 21, p. 5908 - 5920]
[3]Imada, Yasushi; Tonomura, Itoko; Komiya, Naruyoshi; Naota, Takeshi [Synlett, 2013, vol. 24, # 13, p. 1679 - 1682]
[4]Imada, Yasushi; Takagishi, Masamitsu; Komiya, Naruyoshi; Naota, Takeshi [Synthetic Communications, 2013, vol. 43, # 22, p. 3064 - 3071]

24
[ 83-88-5 ]
(4S,4aS,8aS)-5-ethyl-3-methyl-2′,4′:3′,5′-di-O-methylenedioxyriboflavinium perchlorate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: HCl / H₂O / 48 h / 60 °C 2.1: 153 mg / K₂CO₃ / dimethylformamide / 24 h / 20 °C 3.1: NaBH₃CN; Na₂S₂O₄; acetic acid / dimethylformamide / 2 h / 60 °C 3.2: 63 percent / NaNO₂; Na₂S₂O₄; ammonia / HClO₄; NaClO₄ / H₂O; ethanol / 0 - 20 °C
	Multi-step reaction with 3 steps 1: hydrogenchloride / water 2: potassium carbonate / N,N-dimethyl-formamide 3: sodium cyanoborohydride; sodium dithionite / N,N-dimethyl-formamide
	Multi-step reaction with 3 steps 1.1: hydrogenchloride / water / 48 h / 60 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 25 h / 20 °C 3.1: sodium dithionite; acetic acid; sodium cyanoborohydride / 2 h / 60 °C 3.2: 1 h / 0 - 20 °C

Reference： [1]Imada, Yasushi; Iida, Hiroki; Murahashi, Shun-Ichi; Naota, Takeshi [Angewandte Chemie - International Edition, 2005, vol. 44, # 11, p. 1704 - 1706]
[2]Imada, Yasushi; Tonomura, Itoko; Komiya, Naruyoshi; Naota, Takeshi [Synlett, 2013, vol. 24, # 13, p. 1679 - 1682]
[3]Imada, Yasushi; Takagishi, Masamitsu; Komiya, Naruyoshi; Naota, Takeshi [Synthetic Communications, 2013, vol. 43, # 22, p. 3064 - 3071]

25
[ 83-88-5 ]
[ 642988-86-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 95 percent / perchloric acid / acetic acid / 0.5 h / 40 °C 2: 73 percent / potassium carbonate / dimethylformamide / 20 h / 20 °C

Reference： [1]Caelen, Isabelle; Kalman, Andras; Wahlstroem, Lennart [Analytical Chemistry, 2004, vol. 76, # 1, p. 137 - 143]

26
[ 83-88-5 ]
sodium; 1-[7,8-dimethyl-2,4-dioxo-10-(2,3,4,5-tetrahydroxy-pentyl)-4,10-dihydro-2H-benzo[g]pteridin-3-yl]-acetoxy}-2,5-dioxo-pyrrolidine-3-sulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 95 percent / perchloric acid / acetic acid / 0.5 h / 40 °C 2: 73 percent / potassium carbonate / dimethylformamide / 20 h / 20 °C 3: aq. HCl / 2 h / Heating 4: N,N'-dicyclohexylcarbodiimide / dimethylformamide / 48 h / 4 °C

Reference： [1]Caelen, Isabelle; Kalman, Andras; Wahlstroem, Lennart [Analytical Chemistry, 2004, vol. 76, # 1, p. 137 - 143]

27
[ 83-88-5 ]
[ 28714-80-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 95 percent / perchloric acid / acetic acid / 0.5 h / 40 °C 2: 73 percent / potassium carbonate / dimethylformamide / 20 h / 20 °C 3: aq. HCl / 2 h / Heating

Reference： [1]Caelen, Isabelle; Kalman, Andras; Wahlstroem, Lennart [Analytical Chemistry, 2004, vol. 76, # 1, p. 137 - 143]

28
[ 83-88-5 ]
[ 603991-76-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 14 percent / CSA / dimethylformamide / 16 h / 50 °C / 45 Torr 2: 77 percent / molecular sieves / pyridine / 3 h / 20 °C
	Multi-step reaction with 2 steps 1: (1S)-10-camphorsulfonic acid / N,N-dimethyl-formamide / 80 °C / Darkness 2: pyridine / 2 h / 20 °C

Reference： [1]Mees, Alexandra; Behrens, Christoph; Schwoegler, Anja; Ober, Matthias; Carell, Thomas [European Journal of Organic Chemistry, 2003, # 14, p. 2670 - 2677]
[2]Romanucci, Valeria; Oliva, Rosario; Petraccone, Luigi; Claes, Sandra; Schols, Dominique; Zarrelli, Armando; Di Fabio, Giovanni [Bioorganic Chemistry, 2020, vol. 104]

29
[ 83-88-5 ]
10-aminoethyl-7,8-dimethyl-10H-benzo[g]pteridine-2,4-dione hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: aq. orthoperiodic acid dihydrate; sulfuric acid / 2 h / 20 °C 2.1: 83 percent / sodium cyanoborohydride / methanol / 24 h / 20 °C 3.1: H₂ / platinum / acetic acid / 7 h / 70 °C 3.2: 80 percent / HCl / methanol; ethyl acetate

Reference： [1]Matsuo, Takashi; Hayashi, Takashi; Hisaeda, Yoshio [Journal of the American Chemical Society, 2002, vol. 124, # 38, p. 11234 - 11235]

30
[ 83-88-5 ]
7,8-dimethyl-10-(2'-N-benzylaminoethyl)isoalloxazine acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: aq. orthoperiodic acid dihydrate; sulfuric acid / 2 h / 20 °C 2: 83 percent / sodium cyanoborohydride / methanol / 24 h / 20 °C

Reference： [1]Matsuo, Takashi; Hayashi, Takashi; Hisaeda, Yoshio [Journal of the American Chemical Society, 2002, vol. 124, # 38, p. 11234 - 11235]

31
[ 83-88-5 ]
3-(18-{2-[2-(7,8-dimethyl-2,4-dioxo-3,4-dihydro-2H-benzo[g]pteridin-10-yl)-ethylcarbamoyl]-ethyl}-3,8,13,17-tetramethyl-7,12-divinyl-porphyrin-2-yl)-propionic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: aq. orthoperiodic acid dihydrate; sulfuric acid / 2 h / 20 °C 2.1: 83 percent / sodium cyanoborohydride / methanol / 24 h / 20 °C 3.1: H₂ / platinum / acetic acid / 7 h / 70 °C 3.2: 80 percent / HCl / methanol; ethyl acetate 4.1: 72 percent / DPPA; Et₃N / dimethylformamide / 11 h / 20 °C

Reference： [1]Matsuo, Takashi; Hayashi, Takashi; Hisaeda, Yoshio [Journal of the American Chemical Society, 2002, vol. 124, # 38, p. 11234 - 11235]

32
[ 83-88-5 ]
10-(5-hydroxy-6-hydroxymethyl-2-phenyl-[1,3]dioxan-4-ylmethyl)-7,8-dimethyl-10H-benzo[g]pteridine-2,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 90 percent / CSA / dimethylformamide 2: 30 percent / CH₃COOH; HCOOH / H₂O

Reference： [1]Schwoegler, Anja; Carell, Thomas [Organic Letters, 2000, vol. 2, # 10, p. 1415 - 1418]

33
[ 83-88-5 ]
C₁₇H₂₀N₄O₆C₂₈H₂₃O₄P*C₆H₁₅N [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: 50 percent / CSA / dimethylformamide 2.1: pyridine 2.2: PCl₃; DIEA; tetrazol 2.3: 85 percent / pH 7.7

Reference： [1]Schwoegler, Anja; Carell, Thomas [Organic Letters, 2000, vol. 2, # 10, p. 1415 - 1418]

34
[ 83-88-5 ]
[ 127877-17-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 63.4 percent / pyridine / 4 h / 110 °C 2: 100 percent / PPTS / dimethylformamide / 4 h / Ambient temperature 3: 43.9 percent / trifluoroacetic acid / CH₂Cl₂ / 0.5 h / Ambient temperature
	Multi-step reaction with 3 steps 1: 64 percent / pyridine / 1 h / 110 °C 2: 96 percent / PPTS / dimethylformamide / 3 h / Ambient temperature 3: 60 percent / TFA / CH₂Cl₂ / 0.5 h / Ambient temperature

Reference： [1]Takahashi, Hiroyuki; Isobe, Minoru; Goto, Toshio [Tetrahedron, 1991, vol. 47, # 32, p. 6215 - 6222]
[2]Isobe, Minoru; Takahashi, Hiroyuki; Goto, Toshio [Tetrahedron Letters, 1990, vol. 31, # 5, p. 717 - 718]

35
[ 83-88-5 ]
[ 127877-16-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 63.4 percent / pyridine / 4 h / 110 °C 2: 100 percent / PPTS / dimethylformamide / 4 h / Ambient temperature
	Multi-step reaction with 2 steps 1: 64 percent / pyridine / 1 h / 110 °C 2: 96 percent / PPTS / dimethylformamide / 3 h / Ambient temperature

Reference： [1]Takahashi, Hiroyuki; Isobe, Minoru; Goto, Toshio [Tetrahedron, 1991, vol. 47, # 32, p. 6215 - 6222]
[2]Isobe, Minoru; Takahashi, Hiroyuki; Goto, Toshio [Tetrahedron Letters, 1990, vol. 31, # 5, p. 717 - 718]

36
[ 83-88-5 ]
[ 114590-52-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: 63.4 percent / pyridine / 4 h / 110 °C 2: 100 percent / PPTS / dimethylformamide / 4 h / Ambient temperature 3: 43.9 percent / trifluoroacetic acid / CH₂Cl₂ / 0.5 h / Ambient temperature 4: 35.5 mg / BF₃-Et₂O / CH₂Cl₂ / 0 °C 5: 85.5 percent / n-Bu₄NF / CH₂Cl₂; dimethylformamide / 0.5 h / Ambient temperature 6: 52 mg / trifluoroacetic acid / CH₂Cl₂ / 2 h / Ambient temperature
	Multi-step reaction with 5 steps 1: 64 percent / pyridine / 1 h / 110 °C 2: 96 percent / PPTS / dimethylformamide / 3 h / Ambient temperature 3: 60 percent / TFA / CH₂Cl₂ / 0.5 h / Ambient temperature 4: BF₃*OEt₂ / CH₂Cl₂ / 2 h / Ambient temperature 5: TFA / CH₂Cl₂ / 3 h / Ambient temperature

Reference： [1]Takahashi, Hiroyuki; Isobe, Minoru; Goto, Toshio [Tetrahedron, 1991, vol. 47, # 32, p. 6215 - 6222]
[2]Isobe, Minoru; Takahashi, Hiroyuki; Goto, Toshio [Tetrahedron Letters, 1990, vol. 31, # 5, p. 717 - 718]

37
[ 83-88-5 ]
[ 109510-25-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: aerobe bacteria 2: palladium/charcoal; ethanol / Hydrogenation

Reference： [1]Smyrniotis et al. [Journal of the American Chemical Society, 1958, vol. 80, p. 2541,2543]

38
[ 83-88-5 ]
[ 109962-83-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: aerobe bacteria 2: diethyl ether

Reference： [1]Smyrniotis et al. [Journal of the American Chemical Society, 1958, vol. 80, p. 2541,2543]

39
[ 83-88-5 ]
[ 50986-96-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: aerobe bacteria 2: platinum; acetic acid

Reference： [1]Smyrniotis et al. [Journal of the American Chemical Society, 1958, vol. 80, p. 2541,2543]

40
[ 2094-72-6 ]
[ 83-88-5 ]
[ 1198795-97-9 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine for 2h; Heating / reflux;	4 Example 4; Preparation of adamantane acid ester of riboflavin.; In a container with adamantane acyl chloride, 1g of riboflavin and 20ml of pyridine were added, and then heated while stirring constantly until reflux slowly. The reflux was kept on continuously for another 2 hours and the reaction mixture was cooled overnight after all the riboflavin was gradually dissolved. The unreacted riboflavin was filtered and pyridine was removed by distilling under reduced pressure. The residue was dissolved in methanol. Then active carbon was added to decolor and filtrated. Crystals were obtained by pouring the filtration into water. After cooling and filtrating, the crude product was obtained. The crude product was then dissolved in methanol, crystallized coldly, filtrated and dried. The target compound was obtained by using the methods described in Example 1. The melting point of this compound is 118-120°C. The result of element analysis was N5.82 (calculated values,%) and N5.45 (measured values, %).

Reference： [1]Current Patent Assignee: SHENZHEN SALUBRIS PHARMACEUTICALS CO., LTD.; ACADEMY OF MILITARY MEDICAL SCIENCES - EP1553099, 2005, A1 Location in patent: Page/Page column 5

41
[ 112-16-3 ]
[ 83-88-5 ]
5'-lauric acid monoester of riboflavin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38.9%	With pyridine; triethylamine In 1,4-dioxane; water at 5 - 10℃; for 0.583333h;	1 Example I; Preparation of 5'-lauric acid monoester of riboflavin.; 1200 ml pyridine, 1200 ml distilled water and 120 ml triethylamine were mixed and ice-bathed to maintain the inner temperature between 5-10°C. 25.0 g of riboflavin was then added and dissolved by electromagnetic stirring. The mixed solution was composed of lauroyl chloride and dioxane was added drop wisely in 25 min at 10°C. Then the mixture was stirred for 20 min. After lowering the inner temperature to 5°C by cryohydrate bath, the solution of 400 ml concentrated sulfuric acid and 600 ml distilled water was added drop wisely in 45 min, with temperature controlled between 10-15°C. The solution was then placed in ice water for 2.5 h, with the pH value of 6. After filtrated, washed by 2×100 ml water and pressed to dry, the dry product was then washed by 4×200ml diethyl ether and air-dried to gain 22.5 g primary product with the wash liquid discarded. The primary product was dissolved in concentrated hydrochloric acid and filtrated, followed by adding 50% ethanol. After sitting overnight, the solution was filtrated and the precipitated riboflavin was aired to be 20.5 g. The recovery yield was 82%. The mixture stock solution was evaporated under reduced pressure. Red powder was obtained and washed successively with ethyl ester, 5x100 ml dichloromethane and 5×50 ml methanol. The product was then aired, smashed and dried in a dryer containing P2O5 for 48 hours. The weight of the obtained red crude product of monoester of riboflavin was 2.60 g, with a yield of 38.9% (based on the recovered starting materials). 550g coarse silica gel of 100-200 meshes was loaded into a column. 10.45 g of the crude riboflavin monoester was immersed in 500ml mixing solvent of CH2Cl2:CH3OH(95:5) and the supernatant was loaded onto the silica gel column. Then the column was immersed and loaded using the same mixing solvent until all crude samples were dissolved: The mobile phase of the solvent was used to elute. Twenty parts of eluted samples were collected and numbered (1)-(20). Each parts of eluted sample was 500ml. TLC analysis indicated that samples (1) and (2) contained monoesters and a small quantity of polyester, samples (3)-(16) were mainly composed of monoesters and samples (17)-(20) were lack of monoesters and had no other components. 4.08g of red solid was obtained after combining samples (3)-(20) and recovering the mixing solvent under 25-30°C. The red product was immersed respectively in 400ml Et2O and 400ml Et2O:CH2Cl2(4:1) for 8 hours. After filtrated and dried in a dryer containing P2O5, 3.00g of red product was obtained. Treated with the similar method, 0.24g of pure monoester product was obtained from the samples (1) and (2). The total final product was 3.24g and the yield of separation was 31.0%. The final riboflavin monoester product showed homogeneity in HPLC with C18 column and 97% methanol: 3% water as the mobile phase. The melting point of this compound is 249-250°C. The result of element analysis was C62.34,H7.58,N10.03 (calculated values,%) and C62.08,H7.74,N9.68 (measured values, %). The specific rotatory power is [α]25D=-8.4(C0.5,CH2Cl2:CH3OH 1:1). UV(max,CH3OH)225.8 nm,269.2nm,361.4nm,444.2nm.IR(cm-1),3420(br,2 OH), 3178(OH),1728(br,2 C=O),1661(C=O). The molecular weight of the target compound is consistent to the peak in MS. 1H-NMR(C5D5N),δ(ppm),8.19(s,1 H,Ar),7.89(s,1 H,Ar),5.55(m,1 H,HOCH),5.35(m,2H,OCH2),5.10(m,1 H,HOCH),4.90(m,2 H,NCH2),4.60(br,1 H,HOCH), 2.31(t,2 H,COCH2),1.4(s,3 H,ArCH3),2.15(s,3 H,ArCH3),1.59(m,2 H,CH3CH2),0.83(t,3 H,CH3CH2), 13C-NMR(C5D5N), δ(ppm),173.9(C=O),160.91(C),159.9(C),146.6(C), 137.6(C), 136.2(C), 135.0(C), 133.0(C), 131.7(CH), 118.1(CH), 71.5(CH), 71.3(CH), 70.9(CH);67.6(CH2), 49.0(CH2), 48.99(CH2), 32.1(CH2), 29.8(CH2), 29.7 (CH2), 29.5(CH2), 29.4(CH2), 25.3(CH2), 22.9(CH2), 20.8(CH2), 19.8(CH3), 14.4(CH3).

Reference： [1]Current Patent Assignee: SHENZHEN SALUBRIS PHARMACEUTICALS CO., LTD.; ACADEMY OF MILITARY MEDICAL SCIENCES - EP1553099, 2005, A1 Location in patent: Page/Page column 4

42
[ 97-72-3 ]
[ 83-88-5 ]
isobutyrate of riboflavin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With perchloric acid In water at 20℃; for 7h;	2 Example 2; Preparation of isobutyrate of riboflavin; Riboflavin was suspended in isobutyric anhydride while perchloric acid was added drop wisely under room temperature. Then the mixture was stirred for 7h until the reaction mixture turned to be mauve. Ethyl ether was added to precipitate and crystals were obtained by filtering. The crystals were dissolved in 30ml n-butanol and n-butanol was then washed out by excess water. Next, the crystals were again precipitated by adding ethyl ether and filtrating. The crude product was obtained by vacuum-drying and filtrating. The target compound was obtained by using the separation methods described in Example 1. The melting point of this compound is 162-166°C. The result of element analysis was N8.41 (calculated values,%) and N8.32 (measured values, %).

Reference： [1]Current Patent Assignee: SHENZHEN SALUBRIS PHARMACEUTICALS CO., LTD.; ACADEMY OF MILITARY MEDICAL SCIENCES - EP1553099, 2005, A1 Location in patent: Page/Page column 4-5

43
[ 1989-53-3 ]
[ 83-88-5 ]
2,6-dimethoxybenzoate of riboflavin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	at 80 - 90℃; for 1h;	3 Example 3; Preparation of 2,6-dimethoxybenzoate of riboflavin; 5g of riboflavin and 11g of 2,6-dimethoxybenzoylchloride were weighed in an Erlenmeyer flask, then reacted at 80-90°C for 1h with stirring. The mixture was cooled and 10ml methanol was added slowly. The mixture was added into 2L water and yellow crystals were precipitated. The crystals were filtrated, washed by water and dried to obtain crude product of about 11.4g. The crude product was dissolved in 80ml pyridine and filtrated. The filtration was put into 2L water to form crystals. The obtained crystals were dried and weighed 7.8g. The target compound was obtained by using the methods described in Example 1. The melting point of this compound is 162-166°C. The result of element analysis was C61.60,H5.09,N5.42 (calculated values,%) and C61.41,H5.24,N5.29 (measured values, %).

Reference： [1]Current Patent Assignee: SHENZHEN SALUBRIS PHARMACEUTICALS CO., LTD.; ACADEMY OF MILITARY MEDICAL SCIENCES - EP1553099, 2005, A1 Location in patent: Page/Page column 5

44
[ 67-52-7 ]
1-N-D-ribitylamino-3,4-dimethyl-6-phenylazobenzene [ No CAS ]
[ 83-88-5 ]

Yield	Reaction Conditions	Operation in experiment
	With Trimethylacetic acid In 2-methyl-propan-1-ol	EXAMPLES 1 AND 2 AND COMARATIVE EXAMPLES 1 TO 7 EXAMPLES 1 AND 2 AND COMARATIVE EXAMPLES 1 TO 7 A mixture of 40 g (0.111 mole) of 4,5-dimethyl-N-(D)-ribityl-2-phenylazoaniline, 14.2 g (0.111 mole) of barbituric acid and 30 g (0.295 mole) of pivalic acid in 190 ml of isobutanol was stirred under reflux at 105°-110° C. for 10 hours, after which it was cooled to room temperature. The riboflavin precipitated was filtered off, washed with methanol, cold water and hot water, and dried under reduced pressure at 60° C.
	In 2-methyl-propan-1-ol	4 EXAMPLE 4 EXAMPLE 4 36 g (0.1 mole) of 4,5-dimethyl-N-(D)-ribityl-2-phenylazoaniline and 14.2 g (0.111 mole) of barbituric acid in a mixture of 170 ml of isobutanol and 73.5 ml (0.393 mole) of Versatic 10-acid were stirred under reflux for 10 hours, after which the reaction mixture was allowed to cool to room temperature. The precipitate was filtered off, washed with methanol, cold water and then hot water, and dried under reduced pressure at +60° C. 34.9 g (92.8% of theory) of 95.6% pure riboflavin were obtained, the purity being determined by means of a UV measurement.
	In 2-methyl-propan-1-ol	5 EXAMPLE 5 EXAMPLE 5 40 g (0.111 mole) of 4,5-dimethyl-N-(D)-ribityl-2-phenylazoaniline and 15.8 g (0.123 mole) of barbituric acid in a mixture of 190 ml of isobutanol with 80 ml (0.428 mole) of Versatic 10-acid were stirred under reflux for 10 hours, after which the reaction mixture was allowed to cool to room temperature. The precipitate was washed with methanol, cold water and then hot water, and dried under reduced pressure at +60° C. 38.8 g (93% of theory) of 95.6% pure riboflavin were obtained.

Reference： [1]Current Patent Assignee: BASF SE - US4567261, 1986, A
[2]Current Patent Assignee: BASF SE - US4567261, 1986, A
[3]Current Patent Assignee: BASF SE - US4567261, 1986, A

45
[ 83-88-5 ]
O^5'-phosphono-riboflavin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trichlorophosphate In water	2 EXAMPLE 2 EXAMPLE 2 400 ml of γ-butyrolactone were placed in a 1 l four-neck flask and, while stirring, 120 g of riboflavin (drugs quality) and 120 g of POCl3 in 80 ml of γ-butyrolactone were successively introduced. The mixture was left to react at from 30° to 35° C. for 1 h and then heated to 40° C., and it was then pumped within 10 min into 960 ml of deionized water at 80° C. The maximum temperature during this was 87° C. The reaction mixture was stirred at 87° C. for 6 min and then allowed to cool, when riboflavin 5'-phosphate precipitated at about 57° C. To form the sodium salt, 25% strength aqueous NaOH solution was added slowly at below 40° C. until the pH was 5.5.

Reference： [1]Current Patent Assignee: BASF SE - US5095115, 1992, A

46
[ 83-88-5 ]
monosodium salt of riboflavin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trichlorophosphate In water	3 EXAMPLE 3 EXAMPLE 3 120 g of riboflavin (drugs quality) and 120 g of POCl3 were reacted as in Example 2 in 480 ml of γ-butyrolactone at from 30° to 35° C. for 1 h, and then the reaction mixture was heated in a heating bath at 120° C. to about 60° C. and, at this temperature, pumped within 10 in into 960 ml of deionized water at 80° C., during which the maximum temperature was 89° C. The reaction mixture was stirred at 89° C. for 6 min and then worked up as in Example 2 to yield 134.5 g of the monosodium salt of riboflavin, corresponding to 88.2% of theory. HPLC analysis showed that this product contained
	With trichlorophosphate In water	4 EXAMPLE 4 EXAMPLE 4 132 g of crude riboflavin (riboflavin content 93.5%) and 120 g of POCl3 were reacted as in Example 2 in 480 ml of γ-butyrolactone at from 30° to 35° C. for 1 h, and then the reaction mixture was heated within 1 min to 67° C. in a heating bath at 120° C. and was pumped into 960 ml of deionized water at 80° C., during which the maximum temperature was 89° C. The reaction mixture was stirred at 89° C. for 6 min and then worked up as in Example 2 to yield 126.6 g of the monosodium salt of riboflavin. HPLC analysis showed that this product contains
	With trichlorophosphate In water	5 EXAMPLE 5 EXAMPLE 5 132 g of crude riboflavin (riboflavin content 93.5%) were phosphorylated with 120 g of POCl3 in 480 ml of γ-butyrolactone at from 35° to 37° C. as in Example 2. The reaction mixture was then heated to 40° to 45° C. and further heated to 89° C. while slowly adding deionized water. The mixture was kept at 89° C. for 3 min and at from 68° to 75° C. for 25 min in a water bath. Water was added dropwise at 75° C. to make the total volume added 960 ml. The reaction mixture was worked up as in Example 2 to yield 132.4 g of the monosodium salt of riboflavin. HPLC analysis showed that this product contains

Reference： [1]Current Patent Assignee: BASF SE - US5095115, 1992, A
[2]Current Patent Assignee: BASF SE - US5095115, 1992, A
[3]Current Patent Assignee: BASF SE - US5095115, 1992, A

47
[ 67-52-7 ]
[ 110-19-0 ]
1-N-D-ribitylamino-3,4-dimethyl-6-phenylazobenzene [ No CAS ]
[ 83-88-5 ]

Yield	Reaction Conditions	Operation in experiment
	In 2-methyl-propan-1-ol; acetic acid	C.3 COMPARATIVE EXAMPLE 3 COMPARATIVE EXAMPLE 3 20.0 g of 87% pure 4,5-dimethyl-N-(D)-ribityl-2-phenylazoaniline (corresponding to 0.0485 mole) were refluxed with 7.26 g (0.0567 mole) of barbituric acid in a mixture of 80 ml of isobutanol, 14 ml of isobutyl acetate and 10 ml of glacial acetic acid for 10 h. Working up as described in Example 3 gave 15.4 g (84.5% of theory) of riboflavin having a purity of 93.8% (Pharm. Europ.).

Reference： [1]Current Patent Assignee: BASF SE - US4656275, 1987, A

48
[ 67-52-7 ]
Versatic-10-acid [ No CAS ]
4,5-dimethyl-N-(D)-ribityl-2-(o-methoxyphenylazo)-aniline [ No CAS ]
[ 83-88-5 ]

Yield	Reaction Conditions	Operation in experiment
	In 1,4-dioxane; methanol; water	5 EXAMPLE 5 EXAMPLE 5 10.8 g of 97% pure 4,5-dimethyl-N-(D)-ribityl-2-(o-methoxyphenylazo)-aniline (corresponding to 0.0269 mole) and 4.4 g of barbituric acid in a mixture of 35 ml of dioxane and 25 ml of Versatic-10-acid were refluxed for 9 h while stirring. The reaction mixture was cooled to RT, and the crystals formed were filtered off under suction, washed with twice 25 ml of methanol, with 3 times 60 ml of water at 80° C. and again with twice 25 ml of methanol, and dried overnight at +70° C. under reduced pressure. The yield was 9.46 g (93.5% of theory) of riboflavin having a purity of 94.7% (Pharm. Europ.).
	In methanol; 2-methyl-propan-1-ol; water	7 EXAMPLE 7 EXAMPLE 7 10.8 g of 97% pure 4,5-dimethyl-N-(D)-ribityl-2-(o-methoxyphenylazo)-aniline (corresponding to 0.0269 mole) and 4.4 g of barbituric acid in a mixture of 50 ml of isobutanol and 25 ml of Versatic-10-acid were refluxed for 9 h while stirring, after which the reaction mixture was cooled to RT, and the crystals formed were filtered off under suction, washed with twice 20 ml of isobutanol, with twice 25 ml of methanol and with 3 times 60 ml of water at 80° C. and dried overnight at +70° C. under reduced pressure. The yield was 9.73 g (96.2% of theory) of riboflavin having a purity of 94.6% (Pharm. Europ.).

Reference： [1]Current Patent Assignee: BASF SE - US4656275, 1987, A
[2]Current Patent Assignee: BASF SE - US4656275, 1987, A

49
[ 3051-94-3 ]
4,5-dimethyl-N-(D)-ribityl-2-(o-methoxyphenylazo)-aniline [ No CAS ]
[ 83-88-5 ]

Yield	Reaction Conditions	Operation in experiment
	In hydrogenchloride; ethanol; water	4.b Preparation of 4,5-dimethyl-N-(D)-ribityl-2-(o-methoxyphenylazo)-aniline (b) 100 g (0.39 millimole) of 3,4-dimethyl-N-(D)-ribitylaniline were dissolved in 400 ml of 1N hydrochloric acid, and the solution was brought to pH 3 by means of 30% strength aqueous sodium formate solution and then added dropwise, in the course of 1 h, to the diazonium salt solution prepared as described under 2a. The mixture was stirred for a further 3 h at RT and for 30 minutes at 5° C., the crystals formed were filtered off under suction, and the filter cake was washed with 4 times 500 ml of water at 80° C. A sample of the water-moist filter cake was dried and the NMR spectrum showed that the isomeric azo compounds were present in a ratio of 98:2. The major part was dissolved in 350 ml of ethanol, 400 ml of water were added to the hot solution, and the mixture was left to stand overnight. The crystals formed were filtered off under suction, washed with 250 ml of a 1:1 mixture of ethanol and water, and dried at +70° C. under reduced pressure. The yield was 109.5 g (72.2% of theory) of riboflavin of melting point 142°-144° C. Only one isomer was detectable in the NMR spectrum.

Reference： [1]Current Patent Assignee: BASF SE - US4656275, 1987, A

50
[ 15529-90-5 ]
[ 83-88-5 ]
[ 97860-53-2 ]

Reference： [1]Inorganic Chemistry,1985,vol. 24,p. 3425 - 3434

51
[ 103-82-2 ]
[ 83-88-5 ]
[ 1043592-39-7 ]

Yield	Reaction Conditions	Operation in experiment
82%	With pyridine; trichlorophosphate at 73℃; for 4.5h; Inert atmosphere;

Reference： [1]Location in patent: experimental part Cerda, Jose F.; Koder, Ronald L.; Lichtenstein, Bruce R.; Moser, Christopher M.; Miller, Anne-Frances; Dutton, P. Leslie [Organic and Biomolecular Chemistry, 2008, vol. 6, # 12, p. 2204 - 2212]

52
[ 83-88-5 ]
[ 1262315-27-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sulfuric acid; periodic acid / water / 0.5 h / 0 °C / Darkness 1.2: 18 - 25 °C / pH 3.8 - 3.9 2.1: acetic acid / methanol / 2 h / 18 - 25 °C 2.2: 24 h / 18 - 25 °C