Name: 56-17-7|2,2'-Disulfanediyldiethanamine dihydrochloride|98%
Brand: Ambeed
SKU: A210400
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1
[ 56-17-7 ]
[ 2458-50-6 ]

Yield	Reaction Conditions	Operation in experiment
	(i) Cl₂, AcOH, CH₂Cl₂, (ii) H₂O; Multistep reaction;
	(i) SO₂Cl₂, AcOH, CH₂Cl₂, (ii) H₂O; Multistep reaction;

Reference： [1]FIELD; FERRETTI; CRENSHAW; OWEN [Journal of medicinal chemistry, 1964, vol. 7, p. 39 - 44]
[2]Buckman,J.D. et al. [Journal of Organic Chemistry, 1967, vol. 32, p. 1626 - 1627]

2
[ 51513-80-5 ]
[ 56-17-7 ]
[ 142947-56-6 ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 272 - 279

3
[ 24424-99-5 ]
[ 56-17-7 ]
[ 67385-10-8 ]

Yield	Reaction Conditions	Operation in experiment
96%	With triethylamine; In dichloromethane; at 20℃; for 15h;	TEA (37 ml, 264 mmol) and a solution of (Boc)2O (48 g, 220 mmol) in DCM (100 mL) were added to a suspension of cystamine dihydrochloride (20 g, 88.8 mmol) in of DCM (300 mL) and stirred at RT for 15 h. The mixture was concentrated and the residue, after usual aqueous work-up and chromatographic purification, gave 30 g (96%) of tert-butyl 2-({2-[(tet-butoxycarbonyl)amino]ethyl}dithio)ethylcarbamate as a white solid. 1H-NMR (300 MHz, CDCl3): delta 1.43 (s, 18H), 2.78 (t, 4H, J=6.3Hz), 3.44 (q, 4H, J=6.0 Hz), 5.00 (bs, 1H). MS (m/z): 353.18 [M+H]+, 375.24 [M+Na]+.
54%	With sodium hydroxide; In 1,4-dioxane; at 20℃; for 1.58333h;Sealed tube; Inert atmosphere;	Di-tert-butyl-dicarbonate (1.75g, 8mmol, 2eqv) and cystamine dihydrochloride (1g, 4mmol, 1eqv) were charged to a 50mL flask with a stir bar and then the flask was sealed with a rubber septa and placed under a blanket of nitrogen.Dioxane (3.6mL) was charged to the flask and the reactants were allowed to dissolve before adding NaOH (4.4mL of 2M) dropwise over 5min. The reaction was allowed to stir for 90min at room temperature. Dioxane and water were removed in vacuo and the residue was taken up in ethyl acetate (200mL). The organic layer was washed with 1% HCl (3×50mL) followed by brine, and then dried with MgSO4. The solvent was removed to yield white solid. (Yield: 54%) 1H NMR (300MHz, CDCl3) delta 1.44 (s, 18H, Boc), 2.78 (t, 4H, J=6.8Hz, CH2S), 3.43 (m, 2H, CH2N), 5.03 (s, 2H, NH) ppm. ESI-MS: m/z cacld. for C14H28N2O4S2, [M]+: 352.51, found 353.20.
	With sodium hydroxide; In tetrahydrofuran; water; at 0℃;Inert atmosphere;	(0155) (0156) To a cooled (0 C) solution of NaOH (71 g, 1.78 mol) in H2O (630 mL) were added cysteamine dihydrochloride L6 (100 g, 440.0 mmol) and THF (400 mL), and the reaction mixture was stirred until homogeneous. Boc-anhydride (193 g, 880.0 mmol) in THF (230 mL) was then added dropwise via an addition funnel and stirred at RT. The reaction progress was monitored by LC/MS. THF was evaporated and filtered under vacuum to yield crude L7 as a white solid, which was then triturated in hexane, filtered, washed (5x hexane) and dried under vacuum to afford L7 (143 g, 92%) as a white solid. Compound L7 was used in the next step without further purification.

Reference： [1]European Journal of Medicinal Chemistry,1989,vol. 24,p. 503 - 510
[2]Recueil des Travaux Chimiques des Pays-Bas,1992,vol. 111,p. 163 - 169
[3]Patent: US2006/46967,2006,A1 .Location in patent: Page/Page column 131
[4]Journal of the American Chemical Society,2012,vol. 134,p. 769 - 772
[5]Bioorganic Chemistry,2019,vol. 84,p. 394 - 398
[6]Bioconjugate Chemistry,2011,vol. 22,p. 958 - 967
[7]Patent: EP2257637,2015,B1 .Location in patent: Paragraph 0155; 0156

4
[ 156-57-0 ]
[ 56-17-7 ]

Yield	Reaction Conditions	Operation in experiment
98%	With dimethyl sulfoxide at 90℃; for 6h;
96.9%	With 2,2′-benzothiazole disulfide In methanol; chloroform for 2h; Ambient temperature;
93.6%	With glacial acetic acid In dimethyl sulfoxide at 20℃; for 2h;	1-4 Example 3 In the 2000ml four-necked flask, add 500g cysteamine hydrochloride, add Example 2 to filter the mother liquor at room temperature,The temperature was raised to 30°C and kept at 30-35°C, and 45g of dimethyl sulfoxide and 0.75g of glacial acetic acid were slowly added to the system. When the reaction time is up, it is cooled to room temperature and grown for 2h, filtered, the filter cake is washed with 180g methanol (the mother liquor is reserved for mechanical application), dried in vacuum at 55-65°C for 6h, and the material is collected to obtain 468g of cystamine dihydrochloride with a yield of 93.6%, The liquid phase purity is 99.05%, and the content is 100%.

	In methanol oxidation;
	With dimethyl sulfoxide In lithium hydroxide monohydrate
	In dimethyl sulfoxide at 90℃; for 8h;

Reference： [1]Ternay Jr.; Brzezinska; Sorokin; Cook; Lyaschenko [Journal of Applied Toxicology, 2000, vol. 20 Suppl 1, p. S31-34]
[2]Brzezinska, Ewa; Ternay, Andrew L. [Journal of Organic Chemistry, 1994, vol. 59, # 26, p. 8239 - 8244]
[3]Current Patent Assignee: YUN PENG PHARMACEUTICAL GROUP - CN113717084, 2021, A Location in patent: Paragraph 0024-0031
[4]Glotova, T. E.; Nakhmanovich, A. S.; Skvortsova, G. G.; Komarova, T. N.; Kalikhman, I. D.; Voronkov, M. G. [Journal of Organic Chemistry USSR (English Translation), 1981, vol. 17, # 4, p. 653 - 658][Zhurnal Organicheskoi Khimii, 1981, vol. 17, # 4, p. 749 - 755]
[5]Ortiz-Acevedo, Alfonso; Dieckmann, Gregg R. [Tetrahedron Letters, 2004, vol. 45, # 36, p. 6795 - 6798]
[6]Li, Yinghua; Li, Xiaoling; Zheng, Wenjie; Fan, Cundong; Zhang, Yibo; Chen, Tianfeng [Journal of Materials Chemistry B, 2013, vol. 1, # 46, p. 6365 - 6372]

5
[ 56-17-7 ]
[ 98-59-9 ]
[ 23516-74-7 ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium hydroxide; In dichloromethane; water; at 20℃; for 12h;	A 1000 mL three-neck round bottom flask was equipped with a mechanical stirrer and addition funnel. To the flask was added sodium hydroxide (9.96 g, 249 mmol) and water (248 mL). Once the sodium hydroxide dissolved, cystamine dihydrochloride (13.1 g, 58.4 mmol) was added to the stirring solution. To the addition funnel was added p-toluenesulfonylchloride (22.2 g, 116.7 mmol) in 300 mL of methylene chloride. The TsCl solution was added to the flask dropwise at room temperature with vigorous stirring. After the addition was complete, the reaction mixture was allowed to stir for an additional 12 h. The organic layer was separated from the aqueous layer, and the organic layer was washed with 3 M HCl (2 x 45 mL), water (2 x 45 mL), saturated NaCl (1 x 45 mL) and dried over Na2SO4, filtered and concentrated. The crude product was recrystallized from methanol to give N,N?-bis-(paratoluenesulfonyl)cystamine (24.3 g, 52.7 mmol, 90.0%) as a white solid. Consistency of spectral data is shown with the lit. data.1 Melting point: 89-90 C (Lit. 77-78 ºC)1; Rf: 0.10 (30% ethyl acetate in hexanes); IR (film): numax 3281, 2925, 2865, 1595, 1418, 1324, 1157, 1092, and 814, cm-1; 1H NMR (CDCl3, 300 MHz): delta 7.77 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 4.96 (t, J = 6.4 Hz, 1H), 3.26 (q, J = 6.4 Hz, 2H), 2.73 (t, J = 6.4 Hz, 2H), 2.45 (s, 3H); 13C NMR (CDCl3, 75 MHz): delta 21.66, 37.96, 41.78, 127.16, 129.95, 136.82, 143.80.

Reference： [1]Organometallics,2020,vol. 39,p. 1497 - 1510
[2]Tetrahedron,1989,vol. 45,p. 6455 - 6466
[3]Tetrahedron Letters,2012,vol. 53,p. 6548 - 6551,4

6
[ 56-17-7 ]
[ 3674-06-4 ]
[ 87834-34-2 ]

Reference： [1]European Journal of Medicinal Chemistry,1992,vol. 27,p. 809 - 817
[2]Chemistry - A European Journal,2001,vol. 7,p. 4280 - 4295

7
[ 56-17-7 ]
[ 66176-17-8 ]
Bis<2-(2-amino-3-methyl-benzoylamino)ethyl>disulfan [ No CAS ]

Reference： [1]Archiv der Pharmazie,1995,vol. 328,p. 277 - 281

8
[ 56-17-7 ]
[ 292638-85-8 ]
3-[(2-{2-[bis-(2-methoxycarbonyl-ethyl)-amino]-ethyldisulfanyl}-ethyl)-(2-methoxycarbonyl-ethyl)-amino]-propionic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82.97%	With triethylamine; In methanol;Inert atmosphere;	Methyl acrylate (0.213 mol)was mixedwith 10 mL ofMeOH. Cystaminedihydrochloride (8.881 mmol) and TEA (0.018 mol) were dissolvedin 20 mL of MeOH and cystamine solution was added dropwiseto methyl acrylate solution over 30 min. After two days of reaction atroom temperature under a nitrogen atmosphere, MeOH and TEA wereremoved by evaporation. A viscous light yellow liquid interspersedwith white precipitate was dissolved in diethyl ether and extracted with water. Diethyl ether layerswere dried overmagnesium sulfate, filtered,and evaporated (yield: 82.97%, theoretical mass: 496.6 Da).
82.97%	With triethylamine; In methanol; at 20℃; for 48.5h;Inert atmosphere;	Methyl aery late (0.213 mol) was mixed with 10 mL of MeOH. Cystamine dihydrochloride (8.881 mmol) and TEA (0.018 mol) were dissolved in 20 mL of MeOH and cystamine solution was added dropwise to methyl acrylate solution over 30 min. After two days of reaction at room temperature under a nitrogen atmosphere, MeOH and TEA were removed by evaporation by heating to 40 C and stirring for 30 minutes. A viscous light yellow liquid interspersed with white precipitate was dissolved in diethyl ether and extracted with water. Diethyl ether layers were dried over magnesium sulfate, filtered, and evaporated (yield: 82.97%, theoretical mass: 496.6 Da) to obtain a 1st core molecule.

Reference： [1]Tetrahedron,2003,vol. 59,p. 3799 - 3813
[2]Journal of Controlled Release,2015,vol. 220,p. 447 - 455
[3]Patent: WO2017/49209,2017,A1 .Location in patent: Page/Page column 16
[4]Chemical Communications,2013,vol. 49,p. 1229 - 1231

9
[ 24424-99-5 ]
[ 56-17-7 ]
[ 485800-26-8 ]

Yield	Reaction Conditions	Operation in experiment
86%		N-(tert-butoxycarbonyl)-cystamine Cystamine dihydrochloride (4 g, 17.78 mmol) was dissolved in methanol (200 mL) and cooled to 0 C. Triethylamine (7.45 mL, 53.33 mmol) was added and stirred for 30 min. Boc-anhydride (4.05 mL, 17.78 mmol) was then added drop wise over 10 min and allowed to stir for 1 h. The solution was concentrated in vacuo, then washed with diethyl ether (330 mL). 1 M NaOH solution was added to the product and extracted 2 with CH2Cl2. Both organic layers were combined and washed 2* with H2O. The organic layer was then dried over CaCl2 and concentrated in vacuo to yield a white solid (3.9 g, 86% yield). ESI [M+H]+1 expected 253.39 Da, observed 253.1 Da. 1H NMR (CDCl3) delta 1.45 (s, 9H), delta 2.77 (q, 4H, J=6.19 Hz), delta 3.02 (t, 4H, J=6.19 Hz), delta 3.45 (m, 2H), delta 5.02 (s, 1H).
62.25%		(1) Dissolve cystamine dihydrochloride (2 g, 8.88 mmol) in 40 mL of methanol.Add triethylamine (2.8 g, 28.42 mmol) in an ice bath and stir for thirty minutes.The di-tert-butyl dicarbonate (0.68 g, 3.11 mmol) dissolved in 20 mL of methanol was slowly added dropwise under vigorous stirring in an ice bath.React at room temperature for 5 h,The reaction was complete by TLC.Dry the solvent under reduced pressure,Dissolved in 20 mL of dichloromethane,Wash with water (20 mL × 2) and saturated brine (20 mL).Dry over anhydrous sodium sulfate,Dry the solvent under reduced pressure,Purification by chromatography (methylene chloride: ethyl acetate = 8:1)The yield was 62.25%.
46%	With triethylamine; In methanol; at 20℃; for 1h;	A 250 ml round bottom flask was charged with bis-(2-aminoethyl)disulfide dihydrochloride (1.49 g, 6.62 mmol) and MeOH (75 ml). Triethylamine (2.89 ml, 20.8 mmol, 3.15 eq.) was added and when all solids were dissolved, di-tert-butyl dicarbonate (1.45 g, 6.64 mmol, leq.) was added. The mixture was stirred at room temperature for approximately 1 hour. (0455) The mixture was quenched by the addition of aqueous 1M Nal 1 -4 'O f (50 ml) and the organic solvent was removed by evaporation. The aqueous residue was washed with diethyl ether (3x 30 ml), then rendered alkaline using aqueous IN NaOH solution (~70 ml). The aqueous mixture was extracted with diethyl ether (3x 60 ml). The combined organic extracts were dried over NaaSO t and (0456) concentrated under reduced pressure to afford 0.71 g of a colourless oil. The aqueous layers were extracted further with diehloromethane (3x 50 ml), the combined organic extracts were dried over NaaSC and concentrated with the previously isolated amount to afford 0.78 g (46%) of the product as a clear thick oil. LC7MS (SC_BASE) tn 1.83 min, purity 98%, mass found [M+H]+ 253. NMR (400 MHz, Chloroform-d) d 4.93 (s, 1H), 3.53 - 3.39 (m, 2H), 3.03 (t, ,/ = 6.2 Hz, 2H), 2.84 - 2.74 (m, 4H), 1.62 (s, 2H), 1.45 (s, 9H).

44%	With triethylamine; In methanol; at 20℃;	Cystamine dihydrochloride (1.0 g, 4.44 mmol) was dissolved in MeOH (50 mL) Triethylamine (1.85 mL, 3 eq) was added at room temperature, followed by dropwise addition of Boc2O (0.97 g, 4.44 mmol) as a solution in MeOH (5 mL). The resulting reaction mixture was stirred at room temperature for 3 h. It was then concentrated under reduced pressure and the resulting residue was taken up in 1M aqueous NaH2PO4 (20 mL). The aqueous layer was washed with a 1:1 solution of pentane/EtOAc (10 mL), basified to pH 9 with 1M aqueous NaOH, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford tert-butyl 2-(2-(2-aminoethyl)disulfanyl)ethylcarbamate (500 mg, 44%).Separately, nicotinic acid (246 mg, 2.0 mmol) was taken up in CH3CN (10 mL) along with tert-butyl 2-(2-(2-aminoethyl)disulfanyl)ethylcarbamate (503 mg, 2.0 mmol), EDCI (422 mg, 2.2 mmol). The resulting reaction mixture was stirred at room temperature for 4 h and then diluted with EtOAc. The organic layer was washed with dilute aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (CH2Cl2) afforded tert-butyl 2-(2-(2-(nicotinamido)ethyl)disulfanyl)ethylcarbamate (400 mg, 56%).tert-Butyl 2-(2-(2-(nicotinamido)ethyl)disulfanyl)ethylcarbamate (200 mg, 0.56 mmol) was taken up in 25% TFA in CH2Cl2 solution (5 mL) and allowed to stand at room temperature for 4 h. The reaction mixture was then concentrated under reduced pressure to afford the TFA salt of N-(2-(2-(2-aminoethyl)disulfanyl)ethyl)nicotinamide. This material was taken up in CH3CN (10 mL) along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (184 mg, 0.56 mmol), HATU (234 mg, 0.62 mmol) and DIEA (0.30 mL). The resulting reaction mixture was stirred at room temperature for 2 h. It was then diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (5% MeOH-CH2Cl2) afforded (N-(2-(2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)disulfanyl)ethyl)nicotinamide (300 mg, 86%). MS calculated for C32H45N3O2: 567.3; found: [M+H]+568.
44%	With triethylamine; In methanol; at 20℃; for 3h;	Example 7 Preparation of N-(2-(2-(2-(5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenamidoethyl)disulfanyl)ethyl)-5-methyl-4-oxo-5-phenyl-4,5-dihydrofuran-2-carboxamide (I-4) Cystamine dihydrochloride (1.0 g, 4.44 mmol) was dissolved in MeOH (50 mL). Triethylamine (1.85 mL, 3 eq) was added at room temperature, followed by dropwise addition of Boc2O (0.97 g, 4.44 mmol) as a solution in MeOH (5 mL). The resulting reaction mixture was stirred at room temperature for 3 h. It was then concentrated under reduced pressure and the resulting residue was taken up in 1M aqueous NaH2PO4 (20 mL). The aqueous layer was washed with a 1:1 solution of pentane/EtOAc (10 mL), basified to pH 9 with 1M aqueous NaOH, and extracted with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford tert-butyl 2-(2-(2-aminoethyl)disulfanyl)ethylcarbamate (500 mg, 44%).
44%	With triethylamine; In methanol; at 20℃; for 3h;	Example 7 Preparation of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(2-(2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanamido)ethyl)disulfanyl)ethyl)docosa-4,7,10,13,16,19-hexaenamide (Ia-3) Cystamine dihydrochloride (1.0 g, 4.44 mmol) was dissolved in MeOH (50 mL). Triethylamine (1.85 mL, 3 eq) was added at room temperature, followed by dropwise addition of Boc2O (0.97 g, 4.44 mmol) as a solution in MeOH (5 mL). The resulting reaction mixture was stirred at room temperature for 3 h. It was then concentrated under reduced pressure and the resulting residue was taken up in 1M aqueous NaH2PO4 (20 mL). The aqueous layer was washed with a 1:1 solution of pentane/EtOAc (10 mL), basified to pH 9 with 1M aqueous NaOH, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford of tert-butyl 2-(2-(2-aminoethyl)disulfanyl)ethylcarbamate (500 mg, 44%).
44%	With triethylamine; In methanol; at 20℃;	Example 6 Preparation of 5-((2-((2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)ethyl)disulfanyl)ethyl)carbamoyl)-2-methylpyrazine 1-oxide (I-3) Cystamine dihydrochloride (1.0 g, 4.44 mmol) was dissolved in MeOH (50 mL). Triethylamine (1.85 mL, 3 eq) was added at room temperature, followed by dropwise addition of Boc2O (0.97 g, 4.44 mmol) as a solution in of MeOH (5 mL). The resulting reaction mixture was stirred at room temperature for 3 h. It was then concentrated under reduced pressure and the resulting residue was taken up in 1M aqueous NaH2PO4 (20 mL). The aqueous layer was washed with a 1:1 solution of pentane/EtOAc (10 mL), basified to pH 9 with 1M aqueous NaOH, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford tert-butyl 2-(2-(2-aminoethyl)disulfanyl)ethylcarbamate (500 mg, 44%).
44%		Example 12 Preparation of (E)-methyl 4-(2-(2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)disulfanyl)ethylamino)-4-oxobut-2-enoate (Compound I-5) Cystamine dihydrochloride (1.0 g, 4.44 mmol) was dissolved in 50 mL of MeOH. Triethylamine (1.85 mL, 3 eq) was added at room temperature, followed by dropwise addition of Boc2O (0.97 g, 4.44 mmol) as a solution in 5 mL of MeOH. The resulting reaction mixture was stirred at room temperature for 3 h. It was then concentrated under reduced pressure and the resulting residue was taken up in 20 mL of 1M NaH2PO4. The aqueous layer was washed with 10 mL of a 1:1 solution of pentane/EtOAc, basified to pH 9 with 1 M NaOH, and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to afford 500 mg of tert-butyl 2-(2-(2-aminoethyl)disulfanyl)ethylcarbamate (44% yield).
44%	With triethylamine; In methanol; at 20℃; for 3h;	Example 5 Preparation of (S)-N-(2-(2-(2-(5-(1,2-dithiolan-3-yl)pentanamido)ethyl)disulfanypethyl)-2-hydroxybenzamide (I-2) Cystamine dihydrochloride (1.0 g, 4.44 mmol) was dissolved in MeOH (50 mL). Triethylamine (1.85 mL, 3 eq) was added at room temperature, followed by dropwise addition of Boc2O (0.97 g, 4.44 mmol) as a solution in 5 mL of MeOH The resulting reaction mixture was stirred at room temperature for 3 h. It was then concentrated under reduced pressure and the resulting residue was taken up in 1M NaH2PO4 (20 mL). The aqueous layer was washed with 10 mL of a 1:1 solution of pentane/EtOAc, basified to pH 9 with 1M NaOH, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford tert-butyl 2-(2-(2-aminoethyl)disulfanyl)ethylcarbamate (500 mg, 44%).
44%	With triethylamine; In methanol; at 20℃; for 3h;	Example 5; Preparation of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(2-((E)-6-(4-hydroxy-6-methoxy-7- methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4- enamido)ethyl)disulfanyl)ethyl)docosa-4,7,10,13,16,19-hexaenamide (I-4); Cystamine dihydrochloride (1.0 g, 4.44 mmol) was dissolved in MeOH (50 mL). Triethylamine (1.85 mL, 3 eq) was added at room temperature, followed by dropwise addition of Boc2O (0.97 g, 4.44 mmol) as a solution in MeOH (5 mL). The resulting reaction mixture was stirred at room temperature for 3 h. It was then concentrated under reduced pressure and the resulting residue was taken up in 1M aqueous NaH2PO4 (20 mL). The aqueous layer is washed with a 1:1 solution of pentane/EtOAc (10 mL), basified to pH 9 with 1M aqueous NaOH, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford tert-butyl 2-(2-(2-aminoethyl)disulfanyl)ethylcarbamate (500 mg, 44%).tert-Butyl 2-(2-(2-aminoethyl)disulfanyl)ethylcarbamate (1 2 mmol) was taken up in CH3CN (5 mL) along with mycophenolic acid (1.2 mmol) and EDCI (1.3 mmol). The resulting reaction mixture was stirred at room temperature for 18 h and diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (CH2Cl2) to afford (E)-tert-butyl 2-(2-(2-(6-(4-hydroxy-6-methoxy-7- methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4- enamido)ethyl)disulfanyl)ethylcarbamate.(E)-tert-butyl 2-(2-(2-(6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3- dihydroisobenzofuran-5-yl)-4-methylhex-4-enamido)ethyl)disulfanyl)ethylcarbamate (0.56 mmol) was taken up in 5 mL of 4 M HCl in dioxane and allowed to stand at room temperature for 2 h. The resulting reaction mixture is concentrated under reduced pressure to afford the HCl salt of (E)-N-(2-(2-(2-aminoethyl)disulfanyl)ethyl)-6-(4-hydroxy-6-methoxy- 7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enamide. This material is taken up in CH3CN (5 mL) along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19- hexaenoic acid (DHA, 183 mg, 0.56 mmol), HATU (234 mg, 0.62 mmol) and DIEA (290 1.7 mmol). The resulting reaction mixture was stirred at room temperature for 2 h. It was then diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (5% MeOH-CH2Cl2) afforded 200 mg of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(2-9(E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3- dihydroisobenzofuran-5-yl)-4-methylhex-4-enamido)ethyl)disulfanyl)ethyl)docosa- 4,7,10,13,16,19-hexaenamide (47% yield). MS (EI) calcd for C43H60N2O6S2: 764.39; found 765 (M+1).
44%	With triethylamine; In methanol; at 20℃; for 3h;	[0238j Cystamine dihydrochloride (1.0 g, 4.44 mmol) was dissolved in MeOH (50 mL). Triethylamine (1.85 mL, 3 eq) was added at room temperature, followed by dropwise addition of Boc2O (0.97 g, 4.44 mmol) as a solution in MeOH (5 mL). The resulting reaction mixture was stirred at room temperature for 3 h. It was then concentrated under reduced pressure and the resulting residue was taken up in 1M aqueous NaH2PO4 (20 mL). The aqueous layer was washed with a 1:1 solution of pentane/EtOAc (10 mL), basified to pH 9 with 1M aqueous NaOH, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2504, filtered and concentrated under reduced pressure to afford tert-butyl 2-(2-(2-aminoethyl)disulfanyl)ethylcarbamate (500 mg, 44 %).
44%	With triethylamine; In methanol; at 20℃; for 3h;	[0326] Cystamine dihydrochloride (1.0 g, 4.44 mmol) was dissolved in MeOH (50 mL). Triethylamine (1.85 mL, 3 eq) was added at room temperature, followed by dropwise addition of Boc20 (0.97 g, 4.44 mmol) as a solution in MeOH (5 mL). The resulting reaction mixture was stirred at room temperature for 3 h. It was then concentrated under reduced pressure and the resulting residue was taken up in 1M aqueous NaH2P04 (20 mL). The aqueous layer was washed with a 1 : 1 solution of pentane/EtOAc (10 mL), basified to pH 9 with 1M aqueous NaOH, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure to afford tert-butyl 2-(2-(2-aminoethyl)disulfanyl)ethylcarbamate (500 mg, 44 %).
44%	With triethylamine; In methanol; at 20℃; for 3h;	Example 8 Preparation of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethyl)disulfanyl)ethyl)docosa-4,7,10,13,16,19-hexaenamide (I-15) (0380) Cystamine dihydrochloride (1.0 g, 4.44 mmol) was dissolved in MeOH (50 mL). Triethylamine (1.85 mL, 3 eq) was added at room temperature, followed by dropwise addition of Boc2O (0.97 g, 4.44 mmol) as a solution in MeOH (5 mL). The resulting reaction mixture was stirred at room temperature for 3 h, concentrated under reduced pressure and the resulting residue was taken up in 1M aqueous NaH2PO4 (20 mL). The aqueous layer was washed with a 1:1 solution of pentane/EtOAc (10 mL), basified to pH 9 with 1M aqueous NaOH, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford tert-butyl 2-(2-(2-aminoethyl)disulfanyl)ethylcarbamate (500 mg, 44% yield). (0381) tert-Butyl 2-(2-(2-aminoethyl)disulfanyl)ethylcarbamate (150 mg, 0.595 mmol) was taken up in CH2C22 (10 mL) along with indomethacin (213 mg, 0.595 mmol) and EDCI (125 mg, 0.65 mmol). The resulting reaction mixture was stirred at room temperature for 18 h and diluted with CH2Cl2. The organic layer was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by chromatography (CH2Cl2) to afford 312 mg of tert-butyl 2-(2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethyl)disulfanyl)ethylcarbamate (89% yield). (0382) tert-Butyl 2-(2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethyl)disulfanyl)ethylcarbamate (312 mg, 0.528 mmol) was taken up in 6 mL of 4 M HCl in dioxane and allowed to stir at room temperature for 2 h. The resulting reaction mixture was concentrated under reduced pressure to afford the HCl salt of N-(2-(2-(2-aminoethyl)disulfanyl)ethyl)-2-(1-(4-chlorobenzo yl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamide. This material was taken up in CH3CN (5 mL) along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (173 mg, 0.528 mmol), HATU (220 mg, 0.58 mmol) and DIEA (275 muL, 1.6 mmol). The resulting reaction mixture was stirred at room temperature for 2 h, diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (5% MeOH-CH2Cl2) afforded 220 mg of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethyl)disulfanyl)ethyl)docosa-4,7,10,13,16,19-hexaenamide (52% yield). MS (EI) calcd for C45H56ClN3O4S2: 801.34; found 802 (M+1).
32%	With triethylamine; In methanol; at 20℃; for 18h;Reflux; Inert atmosphere;	(0171) Preparation of [2-(2-Amino-ethyldisulfanyl)-ethyl]-carbamic acid tert-butyl ester: Cysteamine dihydrochloride L6 (168.75 g, 750 mmol) was dissolved in a solution of 23% TEA in CH3OH (1600 mL). A solution of di-tert- butyldicarbonate (66 g, 300 mmol) in methanol (150 mL) was added to this mixture with vigorous stirring. The mixture was refluxed for 2 hr and then left to stir at RT for 16 hr. The methanol and TEA were removed in vacuo, and water was added into the mixture. Aqueous NaOH solution (4.0 M) was added slowly to adjust the pH to 4-5 and the filtrate collected by filtration. The precipitate was washed with aqueous HCl (1.0 M, 50 mL). The acidic layer was extracted with EtOAc (250 mL). The pH value was adjusted to 5 with NaOH (4.0 M) and extracted with EtOAc (250 mL), followed by a final extraction (250 mL EtOAc) at pH 11. The combined organic layers were washed carefully with saturated aqueous NaHCO3 solution (2×200 mL), brine (2×200 mL), dried over Na2SO4 and filtered, evaporated to give the product L8 as an orange oil (60 g, 32%). 1H NMR (300 MHz, CDCl3): delta 1.50 (s, 9H), 2.77-2.83 (m, 4H), 3.04 (t, J = 6 Hz, 2H), 3.74-3.49 (m, 2H), 4.97 (m, 1H); LC-MS: (M+H)+ 253; HPLC >95%.
	With triethylamine; In methanol; at 20℃; for 3h;	Cystamine dihydrochloride (1.0 g, 4.44 mmol) is dissolved in MeOH (50 mL). Triethylamine (1.85 mL, 3 eq) is added at room temperature, followed by dropwise addition of Boc2O (0.97 g, 4.44 mmol) as a solution in MeOH (5 mL). The resulting reaction mixture is stirred at room temperature for 3 h. It is then concentrated under reduced pressure and the resulting residue is taken up in 1M aqueous NaH2PO4 (20 mL). The aqueous layer is washed with a 1:1 solution of pentane/EtOAc (10 mL), basified to pH 9 with 1M aqueous NaOH, and extracted with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford tert-butyl 2-(2-(2-aminoethyl)disulfanyl)ethylcarbamate.
	With triethylamine; In methanol; at 20℃; for 0.5h;	200 mg of cystamine dihydrochloride (labeled as cystamine) dissolve in 10 ml of methanol, and then 386 mul of triethylamine was added; the 192.5 mg of di-tert-butyl dicarbonate(BOC anhydride) dissolve in 2 ml of methanol added dropwise to the solution of cystamine dihydrochloride in methanol, the reaction was stirred at room temperature for 30 minutes, and the methanol was evaporated to dryness by rotary evaporation. Continue to add 50ml of sodium dihydrogen phosphate solution (NaH2PO4, 1M), then washed twice with ether to remove the product with BOC anhydride attached to both ends. The pH of the solution was adjusted to 9 using NaOH (1M), extracted with ethyl acetate to obtain cystamine protected by BOC at one end, and the ethyl acetate layer was evaporated to dryness to obtain a white product (labeled as cystamine-BOC).
	With triethylamine; In methanol; at 20℃; for 0.5h;	1) Dissolve 200 mg of cystamine dihydrochloride (labeled cystamine) in 10 ml of methanol.And add 386mul triethylamine;192.5 mg di-tert-butyl dicarbonate (BOC anhydride)Dissolved in 2 ml of methanol,Add dropwise to the cystamine dihydrochloride methanol solution,Stir the reaction at room temperature for 30 minutes and rotovap to dry the methanol.Continue to add 50ml of sodium dihydrogen phosphate solution (NaH2PO4, 1M),Wash twice with ether to remove the product with BOC anhydride attached to both ends.Using NaOH (1M) to adjust the pH of the solution to 9, extracting with ethyl acetate to obtain one-side BOC-protected cystamine, and evaporating to dry the ethyl acetate layer,A white product was obtained (labeled cystamine-BOC).
	With triethylamine; In methanol; at 20℃; for 105h;	Cystamine dihydrochloride3.38gDispersed in 300 ml of methanol, this is liquid A,Dicarbonyl di-tert-butyl ester 3.27gAnd 6.3 mL of triethylamine was dissolved in 25 ml of methanol, which was B solution, and B solution was added dropwise to the solution A in 45 minutes. After the dropwise addition was completed, the reaction was further stirred at normal temperature for 60 minutes.After completion of the reaction, the solvent was removed by vacuum evaporation at 50 C, and 35 ml of sodium dihydrogen phosphate solution 1 M was added thereto, and the mixture was washed three times with 45 ml of diethyl ether, and the solution was adjusted to basic pH = 9 with sodium hydroxide solution 1 M. The mixture was extracted 3 times, and the organic phase was combined, dried over anhydrous sodium sulfate, and evaporated to give a pale yellow liquid by rotary evaporation at 60 C, and dried at 50 C to give the final product.

Reference： [1]ACS Combinatorial Science,2016,vol. 18,p. 287 - 291
[2]Patent: US2017/268032,2017,A1 .Location in patent: Paragraph 0144-0145
[3]Patent: CN105056251,2018,B .Location in patent: Paragraph 0090; 0091; 0092
[4]Molecular Pharmaceutics,2018,vol. 15,p. 5263 - 5276
[5]Organic and Biomolecular Chemistry,2019,vol. 17,p. 5496 - 5499
[6]Patent: WO2020/13696,2020,A1 .Location in patent: Page/Page column 58
[7]Journal of Organic Chemistry,2011,vol. 76,p. 3853 - 3860
[8]Patent: US2011/53990,2011,A1 .Location in patent: Page/Page column 18
[9]Patent: US2011/82202,2011,A1 .Location in patent: Page/Page column 23
[10]Patent: US2011/82210,2011,A1 .Location in patent: Page/Page column 35-36
[11]Patent: US2011/82156,2011,A1 .Location in patent: Page/Page column 18
[12]Patent: US2011/172240,2011,A1 .Location in patent: Page/Page column 35
[13]Patent: US2011/82192,2011,A1 .Location in patent: Page/Page column 28
[14]Patent: US2011/213028,2011,A1 .Location in patent: Page/Page column 27-28
[15]Patent: WO2013/177536,2013,A2 .Location in patent: Paragraph 0238
[16]Patent: WO2014/107730,2014,A2 .Location in patent: Paragraph 0326
[17]Patent: US9216224,2015,B2 .Location in patent: Page/Page column 56-58
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[19]Organic and Biomolecular Chemistry,2006,vol. 4,p. 1817 - 1830
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[25]Patent: US2012/252810,2012,A1 .Location in patent: Page/Page column 30-31
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[29]Patent: CN107469090,2017,A .Location in patent: Paragraph 0064; 0065
[30]Patent: CN107488137,2017,A .Location in patent: Paragraph 0047
[31]Patent: CN109172825,2019,A .Location in patent: Paragraph 0038; 0042; 0054; 0058; 0069; 0073

10
[ 55589-47-4 ]
[ 56-17-7 ]
di-2-(bis((6-methyl-2-pyridyl)methyl)amino)ethyl disulfide [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2001,vol. 123,p. 4087 - 4088

11
[ 72707-66-5 ]
[ 56-17-7 ]
2-[(2-carboxy-allyl)-(2-mercapto-ethyl)-amino]-methyl}-acrylic acid [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2002,vol. 124,p. 2293 - 2298

12
[ 181952-29-4 ]
[ 56-17-7 ]
[ 71989-18-9 ]
[ 71989-23-6 ]
[ 64-19-7 ]
(Ac)EEEIFGEFDap(Ac)-NH(CH₂)2SH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multistep reaction;

Reference： [1]Hah, Jung-Mi; Sharma, Vyas; Li, Haishan; Lawrence, David S. [Journal of the American Chemical Society, 2006, vol. 128, # 18, p. 5996 - 5997]

13
[ 87081-36-5 ]
[ 56-17-7 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; triethylamine; diisopropyl-carbodiimide In dichloromethane at 20℃; for 22h;	2 To a solution of 20 mg of (2E,10E,12E,16Z,18E)-(R)-6-hydroxy-3,5,7,9,11,15,17-heptamethyl-19-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-8-oxo-nonadeca-2,10,12,16,18-pentaenoic acid and 5.6 mg of HOBT (1-hydroxybenzotriazole) in 0.3 ml of dichloromethane, are introduced at a temperature near 20°C, 12.8 mg of dichlorhydrate of cystamine, 7.65 µl of DIC (N,N'-diisopropylcarbodiimide) then 11.6 µl of triethylamine. The reaction mixture is stirred at a temperature near 20°C during 22 hours, then purified by direct deposit on 2 preparative silica gel TLC plates (thickness 0.5 mm, 20x20 cm). The preparative TLC plates were eluted with a mixture of methanol / dichloromethane (5/95 in volumes) then the desired product is extracted from silica gel with a mixture of methanol / dichloromethane (15/85 in volumes). 4.6 mg of bis-[(2-thioethyl)-amid of (2E,10E,12E,16Z,18E)-(R)-6-hydroxy-3,5,7,9,11,15,17-hepta-methyl-19-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-8-oxo-nonadeca-2, 10,12,16,18-pentaenoic acid] are obtained as a white solid blanc whose characteristics are the following : Mass spectra :• ES+: m/z=1167: [M+H]+ • ES-:: m/z=1211: [M-H+HCOOH]-

Reference： [1]Current Patent Assignee: SANOFI - EP1864682, 2007, A1 Location in patent: Page/Page column 12

14
[ 351-32-6 ]
[ 56-17-7 ]
di-2-[(4-acetylamino-2-nitrophenyl)arnino]ethyl disuifide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With sodium hydrogencarbonate; In dimethyl sulfoxide; at 45 - 80℃; for 7h;	5,66 g (25,2 [MMOL)] Cystamin Dihydrochlorid werden in 40 mL Dimethylsulfoxid vorgelegt. 8,46 [G] (100,8 mmol) Natriumhydrogencarbonat werden potionsweise eingetragen. Im Anschluss werden 10,0 g (50,4 [MMOL) (4-FLUOR-3-NITROPHENYL)] acetamid (aus : M. D. McFarlane et al, J. Chem. Soc., Perkin. [TRANS. 1, 1988,] 691- 969) geloest in 100 mL Dimethylsulfoxid bei [45 C] zugetropft. Die Reaktionsmischung wird danach fuer 7 Stunden bei [80 C] geruehrt. Man laesst so dann auf Raumtemperatur abkuehlen, gibt die Reaktionsmischung auf Eiswasser und stellt durch Zugabe von konzentrierter Salzsaeure einen pH-Wert von pH 3 ein. Der resultierende Niederschlag wird abfiltriert, mehrfach mit Wasser gewaschen und im Vakuum getrocknet. Man erhaelt 12,4 g (97%) eines roten Feststoffs.
97%	With sodium hydrogencarbonate; In dimethyl sulfoxide; at 45 - 80℃; for 7h;	5.66 g (25.2 mmol) cystamine dihydrochloride are furnished in 40 ml dimethylsulfoxide.8.46 g (100.8 mmol) sodium hydrogen carbonate are added stepwise.Then 10.0 g (50.4 mmol) 4-fluoro-3-nitrophenylacetamide, dissolved in 100 ml dimethylsulfoxide are added dropwise at 45 C.The reaction mixture is stirred for 7 h at 80 C. and cooled down to room temperature. The reaction mixture is placed on a water/ice mixture and adjusted to pH 3 by addition of conc. HCl.The resultant precipitate is filtered off, washed with water for several times and dried in vacuo.12.4 g (97%) of a red dye are obtained.Mp: 199-201 C.

Reference： [1]Patent: WO2003/99242,2003,A1 .Location in patent: Page 37, 38
[2]Patent: US2009/130045,2009,A1 .Location in patent: Page/Page column 15

15
[ 1892-29-1 ]
[ 56-17-7 ]
[ 15579-01-8 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In methanol; dichloromethane at 0 - 20℃; for 6h;	6 To a solution of cysteamine hydrochloride (15 g, 132 mmol) in MeOH (130 ML) at 0-5° C. was added TEA (37 mL, 264 mmol), followed by a solution of SL-1 (20.4 g, 132 mmol) in DCM (50 mL) and stirred at RT for 6 h. The mixture, which contained the intermediate SL-2, was cooled and (Boc)2O (63.4 g, 290.4 mmol) was added and stirred overnight. MeOH was removed under vacuum. After usual aqueous work-up and chromatographic purification, LI-2c was obtained as a colorless oil (14.6 g, 44%).

Reference： [1]Current Patent Assignee: PIRAMAL ENTERPRISES LIMITED - US2006/46967, 2006, A1 Location in patent: Page/Page column 131

16
[ 1002-84-2 ]
[ 56-17-7 ]
[ 370558-61-5 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h;

Reference： [1]McCaughan, Bridgeen; Kay, Graeme; Knott, Rachel M.; Cairns, Donald [Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 5, p. 1716 - 1719]

17
[ 506-12-7 ]
[ 56-17-7 ]
[ 1022899-15-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 1716 - 1719

18
[ 646-30-0 ]
[ 56-17-7 ]
[ 1022899-16-6 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h;

Reference： [1]McCaughan, Bridgeen; Kay, Graeme; Knott, Rachel M.; Cairns, Donald [Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 5, p. 1716 - 1719]

19
[ 3397-62-4 ]
[ 56-17-7 ]
[ 500999-67-7 ]

Yield	Reaction Conditions	Operation in experiment
81%	With sodium hydroxide In water Reflux;

Reference： [1]Ma, Mingming; Paredes, Angel; Bong, Dennis [Journal of the American Chemical Society, 2008, vol. 130, # 44, p. 14456 - 14458]

20
[ 605-65-2 ]
[ 56-17-7 ]
[ 881013-37-2 ]

Yield	Reaction Conditions	Operation in experiment
53%	With sodium hydrogencarbonate; sodium hydroxide; In water; acetone; at 20℃; for 1.5h;pH 7.5;	Synthesis of model fluorescent nucleophilic thiol, dansyl cystamine: [00064] N,N'-(disulfanediylbis(ethane-2, l-diyl))bis(5-(dimethylamino)naphthalene-l- sulfonamide) (DCYA disulfide). [00065] In a 250 mL round bottom flask, dansyl chloride (876.0 mg, 3.25 mmol) was dissolved in a solution of 90 mL of acetone and 3 mL of water. A solution of cystamine dihydrochloride (364.4 mg, 1.62 mmol, 0.5 equiv.) in 21 mL 0.1 M aqueous NaHCO3 was added in portions. The solution was maintained to pH 7.5 by addition of aqueous 0.5 M sodium hydroxide. After 90 min at room temperature, the reaction mixture was diluted with 100 mL chloroform, and the solution was washed four times with aqueous sodium bicarbonate, followed by water. The organic layer was dried over anhydrous MgSO4, concentrated and purified by column chromatography to 527.7 mg of dimer as a fluffy, crisp yellow solid (0.85 mmol, 53%), TLC Rf = 0.25, 30% acetone in hexanes, mp 71-72 C. [00066] 1H-NMR: (500 MHz, CDC13) delta 8.54 (d, J= 8.5 Hz, 1H), 8.27 - 8.20 (m, 2H), 7.53 (ddd, J = 15.9, 8.6, 7.4 Hz, 2H), 7.17 (d, J= 7.6 Hz, 1H), 5.24 (t, J = 6.2 Hz, 1H), 3.09 (q, J= 6.3 Hz, 2H), 2.88 (s, 6H), 2.48 (t, J= 6.3 Hz, 2H).13C-NMR: (126 MHz, CDCI3) delta 152.2, 134.5, 130.8, 130.0, 129.8, 129.6, 128.7, 123.3, 118.7, 115.4, 45.6, 41.7, 37.9.

Reference： [1]Organic and Biomolecular Chemistry,2014,vol. 12,p. 557 - 560
[2]Bioorganic Chemistry,2008,vol. 36,p. 265 - 270
[3]Angewandte Chemie - International Edition,2016,vol. 55,p. 13765 - 13769
Angew. Chem.,2016,vol. 128,p. 13969 - 13973,5
[4]Chemical Communications,2019,vol. 55,p. 14926 - 14929
[5]Angewandte Chemie - International Edition,2016,vol. 55,p. 12338 - 12342
Angew. Chem.,2016,vol. 128,p. 12526 - 12530,5
[6]Patent: WO2015/200870,2015,A2 .Location in patent: Page/Page column 00063-00065

21
[ 108-55-4 ]
[ 56-17-7 ]
[ 109477-57-8 ]

Yield	Reaction Conditions	Operation in experiment
90%		(1) Synthesis of dithiodiethanediyldiaminodicarbonyl dibutanoic acid (abbr. DGC): Cystamine dihydochloride 10 g (Aldrich, USA) was dissolved into 150 ml distilled water to give a clear and transparent solution. NaOH (4 mol/L) was added into the above solution until pH 10. Then under magnetic stirring, glutaric anhydride 15.2 g (Aldrich, USA) was added, and simultaneously NaOH (4 mol/L) was added to keep solution pH at 7~10. After 2 h reaction at room temperature, HCl (6 mol/L) was added into the solution, the white precipitated product was collected by filtration, washed twice with 200 ml distilled water, and then dried under reduced pressure to give white solid product DGC of approximately 15.5 g (yield is higher than 90%).
> 90%		Cystamine dihydrochloride 10 g (Aldrich, USA) was dissolved into 150 ml distilled water to give a clear and transparent solution. NaOH (4 mol/L) was added into the above solution until pH 10. Then under magnetic stirring, glutaric anhydride 15.2 g (Aldrich, USA) was added, and simultaneously NaOH (4 mol/L) was added to keep solution pH at 710. After 2 h reaction at room temperature, HCl (6 mol/L) was added into the solution, the white precipitated product was collected by filtration, washed twice with 200 ml distilled water, and then dried under reduced pressure to give white solid product DGC of approximately 15.5 g (yield is higher than 90%).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 45 - 47
[2]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 3492 - 3496
[3]Patent: EP2088140,2009,A1 .Location in patent: Page/Page column 9-10
[4]Patent: US2010/48952,2010,A1 .Location in patent: Page/Page column 6

22
[ 56-17-7 ]
[ 814-68-6 ]
N,N’-cystamine-bis-acrylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
Ca. 73%	With sodium hydroxide; In dichloromethane; water; at 0 - 20℃; for 16h;	BAC was prepared as described elsewhere (Sun et al., 2010). Briefly, 50 mL of an aqueous solution (1.0 M) of cystamine dihydrochloride was placed in a 250 mL three-neckflask equipped with a thermometer and two 50-mL dropping funnels. Then, 10 mL acryloyl chloride solution in dichloromethane (15.0 M) and 20 mL NaOH aqueous solution (10.0 M) were simultaneously added, dropwise, at 0-5 C and allowed to react at room temperature (RT) for 16 h. The BAC thus obtained was purified by recrystallization from ethyl acetate. The reaction yield was 73% ca.
55%	With sodium hydroxide; In dichloromethane; water; at 0 - 20℃;	Cystamine dihydrochloride (2.05 g, 9.11 mmol) was dissolved inwater (10 mL). A solution of sodium hydroxide (1.81 g, 45.3 mmol) inwater (10 mL) and a solution of acryloyl chloride (2.2 mL, 27 mmol)in dichloromethane (6 mL) were added dropwise at 0 C. After stirringovernight at room temperature, pH was adjusted to pH = 8 and thewhite precipitate was filtered off. The reaction mixture was extractedthree times using dichloromethane and the organic phase was driedusing magnesium sulfate. Solvents were removed under reduced pressureand the crude product was purified by recrystallization from boilingethyl acetate to afford N,N?-bis(acryloyl)cystamine (2a) as a whitesolid (1.30 g, 55%). 1H NMR (DMSO-d6): delta=8.33 (2H, t, J=5.6 Hz, NH), 6.19, 6.12 (4H,2m, CH2_CH), 5.61 (2H, m, CH2_CH), 3.42 (4H, q, J=6.8Hz, NHCH2),2.82 (4H, t, J=6.8 Hz, SCH2).13C NMR (DMSO-d6): delta = 164.8 (C(O)NH), 131.6 (CH2_CH), 125.4(CH2_CH), 37.9 (NHCH2), 37.1 (SCH2).
	With sodium hydroxide; In dichloromethane; water; at 20℃; for 6h;Cooling with ice;	The cystamine dihydrochloride and sodium hydroxide solids were separately dissolved in pure water, the acryloyl chloride was dissolved in methylene chloride, and then the sodium hydroxide aqueous solution and acryloyl chloride in methylene chloride solution were slowly alternated for 20 min under ice bath conditions. The solution was added dropwise to an aqueous solution of cystamine dihydrochloride, and after completion of the dropwise addition, the reaction was carried out at room temperature for 6 hours. During the reaction, magnetic stirring was performed at a rotation speed of 300 rpm. After the reaction was completed, extraction was performed using dichloromethane extraction, and the solvent was evaporated at 40 C., and then Drying in vacuo at 40 C. for 12 h gave N,N?-bis(acryloyl)cystamine (CBA).The molar ratio of cystamine dihydrochloride, sodium hydroxide and acryloyl chloride is 1:2.7:2.5; the volume ratio of dichloromethane and reaction system solution used for the extraction is 20:1; the pure water used The amount was 4 mass times of cystamine dihydrochloride, which was 2.5 mass times of sodium hydroxide, and the amount of dichloromethane used was 1 volume ratio of acryloyl chloride.

With sodium hydroxide; In water; at 0 - 20℃; for 12.5h;

1.126 g (5 mmol) of cystamine dihydrochloride dissolved in 10 mL of deionized water.Under magnetic stirring and 0 C to 5 C, acryloyl chloride (12 mmol) and 10 mL of aqueous sodium hydroxide (0.8 g, 20 mmol) were added dropwise, and the mixture was dropped in half an hour.The reaction was continued for 12 h at room temperature.It was extracted with dichloromethane and dried over anhydrous magnesium sulfate.Concentrated under reduced pressure and the residue was crystallised from ethyl acetate: heptane (1:2, v/v).N,N'-bis(acryloyl)cystamine (BACy),

Reference： [1]Journal of the Chinese Chemical Society,2014,vol. 61,p. 945 - 952
[2]International Journal of Pharmaceutics,2017,vol. 517,p. 168 - 174
[3]Journal of the Chinese Chemical Society,2013,vol. 60,p. 223 - 228
[4]Biomacromolecules,2010,vol. 11,p. 1840 - 1846
[5]Journal of Controlled Release,2016,vol. 244,p. 357 - 365
[6]Journal of Materials Chemistry B,2019,vol. 7,p. 6994 - 7005
[7]Polymer,2010,vol. 51,p. 5107 - 5114
[8]Soft Matter,2011,vol. 7,p. 7386 - 7394
[9]Organic and Biomolecular Chemistry,2009,vol. 7,p. 4201 - 4210
[10]Macromolecular Bioscience,2016,vol. 16,p. 619 - 626
[11]RSC Advances,2016,vol. 6,p. 33138 - 33147
[12]RSC Advances,2017,vol. 7,p. 47715 - 47725
[13]Patent: CN107510849,2017,A .Location in patent: Paragraph 0059-0061; 0063
[14]Chemical Communications,2018,vol. 54,p. 8218 - 8221
[15]Colloids and Surfaces B: Biointerfaces,2018,vol. 170,p. 373 - 381
[16]Patent: CN109620960,2019,A .Location in patent: Paragraph 0035; 0036

23
[ 82911-69-1 ]
[ 56-17-7 ]
[ 896465-25-1 ]

Yield	Reaction Conditions	Operation in experiment
96%	With sodium carbonate; In water; acetone; at 20℃; for 2.5h;	In a flask, 2 molar equivalents of Fmoc-OSu are solubilized into acetone at 320 g/l. 1 molar equivalent of cystamine 2 HCl and 1.6 molar equivalents of sodium carbonate are added with a water volume identical to the acetone. The mixture harden. A mixture water/50/50 is added for doubling the solvent volume.After 2 h30 stirring at room temperature, acetone is evaporated with rotavapor and the obtained suspension is solubilised into dichloromethane. The aqueous phase is extracted by dichloromethane and the organic phases washed successively with KHSO3 and saturated NaCl.The final organic phase is then dried on sodium sulphate, filtered and evaporated under reduced pressure for providing 2.53 g of Fmoc-cystamine: [M+H]+=598-Purity: 95%-Yield=96%.

Reference： [1]Patent: US2010/75912,2010,A1 .Location in patent: Page/Page column 7; Sheet 3

24
[ 1019837-91-2 ]
[ 56-17-7 ]
[ 1019837-86-5 ]

Yield	Reaction Conditions	Operation in experiment
85%		In a Falcon tube, 1 molar equivalent of cysteamine.dihydrochloride is solubilized into DMF at 11.2 g/l. 2 molar equivalents of M3iPro-6G priorly solubilized into DMF at 100 g/l are added. 5 molar equivalents of pure DIEA are then introduced and the mixture is cooled to 0 C. and stirred during 5 minutes. Then 2.4 molar equivalents of PyBOP priorly solubilized into DMF at 240 g/l are added and the mixture is stirred at room temperature during 1 h.Dimer is purified by preparative HPLC.46.4 mg of M3iPro-6G-cya-cya-M3iPro-6G are obtained: [M+H]+=1123-MTFA=1350-Purity: 95%-Yield=85%.

Reference： [1]Patent: US2010/75912,2010,A1 .Location in patent: Page/Page column 6; Sheet 2

25
[ 24424-99-5 ]
[ 56-17-7 ]
[ 67385-10-8 ]
[ 485800-26-8 ]

Yield	Reaction Conditions	Operation in experiment
45%	With triethylamine In methanol at 20℃; for 0.5h;
	With triethylamine In methanol for 0.333333h; Inert atmosphere;

Reference： [1]Location in patent: experimental part Shirazi, Rahau S.; Ewert, Kai K.; Leal, Cecilia; Majzoub, Ramsey N.; Bouxsein, Nathan F.; Safinya, Cyrus R. [Biochimica et Biophysica Acta - Biomembranes, 2011, vol. 1808, # 9, p. 2156 - 2166]
[2]Galan, M. Carmen; Tran, Anh Tuan; Bernard, Claire [Chemical Communications, 2010, vol. 46, # 47, p. 8968 - 8970]

26
[ 56-17-7 ]
[ 16727-43-8 ]
[ 1297600-20-4 ]

Reference： [1]ACS Combinatorial Science,2011,vol. 13,p. 205 - 208

27
[ 130423-83-5 ]
[ 56-17-7 ]
C₃₀H₂₄N₂O₄S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water; N,N-dimethyl-formamide

Reference： [1]Location in patent: scheme or table Burlingame, Mark A.; Tom, Christopher T. M. B.; Renslo, Adam R. [ACS Combinatorial Science, 2011, vol. 13, # 3, p. 205 - 208]

28
[ 101384-62-7 ]
[ 56-17-7 ]
C₃₀H₂₈Cl₂N₄O₄S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water; N,N-dimethyl-formamide

Reference： [1]Location in patent: scheme or table Burlingame, Mark A.; Tom, Christopher T. M. B.; Renslo, Adam R. [ACS Combinatorial Science, 2011, vol. 13, # 3, p. 205 - 208]

29
[ 50390-76-6 ]
[ 56-17-7 ]
C₂₂H₂₈N₂O₈S₄ [ No CAS ]

Reference： [1]ACS Combinatorial Science,2011,vol. 13,p. 205 - 208

30
[ 22117-85-7 ]
[ 56-17-7 ]
C₂₀H₂₆N₄O₈S₄ [ No CAS ]

Reference： [1]ACS Combinatorial Science,2011,vol. 13,p. 205 - 208

31
[ 4519-39-5 ]
[ 56-17-7 ]
C₁₈H₁₆F₄N₂O₂S₂ [ No CAS ]

Reference： [1]ACS Combinatorial Science,2011,vol. 13,p. 205 - 208

32
[ 86060-98-2 ]
[ 56-17-7 ]
[ 108608-66-8 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In methanol; at 20℃; for 12h;	To a solution of cystamine dihydrochloride 2 0.113 mg (0.5 mmol) in 15 mL methanol was added 204 mg (2.0 mmol) of triethylamine and <strong>[86060-98-2]Fmoc-Lys(Boc)-OPfp</strong> 3 0.635 g (1.0 mmol). The mixture was stirred at room temperature for 12 hours and a jelly-like solid was formed. 15 mL of chloroform was added to make the reaction solution clear. The mixture was passed through a short silica gel column (3.0 g of silica gel) and the solvent was evaporated under vacuum to afford a crude coupling product as a white solid.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 5021 - 5024

33
[ 56-17-7 ]
[ 1200-22-2 ]
cystamine di-(R)-α-lipoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85.3%		Example 6; Cystamine (R) alpha-lipoate; Grams 56.3 of cystamine dihydrochloride (0.25 moles) and 50.6 g of triethyilamine (0.5 moles) are added to 350 mL of 96% ethanol and it is heated, under stirring and reflux, till obtaining a clear solution. It is cooled to below 60C and 103.1 g of (R) thioctic acid (0.5 moles) are added, then stirred at 55 - 60C till obtaining a clear solution (about 15min) and cooled between 0 and -5C maintaining this temperature overnight. The crystallized solid is collected on buckner, washed with little 96% ice-cold ethanol. It is dried in vacuo at 40C. Grams 120.5 g (0.21 moles equal to 85.3% of the theoretical value) of cystamine (R) alpha-lipoate are obtained.

Reference： [1]Patent: EP2386552,2011,A1 .Location in patent: Page/Page column 4

34
[ 56-17-7 ]
[ 51-85-4 ]

Yield	Reaction Conditions	Operation in experiment
75.5%	With sodium hydroxide; In tetrahydrofuran; diethyl ether; water; for 1h;Cooling with ice;	Accurately weighed 12.15 g powdered cystamine dihydrochloride is dissolved in 16 mL deionized water, then 60 mL ether and 24 mL tetrahydrofuran are added under stirring. In the ice bath, 40% NaOH solution (66.7 mL) is added dropwise into the mixture above under magnetic stirring for one hour; the upper organic phase is separated. The lower aqueous phase is extracted with a mixture of 50 mL ether and 18 mL tetrahydrofuran. The organic phase is combined and dried with 4 g NaOH for two hours, after filtration the volatile ether and tetrahydrofuran are removed through evaporation, and finally 6.2 g cystamine is obtained with a yield of 75.5%.
73.1%	With sodium hydroxide; In water; at 0℃; for 1h;	Cystamine Free Base Cystamine dihydrochloride (8.7 g, 0.038 mol) was dissolved in water (30 ml). The mixture was cooled in an ice bath to 0 C., and 15 ml 10 M NaOH was slowly added during 1 hour. Cystamine free base (CT) was extracted with 100 ml dichloromethane, and the organic layer was separated and dried with Na2SO4. Dichloromethane was then evaporated under vacuum resulting 4.3 g (yield 73.1%) of viscous slightly yellow CT. Before use, the product was additionally dried with Na2CO3 and stored at -20 C. 1H NMR (CDCl3), ppm (referenced according to solvent signal): 1.30 (4H, -NH2); 2.58 (4H, -S-CH2-CH2-NH2); 2.80 (4H, 5-CH2-CH2-NH2). 13C NMR (CDCl3), ppm (referenced according to solvent signal): 39.56 (2C, S-CH2-CH2-NH2); 41.29 (2CH, -S-CH2-CH2-NH2).

Reference： [1]Patent: US2018/360753,2018,A1 .Location in patent: Paragraph 0042; 0043
[2]Patent: US2019/48139,2019,A1 .Location in patent: Paragraph 0184
[3]Chinese Journal of Chemistry,2011,vol. 29,p. 531 - 538
[4]Reactive and functional polymers,2017,vol. 119,p. 47 - 56

35
[ 56-17-7 ]
[ 141-75-3 ]
[ 38108-25-7 ]

Yield	Reaction Conditions	Operation in experiment
72%	With pyridine; In dichloromethane; at 0 - 20℃; for 4h;	Butyryl chloride (0.91 ml, 8.8 mmol) was added drop-wise to a suspension of cystamine dihydrochloride (0.90 g, 4.0 mmol) and pyridine (1.3 ml) in CH2CI2 (20 ml) at 0 C and the mixture stirred (r.t., 4 h). Methanol (1 .0 ml) was added to the mixture at 0 C and stirring continued (r.t., 30 min). The mixture was diluted with CH2CI2 (50 ml) and the organic phase collected, then washed with HCI (30 ml, 1 M), dried (MgS04), filtered and evaporated to dryness. The residue was recrystallised from EtOAc/hexanes to give Lambda/,/V'-dibutyrylcystamine as a colorless powder (0.84 g, 72 %). 1H NMR (300.1 MHz, CDCI3) delta = 0.91 (t, 3 H, J = 7.5 Hz, CH3), 1 .63 (tq, 2 H, J = 7.5, 7.5 Hz, CH2CH3), 2.17 (t, 2 H, J = 7.5 Hz, CH2CH2CH3), 2.79 (t, 2 H, J = 6.7 Hz, SCH2), 3.53 (dt, 2 H, J = 6.7, 6.7 Hz, NCH2), 6.66 (bt, 1 H, J = 6.7 Hz, NH); 13C NMR (75.5 MHz, CDCI3) delta = 13.9 (CH3), 19.3, 38.0, 38.5, 38.6 (CH2), 173.9 (C=0). HRMS (ES): m/z = 293.1354; [M + H]+ requires 293.1357.

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 2737 - 2745
[2]Patent: WO2013/75227,2013,A1 .Location in patent: Paragraph 0069

36
[ 80883-54-1 ]
[ 56-17-7 ]
N,N'-(2,2'-disulfanediylbis(ethane-2,1-diyl))bis(2-(7-(dimethylamino)-2-oxo-2H-chromen-4-yl)acetamide) [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2012,vol. 10,p. 7120 - 7133

37
[ 34619-03-9 ]
[ 56-17-7 ]
[ 485800-26-8 ]

Yield	Reaction Conditions	Operation in experiment
44%	With triethylamine In methanol at 20℃; for 3h;	21 The mono-BOC- protected cystamine was prepared as follows: Cystamine dihydrochloride (1.0 g, 4.44 mmol) was dissolved in 50 mL of MeOH. Triethylamine (1.85 mL, 3 eq) was added at room temperature, followed by dropwise addition of Boc20 (0.97 g, 4.44 mmol) as a solution in 5 mL of MeOH The resulting reaction mixture was stirred at room temperature for 3 h. It was then concentrated under reduced pressure and the resulting residue was taken up in 20 mL of 1M NaH2P04. The aqueous layer was washed with 10 mL of a 1 : 1 solution of pentane/EtOAc, basified to pH 9 with 1 M NaOH, and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2S04) and concentrated under reduced pressure to afford 500 mg of tert-butyl 2-(2-(2- aminoethyl)disulfanyl)ethylcarbamate (44 % yield). (4Z,7Z,10Z,13Z,16Z,19Z)-docosa- 4,7,10,13,16,19-hexaenoic acid {2-[2-((5Z,8Z, 11 Z, 14Z, 17Z)-icosa-5 ,8, 11,14,17- pentaenoylamino)-ethyldisulfanyl]-ethyl} -amide was then prepared according to the procedures outlined above using tert-butyl 2-(2-(2-aminoethyl)disulfanyl)ethylcarbamate, (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,l 0,13, 16,19-hexaenoic acid and (5Z,8Z,11Z,14Z,17Z)- eicosa-5,8,l l,14,17-pentaenoic acid. MS (EI) calcd for C48H72N202S2 : 772.50; found 773 (M + 1).

Reference： [1]Current Patent Assignee: CATABASIS PHARMACEUTICALS, INC. - WO2012/115695, 2012, A1 Location in patent: Page/Page column 84-85

38
[ 56-17-7 ]
[ 35013-72-0 ]
[ 135075-40-0 ]

Yield	Reaction Conditions	Operation in experiment
87%	With triethylamine; In water; N,N-dimethyl-formamide; at 20℃;	In accordance to a described procedure ( Wang et al., 2012 ), Biotin-OSuc (14) (300 mg, 0.87 mmol) was completely dissolved in DMF (3 mL) with gentle warming (40 C). After slowly cooling the solution to room temperature without recurring precipitation, it was mixed with an aqueous solution (1 mL) containing cystamine dihydrochloride (107 mg, 0.47 mmol) and Et3N (309 muL, 2.10 mmol). The reaction proceeded at room temperature overnight with stirring. The white solid was filtered and washed with water and EtOH to obtain N,N'-(disulfanediylbis(ethane-2,1-diyl))bis(5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl) pentanamide) (7) as a white solid (250 mg; 87%); 1H NMR (400 MHz, DMSO-d6): delta 8.08-8.04 (br m, 2H), 6.48 (s, 2H), 6.43 (s, 2H), 4.39-4.34 (m, 2H), 4.22-4.17 (m, 2H), 3.42-3.35 (m, 2H), 3.19-3.14 (m, 2H), 2.88-2.81 (m, 6H), 2.64 (d, J = 12.9 Hz, 2H), 2.13 (t, J = 7.3 Hz, 4H), 1.72-1.53 (m, 8H), 1.40-1.34 (m, 4H); 13C NMR (100 MHz, DMSO-d6): delta 25.7, 28.5, 28.7, 35.6, 37.8, 38.3, 40.3, 55.9, 59.7, 61.5, 163.2, 172.7.

Reference： [1]Chemistry and Physics of Lipids,2015,vol. 188,p. 27 - 36
[2]Bioconjugate Chemistry,2012,vol. 23,p. 2417 - 2433
[3]Angewandte Chemie - International Edition,2017,vol. 56,p. 9449 - 9453
Angew. Chem.,2017,vol. 129,p. 9577 - 9581,5
[4]Chemical Communications,2019,vol. 55,p. 14926 - 14929

39
[ 4684-94-0 ]
[ 56-17-7 ]
[ 1446697-17-1 ]

Reference： [1]ChemMedChem,2013,vol. 8,p. 149 - 156

40
[ 56-17-7 ]
[ 17669-01-1 ]
[ 1428361-11-8 ]

Yield	Reaction Conditions	Operation in experiment
100%		24 mul of dry pyridine were added to a solution of 65 mg (0.29 mmol) of cystamine dihydrochloride in 3 mL of absolute EtOH. After stirring 30 min at room temperature, a suspension of 200 mg (0.58 mmol) of usnic acid in 3 mL of absolute EtOH was added, and dry pyridine was added until usnic acid dissolution. The reaction was refluxed under nitrogen atmosphere for 8 h. The solvent was concentrated under reduced pressure, and the crude material was acidified with 1 N HCl until pH 4, then extracted twice with EtOAc. The organic layers were collected and concentrated under reduced pressure, giving 173.2 mg of pale yellow solid, quantitative yield. 1H NMR 400 MHz (CDCl3) delta ppm 1.68 (s, 3H, CH3-13), 2.07 (s, 3H, CH3-16), 2.64 (s, 3H, CH3-15), 2.66 (s, 3H, CH3-18), 3.00 (t, J = 6.5 Hz, 2H, CH2-2'), 3.85-3.89 (m, 2H, CH2-1'), 5.76 (s, 1H, CH-4), 11.81 (br s, 1H, OH-10), 13.33 (s, 1H, OH-8), 13.72 (br s, 1H, NH). 13C NMR 100 MHz (CDCl3) delta ppm 8.18 (C-16), 19.14 (C-15), 31.94 (C-18), 32.66 (C-13), 37.26 (C-2'), 42.98 (C-1'), 58.14 (C-12), 102.04 (C-2 + C-7), 102.92 (C-4), 105.58 (C-11), 108.73 (C-9), 156.48 (C-6), 158.80 (C-10), 164.22 (C-8), 174.97 (C-5), 175.69 (C-14), 191.63 (C-3), 199.20 (C-1), 201.30 (C-17). LC-MS (ESI), positive, m/z found: 805.2 [M+H]+, Calcd for C40H40N2O12S2: 804.2.

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 1834 - 1843

41
[ 487-54-7 ]
[ 56-17-7 ]
[ 1429128-83-5 ]

Yield	Reaction Conditions	Operation in experiment
65%	With N-ethyl-N,N-diisopropylamine; HATU In tetrahydrofuran at 60℃; for 1h;	1 Synthesis of N,N’-(2,2’-(2,2’-disulfanediylbis(ethane-2, 1-diyl)bis(azanediyl))bis(2-oxoethane-2, 1 -diyl))bis(2-hydroxybenzamide) (2-Hydroxyhippuric-Cystamine) To a mixture of 2-hydroxyhippuric acid (1g, 5.12 mmol), cystamine dihydrochloride (0.58 g, 2.56 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU, 1.9 g, 5.12 mmol) in dry tetrahydrofuran (10 mL) was added diisopropylethylamine (DIEA, 1.79 mL, 10.25 mmol). The resulting mixture was heated at 60°C for 1 hour. The reaction mixture was cooled down to room temperature and then concentrated to dryness in vacuo. The oil residue was extracted with ethyl acetate (100 mL) and 5% NaHCO3 (2x100 mL). The organic layer was separated and then washed with 1 N HCl (2x100 mL). The organic layer was separated and kept at room temperature overnight. The white solid was recrystallized from ethyl acetate to yield 0.84 g (65%). 1H NMR (DMSO-d6) δ 12.23 (2H, s), 9.07 (2H, t), 8.21 (2H, t), 7.87 (2H, d), 7.40 (2H, t), 6.90 (4H, m), 3.90 (4H, d), 3.37 (4H, q), 2.79 (4H, t).

Reference： [1]Current Patent Assignee: ABBOTT LABORATORIES INC - WO2013/49294, 2013, A1 Location in patent: Paragraph 0088; 0089

42
[ 56-17-7 ]
[ 17669-01-1 ]
C₄₀H₄₀N₂O₁₂S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%		Example 4 Synthesis of dimer conjugate with cysteamine (MB90) 24 mu of anhydrous pyridine was added to a solution of cystamine dihydrochloride (65 mg, 0.29 mmol) in 3 mL of absolute EtOH. After 30 min stirring at room temperature, a suspension of usnic acid (200 mg, 0.58 mmol) in 3 mL of absolute EtOH was added, and pyridine was then added until completely dissolved. The reaction mixture was refluxed under nitrogen for 8 h. The solvent was evaporated under low pressure, and the solid obtained was acidified with IN HC1 to pH 4, and then extracted twice with EtOAc. The organic phases were combined and concentrated under low pressure, affording 173.2 mg of a pale yellow solid with a quantitative yield. 1H-NM 400 MHz (CDC13) delta ppm 1.68 (3H, CH3-13), 2.07 (3H, s, CH3- 16), 2.64 (3H, s, CH3-15), 2.66 (3H, s, CH3-18), 3.00 (2H, t, J = 6.5 Hz, CH2-2'), 3.87 (2H, m, CH2-1'), 5.76 (1H, s, CH-4), 11.81 (1H, br s, OH- 10), 13.33 (1H, s, OH-8), 13.72 (1H, br s, NH). 1JC-NMR 100 MHz (CDC13) delta ppm 8.18 (C- 16), 19.14 (C-15), 31.94 (C- 18), 32.66 (C-13), 37.26 (C-2'), 42.98 (C-l '), 58.14 (C-12), 102.04 (C-2 + C-7), 102.92 (C-4), 105.58 (C-l l), 108.73 (C-9), 156.48 (C-6), 158.80 (C-10), 164.22 (C-8), 174.97 (C-5), 175.69 (C-14), 191.63 (C-3), 199.20 (C-l), 201.30 (C-17). LC-MS (ESI), positive, m/z 805.2 [M + H]+, calculated for C4oH4oN2O12S2 804.2.

Reference： [1]Patent: WO2013/189950,2013,A1 .Location in patent: Page/Page column 17-18

43
[ 828-51-3 ]
[ 56-17-7 ]
[ 83707-04-4 ]

Yield	Reaction Conditions	Operation in experiment
89%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 72h;Inert atmosphere; Schlenk technique;	Cystamine dihydrochloride (1.13 g, 5.00 mmol) was suspended in DMF (SPPS grade, 40 mL)and degassed for 15 min by bubbling argon through it. Under stirring HOBt·H2O (2.99 g,19.5 mmol), EDC·HCl (3.77 g, 19.7 mmol), 1-adamantancarboxylic acid (3.61 g, 20.0 mmol)and DIPEA (5.24 mL, 30.0 mmol) were added and stirred for 3 d at room temperature. Afteraddition of dH2O (150 mL) and stirring for 15 min the resulting precipitate was collected byfiltration and recrystallized from ethanol. After isolation and drying under reduced pressurethe pure product was obtained as white solid.

Reference： [1]Beilstein Journal of Organic Chemistry,2014,vol. 10,p. 2428 - 2440

44
[ 1120-82-7 ]
[ 56-17-7 ]
C₂₀H₂₈N₁₀S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With triethylamine; In dichloromethane; at 20℃; for 24h;	Cystamine dihydrochloride (1.90 g, 8.43 mmol), N-hydroxymethylpyrazole(3.32 g, 33.9 mmol) and triethylamine (1.76 g,17.5 mmol) dissolved in dichloromethane (50 mL) were stirredfor 24 h at RT. The reaction mixture was extracted with water(30 mL) three times, after which the organic layer was dried overMgSO4 and the solvent was evaporated. This yielded L3 as a colorlessoil (3.96 g, 8.38 mmol, 99%), which was used without furtherpurification. 1H NMR (300 MHz, CD3CN, RT): d 2.65 (t, J = 7 Hz,4H, S-CH2), 2.94 (t, J = 7 Hz, 4H, S-CH2-CH2), 5.07 (s, 8H, N-CH2-Pz), 6.27 (t, J = 2 Hz, 4H, N-CH-CH), 7.47 (d, J = 1 Hz, 4H, N-CH),7.63 (d, J = 2 Hz, N-CH). 13C NMR (75 MHz, CD3CN, RT): d 37.1 (SCH2),50.2 (S-CH2-CH2), 68.9 (N-CH2-Pz), 106.6 (N-CH-CH), 130.8(N-CH), 140.1 (N-CH). ESI-MS found (calculated) for [M+Na]+ m/z495.0 (495.2); [MC3+Na]+ m/z 459.0 (459.2); [M2 C3+Na]+ m/z422.9 (423.2); [M3 C3+Na]+ m/z 387.0 (387.2); [M4 C3+Na]+m/z 350.9 (351.2). IR (neat, cm1): 3110w, 2941w, 1513m,1393m, 1251m, 1121m, 1084s, 1046s, 962m, 743vs, 653m, 614s.

Reference： [1]Inorganica Chimica Acta,2015,vol. 428,p. 193 - 202

45
[ 85264-33-1 ]
[ 56-17-7 ]
C₂₈H₄₄N₁₀S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With triethylamine; In dichloromethane; at 20℃; for 24h;	General procedure: L4 was synthesized in the same manner as L3 starting from Nhydroxymethyl-3,5-dimethylpyrazole (2.89 g, 23.1 mmol), cystaminedihydrochloride (1.27 g, 5.64 mmol) and triethylamine(1.6 mL, 11.5 mmol) in 50 mL dichloromethane. This yielded L4as a viscous, colorless oil (3.22 g, 5.51 mmol, 98%), which was usedwithout further purification. 1H NMR (300 MHz, CD3CN, RT): d 2.11(s, 12H, C-CH3), 2.20 (s, 12H, C-CH3), 2.40 (t, J = 7 Hz, 4H, S-CH2),2.86 Hz (t, J = 7 Hz, 4H, S-CH2-CH2), 4.88 (s, 8H, N-CH2-Pz), 5.81 (s, 4H, N-C(CH3)-CH). 13C NMR (75 MHz, CD3CN, RT): d 11.2 (CCH3),13.7 (C-CH3), 36.9 (S-CH2), 49.9 (S-CH2-CH2), 66.3 (N-CH2-Pz), 106.4 (N-C(CH3)-CH), 140.7 (N-C(CH3)), 147.8 (N-C(CH3)).ESI-MS found (calculated) for [MC5H4+Na]+ m/z 543.0 (543.3);[M2 C5H4+Na]+ m/z 479.0 (479.3); [M3 C5H4+Na]+ m/z 414.9(415.2); [M4 C5H4+Na]+ m/z 350.9 (351.2). IR (neat, cm1):2919m, 1555s, 1456s, 1421s, 1376s, 1314s, 1248s, 1096s, 1029s,975s, 779vs, 732s, 626m.

Reference： [1]Inorganica Chimica Acta,2015,vol. 428,p. 193 - 202

46
[ 13734-34-4 ]
[ 56-17-7 ]
[ 87834-34-2 ]

Yield	Reaction Conditions	Operation in experiment
67%	With 4-methyl-morpholine; triethylamine; isobutyl chloroformate; In tetrahydrofuran; water; at -25 - 20℃;	General procedure: The corresponding Boc-protected amino acid was dissolved in anhydrous THF (10 mL) and cooled to -25 C. N-Methylmorpholine and isobutyl chloroformate were added consecutively to the stirred solution. After dropwise addition of a solution of cystaminium dichloride and Et3N in H2O (10 mL) (for 9 and 11) or 4,4?-dithiodianiline and Et3N in THF (10 mL) (for 12 and 14) to the reaction mixture, precipitation of N-methylmorpholine hydrochloride occurred. The reaction mixture was allowed to warm to r.t. within 30 min and stirred overnight at r.t. After evaporation of the solvent in vacuo, the residue was suspended in H2O (50 mL) and extracted with CH2Cl2 (1 × 50 mL, 2 × 25 mL). The combined organic layers were washed with sat. aq NaHCO3 (2 × 100 mL), 10% KHSO4 (2 × 100 mL), H2O (50 mL), and brine (50 mL). The solvent was dried (Na2SO4) and evaporated in vacuo. The residues were purified by column chromatography on silica gel, preparative HPLC, or recrystallization. Disulfide 9 of (S)-N-(tert-Butyloxycarbonylphenylalanyl)cysteamine From Boc-Phe-OH (0.50 g, 1.88 mmol), N-methylmorpholine (0.19 g, 0.21 mL, 1.88 mmol), isobutyl chloroformate (0.29 g, 0.27 mL, 2.1 mmol), cystaminium dichloride (0.21 g, 0.94 mmol), and Et3N (0.19 g, 0.26 mL, 1.88 mmol); purification: recrystallization from H2O; yield: 410 mg (67%, 0.63 mmol); white solid; mp 166-167 C.

Reference： [1]Synthesis,2015,vol. 47,p. 2609 - 2616

47
[ 3978-80-1 ]
[ 56-17-7 ]
(BocTyr-NH-C₂H₄-S-)2 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With 4-methyl-morpholine; triethylamine; isobutyl chloroformate In tetrahydrofuran; water at -25 - 20℃;	Disulfides 9, 11, 12, and 14; General Procedure General procedure: The corresponding Boc-protected amino acid was dissolved in anhydrous THF (10 mL) and cooled to -25 °C. N-Methylmorpholine and isobutyl chloroformate were added consecutively to the stirred solution. After dropwise addition of a solution of cystaminium dichloride and Et3N in H2O (10 mL) (for 9 and 11) or 4,4′-dithiodianiline and Et3N in THF (10 mL) (for 12 and 14) to the reaction mixture, precipitation of N-methylmorpholine hydrochloride occurred. The reaction mixture was allowed to warm to r.t. within 30 min and stirred overnight at r.t. After evaporation of the solvent in vacuo, the residue was suspended in H2O (50 mL) and extracted with CH2Cl2 (1 × 50 mL, 2 × 25 mL). The combined organic layers were washed with sat. aq NaHCO3 (2 × 100 mL), 10% KHSO4 (2 × 100 mL), H2O (50 mL), and brine (50 mL). The solvent was dried (Na2SO4) and evaporated in vacuo. The residues were purified by column chromatography on silica gel, preparative HPLC, or recrystallization.

Reference： [1]Furtmann, Norbert; Gilberg, Erik; Spütz, Nicola; Gütschow, Michael [Synthesis, 2015, vol. 47, # 17, p. 2609 - 2616]

48
[ 56-17-7 ]
[ 13139-14-5 ]
C₃₆H₄₈N₆O₆S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69.0%		General procedure: The corresponding Boc-protected amino acid, N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU) (0.84 g, 2.2 mmol) and i-Pr2NEt (0.32 g, 0.43 mL, 2.5 mmol) were dissolved in anhydrous DMF (25 mL) and stirred at r.t. After 15 min, 4,4?-dithiodianiline (0.25 g, 1.0 mmol) (for 10) or cystaminium dichloride (0.23 g, 1.0 mmol) (for 13) was added and the mixture was stirred overnight at r.t. After evaporation of the solvent in vacuo, the residue was suspended in H2O (50 mL) and extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were washed with aq 2 M NaOH (2 × 150 mL), 10% KHSO4 (2 × 150 mL), H2O (50 mL), and brine (50 mL). The solvent was dried (Na2SO4) and evaporated in vacuo. The crude products were recrystallized from EtOAc-PE.

Reference： [1]Synthesis,2015,vol. 47,p. 2609 - 2616

49
[ 1345866-66-1 ]
[ 56-17-7 ]
C₂₄H₂₄N₁₀O₂S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 18h;
90%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In chloroform at 20℃;

Reference： [1]Fu, Jiaqi; Yu, Changmin; Li, Lin; Yao, Shao Q. [Journal of the American Chemical Society, 2015, vol. 137, # 37, p. 12153 - 12160]
[2]Dai, Xiaoyang; Kong, Yulong; Liao, Jia-Yu; Qian, Linghui; Shao, Jinning; Wang, Wenchao; Weng, Qinjie; Yan, Jiaqi; Yao, Shao Q.; Zeng, Kui; Zeng, Su; Zhang, Ying [Chemical Communications, 2022, vol. 58, # 9, p. 1314 - 1317]

50
[ 56-17-7 ]
[ 24801-88-5 ]
C₂₄H₅₄N₄O₈S₂Si₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92.8%		An N2-purged 2 l jacketed four-neck flask with precision glass stirrer, reflux condenser, internal thermometer and dropping funnel is initially charged with cystamine dihydrochloride (108.39 g, 0.47 mol, 1.00 eq) which was dissolved in demineralized water (940 ml). By means of a dropping funnel, 50% KOH solution (92.31 g, 0.82 mol, 1.75 eq) is metered in at 17-20 C. and the mixture is stirred for 15 min. Then 3-isocyanatopropyltriethoxysilane (221.05 g, 0.85 mol, 1.8 eq) is metered in at such a rate that an internal temperature of 30 C. is not exceeded. Thereafter, the mixture is stirred at 23 C. for one hour. The white suspension is filtered under pressure, rinsed with 200 ml of demineralized water and dried with dry N2 for 2 h. The filtercake is washed with three portions of hexane (each of 150 ml) and dried again with dry N2 for 1 h. The [(EtO)3Si-(CH2)3-NH-C(?O)-NH-(CH2)2-S-]2 product is a fine white powder (254.78 g, 92.8% of theory);1H NMR (deltappm, 500 MHz, CDCl3): 0.64 (4H, t), 1.22 (18H, t), 1.61 (4H, m), 2.78 (4H, m), 3.15 (4H, m), 3.52 (4H, m), 3.81 (12H, q), 5.2-6.5 (4H, br);13C NMR (deltappm, 125 MHz, CDCl3): 7.7 (2C), 18.3 (6C), 23.8 (2C), 38.8 (2C), 38.9 (2C), 42.8 (2C), 58.3 (6C), 159.0 (2C). 29Si NMR (deltappm, 100 MHz, CDCl3): -45.7 (97.4% silane), -53.5 (2.6% M structures); Soluble fractions in CDCl3 using TPPO internal standard: 94.4%; (0092) Water content (DIN 51777): 0.4%; (0093) Initial melting point: 106-110 C.; (0094) Residual isocyanate content: 0.04%
90.7%		An N2-purged 1 l jacketed four-neck flask with precision glass stirrer, reflux condenser, internal thermometer and dropping funnel is initially charged with cystamine dihydrochloride (108.39 g, 0.47 mol, 1.00 eq) which was dissolved in demineralized water (382 ml). By means of a dropping funnel, 50% KOH solution (92.31 g, 0.82 mol, 1.75 eq) is metered in at 15-23 C. and the mixture is stirred for 30 min. Then 3-isocyanatopropyltriethoxysilane (221.05 g, 0.85 mol, 1.8 eq) is metered in at such a rate that an internal temperature of 30 C. is not exceeded. Thereafter, the mixture is stirred at 24 C. for one hour. The white suspension is filtered under pressure, rinsed with three portions of demineralized water (340 ml in total) and dried with dry N2 for 2 h. The filtercake is dried in an N2 stream in a rotary evaporator at 35 C. and 166 mbar for 7 h, at 35 C. and 150 mbar for 10 h and at 35 C. and 100 mbar for 9 h. The [(EtO)3Si-(CH2)3-NH-C(?O)-NH-(CH2)2-S-]2 product is a fine white powder (246.38 g, 90.7% of theory);1H NMR (deltappm, 500 MHz, DMSO-d6): 0.52 (4H, t), 1.14 (18H, t), 1.42 (4H, m), 2.74 (4H, m), 2.96 (4H, m), 3.29 (4H, m), 3.74 (12H, q), 6.05 (4H, m);13C NMR (deltappm, 125 MHz, DMSO-d6): 7.3 (2C), 18.2 (6C), 23.5 (2C), 38.5 (2C), 39.6 (2C), 42.0 (2C), 57.7 (6C) 157.9 (2C).29Si NMR (deltappm, 100 MHz, DMSO-d6): -45.3 (100% silane);Soluble fractions in d6-DMSO using TPPO internal standard: 86.0%;Water content (DIN 51777): 0.7%;Initial melting point: 97 C.;Residual isocyanate content: 0.08%
90.7%		Comparative Example 1 Preparation of [(EtO)3Si-(CH2)3-NH-C(=O)-NH-(CH2)2-S-]2 in water An N2-purged 1 l jacketed four-neck flask with precision glass stirrer, reflux condenser, internal thermometer and dropping funnel is initially charged with cystamine dihydrochloride (108.39 g, 0.47 mol, 1.00 eq) which was dissolved in demineralized water (382 ml). By means of a dropping funnel, 50% KOH solution (92.31 g, 0.82 mol, 1.75 eq) is metered in at 15-23 C. and the mixture is stirred for 30 min. Then 3-isocyanatopropyltriethoxysilane (221.05 g, 0.85 mol, 1.8 eq) is metered in at such a rate that an internal temperature of 30 C. is not exceeded. Thereafter, the mixture is stirred at 24 C. for one hour. The white suspension is filtered under pressure, rinsed with three portions of demineralized water (340 ml in total) and dried with dry N2 for 2 h. The filtercake is dried in an N2 stream in a rotary evaporator at 35 C. and 166 mbar for 7 h, at 35 C. and 150 mbar for 10 h and at 35 C. and 100 mbar for 9 h. The [(EtO)3Si-(CH2)3-NH-C(?O)-NH-(CH2)2-S-]2 product is a fine white powder (246.38 g, 90.7% of theory); (0163) 1H NMR (deltappm, 500 MHz, DMSO-d6): 0.52 (4H, t), 1.14 (18H, t), 1.42 (4H, m), 2.74 (4H, m), 2.96 (4H, m), 3.29 (4H, m), 3.74 (12H, q), 6.05 (4H, m); (0164) 13C NMR (deltappm, 125 MHz, DMSO-d6): 7.3 (2C), 18.2 (6C), 23.5 (2C), 38.5 (2C), 39.6 (2C), 42.0 (2C), 57.7 (6C) 157.9 (2C). (0165) 29Si NMR (deltappm, 100 MHz, DMSO-d6): -45.3 (100% silane); (0166) Soluble fractions in d6-DMSO using TPPO internal standard: 86.0%; (0167) Water content (DIN 51777): 0.7%; (0168) Initial melting point: 97 C.; (0169) Residual isocyanate content: 0.08%.

Reference： [1]Patent: US2015/329574,2015,A1 .Location in patent: Paragraph 0087-0094
[2]Patent: US2015/329571,2015,A1 .Location in patent: Paragraph 0149-0156
[3]Patent: US2015/329573,2015,A1 .Location in patent: Paragraph 0162-0169

51
[ 56-17-7 ]
[ 16269-66-2 ]
C₁₀H₁₄N₄S₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In N,N-dimethyl-formamide at 60℃; for 48h; Inert atmosphere;	1 Example 1 Compound 4 Example 1 Compound 4 (0176) (0177) A mixture of 4-chlorothieno[3,2-d]pyrimidine (0.698 g, 4.09 mmol) and cystamine dihydrochloride (0.462 g, 2.05 mmol) was suspended in 10 mL of dry dimethylformamide (DMF), and TEA (1.14 mL, 8.2 mmol) was added. The reaction was heated under nitrogen for 2 days at 60 °C, evaporated to dryness, and triturated with 50 mL of water to remove the symmetrical disulfide. The precipitate was washed with 2×25 mL water, and the combined aqueous fractions were treated with tris-2-carboxyethylphosphine hydrochloride (0.59 g, 2.05 mmol) and 7 mL 1 M sodium hydroxide to bring the solution to pH 7. After 20 min the reaction was extracted with 3 × 30 mL EtOAc, the combined organics were rinsed with 40 mL brine, dried over sodium sulfate, filtered, and evaporated to 0.216 g of colorless solid which was purified by silica gel chromatography (95:5 DCM : MeOH, 14.5 × 4.25 cm column) to yield 150 mg of white solid. This was further purified by reverse phase HPLC to yield a total of 89 mg of Compound 4 as a white solid. ES (+) MS m/e = 212 (M+1).

Reference： [1]Current Patent Assignee: SUNESIS PHARMACEUTICALS INC - EP2257637, 2015, B1 Location in patent: Paragraph 0176; 0177

52
[ 56512-49-3 ]
[ 56-17-7 ]
(E)-4-((4-(dimethylamino)phenyl)diazenyl)-N-(2-mercaptoethyl)benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%		47a: (E)-4-((4-(Dimethylamino)phenyl)diazenyl)-N-(2-mercaptoethyl)benzenesulfonamide (0390) To a cooled to 0 C. solution of Dabsyl chloride (1 eq., 100 mg, 0.309 mmol) in dry ACN (3 mL), TEA (7 eq., 218 mg, 0.3 mL, 2.16 mmol) and cystamine dihydrochloride (5 eq., 347 mg, 1.54 mmol) were subsequently added. After 2 hours of stirring, DTT (6 eq., 285 mg, 0.275 mL, 1.85 mmol) was added to the reaction mass. The obtained solution was stirred for another 2 hours, evaporated and the obtained crude product was purified by flash chromatography (cyclohexane-EtOAc) to yield 47a (105.9 mg, 94%) as an orange solid.

Reference： [1]Patent: US2016/145199,2016,A1 .Location in patent: Paragraph 0390

53
[ 33282-16-5 ]
[ 56-17-7 ]
N,N'-(disulfanediylbis(ethane-2,1-diyl))bis(5-(4-methoxyphenyl)isoxazole-3-carboxamide) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; dimethyl sulfoxide; at 20℃; for 24h;Cooling with ice;	General procedure: To a solution of oximic acid (4a-k, 3.6 mmol in 50 mL THF) was added HOBt (3.6 mmol) in an ice-cooled bath. Next, a mixture of cystamine dihydrochloride (1.8 mmol) and TEA (1 mL) in DMSO (6 mL) were added, followed by the addition of EDCI (4.0 mmol). After stirring for 24 h at room temperature, the reaction was quenched with water and extracted with EtOAc (60 mL × 3). The combined organic extracts were washed with brine (50 mL), dried over MgSO4 and then evaporated. The resulting residue was then purified by column chromatography on silica gel as indicated.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 4372 - 4376

54
[ 56-17-7 ]
[ 27069-16-5 ]
N,N'-(disulfanediylbis(ethane-2,1-diyl))bis(5-(4-methoxyphenyl)-1H-pyrazole-3-carboxamide) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; dimethyl sulfoxide; at 20℃; for 24.0h;Cooling with ice;	General procedure: To a solution of oximic acid (4a-k, 3.6 mmol in 50 mL THF) was added HOBt (3.6 mmol) in an ice-cooled bath. Next, a mixture of cystamine dihydrochloride (1.8 mmol) and TEA (1 mL) in DMSO (6 mL) were added, followed by the addition of EDCI (4.0 mmol). After stirring for 24 h at room temperature, the reaction was quenched with water and extracted with EtOAc (60 mL × 3). The combined organic extracts were washed with brine (50 mL), dried over MgSO4 and then evaporated. The resulting residue was then purified by column chromatography on silica gel as indicated.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 4372 - 4376

55
[ 33282-15-4 ]
[ 56-17-7 ]
N,N'-(disulfanediylbis(ethane-2,1-diyl))bis(5-(4-hydroxyphenyl)isoxazole-3-carboxamide) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
9%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; dimethyl sulfoxide; at 20℃; for 24h;Cooling with ice;	General procedure: To a solution of oximic acid (4a-k, 3.6 mmol in 50 mL THF) was added HOBt (3.6 mmol) in an ice-cooled bath. Next, a mixture of cystamine dihydrochloride (1.8 mmol) and TEA (1 mL) in DMSO (6 mL) were added, followed by the addition of EDCI (4.0 mmol). After stirring for 24 h at room temperature, the reaction was quenched with water and extracted with EtOAc (60 mL × 3). The combined organic extracts were washed with brine (50 mL), dried over MgSO4 and then evaporated. The resulting residue was then purified by column chromatography on silica gel as indicated.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 4372 - 4376

56
[ 4053-08-1 ]
[ 56-17-7 ]
[ 950781-06-3 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: cystamine dihydrochioride With potassium hydroxide In ethanol at 50℃; for 0.5h; Inert atmosphere; Stage #2: p-chloro-1,8-naphthalicanhydride In ethanol for 8h; Reflux; Inert atmosphere;	1.1 Step 1: Synthesis of 6-chloro-2-(2-[2-(6-chloro-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)ethyl]disulfanyl}ethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione Procedure: 96.8 g of cystamine dihydrochloride (0.430 mol) and then 860 ml of a solution, prepared beforehand, containing 1 mol/l of potassium hydroxide (0.860 mol) in ethanol (48.16 g) are introduced into a 1 .5 litre Pignat reactor equipped with a condenser, an argon or nitrogen inlet and a mechanical stirring system. The reaction medium is then brought to 50°C and maintained at this temperature for 30 minutes. 200 g of 4-chloro-1 ,8-naphthalic anhydride (0.860 mol) are then added, using a powder funnel, and the medium is then maintained at the reflux point of ethanol for 8 hours while monitoring the reaction progress by TLC (60 F 254 plate): 9/1 dichloromethane/methanol eluent, UV revelation. The medium is then allowed to return to room temperature overnight. The reaction medium is then cooled in a bucket containing 2 litres of water + ice and is kept stirring for 2 hours. A beige-coloured precipitate is then obtained, which is filtered off on a sinter funnel and rinsed thoroughly with 1 litre of cold water. The precipitate is dried under vacuum at 40°C in the presence of P2O5 to constant weight, to obtain the expected compound in the form of a beige-coloured powder. On the basis of the NMR and mass spectrometry, the chemical structure is in accordance with the expected product.

Reference： [1]Current Patent Assignee: L'OREAL SA - WO2018/206661, 2018, A1 Location in patent: Page/Page column 52; 54

57
[ 56-17-7 ]
[ 352305-38-5 ]

Yield	Reaction Conditions	Operation in experiment
94%	With imidazole-1-sulfonyl azide hydrochloride; copper(ll) sulfate pentahydrate; potassium carbonate; In methanol; at 20℃; for 12h;	The synthesis procedures were similar as the methods described above (Scheme S1). Typically, imidazole-1-sulfonyl azide hydrochloride chloride salt (5.0 g, 23.9 mmol) was added to cystamine dihydrochloride salt (2.2, 9.9 mmol), K2CO3 (6.1 g, 44.2 mmol) and CuSO4*5H2O (59.6 mg, 238.5 mumol) in methanol (100 mL) and the mixture was stirred at room temperature for 12 h. Next, the mixture was concentrated, diluted with H2O (200 mL), and extracted with DCM (3×100 mL). The combined organic layers were dried (MgSO4), filtered and concentrated. Flash chromatography gave the aimed product as a yellow oil (DCM/MeOH/NH4OH, 3/1/0.1). The yield was 1.9 g(94%, Rf=0.5). The monomer was characterized by 1H NMR spectroscopy (Fig. S4).

Reference： [1]Journal of Controlled Release,2019,vol. 293,p. 48 - 62

58
[ 4426-83-9 ]
[ 56-17-7 ]
C₂₀H₄₂N₄S₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With triethylamine In dichloromethane at 20℃; for 5.25h; Cooling with ice;

Reference： [1]Baghbanzadeh, Mostafa; Belding, Lee; Yuan, Li; Park, Junwoo; Al-Sayah, Mohammad H.; Bowers, Carleen M.; Whitesides, George M. [Journal of the American Chemical Society, 2019, vol. 141, # 22, p. 8969 - 8980]

59
[ 56-17-7 ]
[ 2752-65-0 ]
C₄₂H₅₄N₂O₇S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%		2.1) Dissolving <strong>[2752-65-0]gambogic acid</strong> (1.57 g, 2.5 mmol) in dichloromethane solution (50 mL),After cooling to 0 C,Add EDCI (623mg, 3.25mmol) and HOBT (439mg, 3.25mmol),The mixture was activated at 0 C for one hour.A solution of cystamine dihydrochloride (1.69 g, 7.5 mmol) in methanol (30 mL) was added to the mixed solution, triethylamine (500 muL, 3.75 mmol) was added, and the mixture was transferred to normal temperature and stirred for 48 h to obtain a reaction solution.2.2) The reaction solution obtained in step 2.1) .2.1 was washed 3 times with 1 mM NaHCO3 solution (20 mL), and the organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and column chromatography (petroleum ether / ethyl acetate 1: 2). Isolated and dried under vacuum to give <strong>[2752-65-0]GA</strong>-SS-NH2 (1.45 g, 76%) as a yellow solid.

Reference： [1]Patent: CN110604820,2019,A .Location in patent: Paragraph 0054; 0062-0065; 0075-0079

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	56-17-7	MDL No. :	MFCD00012905
Formula :	C₄H₁₄Cl₂N₂S₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YUFRRMZSSPQMOS-UHFFFAOYSA-N
M.W :	225.20	Pubchem ID :	5941
Synonyms :	Cystamine dihydrochloride;Cystamine (hydrochloride)	Chemical Name :	2,2'-Disulfanediyldiethanamine dihydrochloride

Num. heavy atoms :	10
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	5
Num. H-bond acceptors :	2.0
Num. H-bond donors :	2.0
Molar Refractivity :	55.87
TPSA :	102.64 Å²

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-7.23 cm/s

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	0.63
Log Po/w (WLOGP) :	1.89
Log Po/w (MLOGP) :	0.61
Log Po/w (SILICOS-IT) :	0.01
Consensus Log Po/w :	0.63

[ CAS No. 56-17-7 ] {[proInfo.proName]}

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[ 56-17-7 ] Synthesis Path-Upstream 1~2

[ 56-17-7 ] Synthesis Path-Downstream 1~59

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[ 56-17-7 ]

Aliphatic Chain Hydrocarbons

Sulfides

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Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Log S (ESOL) :	-1.3
Solubility :	11.2 mg/ml ; 0.0498 mol/l
Class :	Very soluble
Log S (Ali) :	-2.36
Solubility :	0.982 mg/ml ; 0.00436 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-0.99
Solubility :	23.3 mg/ml ; 0.103 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.11

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P264-P270-P301+P312-P330-P501	UN#:	N/A
Hazard Statements:	H302	Packing Group:	N/A
GHS Pictogram:

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P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
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P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
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P241	Use explosion-proof electrical/ventilating/lighting/equipment.
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P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

[ CAS No. 56-17-7 ] {[proInfo.proName]}

Quality Control of [ 56-17-7 ]

Related Doc. of [ 56-17-7 ]

Product Details of [ 56-17-7 ]

Calculated chemistry of [ 56-17-7 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 56-17-7 ]

Application In Synthesis of [ 56-17-7 ]

[ 56-17-7 ] Synthesis Path-Upstream 1~2

[ 56-17-7 ] Synthesis Path-Downstream 1~59

Related Functional Groups of [ 56-17-7 ]

Aliphatic Chain Hydrocarbons

Sulfides

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 56-17-7 ]