Name: 67385-09-5|tert-Butyl (2-mercaptoethyl)carbamate|98%
Brand: Ambeed
SKU: A705834
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1
[ 24424-99-5 ]
[ 156-57-0 ]
[ 67385-09-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: 2-mercaptoethylamine hydrochloride With sodium hydride In tetrahydrofuran at 0 - 20℃; Stage #2: di-<i>tert</i>-butyl dicarbonate In tetrahydrofuran at 0 - 20℃;
95%	With triethylamine In dichloromethane at 20℃; for 16h; Cooling with ice;	1.1 1) Synthesis of intermediate Ra-012-1 Cysteine hydrochloride Ra-016 (2.0 g, 44 mmol) And Boc anhydride(3.5 g, 16 mmol)Was dissolved in dichloromethane (20 mL)Triethylamine was slowly added under ice-water bath(2.5 mL, 18 mmol),Plus 16 hours to complete the reaction at room temperature,Followed by 0.5NHCl wash, saturated sodium chloride wash,The organic phase is dried and dried,To give a colorless oil (2.7 g, 95% yield).A colorless oil is obtained through NMR analytical Ra-012-1.
87%	With triethylamine In 1,4-dioxane; water for 2.5h; Ambient temperature;

87.1%	With triethylamine In dichloromethane at 20℃; Cooling with ice;	5.b b. Synthesis of tert-butyl 2-mercaptoethylaminoformate: [Show Image] 3.5g of ditertbutyl dicarbonate and 2.0g of 2-mercaptoethylamine hydrochloride were added to 200ml of dichloromethane, and I of triethylamine was added dropwise under ice-bath condition. The mixture was warmed to room temperature and stirred overnight. The mixture was washed with 0.5M hydrochloric acid aqueous solution and then with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and distilled to remove the solvent to obtain 2.7g of oily liquid, yield 87.1%.
87.1%	With triethylamine In dichloromethane at 20℃; Cooling with ice;	5.b 3.5 g of ditertbutyl dicarbonate and 2.0 g of 2-mercaptoethylamine hydrochloride were added to 200 ml of dichloromethane, and I of triethylamine was added dropwise under ice-bath condition. The mixture was warmed to room temperature and stirred overnight. The mixture was washed with 0.5M hydrochloric acid aqueous solution and then with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and distilled to remove the solvent to obtain 2.7 g of oily liquid, yield 87.1%.
87%	With triethylamine In dichloromethane at 20℃; Cooling with ice;	1.a The protection of a.Boc 2-mercapto-aminoethane preparation: In the reaction bottle two di-tert-butyl dicarbonate to 35.3g, 2-mercapto-ethylamine hydrochloride 20.4g and 200 ml dichloromethane, under the conditions and in the ice batch add triethylamine 25 ml, stirring the mixture at room temperature for reaction sleepovers, adding excessive 0.5M hydrochloric acid solution, an organic layer is washed with saturated sodium chloride solution, dried anhydrous sodium sulfate, solvent evaporation to dryness Boc protection shall be 2-mercapto-ethylamine 8g (oily liquid), yield 87%.
87%	With triethylamine In dichloromethane at 20℃; Cooling with ice;	1.a Preparation of Boc protected 2-mercaptoethylamine To the reaction flask, 25 g of di-t-butyl dicarbonate, 14.4 g of 2-mercaptoethylamine hydrochloride and 140 ml of methylene chloride were added to 18 ml of triethylamine in portions under ice-cooling. The reaction was stirred overnight at room temperature, Hydrochloric acid solution, the organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness to give 5.7 g (oily liquid) of Boc-protected 2-mercaptoethylamine in 87% yield
87%	With triethylamine In 1,2-dichloro-ethane at 20℃; Cooling with ice;	1.a a.Boc protectedSynthesis of 2-mercaptoethylamine: 35.3 g di-tert-butyl dicarbonate was added to the reaction flask.2-mercaptoethylamine hydrochloride 20.4g and 200ml dichloroethane Triethylamine (25ml) was added in batches under ice-cooling and the reaction was stirred at room temperature overnight.Excessive 0.5M hydrochloric acid solution was added for washing. The organic layer was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate.The solvent was evaporated to dryness to give 8g of an oily liquid, yield 87%
74.6%	With triethylamine In dichloromethane at 20℃; for 12h;	1.S1; 2.S1; 3.S1; 4.S1; 5.S1; 6.S1; 7.S1;8.S1 S1 Preparation of tert-butoxycarbonylaminoethanethiol: Weigh 100g of aminoethanethiol hydrochloride, transfer it into a 2000mL three-necked flask, add 1000mL dichloromethane, stir at 300 rpm, add 262g triethylamine and 311g di-tert-butyl dicarbonate was reacted at room temperature for 16 hours; 500mL of water was added to the reaction solution for dilution and liquid separation. The organic phase was washed three times with 200mL of citric acid with a mass concentration of 10% (the rest being water). The phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent to obtain 174 g of 2-tert-butoxycarbonylaminoethanethiol with a yield of 75.7%.
	With triethylamine In dichloromethane for 2h; Yield given;
	Stage #1: di-<i>tert</i>-butyl dicarbonate; 2-mercaptoethylamine hydrochloride In toluene at 0℃; for 0.166667h; Stage #2: With sodium hydroxide In water; toluene at 0 - 20℃;	1A Example 1; S-[2-[(1-Iminoethyl)amino]ethyl]-2-methyl-L-cysteine, dihydrochloride; Example-1A; N-Boc-cysteamine [0048] A 3L 4-neck RB flask was purged with nitrogen for 20 min and then charged sequentially with 2-aminoethanethiol hydrochloride (113.6 g, 1 mol), di-tert-butyl-dicarbonate (218.3 g, 1 mol) and 500 mL of toluene. The mixture was cooled with an ice-water bath and purged with nitrogen for 10 min. Sodium hydroxide (2.5N, 880 mL, 2.2 mol) was added to the stirring mixture in about 1.5 h at between 0 and 11° C. After the addition of sodium hydroxide was complete, the cooling bath was removed and the resulting reaction mixture was allowed to warm up to room temperature and stirred at ambient temperature overnight. This provided a solution of the title product.
	With sodium hydroxide In water; toluene at 0 - 11℃; for 1.66667h;	1A N-BOC-CYSTEAMINE Example 1: Example 1 S-[2 " TMINOETLLYLEAMINOLETHYL]-2-METHYL-L-CYΤEINES DIHYDROCHLORIDE Example-lA) N-BOC-CYSTEAMINE [0087] A 3L 4-neck RB flask was purged with nitrogen for 20 min and then charged sequentially with 2-aminoethanethiol hydrochloride (113.6 g, 1 mol), di-tert-butyl- dicarbonate (218.3 g, 1 mol) and 500 mL of toluene. The mixture was cooled with an ice- water bath and purged with nitrogen for 10 min. Sodium hydroxide (2. 5N, 880 mL, 2.2 mol) was added to the stirring mixture in about 1.5 h at between 0 and 11 oC. After the addition of sodium hydroxide was complete, the cooling bath was removed and the resulting reaction mixture was allowed to warm up to room temperature and stirred at ambient temperature overnight. This provided a solution of the title product.
	With sodium hydroxide In water; toluene at 0 - 11℃; for 1.66667h;	1A N-BOC-CYSTEAMINE Example-lA) N-BOC-CYSTEAMINE [0085] A 3L 4-neck RB flask was purged with nitrogen for 20 min and then charged sequentially with 2-aminoethanethiol hydrochloride (113.6 g, 1 mol), di-tert-butyl- dicarbonate (218.3 G9 1 mol) and 500 mL of toluene. The mixture was cooled with an ice- water bath and purged with nitrogen for 10 min. Sodium hydroxide (2. 5N, 880 ML, 2.2 mol) was added to the stirring mixture in about 1.5 h at between 0 and 11 oC. After the addition of sodium hydroxide was complete, the cooling bath was removed and the resulting reaction mixture was allowed to warm up to room temperature and STIRRED at ambient temperature overnight. This provided a solution of the title product.
	With sodium hydroxide In water; toluene at 0 - 11℃; for 2h;	1A N-BOC-CYSTEAMINE Example-lA) N-BOC-CYSTEAMINE [0093] A 3L 4-neck RB flask was purged with nitrogen for 20 min and then charged sequentially with 2-aminoethanethiol hydrochloride (113.6 g, 1 mol), di-tert-butyl-dicarbonate (218.3 g, 1 mol) and 500 mL of toluene. The mixture was cooled with an ice-water bath and purged with nitrogen for 10 min. Sodium hydroxide (2. 5N, 880 mL, 2.2 mol) was added to the stirring mixture in about 1.5 h at between 0 and 11 oC. After the addition of sodium hydroxide was complete, the cooling bath was removed and the resulting reaction mixture was allowed to warm up to room temperature and stirred at ambient temperature overnight. This provided a solution of the title product.
	With triethylamine In methanol; ethyl acetate	21 I: 2-(tert-butoxycarbonylamino)-ethylmercaptan (A) I: 2-(tert-butoxycarbonylamino)-ethylmercaptan (A) To a solution of 2-aminoethylmercaptan hydrochloride (11.4 g, 0.1 mole) in methanol (100 ml), triethylamine (14 ml) was added, followed by di-tert-butyl dicarbonate (24 g). After standing for 1 hour at room temperature, the solvent was stripped in vacuo, and the residue was treated with ethyl acetate. Triethylamine hydrochloride was filtered off, and the filtrate was evaporated to dryness, leaving (A) as a colourless oil.
	With triethylamine In dichloromethane
	With triethylamine In methanol at 20℃; for 1h;	2 Example 2 - Synthesis of S,S-bis(2-propionamidoethyl) butanebis(thioate) (NV038, 01-038) To a solution of cysteamine hydrochloride (5.0 g, 44 mmol) in CH3OH (50 ml_) was added Et3N (4.4 g, 44 mmol), followed by (Boc)20 (10.5 g, 48.4 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo. The obtained residue was dissolved in CH2CI2, washed with 2M HCI aqueous solution and brine, dried over Na2S04, filtered and evaporated to yield tert-butyl 2- mercaptoethylcarbamate as a colorless oil which was used in the next step without further purification.

Reference： [1]Kim, Young Zu; Kim, Jae Pil [Synthetic Communications, 2002, vol. 32, # 10, p. 1601 - 1605]
[2]Current Patent Assignee: SOOCHOW UNIVERSITY (SUZHOU) - CN103922981, 2017, B Location in patent: Paragraph 0048; 0049; 0050
[3]Lopez, Susana; Simons, S. Stoney [Journal of Medicinal Chemistry, 1991, vol. 34, # 6, p. 1762 - 1767]
[4]Current Patent Assignee: QILU PHARMACEUTICAL GROUP CO LTD - EP2484678, 2012, A1 Location in patent: Page/Page column 16
[5]Current Patent Assignee: QILU PHARMACEUTICAL GROUP CO LTD - US2012/208833, 2012, A1 Location in patent: Page/Page column 11
[6]Current Patent Assignee: QILU PHARMACEUTICAL GROUP CO LTD - CN103304544, 2016, B Location in patent: Paragraph 0109; 0110; 0111
[7]Current Patent Assignee: QILU PHARMACEUTICAL GROUP CO LTD - CN103819461, 2016, B Location in patent: Paragraph 0090-0093
[8]Current Patent Assignee: QILU PHARMACEUTICAL GROUP CO LTD - CN103819462, 2017, B Location in patent: Paragraph 0080-0083
[9]Current Patent Assignee: XIAN BIRDO MEDICINE TECH - CN111518055, 2020, A Location in patent: Paragraph 0058-0062; 0093; 0100
[10]De Kimpe, Norbert G.; Rocchetti, Maria Teresa [Journal of Agricultural and Food Chemistry, 1998, vol. 46, # 6, p. 2278 - 2281]
[11]Current Patent Assignee: PFIZER INC - US2004/225150, 2004, A1 Location in patent: Page 4
[12]Current Patent Assignee: PFIZER INC - WO2004/80953, 2004, A1 Location in patent: Page 18-19
[13]Current Patent Assignee: PFIZER INC - WO2004/80955, 2004, A1 Location in patent: Page 18
[14]Current Patent Assignee: PFIZER INC - WO2004/80954, 2004, A1 Location in patent: Page 20
[15]Current Patent Assignee: LEO FONDET; SOCIETE ANONYME DE RECHERCHES POUR APPLICATIONS THERAPEUTIQUES (SARATH) - US4246262, 1981, A
[16]El-Gendy, Bahaa El-Dien M.; Ghazvini Zadeh, Ebrahim H.; Sotuyo, Ania C.; Pillai, Girinath G.; Katritzky, Alan R. [Chemical Biology and Drug Design, 2013, vol. 81, # 5, p. 577 - 582]
[17]Current Patent Assignee: ABLIVA AB - WO2015/155231, 2015, A1 Location in patent: Page/Page column 62; 63

2
[ 24424-99-5 ]
[ 60-23-1 ]
[ 67385-09-5 ]

Yield	Reaction Conditions	Operation in experiment
98%	In tetrahydrofuran; lithium hydroxide monohydrate at 20℃; for 4h; Inert atmosphere;
98%	In lithium hydroxide monohydrate at 20℃; for 4h; Inert atmosphere;
79.9%	With triethylamine In dichloromethane at 12℃; for 16h;	1.25.1 1.25.1 Preparation of Compound 2 To a solution of compound 1 (10 g, 129.8 mmol) in DCM (150 mL) added Boc2O (28 g, 129.8 mmol) followed by TEA (19.7 g, 194.7 mmol). The mixture was stirred at 12° C. for 16 h. The mixture was concentrated to give the crude product, which was purified by chromatography on silica gel PE:EA (10:1) to give compound 2 as colorless oil (18.3 g, 79.9%).

79.9%	With triethylamine In dichloromethane at 12℃; for 16h;	I.1.25.1 1.25.1 Preparation of Compound 2 To a solution of compound 1 (10 g, 129.8 mmol) in DCM (150 mL) added Boc2O (28 g, 129.8 mmol) followed by TEA (19.7 g, 194.7 mmol). The mixture was stirred at 12° C. for 16 h. The mixture was concentrated to give the crude product, which was purified by chromatography on silica gel PE:EA (10:1) to give compound 2 as colorless oil (18.3 g, 79.9%).
26%	With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; acetonitrile at 0 - 20℃; for 4h;	87.1 rM)utyl(2-mercaptoethyl)carbamate (339): To the stirred solution of 2- aminoethane-1 -thiol (1.0 g, 12.96 mmol) in acetonitrile(10 mL)/ water (5 mL), NaHCCh (2.18 g, 25.92 mmol) was added. Then di-tert-butyldicarbonate (5.66 g, 25.92 mmol) was added slowly at 0 °C and the reaction mixture was stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC. After completion of starting material, reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 X 100 mL). The combined organic layer was dried over anhydrous NazSCh and concentrated under reduced pressure to get crude compound. The obtained crude compound was purified by silica gel column chromatography using 5% methanol in DCM to afford 600 mg (26% yield) of tert-butyl (2-mercaptoethyl) carbamate (339) as a colorless gum. rH NMR (400 MHz, CDCh) 5 ppm: 5.02 (s, 1H), 3.44 (q, J= 6.0 Hz, 2H), 2.79 (t, J= 6.4 Hz, 2H), 2.67-2.62 (m, 1H), 1.49-1.44(m, 9H).
	With N-ethyl-N,N-diisopropylamine In acetonitrile at 0℃; for 0.5h;
	With triethylamine In dichloromethane at 20℃;
	With triethylamine In dichloromethane at 20℃; Inert atmosphere;	9 REFERENCE EXAMPLE 9tert-butyl N-(2-sulfanylethyl)carbamate Into a 2000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-aminoethane-1-thiol (50 g, 648.10 mmol, 1.00 equiv), dichloromethane (1000 mL), di-tert-butyl dicarbonate (116 g, 531.51 mmol, 1.20 equiv), and TEA (134 g, 1.32 mol, 3.00 equiv). The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of 100 mL of water. The resulting mixture was washed with 2x500 mL of 0.5N hydrogen chloride and 2x500 mL of Brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:8) to give the title compound.
	In lithium hydroxide monohydrate at 20℃; for 6h; Inert atmosphere;	1 Example 1: Preparation of an amine compound represented by the formula (2-1) To a 50 mL round flask was added 17 mL of distilled water2-aminoethanethiolAnd 21.27 g of ditertiary butyl dicarbonateAnd the reaction was carried out in an argon atmosphere to separate the final product TBMC.Then add 13.69 g of the synthesized TBMC and 26.93 ml of triethylamine to the 50-mL round-bottomed flask with argon.Thereafter, an ice bath was installed and 4.15 g (0.035 mol) of divinylsulfone (DVS) was added slowly at 0 ° C.The reaction was allowed to proceed at room temperature for 24 hours. 4.149 g of high purity white powder of sulfonyldicarbamate was obtained.

Reference： [1]Wang, Yanyan; Fan, Jingwei; Darensbourg, Donald J. [Angewandte Chemie - International Edition, 2015, vol. 54, # 35, p. 10206 - 10210][Angew. Chem., 2015, vol. 127, # 35, p. 10344 - 10348,5]
[2]Hossain, Khohinur; Florean, Luca; Del Tedesco, Anna; Cattaruzza, Elti; Geppi, Marco; Borsacchi, Silvia; Canton, Patrizia; Benedetti, Alvise; Riello, Pietro; Scarso, Alessandro [Chemistry - A European Journal, 2021, vol. 27, # 71, p. 17941 - 17951]
[3]Current Patent Assignee: JOHNSON & JOHNSON INC - US2015/197493, 2015, A1 Location in patent: Paragraph 0648; 0649; 0650
[4]Current Patent Assignee: JOHNSON & JOHNSON INC - US2015/225355, 2015, A1 Location in patent: Paragraph 0644
[5]Current Patent Assignee: ELUCIDA ONCOLOGY - WO2022/93800, 2022, A2 Location in patent: Paragraph 00868-00869
[6]Saha, Uttam K.; Roy, Rene [Journal of the Chemical Society. Chemical communications, 1995, # 24, p. 2571 - 2574]
[7]Suzuki, Takayoshi; Hisakawa, Shinya; Itoh, Yukihiro; Suzuki, Nobuaki; Takahashi, Katsumasa; Kawahata, Masatoshi; Yamaguchi, Kentaro; Nakagawa, Hidehiko; Miyata, Naoki [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 15, p. 4208 - 4212]
[8]Current Patent Assignee: MERCK & CO INC - WO2016/206101, 2016, A1 Location in patent: Page/Page column 45; 46
[9]Current Patent Assignee: KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY - KR2018/103401, 2018, A Location in patent: Paragraph 0144; 0145; 0147; 0148

3
[ 67385-09-5 ]
[ 74-88-4 ]
[ 174360-08-8 ]

Yield	Reaction Conditions	Operation in experiment
47%	Stage #1: 2-[(tert-butoxycarbonyl)amino]-1-ethanethiol With sodium hydride In tetrahydrofuran at 20℃; for 1h; Cooling with ice; Inert atmosphere; Stage #2: methyl iodide In tetrahydrofuran at 20℃; for 1h; Cooling with ice;	2.b b. Synthesis of Boc protected 2-methylthioethylamine: [Show Image] 4.8g of NaH was added in batches to the solution of 28g Boc protected 2-mercaptoethylamine in anhydrous tetrahydrofuran (250ml) under ice-bath and nitrogen-protection. The temperature was increased to room temperature, and the mixture was reacted for 1 h, added dropwise with 12ml of iodomethane in tetrahydrofuran under ice-bath condition. Upon the end of the dropping, the reaction was performed at room temperature for about 1 h, and saturated sodium carbonate solution was added to quench the reaction. The reaction liquid was poured into water, and the mixture was extraced with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and distillated off the solvent to obtain oily liquid which was subjected to a column chromatography to obtain 14.2g of the desired product, yield 47%.
47%	Stage #1: 2-[(tert-butoxycarbonyl)amino]-1-ethanethiol With sodium hydride In tetrahydrofuran at 20℃; Cooling with ice; Inert atmosphere; Stage #2: methyl iodide In tetrahydrofuran at 20℃; Cooling with ice;	2.b 4.8 g of NaH was added in batches to the solution of 28 g Boc protected 2-mercaptoethylamine in anhydrous tetrahydrofuran (250 ml) under ice-bath and nitrogen-protection. The temperature was increased to room temperature, and the mixture was reacted for 1 h, added dropwise with 12 ml of iodomethane in tetrahydrofuran under ice-bath condition. Upon the end of the dropping, the reaction was performed at room temperature for about 1 h, and saturated sodium carbonate solution was added to quench the reaction. The reaction liquid was poured into water, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and distillated off the solvent to obtain oily liquid which was subjected to a column chromatography to obtain 14.2 g of the desired product, yield 47%.
47%	Stage #1: 2-[(tert-butoxycarbonyl)amino]-1-ethanethiol With sodium hydride In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; Cooling with ice; Stage #2: methyl iodide In tetrahydrofuran Cooling with ice; Inert atmosphere;	1.b Preparation of protected 2-methylthioethylamine: Ice bath, nitrogen protection conditions, NaH1.2 g was added portionwise to a solution of Boc-protected 2-mercaptoethylamine in 7 g of anhydrous tetrahydrofuran (250 ml) and stirred at room temperature for 1 h,Under ice-cooling, 3 ml of iodine-fired tetrahydrofuran solution was added dropwise, The reaction is about 1h, the saturated sodium carbonate solution is added to quench the reaction, the reaction solution is poured into water and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness to obtain the oily liquid. Column chromatography gave 3.6 g of Boc-protected 2-methylthioethylamine in 47% yield.

47%	Stage #1: 2-[(tert-butoxycarbonyl)amino]-1-ethanethiol With sodium hydride In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; Cooling with ice; Stage #2: methyl iodide In tetrahydrofuran at 20℃; for 1h; Cooling with ice; Inert atmosphere;	1.b b. Synthesis of Boc protected 2-methylthioethylamine: Under an ice bath and nitrogen atmosphere, NaH 4.8g was added in portions to Boc protected 2-mercaptoethylamine 28gIn a solution of anhydrous tetrahydrofuran (250 ml), and the reaction is heated to room temperature for 1 h.A 12 ml tetrahydrofuran solution of methyl iodide was added dropwise under ice-cooling and the reaction was allowed to proceed for about 1 hour at room temperature after completion of the dropwise addition.The reaction was quenched by the addition of saturated sodium carbonate solution, the reaction was poured into water and extracted with ethyl acetate.The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated to give an oily liquid.Column chromatography gave the desired product 14.2 g, yield 47%.
	With N-ethyl-N,N-diisopropylamine In acetonitrile for 3h; Ambient temperature; Yield given;

Reference： [1]Current Patent Assignee: QILU PHARMACEUTICAL GROUP CO LTD - EP2484678, 2012, A1 Location in patent: Page/Page column 16
[2]Current Patent Assignee: QILU PHARMACEUTICAL GROUP CO LTD - US2012/208833, 2012, A1 Location in patent: Page/Page column 11
[3]Current Patent Assignee: QILU PHARMACEUTICAL GROUP CO LTD - CN103819461, 2016, B Location in patent: Paragraph 0090; 0094-0096
[4]Current Patent Assignee: QILU PHARMACEUTICAL GROUP CO LTD - CN103819462, 2017, B Location in patent: Paragraph 0084-0086
[5]Saha, Uttam K.; Roy, Rene [Journal of the Chemical Society. Chemical communications, 1995, # 24, p. 2571 - 2574]

4
[ 67385-10-8 ]
[ 67385-09-5 ]

Yield	Reaction Conditions	Operation in experiment
96%	With hydrogen In toluene for 0.5h; Heating;
93%	With 1,4-dithio-D,L-threitol In N,N-dimethyl-formamide at 90℃; for 12h;
93%	With diothiothreitol In N,N-dimethyl-formamide at 90℃; Inert atmosphere;

89%

With tributylphosphine; sodium hydrogencarbonate In isopropyl alcohol for 0.833333h;

Reference： [1]Arisawa, Mieko; Sugata, Chiyoshi; Yamaguchi, Masahiko [Tetrahedron Letters, 2005, vol. 46, # 36, p. 6097 - 6099]
[2]Ishikawa, Fumihiro; Haushalter, Robert W.; Burkart, Michael D. [Journal of the American Chemical Society, 2012, vol. 134, # 2, p. 769 - 772]
[3]Ishikawa, Fumihiro; Haushalter, Robert W.; Lee, D. John; Finzel, Kara; Burkart, Michael D. [Journal of the American Chemical Society, 2013, vol. 135, # 24, p. 8846 - 8849]
[4]Englebretsen, Darren R.; Robillard, George T. [Tetrahedron, 1999, vol. 55, # 21, p. 6623 - 6634]

5
[ 67385-09-5 ]
[ 67929-87-7 ]
3-(2-tert-butoxycarbonylamino-ethylsulfanyl)-5-methoxy-1H-indole-2-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With N-chloro-succinimide In dichloromethane at 0℃; for 1h;

Reference： [1]Schlosser, Kevin M.; Krasutsky, Alexei P.; Hamilton, Harriet W.; Reed, Jessica E.; Sexton, Karen [Organic Letters, 2004, vol. 6, # 5, p. 819 - 821]

6
[ 1777-03-3 ]
[ 67385-10-8 ]
(2-triethylsilanylethynylsulfanyl-ethyl)-carbamic acid <i>tert</i>-butyl ester [ No CAS ]
[2-(1-triethylsilanyl-vinylsulfanyl)-ethyl]-carbamic acid <i>tert</i>-butyl ester [ No CAS ]
[ 67385-09-5 ]

Yield	Reaction Conditions	Operation in experiment
1: 77% 2: 24.4 mg 3: 2.5 mg	With 1,1'-bis-(diphenylphosphino)ferrocene; hydridotetakis(triphenylphosphine)rhodium(I) In acetone for 1h; Heating;

Reference： [1]Arisawa, Mieko; Fujimoto, Kenji; Morinaka, Satoshi; Yamaguchi, Masahiko [Journal of the American Chemical Society, 2005, vol. 127, # 35, p. 12226 - 12227]

7
[ 67385-09-5 ]
[ 34237-59-7 ]
[ 439948-77-3 ]

Yield	Reaction Conditions	Operation in experiment
94%	With N-ethyl-N,N-diisopropylamine In chloroform for 12h;
94%	With N-ethyl-N,N-diisopropylamine In chloroform for 12h;
94%	With N-ethyl-N,N-diisopropylamine In chloroform for 12h; Inert atmosphere;	1 2,6-Dinitro-4-t-butyl-1-(2-t-butoxycarbonylaminoethyl)sulfanyl benzene (12) 2,6-Dinitro-4-t-butyl-1-(2-t-butoxycarbonylaminoethyl)sulfanyl benzene (12) Compound 11 (13 mmol), 2-Boc-aminoethanthiol (16 mmol) and DIEA (13 mmol) were dissolved in 50 ml chloroform. The solution was stirred under nitrogen for 12 hours. The solution was washed with 0.5 M NaOH, 10% citric acid, sat. Na2CO3 and sat. NaCl, and dried with MgSO4. The solution volume was reduced to 15 ml by rotary evaporation. After addition of 80 ml hexane the product crystallized as a bright yellow solid in. 94% yield. 1H NMR (500 MHz, CDCl3): δ 7.81(s,2H), 4.87(s,1H), 3.31(t,2H), 310(t,2H), 1.44(s,9H), 1.39(s,9H). ESI-MS: m/z: 422.4(M+Na+).

Reference： [1]Yin, Hang; Frederick, Kendra K.; Liu, Dahui; Wand, A. Joshua; DeGrado, William F. [Organic Letters, 2006, vol. 8, # 2, p. 223 - 225]
[2]Yin, Hang; Gerlach, Lars Ole; Miller, Meredith W.; Moore, David T.; Liu, Dahui; Vilaire, Gaston; Bennett, Joel S.; DeGrado, William F. [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 13, p. 3380 - 3382]
[3]Current Patent Assignee: UNIVERSITY OF PENNSYLVANIA - US9241917, 2016, B2 Location in patent: Page/Page column 83-84; 107

8
[ 67385-09-5 ]
[ 119111-31-8 ]
[ 866415-66-9 ]

Yield	Reaction Conditions	Operation in experiment
65%	With 1,1-bis(tert-butylperoxy)cyclohexane In toluene at 110℃; for 4h;

Reference： [1]Wolfenden, Mark L.; Cloninger, Mary J. [Journal of the American Chemical Society, 2005, vol. 127, # 35, p. 12168 - 12169]

9
[ 67385-09-5 ]
allyl-2,3,4,6-tetra-O-acetyl-α-D-glucopyranoside [ No CAS ]
[ 866415-67-0 ]

Yield	Reaction Conditions	Operation in experiment
74%	With 1,1-bis(tert-butylperoxy)cyclohexane In toluene at 110℃; for 4h;

Reference： [1]Wolfenden, Mark L.; Cloninger, Mary J. [Journal of the American Chemical Society, 2005, vol. 127, # 35, p. 12168 - 12169]

10
[ 67385-09-5 ]
2,3,4,6-tetra-O-acetyl-1-O-allyl-α-D-galactopyranoside [ No CAS ]
[ 866415-68-1 ]

Yield	Reaction Conditions	Operation in experiment
76%	With 1,1-bis(tert-butylperoxy)cyclohexane In toluene at 110℃; for 4h;

Reference： [1]Wolfenden, Mark L.; Cloninger, Mary J. [Journal of the American Chemical Society, 2005, vol. 127, # 35, p. 12168 - 12169]

11
[ 2127-03-9 ]
[ 67385-09-5 ]
[ 535943-48-7 ]

Yield	Reaction Conditions	Operation in experiment
83%	With sodium dihydrogenphosphate In methanol Inert atmosphere;	12 tert-Butyl 2-(pyridin-2-yldisulfanyl)ethylcarbamate (217) [268] To the solution of 2,2'-dithiolpyridine (3.97 g, 18.02 mmol) in 100 ml of methanol and 80 ml of 1 M NaH2PO4, pH 6.8 was added tert-Butyl 2-mercaptoethylcarbamate (1.00 g, 5.65 mmol) in 50 ml of methanol. The mixture was stirred under Ar overnight, concentrated, extracted with dichloromethane, dried over MgSO4, filtered, evaporated and purified on SiO2 chromatography eluted with EtAc/Hexane (1 : 10 to 1 :6) to afford 1.341 g (83%) of the title compound. 1H NMR (CDCl3) 8.39 (m, IH), 7.56 (m, IH), 7.49 (m, IH), 7.03 (m, IH), 7.00 (m, IH), 3.34 (m, 2H), 2.84 (m, 2H),1.37 (s, 9H); 13C NMR 160.05, 159.39, 159.07, 149.87, 137.21, 120.78, 79.48, 39.58, 38.96, 28.57; MS m/z+ 309.2 (M + Na).
61.9%	In methanol at 20℃; for 3h;	Synthesis of Intermediate V-1 2-(2-Pyridyldisulfanyl)pyridine (746 mg, 3.38 mmol) was dissolved in MeOH (15 mL) and to it was added tert-butyl N-(2-sulfanylethyl)carbamate (200 mg, 1.13 mmol). The reaction was stirred for 3 h at room temperature. The mixture was concentrated and the residue purified by column chromatography (0-50% EtOAc/hexanes) to give tert-butyl N-[2-(2-pyridyldisulfanyl)ethyl]carbamate (200 mg, yield: 61.9%). MS m/z 287.1 [M+H]+.
	In methanol at 20℃;

Reference： [1]Current Patent Assignee: IMMUNOGEN INC - WO2010/91150, 2010, A1 Location in patent: Page/Page column 152
[2]Current Patent Assignee: CYBREXA 3 - US2021/9536, 2021, A1 Location in patent: Paragraph 0320-0321
[3]Suzuki, Takayoshi; Hisakawa, Shinya; Itoh, Yukihiro; Suzuki, Nobuaki; Takahashi, Katsumasa; Kawahata, Masatoshi; Yamaguchi, Kentaro; Nakagawa, Hidehiko; Miyata, Naoki [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 15, p. 4208 - 4212]

12
[ 67929-86-6 ]
[ 67385-09-5 ]
3-(2-tert-butoxycarbonylamino-ethylsulfanyl)-5-methoxy-1H-indole-2-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With N-chloro-succinimide In dichloromethane at -78 - 0℃;

Reference： [1]Current Patent Assignee: Wall Hamilton, Harriet; Krasutsky, Alexei P.; Reed, Jessica; Schlosser, Kevin - US2004/133014, 2004, A1 Location in patent: Page 5

13
[ 67385-09-5 ]
[ 78-95-5 ]
[ 364068-28-0 ]

Yield	Reaction Conditions	Operation in experiment
96.7%	In toluene at 0 - 20℃;	1B Example-1B [0050] The product solution of Example-1A was cooled with an-ice-water bath. A sample of chloroacetone (101.8 g, 1.1 mol) was added to the vigorously stirred reaction mixture over about 50 min at between 8 and 11° C. After the addition of chloroacetone was completed, the cooling bath was removed and the resulting reaction mixture was allowed to stir at room temperature overnight. The toluene layer was separated, washed with water (250 mL) and concentrated on a rotary evaporator at 85° C. under house vacuum followed by high vacuum to give the crude titled compound (225.7 g, 96.7%). 1H NMR (CDCl3, 400 MHz) δ 4.95 (bs, 1H), 3.20 (m, 4H), 2.54 (t, 2H), 2.20 (s, 3H), 1.35 (s, 9H).
96.7%	In H₂₀; toluene at 8 - 11℃; for 0.833333h;	1B Example-1B) [0088] The product solution of Example-lA was cooled with an ice-water bath. A sample of chloroacetone (101. 8 g, 1.1 mol) was added to the vigorously stirred reaction mixture over about 50 min at between 8 and 11 oC. After the addition of chloroacetone was completed, the cooling bath was removed and the resulting reaction mixture was allowed to stir at room temperature overnight. The toluene layer was separated, washed with water (250 mL) and concentrated on a rotary evaporator at 85 oC under house vacuum followed by high vacuum to give the crude titled compound (225.7 g, 96. 7%). H NMR (CDCIS, 400 MHz) 8 4.95 (BS, 1H), 3.20 (M, 4H), 2.54 (T9 2H), 2.20 (s, 3H), 1.35 (s, 9H).
96.7%	In water; toluene at 8 - 11℃; for 0.833333h;	1B Example-lB) Example-lB) [0094] The product solution of Example-lA was cooled with an ice-water bath. A sample of chloroacetone (101. 8 g, 1.1 mol) was added to the vigorously stirred reaction mixture over about 50 min at between 8 and 11 oC. After the addition of chloroacetone was completed, the cooling bath was removed and the resulting reaction mixture was allowed to stir at room temperature overnight. The toluene layer was separated, washed with water (250 mL) and concentrated on a rotary evaporator at 85 oC under house vacuum followed by high vacuum to give the crude titled compound (225.7 g, 96. 7%). JH NMR (CDC13, 400 MHz) 124. 95 (bs, 1H), 3.20 (m, 4H), 2.54 (t, 2H), 2.20 (s, 3H), 1.35 (s, 9H).

96.7%

In water; toluene at 0 - 11℃; for 0.833333h;

1B EXAMPLE-LB) [0086] The product solution of Example-lA was cooled with an ice-water bath. A sample of chloroacetone (101. 8 g, 1. 1 mol) was added to the vigorously stirred reaction mixture over about 50 min at between 8 and 11 oC. After the addition of CHLOROACETONE was completed, the cooling bath was removed and the resulting reaction mixture was allowed to stir at room temperature overnight. The toluene layer was separated, washed with water (250 mL) and concentrated on a rotary evaporator at 85 oC under house vacuum followed by high vacuum to give the crude titled compound (225.7 g, 96. 7%). 1H NMR (CDCl3, 400 MHz) 8 4.95 (bs, 1H), 3.20 (m, 4H), 2.54 (t, 2H), 2.20 (s, 3H), 1.35 (s, 9H).

Reference： [1]Current Patent Assignee: PFIZER INC - US2004/225150, 2004, A1 Location in patent: Page 4
[2]Current Patent Assignee: PFIZER INC - WO2004/80953, 2004, A1 Location in patent: Page 19
[3]Current Patent Assignee: PFIZER INC - WO2004/80954, 2004, A1 Location in patent: Page 20-21
[4]Current Patent Assignee: PFIZER INC - WO2004/80955, 2004, A1 Location in patent: Page 18-19

14
[ 281209-13-0 ]
[ 67385-09-5 ]
C₁₆H₁₆Cl₂F₃N₃O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 40% potassium fluoride/alumina In DMF (N,N-dimethyl-formamide) at 20℃;	34 Tert-butyl 2-[6,7-dichloro-3-(trifluoromethyl)-2-quinoxalinyl]sulfonyl}ethylcarbamate To a solution of 2,6,7-trichloro-3-trifluoromethylquinoxaline (100 mg, 0.33 mmol) in DMF (3 ml) was added one small scoop of potassium fluoride 40% wt on alumina followed by tertbutyl N-(2-mercaptoethyl)carbamate (0.06 ml, 0.37 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate. Water was added, the layers were separated and the aqueous layer was extracted twice with ethyl acetate. After combining and concentrating the organic layers, the crude alkylation product was dissolved in 1,2-dichloroethane (5 ml), then mCPBA (574 mg, 1.32 mmol) was added and the mixture was stirred at room temperature overnight.The reaction mixture was quenched by addition of a saturated solution of sodium bicarbonate. The layers were separated and the aqueous layer was extracted twice with 1,2-dichloroethane. The product was purified by flash column chromatography using ethyl acetate:hexane 1:5.1H NMR (CDCl3): δ 0.39 (s, 9H), 3.80 (m, 2H), 3.99 (m, 2H), 5.20 (bs, 1H), 8.44 (s, 1H), 8.47 (s, 1H). MS (APCI negative) 472.9.

Reference： [1]Current Patent Assignee: PFIZER INC - US6927214, 2005, B1 Location in patent: Page/Page column 53

15
[ 869311-07-9 ]
[ 67385-09-5 ]
[ 869311-08-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; sodium iodide In DMF (N,N-dimethyl-formamide); dimethyl sulfoxide at 20℃;	c Intermediate 59b (0.147 g, 0.38 mmol) was suspended in DMF (5mL) and treated with sodium iodide (0.058 g, 0.384 mmol), 1,1-dimethylethyl (2-mercaptoethyl) carbamate (0.047 mL, 0.576 mmol) and potassium carbonate (0.0.265 g, 1.42 mmol). After 4.5 h at room temperature a further portion of 1,1-dimethylethyl (2-mercaptoethyl) carbamate (0.097 mL, 1.18 mmol), potassium carbonate (0.08 g, 0.57 mmol) and DMSO (5mL) was added. After stirring overnight the mixture diluted with dichloromethane and filtered. The fitlrate was evaporated and subjected to freeze- drying to remove the DMSO. The residue was purified by mass-directed autoprep eluting with formic acid/water/acetonitrile to yield the title compound (0.113 g). ESMS m/z [MH] += 465.3.

Reference： [1]Current Patent Assignee: GALAPAGOS - WO2005/108412, 2005, A1 Location in patent: Page/Page column 90

16
[ 67385-09-5 ]
[ 42835-47-2 ]
[ 885696-79-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 24h;	16.b b) 9-(2-tert-Butoxycarbonylamino-ethylsulfanyl)-5-methyl-1 -oxo-6,7-dihydro-1 H,5H- pyrido[3,2,1-//]quinoIine-2-carboxyIic acid ethyl ester; A suspension of Intermediate 16a (1.1 g), fe/t-butyl Λ/-(2-mercaptoethyl)-carbamate (2.89 mL) and potassium carbonate (2.36 g) in dimethylsulfoxide (60 mL) was heated at 1000C for 24 h. The reaction mixture was cooled, filtrated then partitionned between water and DCM. The combined organic extracts were dried (MgSO4), concentrated in vacuo and the residue was purified by chromatography (silica gel, 0 to 3% [9:1 MeOH/20M aqueous ammonia] in DCM to give the title compound as a beige solid (1.7 g) contaminated with terf-butyl /V-(2-mercaptoethyl)-carbamate (0.8 g); ESMS m/z 447.3 [M+H]+.
	With potassium carbonate In dimethyl sulfoxide at 100℃; for 24h;	1.b b) Ethyl 9-(2-te/t-Butoxycarbonylaminoethylthio)-5-(R,S)-methyl-1 -oxo-6,7- dihydro-1 H,5H-pyrido[3,2,1 -//]quinoline-2-carboxylate; A suspension of Intermediate 1a (1.1 g, 3.8 mmol), te/t-butyl Λ/-(2-mercaptoethyl)- carbamate (2.89 mL, 17.1 mmol) and potassium carbonate (2.36 g, 17.1 mmol) in dimethylsulfoxide (60 mL) was heated at 1000C. After 24 h the reaction mixture was cooled, filtered and partitioned between water/dichloromethane. The organic phase was separated, dried and evaporated. The residue was purified by chromatography (silica gel, 100% hexane - 100% dichloromethane then 0 - 3% [9:1 methanol/20 M ammonia] in dichloromethane) to give the title compound (1.1 g); ESMS m/z 447.4 [M+H]+.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2006/50940, 2006, A1 Location in patent: Page/Page column 50
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2006/50941, 2006, A1 Location in patent: Page/Page column 35

17
[ 887124-93-8 ]
[ 67385-09-5 ]
6-[(2-tert-butylcarbonylamino-ethyl)sufanyl]-1-dimethylamino-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 55℃; for 2.25h;	17.d d) 6-(2-tert-Butylcarbonylaminoethylsufanyl)-1 -dimethylamino-4-oxo-1 ,4-dihydro- [1,8]-naphthyridine-3-carboxylic acid ethyl esterIntermediate 17c (1.5 g) was suspended in DMSO (20 mL) treated with potassium carbonate (1.12 g) and ferf-butyl Λ/-(2-mercaptoethyl)-carbamate (1.06 g). The mixture was stirred at 55°C for 2.25 h and then cooled, poured into water and extracted with EtOAc. The EtOAc extracts were dried (MgSO4) evaporated, and the residue triturated with diethyl ether/ petroleum ether [b.p. 40-600C] ( 1 :1 , 20 mL) to give the title compound as a yellow solid (1.46 g); ESMS m/z 437.2 [M+H]+.
	With potassium carbonate In dimethyl sulfoxide at 55℃; for 2.25h;	19.d d) 6-(2-tert-Butylcarbonylaminoethylsufanyl)-1 -dimethylamino-4-oxo-1 ,4-dihydro- [1,8]-naphthyridine-3-carboxylic acid ethyl esterIntermediate 19c (1.5 g) was suspended in dimethyl sulfoxide (20 mL) treated with potassium carbonate (1.12 g) and ferf-butyl Λ/-(2-mercaptoethyl)-carbamate (1.06g). The mixture was stirred at 55°C for 2.25 h and then cooled, poured into water and extracted with EtOAc. The EtOAc extracts were dried (MgSO4) evaporated, and the residue triturated with diethyl ether/ petroleum ether [b.p. 40-600C] ( 1:1 , 2OmL) to give the title compound as a yellow solid (1.46 g); ESMS m/z 437.2 [M+H]+.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2006/50940, 2006, A1 Location in patent: Page/Page column 52
[2]Current Patent Assignee: GALAPAGOS; GLAXOSMITHKLINE PLC - WO2006/50942, 2006, A1 Location in patent: Page/Page column 60

18
[ 887124-56-3 ]
[ 67385-09-5 ]
[ 887124-57-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 23h;	10.b b) Ethyl 6-(3-te/t-butoxycarbonylaminoethylsulfanyl)-1-dimethylamino-4-oxo-1,4- dihydro-[1,7]-naphthyridine-3-carboxylate; A stirred mixture of Intermediate 10a (1.5 g), terf-butyl 2-mercaptoethylcarbamate (1.05 mL) and potassium carbonate (1.05 g) in DMF (15 mL) was heated at 700C for 18h. Further fe/τf-butyl 2-mercaptoethylcarbamate (0.5 mL) was added and heating continued for 5h. The mixture was cooled to 2O0C, diluted with water and extracted with DCM (2x). The combined extracts were dried (Na2SO4) and evaporated. The residue was flash chromatographed (silica gel 30-50% EtOAc in DCM) to give the title compound as a yellow solid (2.8 g); APCI m/z 437.1 [M+H]+.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2006/50940, 2006, A1 Location in patent: Page/Page column 43

19
[ 887124-72-3 ]
[ 67385-09-5 ]
[ 887124-73-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 70℃; for 21h;	13.d d) 6-(2-te/t-Butoxycarbonylamino-ethylsulfanyl)-1 -dimethylamino-4-oxo-1 ,4-dihydro- quinoline-3-carboxylic acid ethyl ester; A mixture of Intermediate 13c (1.0 g) and potassium carbonate (0.99 g) in DMSO (18 mL) was treated with terf-butyl Λ/-(2-mercaptoethyl)-carbamate (1.3 mL) and heated to7O0C. After 21 h the mixture was allowed to cool then diluted with water and extracted with EtOAc. The organic extracts were combined, dried (MgSO4), filtered, and concentrated in vacuo to give a residue which was purified by flash chromatography (silica gel, 20-100% EtOAc in petroleum ether [b.p. 40-600C]) to give the title compound as a white solid (1.08 g); ESMS m/z 436.2 [M+H]+.
	With potassium carbonate In dimethyl sulfoxide at 70℃; for 21h;	15.d d) 6-(2-terf-Butoxycarbonylamino-ethylsulfanyl)-1-(dimethylamino)-4-oxo-1,4- dihydro-quinoline-3-carboxylic acid ethyl esterA mixture of Intermediate 15c (1.00 g, 3.60 mmol), and potassium carbonate (0.99 g, 7.16 mmol) in dimethyl sulfoxide (18 mL) was treated with tert-butyl Λ/-(2-mercaptoethyl)- carbamate (1.3 mL, 7.7 mmol) and heated to 7O0C. After 21 h the mixture was allowed to cool to room temperature then diluted with water and extracted with EtOAc. The organic extracts were combined, dried (MgSO4), filtered, and concentrated under reduced pressure to give a residue which was purified by flash chromatography (silica gel, 20- 100% EtOAc in petroleum ether [b.p. 40-600C]) to give the title compound as a white solid (1.08 g); ESMS m/z 436.2 [M+H]+.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2006/50940, 2006, A1 Location in patent: Page/Page column 47
[2]Current Patent Assignee: GALAPAGOS; GLAXOSMITHKLINE PLC - WO2006/50942, 2006, A1 Location in patent: Page/Page column 56

20
[ 67385-09-5 ]
[ 267663-95-6 ]
[ 367261-63-0 ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium carbonate In ethyl acetate; toluene	74 Intermediate S2: Methyl 2-({2-[(tert-Butoxycarbonyl)amino]ethyl}thio)-3-cyano-1-naphthoate Intermediate S2: Methyl 2-({2-[(tert-Butoxycarbonyl)amino]ethyl}thio)-3-cyano-1-naphthoate To a suspension (vacuum degassed 3 times) of potassium carbonate (110 mg, 0.78 mmol) in toluene (5 mL) under nitrogen was added tert-butyl 2-mercaptoethylcarbamate (131 μL, 0.78 mmol) followed by stirring at ambient temperature for 1 h. To this suspension was added by cannula a solution (vacuum degassed 3 times) of methyl 3-cyano-2-[(trifluoromethyl)-sulfonyl]oxy}-1-naphthoate (Intermediate 1, 200 mg, 0.56 mmol), (R)-Tol-BINAP (44.1 mg, 0.07 mmol), and palladium(II) acetate (14 mg, 0.06 mmol) in toluene (10 mL). The resulting suspension was stirred at 80° C. for 20 h, cooled,(reduced volume by 1/2 under reduced pressure, diluted with ether (12 ml) and methylene chloride (6 ml), washed organic layer with 20% K2CO3 (2*15 ml), water and brine, dried over Na2SO4, filtered, and evaporated to dryness. The residue was precipitated from 10% ethyl acetate in hexanes to give 150 mg of the title compound. An additional 40 mg (88% overall yield) of the title compound was isolated from the mother liquor by chromatography on silica gel in 20% ethyl acetate/hexanes.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - US2003/158170, 2003, A1

21
3-chloromethyl-4-chloropirydine hydrochloride [ No CAS ]
[ 67385-09-5 ]
3-(N-tert-butoxycarbonylaminoethylthiomethyl)-4-chloropyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With sodium iodide; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide	22 3-(N-tert-butoxycarbonylaminoethylthiomethyl)-4-chloropyridine Example 22 3-(N-tert-butoxycarbonylaminoethylthiomethyl)-4-chloropyridine To a solution of 3-chloromethyl-4-chloropirydine hydrochloride (513 mg, 2.59 mmol) in DMF (6 mL) at room temperature were added sodium iodide (386 mg, 2.59 mmol), diisopropylethylamine (1.12 mL, 6.47 mmol) and 2-(N-tert-butoxycarbonylamino)ethanethiol (458 mg, 2.59 mmol). After 2 h, the reaction mixture was partitioned between dilute HCl and ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated to yield 750 mg of the oily product (96%), which was used for the next step without further purification. 1H NMR (CDCl3) δ1.43 (s, 9H), 2.61 (m, 2H), 3.35 (m, 2H), 3.81 (s, 2H), 4.90 (br s, 1H), 7.35 (d, 1H, J=4), 8.40 (d, 1H, J=4), 8.57 (s, 1H).
96%	With sodium iodide; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide	22 3-(N-tert-butoxycarbonylaminoethylthiomethyl)-4-chloropyridine Example 22 3-(N-tert-butoxycarbonylaminoethylthiomethyl)-4-chloropyridine To a solution of 3-chloromethyl-4-chloropirydine hydrochloride (513 mg, 2.59 mmol) in DMF (6 mL) at room temperature were added sodium iodide (386 mg, 2.59 mmol), diisopropylethylamine (1.12 mL, 6.47 mmol) and 2-(N-tert-butoxycarbonylamino)ethanethiol (458 mg, 2.59 mmol). After 2 h, the reaction mixture was partitioned between dilute HCl and ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated to yield 750 mg of the oily product (96%), which was used for the next step without further purification. 1H NMR (CDCl3) δ 1.43 (s, 9H), 2.61 (m, 2H), 3.35 (m, 2H), 3.81 (s, 2H), 4.90 (br s, 1H), 7.35 (d, 1H, J=4), 8.40 (d, 1H, J=4), 8.57 (s, 1H).

Reference： [1]Current Patent Assignee: TRINE PHARMACEUTICALS INC - US6025352, 2000, A Current Patent Assignee: LITEL INTERCONNECT - US6030965, 2000, A
[2]Current Patent Assignee: TELAIYING PHARMACEUTICAL - EP1059293, 2000, A1 Current Patent Assignee: TELAIYING PHARMACEUTICAL - US6066630, 2000, A Current Patent Assignee: TELAIYING PHARMACEUTICAL - US6087355, 2000, A Current Patent Assignee: TELAIYING PHARMACEUTICAL - US5859256, 1999, A

22
[ 178747-50-7 ]
[ 67385-09-5 ]
[ 178747-51-8 ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium carbonate; In N-methyl-acetamide;	(b) 3-(2-(N-t-Butoxycarbonylamino)ethylthio)-5-fluoro-1,2-benzisoxazole. To a solution of <strong>[178747-50-7]3-chloro-5-fluoro-1,2-benzisoxazole</strong> (0.83 g) in dimethylformamide (8 ml) was added 2-t-butoxycarbonylaminoethanethiol (0.86 g) and potassium carbonate (0.67 g) with stirring under nitrogen atmosphere, and the mixture was then stirred at 80 C. for 3 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate and the combined extracts were washed with brine and dried over anhydrous magnesium sulphate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography, to give the title compound (1.21 g, 80%) as a colorless powder. NMR spectrum(CDCl3)deltappm: 1.44(9H,s), 3.41(2H,t,J=6.2 Hz), 3.58(2H,td,J=6.2 Hz,J=6.2 Hz), 4.98(1H,brs), 7.21-7.51(3H,m).

Reference： [1]Patent: US5965591,1999,A

23
3-chloromethyl-4-chloropirydine hydrochloride [ No CAS ]
[ 67385-09-5 ]
[ 189449-57-8 ]

Yield	Reaction Conditions	Operation in experiment
96%	With sodium iodide; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide	22 3-(N-tert-butoxycarbonylaminoethylthiomethyl)-4chloropyridine Example 22 3-(N-tert-butoxycarbonylaminoethylthiomethyl)-4chloropyridine To a solution of 3-chloromethyl-4-chloropirydine hydrochloride (513 mg, 2.59 mmol) in DMF (6 mL) at room temperature were added sodium iodide (386 mg, 2.59 mmol), diisopropylethylamine (1.12 mL, 6.47 mmol) and 2-(N-tert-butoxycarbonylamino)ethanethiol (458 mg, 2.59 mmol). After 2 h, the reaction mixture was partitioned between dilute HCl and ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated to yield 750 mg of the oily product (96%), which was used for the next step without further purification. 1H NMR (CDCl3) δ1.43 (s, 9H), 2.61 (m, 2H), 3.35 (m, 2H), 3.81 (s, 2H), 4.90 (br s, 1H), 7.35 (d, 1H, J=4), 8.40 (d, 1H, J=4), 8.57 (s, 1H).

Reference： [1]Current Patent Assignee: TELAIYING PHARMACEUTICAL - US6057312, 2000, A

24
[ 876345-75-4 ]
[ 67385-09-5 ]
[ 876345-86-7 ]

Yield	Reaction Conditions	Operation in experiment
78%	With sodium hydride In N,N-dimethyl-formamide at 25℃; for 12h;	7.a Example 7; Preparation of 6-(ir2-((1 -r6-(methvloxv)-1,5-naphthyridin-4-vl1-3-PVrrolidinvl)thio)ethvnamino)methvl)-2H-pyridor3,2-£)iri.41thiazin-3(4/-/)-one; (a) 1,1 -dimethylethyl [2-({1 -[6-(methyloxy)-1,5-naphthyridin-4-yl]-3-pyrrolidinyl}thio)ethyl]carbamate; To a solution of methanesulfonic acid 1-(6-methoxy-[1,5]naphthyridin-4-yl)-prrrolidin-3-yl ester (650 mg, 2mmol, prepared as Example 2b) in DMF (3 ml_) was added NaH (89 mg, 2.2 mmol, 65% in mineral oil) followed by 1,1-dimethylethyl (2-mercaptoethyl)carbamate (0.373 ml_, 2.2 mmol). The resulting mixture was stirred at 25 °C for 12h and then diluted with brine. Chloroform was used the extracted the aqueous solution. The organic fractions were pooled, concentrated and purified with column chromatography (silica, 10% MeOH in CDCI3 (1% NH4OH)) to afford the title compound as an off-white solid (630 mg, 78%): LC/MS m/z 405 (M+H)+.

Reference： [1]Current Patent Assignee: HONDA MOTOR CO., LTD. - WO2006/17326, 2006, A1 Location in patent: Page/Page column 35-36

25
[ 911368-98-4 ]
[ 67385-09-5 ]
[ 911369-01-2 ]

Yield	Reaction Conditions	Operation in experiment
	With N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide In dichloromethane at 20℃;	20.A . {2-[1,3-Bis-(4-methoxy-benzyl)-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-ylsulfanyl]-ethyl}-carbamic acid tert-butyl ester (Cpd 20a). To a solution of 2-(boc-amino)ethanethiol (87 μL, 0.52 mmol), 3M NaOH (1.7 mL, 5.2 mmol), and benzyltriethyammonium chloride (5 mL) was added a mixture of compound 19a (100 mg, 0.26 mmol) in dichloromethane (5 mL). The mixture was allowed to stir overnight at rt. The mixture was separated, and the aqueous layer was washed with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, and the filtrate was concentrated. The concentrate was triturated in MeOH and collected to obtain the title compound 20a as a white solid. M+ (ES+)527.8.
	With sodium hydroxide; N-benzyl-N,N,N-triethylammonium chloride In dichloromethane; water at 20℃;	20.A To a solution of 2- (boc-amino)ethanethiol (87 μl_, 0.52 mmol), 3M NaOH (1.7 mL, 5.2 mmol), and benzyltriethyammonium chloride (5 mL) was added a mixture of compound 19a (100 mg, 0.26 mmol) in dichloromethane (5 mL). The mixture was allowed to stir overnight at rt. The mixture was separated, and the aqueous layer was washed with dichloromethane. The combined organic extracts were dried over magnesium EPO sulfate, filtered, and the filtrate was concentrated. The concentrate was triturated in MeOH and collected to obtain the title compound 20a as a white solid. M+ (ES+) = 527.8.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US2011/319418, 2011, A1 Location in patent: Page/Page column 39
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2006/104713, 2006, A1 Location in patent: Page/Page column 102-103

26
N-[5-chloromethanesulfonylaminomethyl-4-(2,2-dimethylpropionyl)-5-phenyl-4,5-dihydro[1,3,4]thiadiazol-2-yl]-2,2-dimethylpropionamide [ No CAS ]
[ 67385-09-5 ]
[2-([3-(2,2-dimethylpropionyl)-5-(2,2-dimethyl-propionylamino)-2-phenyl-2,3-dihydro[1,3,4]thiadiazol-2-ylmethyl]sulfamoyl}-methylsulfanyl)ethyl]carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%	With sodium hydrogencarbonate In water; N,N-dimethyl-formamide at 70℃; for 5.5h;	18.2 N-[5-Chloromethanesulfonylaminomethyl-4-(2,2-dimethylpropionyl)-5-phenyl-4,5-dihydro[1,3,4]thiadiazol-2-yl]-2,2-dimethylpropionamide (3.818 g, 7.807 mmol) obtained in Step 1 mentioned above was dissolved in DMF (70 mL), and tert-butyl N-(2-mercaptoethyl)carbamate (13.3 mL, 78.1 mmol) and saturated aqueous sodium hydrogencarbonate (15 mL) were added, then the mixture was stirred at 70°C for 5.5 hours. After cooling, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate = 9/1 -> 7/3), and then triturated with diisopropyl ether to give [2-([3-(2,2-dimethylpropionyl)-5-(2,2-dimethylpropionylamino)-2-phenyl-2,3-dihydro[1,3,4]thiadiazol-2-ylmethyl]sulfamoyl}-methylsulfanyl)ethyl]carbamic acid tert-butyl ester (1.926 g, 39%). APCI-MS m/z: 630 (M+1)+.
39%	With sodium hydrogencarbonate In water; N,N-dimethyl-formamide at 70℃; for 5.5h;
39%	With sodium hydrogencarbonate In water; N,N-dimethyl-formamide at 70℃; for 5.5h;	36.2 Compound 19: Step 2: N-[5-Chloromethanesulfonylaminomethyl-4-(2,2-dimethylpropionyl)-5-phenyl-4,5-dihydro[1,3,4]thiadiazol-2-yl]-2,2-dimethylpropionamide (3.818 g, 7.807 mmol) obtained in Step 1 mentioned above was dissolved in DMF (70 mL), and tert-butyl N-(2-mercaptoethyl)carbamate (13.3 mL, 78.1 mmol) and saturated aqueous sodium hydrogencarbonate (15 mL) were added, then the mixture was stirred at 70°C for 5.5 hours. After cooling, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate = 9/1 -> 7/3), and then triturated with diisopropyl ether to give [2-([3-(2,2-dimethylpropionyl)-5-(2,2-dimethyl-propionylamino)-2-phenyl-2,3-dihydro[1,3,4]thiadiazol-2-ylmethyl]sulfamoyl}-methylsulfanyl)ethyl]carbamic acid tert-butyl ester (1.926 g, 39%). APCI-MS m/z: 630 (M+1)+.

Reference： [1]Current Patent Assignee: FUJIFILM HOLDINGS CORP.; KIRIN HOLDINGS CO., LTD.; Kyowa Kirin (in: Kirin Holdings) - EP1867640, 2007, A1 Location in patent: Page/Page column 46
[2]Current Patent Assignee: FUJIFILM HOLDINGS CORP.; KIRIN HOLDINGS CO., LTD.; Kyowa Kirin (in: Kirin Holdings) - WO2006/137490, 2006, A1 Location in patent: Page/Page column 86
[3]Current Patent Assignee: Kyowa Kirin (in: Kirin Holdings); FUJIFILM HOLDINGS CORP.; KIRIN HOLDINGS CO., LTD. - EP1870404, 2007, A1 Location in patent: Page/Page column 39

27
[ 7250-84-2 ]
[ 67385-09-5 ]
[ 331779-80-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In <i>N</i>-methyl-acetamide; methanol; dichloromethane	42 2-Amino-4-(2-t-butyloxycarbonylaminoethylthiomethyl)-1,3-thiazole Example 42 2-Amino-4-(2-t-butyloxycarbonylaminoethylthiomethyl)-1,3-thiazole To a solution of 2-amino-4-chloromethyl-1,3-thiazole (16.2 g, 0.108 mol) in dimethylformamide (80 mL) was added 2-t-butyloxycarbonylaminoethanethiol (28.9 g, 0.163 mol) followed by potassium carbonate (45 g, 0.326 mol). After 1 hour of vigorous stirring reaction mixture was partitioned between ethyl acetate and water. Organic layer was thoroughly washed with water, dried over sodium sulfate and concentrated under reduced pressure. Flash column chromatography of the oily residue (2% methanol in methylene chloride) afforded oily product (20.0 g). 1H NMR (CDCl3) δ 1.42 (s, 9H), 2.65 (m, 2H), 3.35 (m, 2H), 3.80 (s, 2H), 2.65 (m, 2H), 5.00 (s, 1H).

Reference： [1]Current Patent Assignee: TRINE PHARMACEUTICALS INC - US6723716, 2004, B1

28
[ 10431-98-8 ]
[ 67385-09-5 ]
[ 333-27-7 ]
M-PEOZ-T-NH(Boc) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	Stage #1: 2-ethyl-4,5-dihydrooxazole; methyl trifluoromethanesulfonate In chlorobenzene at 20 - 110℃; for 0.666667h; Stage #2: 2-[(tert-butoxycarbonyl)amino]-1-ethanethiol With potassium <i>tert</i>-butylate In chlorobenzene at 0 - 20℃; for 23h;	14 Methyl triflate (0.283 mL, 0.0025 mol) was added into a solution of 2-ethyl-2- oxazoline (5.05 mL, 0.05 mol) in chlorobenzene (25 mL). After the stirring for 10 minutes at room temperature, the mixture was heated to 110 °C for 30 minutes followed by cooling down to 0 °C. To obtain a terminating reagent, Boc-cysteamine (0.84 mL, 0.0075 mol) was added dropwise into a suspension of potassium tert-butoxide (0.561 g, 0.005 mol) in chlorobenzene (5 mL) at 0°C. After the mixture was stirred for 1 hour in the cold to give a clear solution, the solution of M-PEOZ+ in chlorobenzene was added dropwise using a syringe at 0°C. The mixture was stirred in the cold for 4 hours and then stirred for 18 hours at room temperature. The mixture was slowly added to diethyl ether to give a white precipitate. The ether was decanted and the residue was dissolved in water followed by extraction with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, concentrated, and precipitated by addition to ether. The mixture was filtered and the resulting white powder was dried under vacuum to give 4.0 g of targeted compound in 87% yield.NMR (Varian, 500 MHz, 10 mg/mL CDCl3) shows the usual backbone peaks at 1.12 ppm (s, 3H, CH5CH2CO-); 2.31 ppm (s) and 2.41 (s) (total area 2H, CH3CH2CO-); and 3.47 ppm (s, 4η, -NCH2CH2N-). The initiating methyl peak appears as two singlets at 2.9 ppm and 3.03 ppm (CHJ-NCH2CH2). The Boc cysteamine terminal group peaks are at 1.44 ppm (s, 9H, -CH2NRBoC), 2.67 ppm (m, 2H, -SCH2CH2NHBoC), 2.71 ppm (m, 2H, - CH2SCH2CH2NHBoC), and 3.32 ppm (m, 2H, -SCH2CH2NHBoc). The crude mixture contains approximately 8% of M-PEOZ-OH species based on the NMR integration. GPC produces a sharp peak with a Mn = 1790 Da, PD = 1.07.

Reference： [1]Current Patent Assignee: SERINA THERAPEUTICS, INC. - WO2008/106186, 2008, A2 Location in patent: Page/Page column 45

29
[ 67385-09-5 ]
[ 223420-33-5 ]
[ 958852-26-1 ]

Yield	Reaction Conditions	Operation in experiment
52%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran Heating / reflux;	1 A solution of compound 18 (1.33 g, 4.6 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (800 l), and N-(tert-butoxycarbonyl)-aminoethanethiol (0.88 ml, 5.2 mmol) in tetrahydrofuran (THF) (50 ml) were heated at reflux overnight in the dark under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was evaporated to dryness, taken up in ethyl acetate (EtOAc) and washed with dilute aqueous hydrochloric acid (HCl) and brine. The organic phase was separated, dried over anhydrous magnesium sulfate (MgSO4) and evaporated to an orange-colored oil which was chromatographed on silica gel (6% MeOH in CH2Cl2) to provide a clear, viscous oil, which solidified on standing (yield 1.00 g, 52%). Proton (1H) NMR (acetone-d6, ppm): 1.40 (s, 9H), 2.68 (t, 2H, J=6.8 Hz), 3.31 (m, 2H), 3.99 (s, 2H), 6.16 (br s, 1H), 6.33 (s, 1H), 6.92 (s, 1H), 8.04 (s, 1H), 9.99 (s, 1H). 13C NMR (acetone-d6, ppm): 28.7, 32.1, 32.4, 40.6, 104.6, 106.7, 113.3, 130.6, 151.9, 155.9, 157.9. HRMS: calcd for [C17H20NO5SBr.Na] 452.0137, found 452.0149.

Reference： [1]Current Patent Assignee: SHOICHET MOLLY S - US2008/286360, 2008, A1 Location in patent: Page/Page column 4-5

30
[ 1892-29-1 ]
[ 67385-09-5 ]
[ 877864-07-8 ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: bis(2-hydroxyethyl) disulfide; 2-[(tert-butoxycarbonyl)amino]-1-ethanethiol In methanol; dichloromethane at 20℃; for 12h; Darkness; Stage #2: With iodine In methanol; dichloromethane

Reference： [1]Pires, Marcos M.; Chmielewski, Jean [Organic Letters, 2008, vol. 10, # 5, p. 837 - 840]

31
[ 1000210-74-1 ]
[ 67385-09-5 ]
[ 1000210-75-2 ]
C₁₆H₁₉ClN₂O₂S [ No CAS ]
C₂₃H₃₃N₃O₄S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95.6%	With potassium carbonate In N,N-dimethyl-formamide at 60 - 75℃;	9 [2-(7-Chloro-isoquinolin-5-ylsulfanyl)-ethyl]-carbamic Acid Tert-butyl Ester Potassium carbonate (1952 g; 14.12 moles) is charged to a 22 L flask equipped with overhead stirring, addition funnel, nitrogen inlet, and thermocouple. Dimethylformamide (4 L) is added. The 5,7-dichloro-isoquinoline hydrochloride (646.1 g; 1.00 equiv; 2.76 moles) is added in portions and along with DMF (330 mL). The Boc-Cysteamine (514 g; 1.05 equiv; 2.90 moles) is dissolved in dimethylformamide (1520 mL) and is charged to the addition funnel. The mixture is warmed to 60° C. Nitrogen is purged through the head space for 15 minutes while the mixture is warming. The Boc-Cysteamine solution is added over 2 hrs and 15 minutes at 60° C. HPLC 1 hour and 20 minutes after the addition indicates 28.1% starting material, 67.26% product, 4.22% isomer, and 0.25% bis. The reaction is warmed to 75° C. The HPLC data in Table A is collected at 75° C. TABLE A Reaction HPLC Data for the Preparation of [2-(7-chloro-isoquinolin- 5-ylsulfanyl)-ethyl]-carbamic acid tert-butyl ester % [2-(7-Chloro- % 5,7- isoquinolin-5- dichloro- ylsulfanyl)- Time at isoquinoline ethyl]-carbamic % bis 75° C. HCl acid tert-butyl ester % isomer substituted 30 minutes 2.75 90.27 5.54 1.44 1 hour 0.93 91.39 5.52 2.16 1.5 hours 0.20 91.25 5.32 3.23 After 1.5 hours the mantle is replaced with a cooling bath. The reaction is cooled to 20-25° C. The solid is filtered and is washed with DMF (2×810 mL). The DMF solution is diluted with MTBE (5.15 L) and 5% LiCl (5.15 L). After stirring in a 50 L bottom outlet flask, the layers are separated. The aqueous layer is extracted with MTBE (2.9 L). The MTBE layers are combined and washed with 5% LiCl (2×2.9 L). The MTBE layer is gravity filtered through fluted paper and is concentrated using Buchi flask with the water bath set at 35° C. to give 892.7 g (95.6% of theory, uncorrected) of [2-(7-chloro-isoquinolin-5-ylsulfanyl)-ethyl]-carbamic acid tert-butyl ester. Mass Spectrum (LCMS) m/z=339.85) (M+H+).

Reference： [1]Current Patent Assignee: ELI LILLY & CO - US2009/221633, 2009, A1 Location in patent: Page/Page column 5

32
[ 1347626-88-3 ]
[ 67385-09-5 ]
tert-butyl [2-([3-chloro-4-[5-[4-(methylthio)phenyl]-3-oxo-2-[4-(trifluoro-methyl)benzyl]-3,5-dihydro-2H-pyrazolo[4,3-c]pyridazin-6-yl]phenyl]thio)ethyl]-carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-[(tert-butoxycarbonyl)amino]-1-ethanethiol With sodium hydride In xylene; mineral oil at 60℃; for 1h; Stage #2: 6-(4-bromo-2-chlorophenyl)-5-[4-(methylthio)phenyl]-2-[4-(trifluoromethyl)benzyl]-2,5-dihydro-3H-pyrazolo[4,3-c]pyridazin-3-one In xylene; mineral oil Heating; Reflux;	21.A A) tert-Butyl[2-[(3-chloro-4-[5-[4-(methylthio)phenyl]-3-oxo-2-[4-(trifluoro-methyl)benzyl]-3,5-dihydro-2H-pyrazolo[4,3-c]pyridazin-6-yl]phenyl]thio]ethyl]-carbamate A mixture of 3.33 ml of tert-butyl (2-mercaptoethyl)carbamate and 0.31 g of NaH at 60% in oil, in 50 ml of xylene, is left to stir for 1 hour at 60° C. 4.63 g of compound No. 89, 0.56 g of Pd2(dba)3 and 0.4 g of xantphos are then added and the mixture is refluxed overnight. The reaction mixture is concentrated under vacuum, the residue is taken up with a 10% HCl solution, the mixture is extracted with EtOAc, an insoluble material is filtered off, the product is separated by settling out, the organic phase is dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel, elution being carried out with a mixture of DCM/EtOAc (100/40; V/V). 4.15 g of the expected compound are obtained after crystallization from iso ether.

Reference： [1]Current Patent Assignee: SANOFI - US2009/281107, 2009, A1 Location in patent: Page/Page column 26

33
[ 591-50-4 ]
[ 67385-09-5 ]
[ 104-15-4 ]
[ 1197199-74-8 ]

Yield	Reaction Conditions	Operation in experiment
45%	Stage #1: iodobenzene; 2-[(tert-butoxycarbonyl)amino]-1-ethanethiol With copper(l) iodide; potassium carbonate In 1,2-dimethoxyethane at 80℃; for 72h; Stage #2: toluene-4-sulfonic acid In acetonitrile for 2h;	17 Example 17Preparation of 3-nitro-4- (2- (phenylthio) ethylamino) benzenesulfonamide (b) : As per the procedure of Kwong and Buchwald (Org. Lett. 2002, 4:3517-3520), CuI (160mg) , K2CO3 (8mmol) , PhI (4mmol) and BOCNHCH2CH2SH (a) (4mmol) in DME (ImI) stirred 80 deg. 3 days in capped screw-top vial. At the end of this time, ca 5ml DCM was added and the reaction mixture filtered through a silica plug to remove low rf impurities. After removal of the solvent in vacuo, the residue was dissolved in MeCN containing ca 20 mmol TsOH and stood 2 h. The resulting product b was filtered off as colourless plates in 45% overall yield(590mg) . ES+ 154; 1H NMR (d6-DMSO) : 7.81, bs, 3H, NH3; 7.45, d, 2H, Ts; 7.35, m, 4H, 4xArH; 7.24, m, IH, Ix ArH; 7.08, d, 2H, Ts; 3.15, m, 2H, CH2; 2.93, m, 2H, CH2; 2.25, s, 3H, CH3.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG; THE WALTER AND ELIZA HALL INSTITUTE OF MEDICAL RESEARCH - WO2009/143246, 2009, A2 Location in patent: Page/Page column 222

34
[ 1192022-82-4 ]
[ 67385-09-5 ]
[ 1192022-83-5 ]

Yield	Reaction Conditions	Operation in experiment
74%	Stage #1: 2-[(tert-butoxycarbonyl)amino]-1-ethanethiol With sodium hydride In N,N-dimethyl-formamide at 20 - 80℃; for 0.5h; Inert atmosphere; Stage #2: heptakis(2-O-allyl-6-bromo-6-deoxy)-β-cyclodextrin In N,N-dimethyl-formamide at 20℃; Inert atmosphere;
74%	Stage #1: 2-[(tert-butoxycarbonyl)amino]-1-ethanethiol With sodium hydride In N,N-dimethyl-formamide at 20 - 80℃; for 0.5h; Inert atmosphere; Stage #2: heptakis(2-O-allyl-6-bromo-6-deoxy)-β-cyclodextrin In N,N-dimethyl-formamide at 20℃; for 18h; Inert atmosphere;	2.b b) Preparation of heptakis[2-O-allyl-6-(2′-aminoethylthio)]-β-cyclodextrin hepta-N-tBoc derivative b) Preparation of heptakis[2-O-allyl-6-(2′-aminoethylthio)]-β-cyclodextrin hepta-N-tBoc derivative (0149) (0150) N-(2-Mercaptoethyl)-carbamic acid tert-butyl ester (1.43 g, 8.085 mmol) was dissolved in anhydrous DMF (10 mL) and sodium hydride (0.19 g, 7.546 mmol) was added portionwise carefully with gentle stirring. This solution was stirred for a further 10 minutes under nitrogen and then for 20 minutes at 80° C. before allowing to cool slowly back to room temperature. Heptakis(2-O-allyl-6-bromo-6-deoxy)-β-cyclodextrin (1.0 g, 0.539 mmol) was dissolved in anhydrous DMF (5 mL) and added dropwise to the reaction vessel and the solution was then stirred for 18 hours under a nitrogen atmosphere. TLC analysis indicated that the reaction had gone to completion; the solvent system used was ethyl acetate:cyclohexane (6:4). (Rf starter=0.8, Rf product=0.65). The reaction mixture was concentrated under reduced pressure to yield an oily residue which was taken up in ethyl acetate (30 mL) and washed with deionised water (40 mL) followed by brine (40 mL). The organic layer was then dried over MgSO4, filtered and the ethyl acetate evaporated off. The crude residue was purified by column chromatography on silica gel using cyclohexane:ethyl acetate (1:1, Rf product=0.29) as eluent yielding a creamy powder as product (Yield 1.0 g, 74%). (0151) 1H NMR (500 MHz, CDCl3): δ 5.97-5.89 (m, 7H, CH═CH2); 5.32-5.21 (m, 21H, CH2═CH, NH); 4.96-4.92 (m, 14H, OH-3, H-1); 4.47 (dd, J=5.3 Hz, J=12.5 Hz, 7H, OCHb); 4.23 (dd, J=6.9 Hz, J=12.4 Hz, 7H, OCHa); 3.91-3.87 (m, 14H, H-3, H-5); 3.41-3.39 (m, 14H, H-4, H-2); 3.3 (br s, 7H, NCH2); 3.05-2.87 (m, 14H, H-6b, H-6a); 2.73 (br s, 14H, SCH2); 1.43 (s, 63H, C(CH3)3). (0152) 13C NMR (125 MHz, CDCl3): δ 156.0 (C═O); 134.2 (CH═CH2); 118.9 (CH2═CH); 101.8 (C-1); 86.2 (C-4), 79.3 (C-2, C(CH3)3); 73.6 (OCH2); 73.3 (C-3); 71.0 (C-5); 40.2 (CH2N); 33.7 (SCH2, C-6); 28.7 (C(CH3)3). (0153) Elemental Analysis: C112H189O42N7S7 Theory: C 53.17, H 7.53, N 3.88, S 8.87%, Found: C 52.98, H 7.46, N 3.74, S 9.17%.

Reference： [1]Location in patent: experimental part Byrne, Colin; Sallas, Florence; Rai, Dilip K.; Ogier, Julien; Darcy, Raphael [Organic and Biomolecular Chemistry, 2009, vol. 7, # 18, p. 3763 - 3771]
[2]Current Patent Assignee: NATIONAL UNIVERSITY OF IRELAND - US8852895, 2014, B2 Location in patent: Page/Page column 18-19

35
[ 1203604-04-9 ]
[ 67385-09-5 ]
[ 1203605-40-6 ]

Yield	Reaction Conditions	Operation in experiment
40%	With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 100℃; Inert atmosphere;	84.a Under argon, to a solution of [5-(4-bromo-2,6-dimethyl-phenyl)-[1,2,4]triazin-3-yl]-(5-methoxy-benzothiazol-2-ylmethyl)-amine (50 mg, 0.11 mmol, prepared as in example 79), Xantphos (3.2 mg, 0.006 mmol), tris(dibenzylideneacetone)-dipalladium(0) (2.5 mg, 0.003 mmol) in degassed anhydrous 1,4-dioxane (0.25 mL) were successively added tert-butyl N-(2-mercaptoethyl)carbamate (24 µL, 0.14 mmol) and diisopropylethylamine (39 µL, 0.22 mmol). Then the reaction mixture was degassed, placed under argon atmosphere and stirred at 100°C overnight. The solution was then concentrated and purified by preparative TLC (silica gel, dichloromethane/methanol 94/6) to afford tert-butyl [2-(4-{3-[(5-methoxy-benzothiazol-2-ylmethyl)-amino]-[1,2,4]triazin-5-yl}-3,5-dimethyl-phenylsulfanyl)-ethyl]-carbamate (24 mg, 40%) as a yellow oil. ESI-MS m/z 553 (M+H)+.

Reference： [1]Current Patent Assignee: PHARMA OMNIUM INTERNATIONAL P O I - EP2141164, 2010, A1 Location in patent: Page/Page column 55

36
[ 1203605-46-2 ]
[ 67385-09-5 ]
[ 1203605-47-3 ]

Yield	Reaction Conditions	Operation in experiment
57%	With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 100℃; Inert atmosphere;	94.b Under argon, to a solution of N-[(5-bromo-1,3-benzothiazol-2-yl)methyl]-5-(2,6-dichlorophenyl)-1,2,4-triazin-3-amine (93.4 mg, 0.2 mmol), Xantphos (5.8 mg, 0.01 mmol), tris(dibenzylideneacetone)dipalladium(0) (4.6 mg, 0.005 mmol) in degassed anhydrous 1,4-dioxane (0.5 mL) were successively added tert-butyl N-(2-mercaptoethyl)carbamate (46 µL, 0.27 mmol) and diisopropylethylamine (70 µL, 0.4 mmol). Then the reaction mixture was degassed, placed under argon atmosphere and stirred at 100°C overnight. The solution was then concentrated and purified by preparative TLC (silica gel, dichloromethane/methanol 94/6) to afford tert-butyl [2-([5-(2,6-dichlorophenyl)-1,2,4-triazin-3-yl]amino}methyl)-1,3-benzothiazol-5-yl]thio}ethylcarbamate (65.1 mg, 57%) as a yellow solid. ESI-MS m/z 563 and 565 (M+H)+.

Reference： [1]Current Patent Assignee: PHARMA OMNIUM INTERNATIONAL P O I - EP2141164, 2010, A1 Location in patent: Page/Page column 61

37
[ 67385-09-5 ]
[ 5605-63-0 ]
[ 1387563-70-3 ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: 2-[(tert-butoxycarbonyl)amino]-1-ethanethiol With sodium methylate In methanol for 0.25h; Inert atmosphere; Stage #2: ((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 4-methylbenzenesulfonate In methanol for 5h; Reflux; Inert atmosphere;	4.1.2. 2-[6-(6-Amino-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethylsulfanyl]-ethyl}-carbamic acid tert-butyl ester (3) A solution of compound 2 (1.77 g, 10.0 mmol) in NaOCH3 (0.5 M in methanol, 20.2 mL, 10.1 mmol) was stirred under a nitrogen atmosphere for 15 min. Compound 1 (3.23 g, 7.0 mmol) was then added and the mixture was reflux for 5 h. After the reaction was finished, the solvent was removed under vacuum; the crude material was dissolved in ethyl acetate. The ethyl acetate solution was washed with saturated NaHCO3, 5% HCl, and brine. The ethyl acetate solution was then dried with MgSO4, filtered and evaporated to give the crude product. The title compound was obtained in 90% yield (2.94 g) after purification by flash chromatography. IR, νmax (neat, cm-1) 3332, 2980, 2934, 1696, 1640, 1598, 1366, 1248, 1208, 1161, 1086, 868. NMR δH (400 MHz; CD3OD), 1.38 (3H, s), 1.41 (9H, s), 1.58 (3H, s), 2.60 (2H, t), 2.83 (2H, m), 3.17 (2H, m), 4.34 (1H, m), 5.06 (1H, m), 5.52 (1H, m), 6.18 (1H, d), 8.25 (1H, s), 8.28 (1H, s); δ13C (100 MHz; CD3OD), 158.03 (1C), 157.23 (1C), 153.95 (1C), 150.08 (1C), 141.66 (1C), 120.48 (1C), 115.36 (1C), 91.52 (1C), 87.73 (1C), 85.06 (1C), 84.93 (1C), 79.97 (1C), 41.08 (1C), 34.90 (1C), 33.03 (1C), 28.74 (3C), 27.39 (1C), 25.55 (1C); HRMS (ESI-MS) calcd for C20H30N6O5S (MH+): 467.2071; found: 467.2082.
	In methanol

Reference： [1]Location in patent: experimental part Shi, Genbin; Shaw, Gary; Li, Yue; Wu, Yan; Yan, Honggao; Ji, Xinhua [Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 14, p. 4303 - 4309]
[2]Location in patent: scheme or table Isakovic, Ljubomir; Saavedra, Oscar M.; Llewellyn, David B.; Claridge, Stephen; Zhan, Lijie; Bernstein, Naomy; Vaisburg, Arkadii; Elowe, Nadine; Petschner, Andrea J.; Rahil, Jubrail; Beaulieu, Norman; Gauthier, France; MacLeod, A. Robert; Delorme, Daniel; Besterman, Jeffrey M.; Wahhab, Amal [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 10, p. 2742 - 2746]

38
[ 1147849-22-6 ]
[ 67385-09-5 ]
[ 1147849-23-7 ]

Yield	Reaction Conditions	Operation in experiment
96%	With potassium carbonate In N,N-dimethyl-formamide at 20℃;	18.5 Step 5: The mixture of the 4-(/ert-butylthio)-3-(chloromethyl)pyridine 5 (0.8 g, 4.1 mmol), N-Boc-aminoethanethiol 3.46 mL (20.5 mmol), NaI 0.15 g(1.0 mmol) and DMF (15 mL) was stirred at rt for 1 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated and the residue was purified by column chromatography (PE:EA = 2:1) to afford 1.39 g oil, yield 96%. 1H NMR (400 MHz, CDCl3): 8.56 (s, IH), 8.41 (d, IH), 7.44 (d, IH), 4.96 (s, IH), 4.12 (s, 2H), 3.35 (m, 2H), 2.61 (m, 2H), 1.40 (m, 9H), 1.27(m, 9H).
96%	With potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 20℃; for 12h;	18.5 Step 5: The mixture of the 4-(tert-butylthio)-3-(chloromethyl)pyridine 5 (0.8 g, 4.1 mmol), N-Boc-aminoethanethiol 3.46 mL (20.5 mmol), NaI 0.15 g(1.0 mmol) and DMF (15 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with EA. The organic layer was concentrated and the residue was purified by column chromatography (P.E/EA 2:1) to afford 1.39 g oil, yield 96%. 1HNMR (400MHz, CDCl3): 8.56 (s, 1H), 8.41 (d, 1H), 7.44 (d, 1H), 4.96 (s, 1H), 4.12 (s, 2H), 3.35 (m, 2H), 2.61 (m, 2H), 1.40 (m, 9H), 1.27(m, 9H).

Reference： [1]Current Patent Assignee: ACHAOGEN INC - WO2010/30811, 2010, A2 Location in patent: Page/Page column 74
[2]Current Patent Assignee: ACHAOGEN INC - WO2009/55696, 2009, A1 Location in patent: Page/Page column 87-88

39
[ 1147849-27-1 ]
[ 67385-09-5 ]
[ 331780-05-3 ]

Yield	Reaction Conditions	Operation in experiment
95.5%	With potassium carbonate In N,N-dimethyl-formamide at 23℃;	23.1 Example 23; Preparation of Di-ter£-butyl-2,2'-(3,3'-disulfanediylbis(pyridine-3,2-diyl)bis (methyl ene))bis(sulfanediyl)bis(ethane-2, 1 -diyl)dicarbamate; NHBoc; Step 1 : A mixture of 3-(fert-butylthio)-2-(chloromethyl)pyridine 1 (0.8 g, 4.1 mmol) (obtained from example 20 step 7), N-Boc-aminoethanethiol (3.46 mL, 20.5 mmol), NaI (0.15 g, 1.0 mmol) and DMF (15 mL) was stirred at rt for 1 hr. Then, the reaction mixture was extracted with ethyl acetate from sat. aq. Na2CO3. The organic layer was washed with brine, concentrated and the residue was purified by column chromatography with PE:EA = 2:1 as eluent, 1.39 g of tert-buty-2-((3-(tert- butylthio)pyridin-2-yl)methylthio)ethylcarbamate 2 was obtained as a slight oil, yield 95.5%.
95.5%	With potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 23℃; for 48h;	23.1; 25.1 Step 1 : A mixture of 3-(tert-butylthio)-2-(chloromethyl)pyridine 1 (0.8 g, 4.1 mmol) (obtained from example 20 step 7), N-Boc-aminoethanethiol (3.46 mL, 20.5 mmol), NaI (0.15 g, 1.0 mmol) and DMF (15 mL) was stirred at room temperature for 1 hour. Then, the reaction mixture was extracted with EA from sat. aq. Na2CO3. The organic layer was washed with brine, concentrated and the residue was purified by column chromatography with PE:EA=2: 1 as eluent, 1.39 g of -b tuertytl 2-((3-(tert- butylthio)pyridin-2-yl)methylthio)ethylcarbamate 2 was obtained as a slight oil, yield 95.5%.; Step 1 : A mixture of 3-(tert-butylthio)-2-(chloromethyl)pyridine 1 (0.8 g, 4.1 mmol), N-Boc aminoethanethiol (3.46 mL, 20.5 mmol), NaI (0.15 g, 1.0 mmol) and DMF (15 mL) was stirred at room temperature for 1 h. Then, the reaction mixture was extracted with EA from sat. aq. Na2CO3. The organic layer was washed with brine, concentrated and the residue was purified by column chromatography with P.E:EA = 2:1 as eluent, 1.39 g oil was obtained, yield 96%.

Reference： [1]Current Patent Assignee: ACHAOGEN INC - WO2010/30811, 2010, A2 Location in patent: Page/Page column 81-82
[2]Current Patent Assignee: ACHAOGEN INC - WO2009/55696, 2009, A1 Location in patent: Page/Page column 96; 99

40
[ 33252-28-7 ]
[ 67385-09-5 ]
[ 1059191-68-2 ]

Yield	Reaction Conditions	Operation in experiment
91%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere;	42A Example 42A; tert-Butyl {2-[(5-cyanopyridin-2-yl)thio]ethyl}carbamate 2-Chloro-5-cyanopyridine (500 mg, 3.6 mmol), tert-butyl (2-mercaptoethyl)carbamate (426 mg, 2.4 mmol) and 1,8-diazabicyclo(5.4.0)undec-7-ene (549 mg, 3.6 mmol) are dissolved in DMF (5 ml) and stirred at RT under argon for 12 h. The reaction mixture is diluted with water (100 ml) and extracted with ethyl acetate (3×75 ml). The combined organic phases are washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. After removal of the solvent, the residue is purified by preparative RP-HPLC (gradient of eluent: water/acetonitrile 90:10 to 10:90). 612 mg (91% of theory) of the product are obtained as a solid.LCMS (method 6): Rt=1.80 min. (m/z=280 (M+H)+)1H-NMR (400 MHz, DMSO-d6): δ=8.86 (d, 1H), 8.07 (dd, 1H), 7.54 (dd, 1H), 7.08 (br s, 1H), 3.24 (m, 4H), 1.36 (s, 9H).

Reference： [1]Current Patent Assignee: BAYER AG - US2010/113441, 2010, A1 Location in patent: Page/Page column 34

41
[ 67385-09-5 ]
[ 23735-43-5 ]
[ 1221430-02-9 ]

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 3198 - 3213

42
[ 14432-16-7 ]
[ 67385-09-5 ]
C₁₂H₁₇N₃O₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-[(tert-butoxycarbonyl)amino]-1-ethanethiol With sodium hydride In tetrahydrofuran for 0.75h; Inert atmosphere; Stage #2: 2-chloro-4-nitropyridine-N-oxide In tetrahydrofuran at -78 - 20℃; for 4.75h; Inert atmosphere;	3.5. Preparation of 2-(4'-nitropyridin-2'-ylsulfanyl)-ethanamine (6k) (4-NO₂-2-PSEA) tert-Butyl (2-sulfanylethyl)carbamate (1.38 g, 7.81 mmol) was dissolved in dry THF (20 mL) under a nitrogen atmosphere. NaH (dry, 95%) (0.24 g, 10.2 mmol) was added portion-wise over 45 min and the mixture was then cooled to -78 °C. A solution of 2-chloro-4-nitropyridine N-oxide (1.50 g, 8.59 mmol) in dry THF (40 mL) was added dropwise over 45 min to the cold carbamate solution. The mixture was warmed to ambient temperature over 2 h, stirred for a further 2 h and the THF was removed under reduced pressure. The residue was treated with CHCl3 (50 mL) followed by dropwise addition of PCl3 (3 mL). The reaction mixture was stirred at ambient temperature for 16 h and then poured slowly into water (50 mL). The organic layer was separated and the aqueous layer washed with CHCl3 (4×15 mL). The aqueous layer was basified (pH 8.5-10) with 2 M NaOH solution and extracted several times with CH2Cl2. The combined organic extract was dried (MgSO4), filtered and solvent removed in vacuo to give the title compound 6k as a red-brown oil (ca. 95% pure) (1.06 g, ca. 68%). Preparative TLC (SiO2, CH2Cl2/MeOH/NH3 in MeOH, 9:0.8:0.2) using a sample of crude oil gave the pure title compound 6k as a yellow oil.

Reference： [1]Location in patent: experimental part Mountford, Simon J.; Campi, Eva M.; Robinson, Andrea J.; Hearn, Milton T.W. [Tetrahedron, 2011, vol. 67, # 2, p. 471 - 485]

43
[ 5061-21-2 ]
[ 67385-09-5 ]
C₁₁H₁₉NO₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In acetonitrile at 80℃; for 16h;	B.1.29 Intermediate 29: 3-(2-Amino-ethylsulfanyl -dih ro-furan-2-one3-Bromo-dihydro-furan-2-one (2.49g, 15.1 mmol) and 2-(Boc-amino)ethanethiol (2.9g, 16.5mmol) were dissolved in 40mL of CH3CN.Then K2C03(4.14g, 30mmol) wasn added to the solution. Let it stir at 80°C for 16h. The solvent was evaporated to dryness and the residue was purified by column chromatography (PE/EtOAc=4/1 ) to 3.8g of BOC protected Intermediate 29 as colorless oil.
	With potassium carbonate In acetonitrile at 80℃; for 16h;	To a solution of 3-Bromo-dihydro-furan-2-one (2.49g, 15.1 mmol) and 2-(Boc-amino)ethanethiol (2.9g, 16.5mmol) in CH3CN (40 ml) was added K2C03 (4.14g, 30mmol. The mixture was stirred at 80°C for 16h and the solvent was evaporated to dryness. The residue was then purified by column chromatography (PE/EtOAc=4/1 ) to give the expected Boc protected Intermediate 8 (3.8g) as colorless oil.
3.8 g	With potassium carbonate In acetonitrile at 80℃; for 16h;	B.B.1 Intermediate 8: 3-(2-Amino-ethylsulfanyl)-dihydro-furan-2-one To a solution of 3-Bromo-dihydro-furan-2-one (2.49 g, 15.1 mmol) and 2-(Boc-amino)ethanethiol (2.9 g, 16.5 mmol) in CH3CN (40 ml) was added K2CO3 (4.14 g, 30 mmol. The mixture was stirred at 80° C. for 16 h and the solvent was evaporated to dryness. The residue was then purified by column chromatography (PE/EtOAc=4/1) to give the expected Boc protected Intermediate 8 (3.8 g) as colorless oil. The previous compound (3.7 g, 14.16 mmol) was dissolved in 10 ml of EtOAc. Then 40 mL of 4N HCl/EtOAc was added to the solution, which was then stirred at 25° C. for 2 h. The white solid was filtered and washed with PE to give the expected Intermediate 8 (2 g),

Reference： [1]Current Patent Assignee: PH PHARMA CO LTD - WO2011/107608, 2011, A1 Location in patent: Page/Page column 76
[2]Current Patent Assignee: AMAKEM - WO2012/146724, 2012, A2 Location in patent: Page/Page column 51
[3]Current Patent Assignee: AMAKEM - US2014/57942, 2014, A1 Location in patent: Paragraph 0350-0351

44
[ 67385-09-5 ]
[ 82632-80-2 ]
[ 1333307-92-8 ]

Reference： [1]Angewandte Chemie - International Edition,2011,vol. 50,p. 7865 - 7869

45
[ 1334423-24-3 ]
[ 67385-09-5 ]
[ 1334423-43-6 ]

Yield	Reaction Conditions	Operation in experiment
71%	With sodium hydride In tetrahydrofuran; mineral oil at 23℃; for 4h; Inert atmosphere;	16 Example 16tert-butyl [2-({3-[4-(cyclopropylcarbamoyl)phenyl]-6-phenylimidazo[1 ,2- a]pyrazin-8-yl}sulfan l)ethyl]carbamate234 μΙ_ tert-butyl (2-sulfanylethyl)carbamate were added to a suspension of 55.5 mg sodium hydride (60% in white oil) in 2.5 mL tetrahydrofuran at 23°C. After 5 minutes of stirring, a solution of 100 mg (231 μητιο) N-Cyclopropyl-4-[8- (methylsulfonyl)-6-phenylimidazo[1 ,2-a]pyrazin-3-yl] benza mide whi ch was prepared according to example 3 in 1 .5 mL tetrahydrofurane were added and stirring was continued for four hours. Water was added and the mixture extracted with dichloromethane and dried over sodium sulfate. After filtration and solvent removal the residue was purified by chromatography to give 87.3 mg (71 %) of the title compound.1 H-NMR (CDCI3): δ= 0.67 (2H), 0.92 (2H), 1 .41 (9H), 2.96 (1 H), 3.61 (4H), 5.21 (1 H), 6.35 (1 H), 7.37-7.52 (3H), 7.65 (2H), 7.79 (1 H), 7.90 (2H), 7.94 (2H), 8.31 (1 H) ppm.

Reference： [1]Current Patent Assignee: BAYER AG - WO2011/113862, 2011, A1 Location in patent: Page/Page column 67

46
[ 67385-09-5 ]
[ 53784-83-1 ]
[ 1002752-75-1 ]

Yield	Reaction Conditions	Operation in experiment
99%	With caesium carbonate In N,N-dimethyl-formamide at 60℃; for 48h; Inert atmosphere;

Reference： [1]Location in patent: experimental part Díaz-Moscoso, Alejandro; Vercauteren, Dries; Rejman, Joanna; Benito, Juan M.; Ortiz Mellet, Carmen; De Smedt, Stefaan C.; Fernández, José M. García [Journal of Controlled Release, 2010, vol. 143, # 3, p. 318 - 325]

47
[ 1258834-71-7 ]
[ 67385-09-5 ]
[ 1258834-72-8 ]

Yield	Reaction Conditions	Operation in experiment
51%	With chloroformic acid ethyl ester; triethylamine In dichloromethane at 0 - 20℃; for 16h;	50.2 Step 2 Synthesis of (S)-1-{2-(tert-butoxycarbonylamino)ethylthio}-6-(4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl)isoquinoline 320 mg of (S)-6-(4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl)isoquinoline 2-oxide was dissolved in dichloromethane, and 0.1 mL of ethyl chlorocarbonate, 0.42 mL of 2-(N-tert-butoxycarbonylamino)ethanethiol, and 0.21 mL of triethylamine were added at 0° C. The reaction solution was stirred at room temperature for 16 hours and then concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane:acetone=4:1) to obtain 223 mg of the compound of interest as a colorless oil (51%). 1H-NMR spectrum (CDCl3, δ ppm): 0.88-0.98 (m, 3H), 1.39 (s, 9H), 1.45 (s, 9H), 1.67-1.72 (m, 2H), 3.08-3.15 (m, 3H), 3.50-3.54 (m, 4H), 3.60-3.68 (m, 2H), 3.81-3.92 (m, 2H), 4.38-4.42 (m, 1H), 7.43 (d, J=5.5 Hz, 1H), 7.85 (d, J=9.0 Hz, 1H), 8.27-8.29 (m, 2H), 8.38 (d, J=5.5 Hz, 1H)

Reference： [1]Current Patent Assignee: D.WESTERN THERAPEUTICS INSTITUTE INC; WESTERN THERAPEUTICS INST D; D WESTERN THERAPEUTICS INST - US2012/35159, 2012, A1 Location in patent: Page/Page column 42

48
[ 67385-09-5 ]
[ 433-06-7 ]
[ 1275596-03-6 ]

Yield	Reaction Conditions	Operation in experiment
53.8%	Stage #1: 2-[(tert-butoxycarbonyl)amino]-1-ethanethiol With sodium hydride In N,N-dimethyl-formamide for 1h; Stage #2: 2,2,2-Trifluoroethyl p-toluenesulfonate In N,N-dimethyl-formamide at 20℃;	5.c c. Synthesis of tert-butyl 2-(2,2,2-trifluoroethylthio)ethylaminoformate: [Show Image] 1.7g of sodium hydride was added to 30ml of dry dimethylformamide, and then 7.5g of tert-butyl 2-mercaptoethylaminoformate. Upon the end of the addition, the mixture was stirred for 1 h, and then slowly added with 2,2,2-trifluoroethyl (4-methylphenyl)sulfonate. Upon the end of the addition, the mixture was warmed to room temperature, and stirred overnight. The mixture was poured to water, extracted with diethyl ether, washed with 0.5M sodium hydroxide aqueous solution and then with saturated sodium chloride solution, dried over anhydrous sodium sulfate, distilled to remove the solvent, and subjected to a column chromatography to obtain 5.4g of light yellow oily liquid, yield 53.8%.
53.8%	Stage #1: 2-[(tert-butoxycarbonyl)amino]-1-ethanethiol With sodium hydride In N,N-dimethyl-formamide for 1h; Stage #2: 2,2,2-Trifluoroethyl p-toluenesulfonate In N,N-dimethyl-formamide at 20℃;	5.c 1.7 g of sodium hydride was added to 30 ml of dry dimethylformamide, and then 7.5 g of tert-butyl 2-mercaptoethylaminoformate. Upon the end of the addition, the mixture was stirred for 1 h, and then slowly added with 2,2,2-trifluoroethyl (4-methylphenyl)sulfonate. Upon the end of the addition, the mixture was warmed to room temperature, and stirred overnight. The mixture was poured to water, extracted with diethyl ether, washed with 0.5M sodium hydroxide aqueous solution and then with saturated sodium chloride solution, dried over anhydrous sodium sulfate, distilled to remove the solvent, and subjected to a column chromatography to obtain 5.4 g of light yellow oily liquid, yield 53.8%.

Reference： [1]Current Patent Assignee: QILU PHARMACEUTICAL GROUP CO LTD - EP2484678, 2012, A1 Location in patent: Page/Page column 20
[2]Current Patent Assignee: QILU PHARMACEUTICAL GROUP CO LTD - US2012/208833, 2012, A1 Location in patent: Page/Page column 15

49
[ 2127-03-9 ]
[ 67385-09-5 ]
[ 535943-48-7 ]
[ 67385-10-8 ]

Yield	Reaction Conditions	Operation in experiment
	In chloroform at 20℃; for 96h;	2 The intermediate compound tert-B tyl (2-(pyridin-2- yldisulfanyl)ethyl)carbamate identified as compound (10) in Reaction 2 above was prepared by adding 5.0 g of compound (9) (28.2 mmols) and 6.82 g of compound (2) (31 mmols) to 100 ml chloroform ( 100 ml) and stirring at room temperature for four days to form a solution. The solvent was evaporated and the resulting yellow solid was purified by flash chromatography (Si0 , 50-100 % ethyl acetate in hexanes) to provide 9.0g of impure compound (10). NMR showed the presence of the desired material (56% by weight), together with starting material compound (2) (24%) and a disulfide compound (11) (20 %) identified below. The mixture obtained was used on the following step without further purification. NMR (300 MHz, DMSO-d6) δ8.55-8.45 (m, 1H), 7.9-7.8 (m, 2H), 7.3-7.2 (m, 1 H), 7.07 (bt, J = 5 Hz, 1H), 3:25-3.15 (m, 2H), 2.87 (t, J = 7 Hz, 2H), 1.37 (s, 9H). MS (APCI, Pos) 287 (M+l ), 231 (M+l -C4H8).

Reference： [1]Current Patent Assignee: SANOFI; Translate Bio (in: Sanofi) - WO2012/170889, 2012, A1 Location in patent: Page/Page column 62-64

50
[ 67385-09-5 ]
[ 1425107-54-5 ]
[ 1425107-66-9 ]
[ 67385-10-8 ]

Yield	Reaction Conditions	Operation in experiment
1: 36% 2: 46%	With sodium hydroxide In water; acetonitrile at 20℃; for 24h; Inert atmosphere;

Reference： [1]Tiwari, Rohit; Moraski, Garrett C.; Krchňák, Viktor; Miller, Patricia A.; Colon-Martinez, Mariangelli; Herrero, Eliza; Oliver, Allen G.; Miller, Marvin J. [Journal of the American Chemical Society, 2013, vol. 135, # 9, p. 3539 - 3549]

51
[ 68617-64-1 ]
[ 67385-09-5 ]
[ 485800-27-9 ]

Reference： [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 720 - 723

52
[ 26555-40-8 ]
[ 67385-09-5 ]
C₉H₁₇NO₄S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With N-ethyl-N,N-diisopropylamine In methanol at 0℃; for 2h; Inert atmosphere;	7 Synthesis of cysteamine-S-S-mercaptobenzyl 4-nitrophenyl carbonate ester linker (3) Methoxycarbonylsulfenyl chloride (2.8 g, 15.8 mmol) was dissolved in 20 mL anhydrous methanol under inert atmosphere and chilled to 0° C. To this solution TBOC-cysteamine (2.0 g, 15.8 mmol) and N,N-diisopropylethylamine (DIPEA, 2.75 mL, 15.8 mmol) dissolved in 20 mL methanol were added dropwise while stirring at 0° C. The reaction mixture was stirred at 0° C. for 2 hours. Solvent was removed under vacuum and the resulting liquid was purified by flash column chromatography in methylene chloride to yield intermediate 1 (2.2 g, 52% yield). ESI MS expected: 267.06 Found: 290.28 (m+Na).
2.2 g	With N-ethyl-N,N-diisopropylamine In methanol at 0℃;	7 Synthesis of cysteamine-S-S-mercaptobenzyl 4-nitrophenyl carbonate ester Linker (3) Methoxycarbonylsulfenyl chloride (2.8g, 15.8 mmol) was dissolved in 20 mL anhydrous methanol under inert atmosphere and chilled to 0° C. To this solution TBOC-cysteamine (2.0 g, 15.8 mmol) and N,N-diisopropylethylamine (DIPEA, 2.75 mL, 15.8 mmol) dissolved in 20 mL methanol were added dropwise while stirring at 0° C. The reaction mixture was stirred at 0° C. for 2 hours. Solvent was removed under vacuum and the resulting liquid was purified by flash column chromatography in methylene chloride to yield intermediate 1 (2.2 g, 52% yield). ESI MS expected: 267.06 Found: 290.28 (m+Na).

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US2013/196906, 2013, A1 Location in patent: Paragraph 1465; 1466
[2]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US2018/193486, 2018, A1 Location in patent: Paragraph 1424; 1425

53
[ 67385-09-5 ]
[ 104-88-1 ]
C₁₄H₁₉NO₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	Stage #1: 2-[(tert-butoxycarbonyl)amino]-1-ethanethiol With potassium hydroxide In ethanol at 0℃; for 0.5h; Schlenk technique; Inert atmosphere; Stage #2: 4-chlorobenzaldehyde In ethanol at 75 - 78℃; for 3h; Schlenk technique; Inert atmosphere;	Preparation of p-Boc-NHC2H4SC6H4CHO (4) A solution of KOH (1.13 g, 20.2 mmol) in EtOH (25 mL) at 0 °C was treated dropwise with a solution of Boc-NHC2H4SH (3.54 g, 20.0 mmol) in EtOH (5 mL). After the mixture was stirred at 0 °C for 30 min, p-ClC6H4CHO (2.70 g, 19.2 mmol) was added, and then the new mixture was stirred at 75-78 °C for 3 h, resulting in a pale yellow solution with some KCl precipitates. To this mixture was added water (70 mL), and then the resulting solutionwas extracted with CCl4 (20 mL 4). After CCl4 was removed from the extracts in vacuum, the residue was subjected to fluorescence TLC separation using acetone/petroleum ether (1:5 ¼ v/v) as eluent. From the major band, 4 was obtained as a white solid (2.69 g, 50%), m.p. 51-52 °C. Anal. Calcd for C14H19NO3S: C, 59.76; H, 6.81; N, 4.98. Found: C, 59.70; H, 6.70; N, 5.07. IR (KBr disk): νC=O 1691 (vs), 1682 (s) cm 1. 1H NMR (400 MHz, CDCl3): δ = 1.44 (s, 9H, C(CH3)3), 3.17 (t, 2H, J = 6.4 Hz, NCH2CH2S), 3.40, 3.42 (2s, 2H, NCH2CH2S), 4.90 (s, 1H, NH), 7.42 (d, 2H, J ¼ 8.0 Hz, 2m-H of C6H4CHO), 7.78 (d, 2H, J = 8.4 Hz, 2o-H of C6H4CHO), 9.93 (s, 1H, CHO) ppm.

Reference： [1]Song, Li-Cheng; Wang, Liang-Xing; Li, Chang-Gong; Li, Fengyu; Chen, Zhongfang [Journal of Organometallic Chemistry, 2014, vol. 749, p. 120 - 128]

54
[ 67385-09-5 ]
[ 69655-76-1 ]
[ 1588948-20-2 ]

Reference： [1]Chemical Science,2014,vol. 5,p. 1046 - 1053

55
[ 118-96-7 ]
[ 67385-09-5 ]
[ 1608182-16-6 ]

Yield	Reaction Conditions	Operation in experiment
72%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2h;	5 4.2. General procedure for the synthesis of 4,6-dinitro-2-sulfanyltoluenes 1 General procedure: To a solution of 2,4,6-trinitrotoluene (5g, 0.022 mol) and a corresponding thiol (0.022 mol) in 50 mL of DMF K2CO3 (3.1 g, 0.022 mol) was added. The mixture was stirred at room temperature for 2h (TLC monitoring) and poured into 500 mL of 5% HCl. The precipitate was collected by filtration and re-crystallized from iPrOH (in case of 1i from MeCN) to give an analytically pure products 14.2.5 tert-Butyl (2-((2-methyl-3,5-dinitrophenyl)thio)ethyl)carbamate (1f) Yield: 5.7 g, 72%; mp=120-122 °C. 1H NMR (500 MHz, CDCl3) δ (ppm): 8.37 (1H, d, J 2.1 Hz, Harom), 8.32 (1H, d, J 2.1 Hz, Harom), 4.96 (1H, br, NH), 3.47 (2H, m, SCH2CH2NHBoc), 3.25(2H, t, J 6.2 Hz, SCH2CH2NHBoc), 2.56 (3H, s, Me), 1.45 (9H, s, tBu). 13C NMR (125 MHz, CDCl3) δ (ppm): 155.7, 150.8, 146.0, 143.0, 137.0, 122.9, 115.6, 80.1, 39.2, 33.3, 28.4, 16.6. νmax (KBr): 3290 (NH), 3070 (CH), 2980 (CH), 1680 (C=O), 1530 (NO2), 1370(NO2) cm-1. Anal. found %: C 47.09; H 5.41; N 11.81; S 9.05; Anal. Calcd for C14H19N3O6S %: C, 47.05; H, 5.36; N, 11.76; S, 8.97.

Reference： [1]Rozhkov, Vladimir V. [Tetrahedron, 2014, vol. 70, # 22, p. 3595 - 3600]

56
[ 67385-09-5 ]
[ 1417162-29-8 ]
[ 76-05-1 ]
[ 1612753-05-5 ]

Yield	Reaction Conditions	Operation in experiment
41%	Stage #1: 2-[(tert-butoxycarbonyl)amino]-1-ethanethiol; 3-chloro-1-(3,4-dichloro-phenyl)-4-(4-methoxy-phenyl)-pyrrole-2,5-dione With potassium carbonate In tetrahydrofuran at 20℃; Stage #2: trifluoroacetic acid In dichloromethane for 2h;	11 3-chloro-l-(3,4-dichlorophenyl)-4-(4-methoxyphenyl)-lH-pyrrole-2,5- dione (6a) (0.190 g, 0.5 mmol), tert-butyl (2-mercaptoethyl)carbamate (0.177 g, 1 mmol), anhydrous potassium carbonate (0.138 g, 1 mmol) and 4 mL of THF were stirred at room temperature overnight. Solvents were removed under reduced pressure and the residue was dissolved in methylene chloride and extracted twice with water and once with brine. Organic phase was dried with sodium sulfate. Residue after evaporation of solvent was dissolved in 5 mL of methylene chloride, 5mL of TFA was added and solution was stirred for 2 h. Solvents were evaporated, residue dissolved in methylene chloride, extracted with sodium bicarbonate, water and brine. Organic phase was dried with sodium sulfate and residue, after evaporation of solvents, was chromatographed on silica gel using hexane and ethyl acetate as eluents (2: 1). The compound was further purified by preparative HPLC to afford 106 mg (41 %) of 3-((2-aminoethyl)thio)-l-(3,4-dichlorophenyl)-4-(4-methoxyphenyl)-lH-pyrrole-2,5-dione TFA salt (MMP-1-75) as a yellow solid. 1H-NMR (400 MHz, DMSO-d6): δ 8.03(bs, 3H), 7.82 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.48 (dd, J = 8.8 Hz, J = 2.0 Hz, 1H), 7.13 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H), 3.54 (m, 2H), 3.16 (m, 2H). 13C- NMR (100 MHz, DMSO-d6): δ 167.3, 166.6, 161.1, 136.1, 133.1, 132.1, 131.9, 131.5, 131.3, 130.8, 129.0, 127.5, 121.2, 114.5, 55.5, 39.9, 29.1

Reference： [1]Current Patent Assignee: UNIVERSITY OF CHICAGO - WO2014/85545, 2014, A1 Location in patent: Page/Page column 61

57
[ 415713-60-9 ]
[ 67385-09-5 ]
[ 76-05-1 ]
3-((2-aminoethyl)thio)-1-(3,4-dichlorophenyl)-4-morpholino-1H-pyrrole-2,5-dione trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%		l-(3,4-Dichlorophenyl)-3-chloro-4-morpholino-lH-pyrrole-2,5-dione (<strong>[415713-60-9]RI-1</strong>) (0.190 g, 0.5 mmol), tert-butyl (2-mercaptoethyl)carbamate (0.177 g, 1 mmol), anhydrous potassium carbonate (0.138 g, 1 mmol) and 4 mL of THF were stirred at room temperature overnight. Solvents were removed under reduced pressure and the residue was dissolved in methylene chloride and extracted twice with water and once with brine, organic phase was dried with sodium sulfate. Residue was dissolved in 5 mL of methylene chloride, 5mL of TFA was added and solution was stirred for 2 h. Solvents were evaporated, residue dissolved in methylene chloride, extracted with sodium bicarbonate, water and brine. Organic phase was dried with sodium sulfate and residue, after evaporation of solvents, was chromatographed on silica gel using hexane and ethyl acetate as eluents (2:1). The compound was further purified by preparative HPLC to afford 94 mg (38 %) of 3-((2- aminoethyl)thio)- 1 -(3 ,4-dichlorophenyl)-4-morpholino- lH-pyrrole-2,5-dione TFA salt (MMP-1-14) as a yellow oil. 1H-NMR (400 MHz, DMSO-d6): delta 752 (m, 2H), 7.26 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 4.24 (t, J = 4.8 Hz, 4H), 3.76 (t, J = 4.8 Hz, 4H), 3.07 (t, J= 6.0 Hz, 2H), 2.82 (t, J = 6.0 Hz, 2H),. 'T-NMR OO MHz, DMSO-d6): delta 171.5, 164.2, 149.8, 132.9, 132.2, 130.8, 128.1 , 152.7, 89.2, 67.1 , 49.3, 38.6, 34.6.

Reference： [1]Patent: WO2014/85545,2014,A1 .Location in patent: Page/Page column 62; 63

58
[ 538-86-3 ]
[ 67385-09-5 ]
[ 207554-43-6 ]

Yield	Reaction Conditions	Operation in experiment
71%	With di-tert-butyl peroxide In neat (no solvent) at 120℃; for 24h; Sealed tube;

Reference： [1]Feng; Lv; Lu; Cai [Organic and Biomolecular Chemistry, 2015, vol. 13, # 3, p. 677 - 681]

59
[ 15307-86-5 ]
[ 67385-09-5 ]
C₂₁H₂₄Cl₂N₂O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 16h;
	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 18h; Cooling with ice;	1.2 2) Synthesis of intermediate Ra-012-2 Ice water bath,Diclofenac Ra-009 was added(100 mg, 0.34 mmol)And Ra-012-1 were dissolved in dichloromethane (5 mL)A catalytic amount of DMAP (4 mg) and DCC (140 mg, 0.68 mmol) were added sequentially. Rose to room temperature,For 18 hours.Ethyl acetate (10 mL) was added,filter,The filtrate was dried.The residue was chromatographed on a gel column(Petroleum ether: ethyl acetate = 10: 1)To give a mixture of a white solid (110 mg)Containing a small amount of diclofenac by itself condensation of by-products,Directly for the next step.

Reference： [1]Xu, Zhixiang; Wu, Jing; Zheng, Jiyue; Ma, Haikuo; Zhang, Hongjian; Zhen, Xuechu; Zheng, Long Tai; Zhang, Xiaohu [International Immunopharmacology, 2015, vol. 25, # 2, p. 528 - 537]
[2]Current Patent Assignee: SOOCHOW UNIVERSITY (SUZHOU) - CN103922981, 2017, B Location in patent: Paragraph 0048; 0051; 0052

60
[ 67385-09-5 ]
[ 106-89-8 ]
C₁₀H₁₉NO₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83.8%	With potassium carbonate In ethanol at 0℃; for 16h;	1.25.2 1.25.2 Preparation of Compound 4 Compound 2 (1.0 g, 6.2 mmol) and compound 3 (960.8 mg, 10.5 mmol) in EtOH (12 mL) were cooled to 0° C. and treated with K2CO3 (960.8 mg, 6.96 mmol). The mixture was stirred at 12 r for 16 h. The mixture was diluted with EA (100 mL) amd filtered through celite. The volatiles were removed under reduced pressure to give give compound 4 as colorless oil (1.4 g, 83.8%).
83.8%	With potassium carbonate In ethanol at 0 - 12℃; for 16h;	I.1.25.2 1.25.2 Preparation of Compound 4 Compound 2 (1.0 g, 6.2 mmol) and compound 3 (960.8 mg, 10.5 mmol) in EtOH (12 mL) were cooled to 0 r and treated with K2CO3 (960.8 mg, 6.96 mmol). The mixture was stirred at 12 r for 16 h. The mixture was diluted with EA (100 mL) and filtered through celite. The volatiles were removed under reduced pressure to give give compound 4 as colorless oil (1.4 g, 83.8%).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US2015/197493, 2015, A1 Location in patent: Paragraph 0648; 0651; 0652
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - US2015/225355, 2015, A1 Location in patent: Paragraph 0646

61
[ 67385-09-5 ]
[ 3680-69-1 ]
C₁₃H₁₈N₄O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol; acetonitrile at 80℃; for 20h; Inert atmosphere;	7 Example 7 Compound 17 Example 7 Compound 17 (0194) (0195) A mixture of 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (0.077 mg, 0.500 mmol), (2-mercapto-ethyl)-carbamic acid tert-butyl ester (0.088 g, 0.500 mmol) and DIEA (0.096 mL, 1.0 mmol) was dissolved in i-PrOH (1 mL) and CH3CN (1 mL). The resulting solution was stirred at 80 °C for 20 hr and the volatile had been removed in vacuo. Purified by silica gel chromatography (EtOAc/Hexanes 10%-50%) to afford Intermediate 6 (0.112 g, 0.38 mmol, 76 % yield). To a solution of Intermediate 6 (59.1 mg, 0.2 mmol) in MeOH (1 mL) a solution of 4 N HCl/dioxane (1 mL) was added. The resulting solution was stirred at RT for 3 hr and after the volatile was removed in vacuo. The mixture was re-dissolved in DMF (1 mL) followed by the addition of DIEA (0.058 mL, 0.6 mmol) and the solution was added into a mixture of 4-aminosalicylic acid (0.031 g, 0.200 mmol), 1,1'-carbonyldiimidazole (0.033 g, 0.2 mmol), and DIEA (0.038 mL, 0.4 mmol) in DMF (1 mL). The resulting mixture was stirred at RT for 16 hr. Concentrated and purified by purified by reverse phase HPLC to afford Compound 17 (16 mg, 0.042 mmol, 21% yield). ES (+) MS m/e = 374 (M+1).

Reference： [1]Current Patent Assignee: SUNESIS PHARMACEUTICALS INC - EP2257637, 2015, B1 Location in patent: Paragraph 0194; 0195

62
[ 67385-09-5 ]
[ 107-96-0 ]
[ 485800-27-9 ]

Yield	Reaction Conditions	Operation in experiment
70%	In dimethyl sulfoxide; at 70℃; for 24h;Inert atmosphere;	3-(2-tert-Butoxycarbonylamino-ethyldisulfanyl)-propionic acid (0149) (0150) To a solution of L1 (75 mL, 424.0 mmol) in DMSO (133.5 mL) was added L2 (41.17 mL, 424.0 mmol) and the reaction mixture was then heated at 70 C for 24 hr. The reaction progress was monitored by LCMS. The reaction mixture was cooled and ethyl acetate (EtOAc) (400 mL) was added with stirring and then extracted with 1M HEPES (pH 7.0, 2× 400 mL) and the aqueous layer was discarded (di-acid). The organic layer was then extracted with saturated NaHCO3 (3× 300 mL), The combined aqueous layer was then acidified with 3M HCl to pH 1-2 and extracted with EtOAc (3x 300 mL). The organic layer was dried (Na2SO4) and solvent was evaporated to give compound L3 (81 g, 70% yield, white powder). Compound L3 was characterized by LCMS and 1H NMR (dmso-d6) and was stored at -78 C to avoid decomposition.

Reference： [1]Patent: EP2257637,2015,B1 .Location in patent: Paragraph 0149; 0150

63
[ 40741-46-6 ]
[ 67385-09-5 ]
C₁₃H₂₁N₃O₄S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 120℃; for 16h;	Step 1. A mixture of <strong>[40741-46-6]6-chloropyridine-3-sulfonamide</strong> (1 equiv.), tert-butyl N-(2-sulfanylethyl)carbamate (1.2 equiv.), and Hunig?s base (2 equiv.) in 2-propanolwas stirred at 120 00 for 16 h. The mixture was then concentrated, dissolved in DCM and passed through a short plug of silica. After concentration the crude residue was used without further purification in step 2.

Reference： [1]Patent: WO2015/187088,2015,A1 .Location in patent: Page/Page column 111

64
[ 67385-09-5 ]
[ 40517-43-9 ]
tert-butyl N-[2-[(4-methylsulfonylphenyl)methylsulfanyl]ethyl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In N,N-dimethyl-formamide at 60℃; for 16h;	176.1 A mixture of 1-(chloromethyl)-4-methylsulfonyl-benzene (1 equiv.), tertbutyl N-(2-sulfanylethyl)carbamate (1 equiv.), and Cs2003 (1 equiv.) was stirred in DMF at 60 00 for 16 h. Then the mixture was poured into sat. NaHCO3 and extracted with DCM x3. The combined organics were dried (Mg504),concentrated, and purified by silica gel chromatography to afford tert-butyl N-[2- [(4-methylsulfonylphenyl)methylsulfanyl]ethyl]carbamate. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.90 (d, J=8.5 Hz, 2 H), 7.55 (d, J=8.5 Hz, 2 H), 3.80 (5, 2 H), 3.27-3.35 (m, 2 H), 3.07 (5, 3 H), 2.55 (t, J=6.8 Hz, 2 H), 1.46 (5, 9 H).
	With caesium carbonate In N,N-dimethyl-formamide at 60℃; for 16h;	689.1 Step 1. A mixture of 1-(chloromethyl)-4-methylsulfonyl-benzene (1 equiv.), tert- butyl N-(2-sulfanylethyl)carbamate (1 equiv.), and Cs2C03 (1 equiv.) was stirred in DMF at 60 °C for 16 h. Then the mixture was poured into sat. NaHC03 and extracted with DCM *3. The combined organics were dried (MgS04), concentrated, and purified by silica gel chromatography to afford tert-butyl N-[2- [(4-methylsulfonylphenyl)methylsulfanyl]ethyl]carbamate. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.90 (d, J=8.5 Hz, 2 H), 7.55 (d, J=8.5 Hz, 2 H), 3.80 (s, 2 H), 3.27 - 3.35 (m, 2 H), 3.07 (s, 3 H), 2.55 (t, J=6.8 Hz, 2 H), 1.46 (s, 9 H).

Reference： [1]Current Patent Assignee: THOMAS HELLEDAYS STIFTELSE FOR MEDICINSK FORSKNING - WO2015/187088, 2015, A1 Location in patent: Page/Page column 108
[2]Current Patent Assignee: THOMAS HELLEDAYS STIFTELSE FOR MEDICINSK FORSKNING - WO2015/187089, 2015, A1 Location in patent: Page/Page column 274; 275

65
[ 2417-72-3 ]
[ 67385-09-5 ]
methyl 4-(((2-((tert-butoxycarbonyl)amino)ethyl)thio)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	Stage #1: 2-[(tert-butoxycarbonyl)amino]-1-ethanethiol In N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere; Stage #2: Methyl 4-(bromomethyl)benzoate In N,N-dimethyl-formamide	20 Intermediate 20: 4-(((2-((ferf-butoxycarbonyl)amino)ethyl)sulfonyl) methyl)benzoic acid [00371] Sodium hydride (60%, 236 g, 9.82 mmol) was added slowly to a solution of BOC- cysteamine (1.66 ml_, 9.82 mmol) in anhydrous DMF (10 ml_), with stirring at room temperature under nitrogen for 1 hour. A solution of methyl-4-bromomethyl benzoate (750 mg, 3.27 mmol) in anhydrous DMF (5 ml_) was then added drop-wise, with continued stirring overnight. The reaction mixture was then separated between diethyl ether and water, the organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was which was purified using flash column chromatography over silica, eluting with 5-80% ethyl acetate/petroleum ether, to give methyl 4-(((2-((terf-butoxycarbonyl)amino)ethyl)thio)methyl) benzoate (664 mg, 62% yield) as a clear colourless oil. 1H NMR (CDCh, 300 MHz) d 7.97 (d, 2H, J = 8.5 Hz), 7.38 (d, 2H, J = 8.5 Hz), 4.84 (br s, 1 H), 3.89 (s, 3H), 3.74 (s, 2H), 3.26 (q, 2H, J = 6.2 Hz), 2.52 (t, 2H, J = 6.6 Hz), 1.42 (s, 9H) ppm.
	With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 16h;	181.1 Step 1. A mixture of methyl 4-(bromomethyl)benzoate (1 equiv.), tert-butyl N-(2- sulfanylethyl)carbamate (1.3 equiv.), and K2003 (1.1 equiv.) were stirred in DMFat 60 00 for 16 h. The mixture was poured into water and extracted with DCM x3. The combined organics were dried (Mg504), concentrated, and purified by silica gel chromatography to afford methyl 4-[2-(tert- butoxycarbonylamino)ethylsulfanylmethyl]benzoate.
	With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 16h;	699.1 Step 1. A mixture of methyl 4-(bromomethyl)benzoate (1 equiv.), tert-butyl N-(2- sulfanylethyl)carbamate (1.3 equiv.), and K2C03 (1.1 equiv.) were stirred in DMF at 60 °C for 16 h. The mixture was poured into water and extracted with DCM *3. The combined organics were dried (MgS04), concentrated, and purified by silica gel chromatography to afford methyl 4-[2-(tert- butoxycarbonylamino)ethylsulfanylmethyl]benzoate.

Reference： [1]Current Patent Assignee: UNIVERSITY OF LONDON - WO2020/99886, 2020, A1 Location in patent: Paragraph 00371
[2]Current Patent Assignee: THOMAS HELLEDAYS STIFTELSE FOR MEDICINSK FORSKNING - WO2015/187088, 2015, A1 Location in patent: Page/Page column 111
[3]Current Patent Assignee: THOMAS HELLEDAYS STIFTELSE FOR MEDICINSK FORSKNING - WO2015/187089, 2015, A1 Location in patent: Page/Page column 280

66
[ 67385-09-5 ]
[ 53784-83-1 ]
[ 76-05-1 ]
heptakis-[2-aminoethylthio]-β-cyclodextrin trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%	Stage #1: 2-[(tert-butoxycarbonyl)amino]-1-ethanethiol With sodium hydride In N,N-dimethyl-formamide at 60℃; for 2h; Inert atmosphere; Stage #2: heptakis(6-bromo-6-deoxy)-β-cyclodextrin In N,N-dimethyl-formamide for 17h; Inert atmosphere; Stage #3: trifluoroacetic acid In dichloromethane at 20℃; for 6h; Inert atmosphere;	2.2.3 Synthesis of heptakis-[2-aminoethylthio]-β-cyclodextrin trifluoroacetate (C) 2-(Boc-amino) ethanethiol (605μL, 3.58mmol) was dissolved in anhydrous DMF (20ml) and sodium hydride (82mg, 3.41mmol) was added. The mixture was heated to 60°C and stirred under nitrogen for 2h. The mixture was then cooled to room temperature and heptakis-6-bromo-6-deoxy-β-cyclodextrin (250mg, 0.16mmol) was added in anhydrous DMF (5ml). The mixture was heated to 60°C and stirred under nitrogen overnight. The solvent was removed in vacuo and the residue washed several times with cyclohexane and water. The product was dissolved in DCM/ TFA (1:1, 10ml) and stirred for 6h under nitrogen. The mixture was concentrated and the product precipitated from diethyl ether. The product C was purified on Sephadex LH20 (MeOH: 100%) (159mg, 42%). 1H NMR (400MHz, DMSO-d6) δ 7.97 (s, 3H), 5.91 (m, 2H), 4.87 (s, 1H), 3.81-3.22 (m, 10H), 3.07-2.89 (m, 2H), 2.89-2.65 (m, 2H). (0019) 13C NMR (101MHz, DMSO-d6) δ 102.4, 84.8, 72.9, 72.5, 72.2, 65.2, 33.1, 30.3. (0020) MS (MALDI-TOF) m/z: [M+Na]+ 1575.6176

Reference： [1]Fitzgerald, Kathleen A.; Malhotra, Meenakshi; Gooding, Matt; Sallas, Florence; Evans, James C.; Darcy, Raphael; O'Driscoll, Caitriona M. [International Journal of Pharmaceutics, 2016, vol. 499, # 1-2, p. 131 - 145]

67
[ 40741-46-6 ]
[ 67385-09-5 ]
C₁₂H₁₉N₃O₄S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 120℃; for 16h;	Step 1. A mixture of <strong>[40741-46-6]6-chloropyridine-3-sulfonamide</strong> (1 equiv.), tert-butyl N-(2- sulfanylethyl)carbamate (1.2 equiv.), and Hunig's base (2 equiv.) in 2-propanol was stirred at 120 C for 16 h. The mixture was then concentrated, dissolved in DCM and passed through a short plug of silica. After concentration the crude residue was used without further purification in step 2.

Reference： [1]Patent: WO2015/187089,2015,A1 .Location in patent: Page/Page column 279; 280

68
[ 67385-09-5 ]
methyl 3-bromo-6-methoxypyridine-2-carboxylate [ No CAS ]
3-((2-((tert-butoxycarbonyl)amino)ethyl)thio)-6-methoxypicolinic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
6.7%	Stage #1: 2-[(tert-butoxycarbonyl)amino]-1-ethanethiol; methyl 3-bromo-6-methoxypyridine-2-carboxylate With potassium carbonate In dimethyl sulfoxide at 60℃; for 3h; Sealed tube; Stage #2: With sodium hydroxide In tetrahydrofuran; methanol at 20℃;	9.1 3-((2-((tert-Butoxycarbonyl)amino)ethyl)thio)-6-methoxypicolinic acid Step 1: 3-((2-((tert-Butoxycarbonyl)amino)ethyl)thio)-6-methoxypicolinic acid A pressure tube was charged with methyl 3-bromo-6-methoxypicolinate (2.00 g, 8.1 mmoles), potassium carbonate (4.77 g, 34.5 mmoles), tert-butyl (2-mercaptoethyl)carbamate (5.15 ml, 30.5 mmoles) and DMSO (20 mL) and the reaction mixture heated to 60° C. for 3 h in the sealed tube. The reaction mixture was cooled to room temperature and quenched with water and extracted with ethyl acetate (240 mL), washed with brine and dried over MgSO4. The organic solvents were concentrated to dryness under reduced pressure to give a white solid (2 g). This was taken in methanol (30 mL), THF (30 mL) and 3 mL of 8N NaOH was added and the reaction mixture was stirred at room temperature overnight. The solvents were removed under reduced pressure and the residue was taken in water (20 mL) and extracted with ethyl acetate (260 mL). The organic layer contained only impurity and was discarded. The aqueous layer was neutralized with 3N HCl and extracted with IPA/CHCl3 (1:3, 3*100 mL), washed with water, brine and then dried over MgSO4. The solvents were concentrated to dryness under reduced pressure to give the desired compound as an oil (450 mg, 6.7%). LC/MS: 328.8 [M]+1H NMR (300 MHz, CDCl3): δ 7.90 (d, J=8.4 Hz, 1H), 7.05 (d, J=9.0 Hz, 1H), 4.98 (bs, 1H), 3.98 9s, 3H0, 3.43-3.37 (m, 2H0, 3.12-3.08 (m, 2H), 1.44 (s, 9H).

Reference： [1]Current Patent Assignee: MYOTHERIX - US2016/207893, 2016, A1 Location in patent: Paragraph 0565-0566

69
[ 67385-09-5 ]
methyl 2-chloro-5-methoxynicotinate [ No CAS ]
methyl 2-((2-((tert-butoxycarbonyl)amino)ethyl)thio)-5-methoxynicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 2h; Inert atmosphere;	13.2 Methyl 2-((2-((tert-butoxycarbonyl)amino)ethyl)thio)-5-methoxynicotinate Step 2: Methyl 2-((2-((tert-butoxycarbonyl)amino)ethyl)thio)-5-methoxynicotinate A round bottom flask was charged with methyl 2-chloro-5-methoxynicotinate (5.08 g, 25.2 mmoles), DMF (50 mL) and cesium carbonate (16.42 g, 50.4 mmoles) and tert-butyl (2-mercaptoethyl)carbamate (6.39 ml, 37.8 mmoles) under nitrogen and the reaction mixture stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate (3*100 ml). The combined organic solvents were washed with brine and dried over MgSO4. The solvents were concentrated to dryness under reduced pressure and the residue purified (0-30% ethyl acetate in hexanes) to give the product as a colorless oil (2.23 g, 25%). 1H NMR (300 MHz, CDCl3): δ 8.3 (d, J=3.0 Hz, 1H), 7.76 (d, J=2.4 Hz, 1H), 3.94 (s, 3H), 3.87 (s, 3H), 3.31 (d, J=6.0 Hz, 2H), 2.80 (t, J=6.2 Hz, 2H), 1.43 (s, 9H).

Reference： [1]Current Patent Assignee: MYOTHERIX - US2016/207893, 2016, A1 Location in patent: Paragraph 0595-0596

70
[ 67385-09-5 ]
methyl 5-iodo-2-methoxyisonicotinate [ No CAS ]
methyl 5-((2-((tert-butoxycarbonyl)amino)ethyl)thio)-2-methoxyisonicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75.9%	With copper(l) iodide; potassium carbonate In 1,2-dimethoxyethane at 80℃; for 72h;	2.1 Methyl 5-((2-((tert-butoxycarbonyl)amino)ethyl)thio)-2-methoxyisonicotinate Step 1: Methyl 5-((2-((tert-butoxycarbonyl)amino)ethyl)thio)-2-methoxyisonicotinate A pressure tube was charged with methyl 5-iodo-2-methoxyisonicotinate (7.00 g, 23.9 mmoles), copper(I)iodide (0.910 g, 4.8 mmoles), potassium carbonate (6.60 g, 47.8 mmoles), tert-butyl (2-mercaptoethyl)carbamate (4.04 ml, 23.9 mmoles) and DME (15 ml) and the reaction mixture heated to 80° C. for 3 days. The reaction mixture was filtered over celite and the celite pad washed with DCM (500 mL). The solvents were concentrated to dryness under reduced pressure and the residue purified by flash chromatography over silica gel (0-50% ethyl acetate in hexanes) to give the product as a colorless oil (6.7 g, 75.9%). LC/MS: 342.7 [M+1]+. 1H NMR (300 MHz, CDCl3): δ 8.31 s, 1H), 7.03 (s, 1H), 3.95 (s, 6H), 3.32-3.27 (m, 2H), 3.01 (t, J=6.0 Hz, 2H), 1.43 9s, 9H).

Reference： [1]Current Patent Assignee: MYOTHERIX - US2016/207893, 2016, A1 Location in patent: Paragraph 0522-0523

71
[ 67385-09-5 ]
6-[1-(3-chloro-propyl)-1H-pyrazol-4-yl]-pyridine-2-carboxylic acid methyl ester [ No CAS ]
6-{1-[3-(2-tert-butoxycarbonylamino-ethylsulfanyl)-propyl]-1H-pyrazol-4-yl}-pyridine-2-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80.8%	With caesium carbonate In N,N-dimethyl-formamide at 60℃; for 3h;	6-{1-[3-(2-tert-Butoxycarbonylamino-ethylsulfanyl)-propyl]-1H-pyrazol-4-yl}-pyridine-2-carboxylic acid methyl ester 6-{1-[3-(2-tert-Butoxycarbonylamino-ethylsulfanyl)-propyl]-1H-pyrazol-4-yl}-pyridine-2-carboxylic acid methyl ester A mixture of (2-Mercapto-ethyl)-carbamic acid tert-butyl ester (0.29 mL; 1.68 mmol; 1.30 eq.), Cs2CO3 (548 mg; 1.68 mmol; 1.30 eq.) and 6-[1-(3-Chloro-propyl)-1H-pyrazol-4-yl]-pyridine-2-carboxylic acid methyl ester (362 mg; 1.29 mmol; 1.00 eq.) in DMF (3 mL) was stirred at 60° C. for 3 hr. The reaction mixtue was diluted with water, extracted with EA, concentrated, got residue was purified by SNAP column (25 g, eluent with 20% -100% EA in hexane), providing the title compound (440 mg, yield 80.8%). LC-MS (M+1): 421.

Reference： [1]Current Patent Assignee: MERCK KGAA - US2016/229856, 2016, A1 Location in patent: Paragraph 0363; 0364

72
[ 67385-09-5 ]
[ 74-88-4 ]
[ 1275596-02-5 ]

Yield	Reaction Conditions	Operation in experiment
47%	Stage #1: 2-[(tert-butoxycarbonyl)amino]-1-ethanethiol With sodium hydride In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; Cooling with ice; Stage #2: methyl iodide In tetrahydrofuran at 20℃; for 1h; Cooling with ice;	1.b The protection of b.Boc 2-methylthioamphetamine yl ethylamine preparation: Ice-bath, under the conditions of protection of nitrogen, the NaH4.8g Boc protection added in batches 2-mercapto-ethylamine 28g anhydrous tetrahydrofuran (250 ml) solution, to room temperature reaction 1h, and ice dropping under the conditions of 12 ml tetrahydrofuran solution of iodine of methane, react about room temperature after the drop finishes 1h, the reaction is quenched by adding saturated sodium carbonate solution, water the fluid leans in the reaction, ethyl acetate extraction, the organic phase is washed with saturated sodium chloride solution, anhydrous sodium sulfate for drying, steaming dry solvent to obtain oily liquid. Boc protection column chromatography to obtain 2-methylthioamphetamine base ethylamine 14.2g, yield 47%.

Reference： [1]Current Patent Assignee: QILU PHARMACEUTICAL GROUP CO LTD - CN103304544, 2016, B Location in patent: Paragraph 0112; 0113; 0114

73
[ 67385-09-5 ]
[ 111625-28-6 ]
[ 877864-07-8 ]

Yield	Reaction Conditions	Operation in experiment
86%	With pyridine In methanol	1.2 2-(N-tert-butoxyamido-ethyl) 2-yl-disulfanyl)ethanol (27). To a solution of 26 (0.9 g, 4.8 mmol) in methanollpyridine (40/i mL) was added BOC-cysteamine (2.ig, 11.8 mmol) and the mixture was stirred overnight. The reaction was concentrated and the residue was purified by flash chromatography on silica gel. The desired product was obtained with 40-60% ethanol in hexanes gradient as colorless oil (i.04g, 86%). 1H-NMR (CDC13) 4.89 (br s, 1H, OH), 3.88-3.91 (t, J= 5.6 Hz, 2H, OCH2), 3.46-3.48 (m, 2H, NCH2), 2.88-2.91 (t, J= 6.0 Hz, 2H, SCH2), 2.80-2.2.83 (t, J= 6.8 Hz, 2H, SCH2), 1.45 (s, 9H, C(CH3)3). Mass calcd for C9H19N03S2, 253.0, Found (M+Na) 276.
86%	With pyridine In methanol	tert- Butyl (2-((2-hydroxyethyl)disulfaneyl)ethyl)carbamate (9). To a solution of Compound 8 (0.9 g, 4.8 mmol) in methanol/pyridine (40/1 mL) was added BOC- cysteamine (2.1 g, 11.8 mmol) and the mixture was stirred overnight. The reaction was concentrated and the residue was purified by flash chromatography on silica gel. The product 9 was obtained with 40-60% ethanol in hexanes gradient as a colorless oil (l .04g, 86%). 1H- NMR (CDC13) d 4.89 (br s, 1H, OH), 3.88-3.91 (t, J= 5.6 Hz, 2H, OCH2), 3.46-3.48 (m, 2H, NCH2), 2.88-2.91 (t, j= 6.0 Hz, 2H, SCH2), 2.80-2.83 (t, j= 6.8 Hz, 2H, SCH2), 1.45 (s, 9H, C(CH3 )3). Mass calcd for C9Hi9N03S2, 253.0, found (M+Na) 276.

Reference： [1]Current Patent Assignee: CENTRILLION TECHNOLOGY HOLDINGS CORPORATION - WO2016/182984, 2016, A1 Location in patent: Paragraph 00129
[2]Current Patent Assignee: CENTRILLION TECHNOLOGY HOLDINGS CORPORATION - WO2020/69424, 2020, A1 Location in patent: Paragraph 00067; 00200

74
[ 4530-20-5 ]
[ 67385-09-5 ]
C₁₄H₂₆N₂O₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With dmap; bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; triethylamine In dichloromethane at 20℃; for 13h; Cooling with ice;	11.1 In substantially the same manner as in Example 1 (Step 1) except that Boc-ethanolamine used in Example 1 (Step 1) was replaced by Compound 32, EDCI was replaced by 1.20 eq of bis(2-oxo-3-oxazolydinyl)phosphinic chloride (BOP-Cl) relative to Compound 32 and triethylamine was further added in 2.40 eq relative to Compound 32, Compound 33 (3.78 g, 11.3 mmol) was obtained from Compound 32 (2.00 g, 11.3 mmol) and Compound 1 (2.17 g, 12.4 mmol) as a colorless transparent viscous liquid (yield 100%). (0356) 1H-NMR(500 MHz,CDCl3,δ) 1.44-1.47(18H, m, Boc×2), 3.03-3.07(2H, m, CH2), 3.30-3.31(2H, m, CH2),4.05(2H, d, J=6 Hz, CH2), 4.82(1H, brs, NH), 5.12-5.22(1H, m, NH) (0357) ESI-MS: Calcd for C14H26N2O5S [M+H]+, 335.2; found 335.2

Reference： [1]Current Patent Assignee: SEIKAGAKU CORPORATION - US2017/1948, 2017, A1 Location in patent: Paragraph 0352; 0354-0357

75
[ 67385-09-5 ]
7-bromo-2-(chloromethyl)-5-cyclopropyl-6-methyl-oxazolo[4,5-c]quinolin-4-one [ No CAS ]
tert-butyl-N-[2-[(7-bromo-5-cyclopropyl-6-methyl-4-oxo-oxazolo[4,5-c]quinolin-2-yl)methylsulfanyl]ethyl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With potassium phosphate In N,N-dimethyl-formamide at 20℃; for 3h; Inert atmosphere;	30.a (a) teit-butyl-N-[2-[(7-bromo-5-cyclopropyl-6-methyl-4-oxo-oxazolo[4, 5-c]qui nol in-2- yl) methylsulfanyl]ethyl]carbamate To a N2 purged microwave vial containing 7-bromo-2-(chloromethyl)-5-cyclopropyl-6-methyl- oxazolo[4,5-c]quinolin-4-one (Intermediate 2; 250 mg, 0.68 mmol) and potassium phosphate tribasic (434 mg, 2.04 mmol) was added teit-butyl(2-sulfanylethyl)carbamate (0.14 mL, 0.81 mmol) as a solution in DMF (8 mL) and the reaction mixture was allowed to stir at room temperature. After 3 h DCM (50 mL) was added and the layers were separated. The aq. layer was then extracted with DCM (3 x 20 mL). The combined organics were dried over MgSO4, filtered and the solvent was removed under reduced pressure to leave the crude reaction product. Purification was by flash silica chromatography using 0-75% EtOAc in petroleum ether (40-60) to give teit-butyl-N-[2-[(7-bromo-5-cyclopropyl-6-methyl-4-oxo- oxazolo[4,5-c]quinolin-2-yl)methylsulfanyl]ethyl]carbamate (249 mg, 72 % yield) as a pale yellow gum.

Reference： [1]Current Patent Assignee: REDX PHARMA PLC - WO2017/46606, 2017, A1 Location in patent: Page/Page column 125

76
[ 67385-09-5 ]
[ 201611-92-9 ]
C₂₂H₃₁N₃O₃S₄ [ No CAS ]

Reference： [1]Journal of Polymer Science, Part A: Polymer Chemistry,2017,vol. 55,p. 2061 - 2070

77
[ 67385-09-5 ]
4‐(3‐bromo‐4‐fluorophenyl)‐3‐(4‐nitro‐1,2,5‐oxadiazol‐3‐yl)‐4,5‐dihydro‐1,2,4‐oxadiazol‐5‐one [ No CAS ]
tert-butyl (2-((4-(4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol- 3-yl)-1,2,5-oxadiazol-3-yl)thio)ethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97.47%	With sodium hydrogencarbonate In tetrahydrofuran; water at 14℃; for 16h;	5.1 Step 1: Synthesis of Compound BB-5-2 The compound BB-1 (2.50 g, 6.72 mmol, 1.00 eq) was dissolved in tetrahydrofuran (20.00 mL) and water (1.00 mL). Sodium bicarbonate (846.74 mg, 10.08 mmol, 392.01 uL, 1.50 eq) was added. The mixed solution was allowed to react at 14° C. for 16 hours. Complete reaction of raw materials was observed by LCMS monitoring and a main new product peak was generated. Twenty mL of water was added to the reaction, followed by extraction with ethyl acetate (30 mL*3). Organic phases were combined, dried over anhydrous sodium sulfate, and filtered. A filtrate was dried by rotary evaporation under reduced-pressure distillation. Purification was performed by flash silica gel column chromatography (petroleum ether:ethyl acetate=4:1). The reaction succeeded, and a white solid product BB-5-2 (3.29 g, yield: 97.47%) was obtained. MS (ESI) m/z: 502, 504 [M+H]+.
90%	With sodium hydroxide In tetrahydrofuran for 2h;	7.1 Step 1 tert-butyl (2-((4-(4-(3-bromo-4-fluorophenyl)-4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-yl)thio)ethyl)carbamate The 4 - (3 - bromo -4 - fluoro phenyl) -3 - (4 - nitro - 1, 2, 5 - oxadiazole -3 - yl) - 1, 2, 4 - oxadiazole -5 (4H) - ketone 1b (200 mg, 0 . 54mmol), adding (2 - mercapto-ethyl) carbamic acid tert-butyl 7a (400 mg, 1 . 08mmol, using known method "Journal of the American Chemical Society, 2013, 135 (24), 8846 - 8849" prepared) is dissolved in 10 ml in tetrahydrofuran, add 3 ml 1M sodium hydroxide solution, stirring 2 hours. Dropwise 2M hydrochloric acid to the reaction solution to pH 5 - 6, extracted with ethyl acetate (15 ml × 3), combined with the organic phase, for 20 ml saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, the filtrate is concentrated under reduced pressure, with silica gel column chromatography using eluent system B purifying the obtained residue, to obtain the title product (2 - ((4 - (4 - (3 - bromo -4 - fluoro phenyl) -5 - carbonyl - 4, 5 - dihydro - 1, 2, 4 - oxadiazole -3 - yl) - 1, 2, 5 - oxadiazole -3 - yl) thio) ethyl) carbamic acid tert-butyl 7b (487 mg, brownish oily matter), yield 90%.

Reference： [1]Current Patent Assignee: LUYE PHARMA GROUP LTD. - US2019/169140, 2019, A1 Location in patent: Paragraph 0104; 0105; 0106; 0107
[2]Current Patent Assignee: JIANGSU HENGRUI MEDICINE CO., LTD. - CN106565696, 2017, A Location in patent: Paragraph 0277; 0278; 0279; 0280

78
[ 67385-09-5 ]
2-(6-chloro-2-methanesulfonyl-pyrimidin-4-ylamino) thiazole-5-carbonitrile [ No CAS ]
tert-butyl 2-(4-chloro-6-(5-cyanothiazol-2-ylamino)pyrimidin-2-ylthio)ethylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%	With triethylamine In tetrahydrofuran at 20℃; for 4h; Inert atmosphere;	5 Tert-butyl 2-(4-chloro-6-(5-cyanothiazol-2-ylamino)pyrimidin-2-ylthio)ethylcarbamate Tert-butyl 2-(4-chloro-6-(5-cyanothiazol-2-ylamino)pyrimidin-2-ylthio)ethylcarbamate To a stirring solution at room temperature under N2 of 2-(6-chloro-2-methanesulfonylpyrimidin-4-ylamino)thiazole-5-carbonitrile (2.80 g, 8.87 mmol) and triethylamine (3.1 mL, 22.24 mmol) in 50 ml of THF was added dropwise a solution of Boc-cysteamine (2.00 g, 11.28 mmol) in 10 mL of THF. The reaction was stirred for 4 h, concentrated, then partitioned between EtOAc and sat. NaHCO3 solution. The organic extract was washed with saturated aqueous NaCl solution, dried (MgSO4), filtered and concentrated to a brown oil and solid. The sample was suspended into 30 mL of EtOAc, stirred at room temperature for 30 min and filtered. The solid was washed with cold EtOAc and vacuum dried to give 1.44 g (39%) of the title compound as tan solid. MS (APCI) m/z 435/437 (M+23, 100/43%), 413/415 (M+1, 10/4%) and 357/359 (M-55, 20/8%). TLC (SiO2, 50% EtOAc in hexanes), a single component at Rf 0.37.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2017/174691, 2017, A1 Location in patent: Paragraph 0725; 0726

79
[ 762-51-6 ]
[ 67385-09-5 ]
tert-butyl (2-((2-fluoroethyl)thio)ethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	Stage #1: 2-[(tert-butoxycarbonyl)amino]-1-ethanethiol With sodium hydride In N,N-dimethyl-formamide; paraffin oil at 0℃; for 0.333333h; Stage #2: 1-fluoro-2-iodoethane In N,N-dimethyl-formamide; paraffin oil	32 Example 32: Preparation of tert-butyl (2-((2-fluoroethyl)thio)ethyl)carbamate (C166) Example 32: Preparation of tert-butyl (2-((2-fluoroethyl)thio)ethyl)carbamate (C166) (0788) (0789) 337 Sodium hydride (60% dispersion in 719 paraffin, 1.0 g, 25 mmol) was added to 720 tert-butyl (2-mercaptoethyl)carbamate (4.0 g, 22.6 mmol) in 73 N,N-dimethylformamide (59.8 mL) at 0° C. After stirring 20 minutes, 696 1-fluoro-2-iodoethane (2.6 g, 15.0 mmol) was added and the reaction mixture was left to stir overnight. The reaction mixture was diluted with water and extracted with diethyl ether (2×). The organic layer was washed with water and brine, dried with magnesium sulfate, filtered, and concentrated. The resulting liquid was purified by flash silica chromatography. The 721 title compound was isolated as a colorless liquid (1.5 g, 43%): 1H NMR (500 MHz, DMSO-d6) δ 6.98-6.86 (m, 1H), 4.53 (dt, J=47.3, 6.3 Hz, 2H), 3.08 (dt, J=7.6, 6.1 Hz, 2H), 2.81 (dt, J=21.7, 6.3 Hz, 2H), 2.57 (dd, J=7.9, 6.4 Hz, 2H), 1.38 (s, 9H); 13C NMR (126 MHz, DMSO-d6) δ 155.96, 83.26 (d, J=167.6 Hz), 78.17, 40.40, 31.66, 31.27 (d, J=20.7 Hz), 28.69; 19F NMR (471 MHz, DMSO-d6) δ -211.77 (tt, J=47.3, 21.7 Hz); IR (thin film) 1689 cm-1; HRMS-ESI (m/z) [M+Na]+ calcd for C9H18FNO2S, 246.0934; found, 246.0937.
43%	Stage #1: 2-[(tert-butoxycarbonyl)amino]-1-ethanethiol With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.333333h; Stage #2: 1-fluoro-2-iodoethane In N,N-dimethyl-formamide; mineral oil	54 Example 54: Preparation of tert-butyl (R)-(1-((2-fluoroethyl)thio)propan-2-yl)carbamate (C122) Example 54 Preparation of tert-butyl (R)-(1-((2-fluoroethyl)thio)propan-2-yl)carbamate (C122) Sodium hydride (60% dispersion in paraffin, 1.0 g, 25 mmol) was added to tert-butyl (2-mercaptoethyl)carbamate (4 g, 22.57 mmol) In N,N-dimethylformamide (59.8 mL) at 0° C. After stirring for 20 minutes 1-fluoro-2-iodoethane (2.6 g, 14.95 mmol) was added and the reaction mixture was left to stir overnight. The reaction mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with water and brine, dried with magnesium sulfate, filtered, and concentrated. The resulting residue was purified by flash silica chromatography. The title compound was isolated as a colorless liquid (1.5 g, 43%): 1H NMR (500 MHz, DMSO-d6) δ 6.98-6.86 (m, 1H), 4.53 (dt, J=47.3, 6.3 Hz, 2H), 3.08 (dt, J=7.6, 6.1 Hz, 2H), 2.81 (dt, J=21.7, 6.3 Hz, 2H), 2.57 (dd, J=7.9, 6.4 Hz, 2H), 1.38 (s, 9H); 13C NMR (126 MHz, DMSO-d6) δ 155.96, 83.26 (d, J=167.6 Hz), 78.17, 40.40, 31.66, 31.27 (d, J=20.7 Hz), 28.69; 19F NMR (471 MHz, DMSO-d6) δ -211.77 (tt, J=47.3, 21.7 Hz); IR (thin film) 1689 cm-1; HRMS-ESI (m/z) [M+Na]+ calcd for C9H18FNO2S, 246.0934; found, 246.0937.

Reference： [1]Current Patent Assignee: CORTEVA INC - US2017/208806, 2017, A1 Location in patent: Paragraph 0788; 0789
[2]Current Patent Assignee: CORTEVA INC - US2017/210723, 2017, A1 Location in patent: Paragraph 0710-0711

80
[ 67385-09-5 ]
N’-[4-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)benzoyl]hydrazine carboxylic acid tert-butyl ester [ No CAS ]
N’-{4-[3-(2-tert-butoxycarbonylaminoethylsulfanyl)-2,5-dioxopyrrolidin-1-yl]benzoyl}hydrazinecarboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	In methanol at 22 - 50℃; for 3h;	8 Preparation of N'-{4-[3-(2-tert-butoxycarbonylaminoethylsulfanyl)-2,5-dioxo-pyrrolidin-1-yl]-benzoyl}-hydrazinecarboxylic acid tert-butyl ester (13) To a solution of 4 (115 mg, 0.34 mmol) dissolved in methanol (3 mL) was added 2-(Boc-amino) ethanethiol (70 μ, 73 mg, 0.41 mmol). The mixture was stirred at 22 C for 2 hours and at 50 C for 1 hour. The organic phase was diluted with ethyl acetate (30 mL) directly into an extraction funnel and washed successively with a 5% sodium bicarbonate aqueous solution (2 x 10 mL) and with water (2 x 20 mL). The organic phase was dried with anhydrous magnesium sulfate, filtered and evaporated to the crude material (191 mg). The product was purified by flash column chromatography using a mixture of hexanes / acetone (3/2) to give 107 mg (61%) of the desired material 15. IR (v, cm"1): 3300 (NH), 1707 (C=0), 1680 (C=0);XH NMR (CDC13, δ ppm): 8.80 (br s, 1H, NH), 7.86 and 7.34 (2 x d, J = 8.2 Hz, 4H, aromatic), 6.90 (br s, 1H, NH), 5.07 (br s, 1H, NH), 3.98 (1H, m, -CHS-) 2.6-3.6 (several m, 6H, 3 x -CH2-), 1.50 and 1.45 (2 x s, 18H, 2 x 3 x CH3);13C NMR (CDC13, δ ppm): 175.4, 173.2, 165.8, 155.9 (2), 134.8, 131.7, 128.2 (2), 126.4 (2), 82.1, 79.7, 39.4, 38.9, 36.1, 32.7, 28.4 (3), 28.2 (3); ESI+ HRMS: (M+Na)+ calculated for C23H32N4N.1O7S = 531.1884; found = 531.1881.
61%	In methanol at 22 - 50℃; for 3h;	8 Example 8. Preparation of /V'-{4-[3-(2-te/7-butoxycarbonylamino- ethylsulfanyl)-2,5-dioxo-pyrrolidin-l-yl]-benzoyl}- hydrazinecarboxylic acid /

Reference： [1]Current Patent Assignee: 3R VALO S; UNIVERSITY OF QUEBEC SYSTEM; 3R VALO - WO2017/177316, 2017, A1 Location in patent: Paragraph 00148
[2]Current Patent Assignee: 3R VALO S - WO2020/77459, 2020, A1 Location in patent: Paragraph 00164

81
[ 67385-09-5 ]
1-(allyloxy)-4-(bromomethyl)azetidin-2-one [ No CAS ]
tert-butyl (2-(((1-(allyloxy)-4-oxoazetidin-2-yl)methyl)thio)ethyl)-carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With potassium carbonate In acetonitrile at 20℃; for 15h; Inert atmosphere;
70%	With potassium carbonate In acetonitrile at 20℃; Inert atmosphere;	2 tert-Butyl (2-(((1-(allyloxy)-4-oxoazetidin-2-yl)methyl)thio)ethyl)carbamate (18d). Compound 17 (4.0 g, 18.2 mmol) was dissolved in dry CH3CN (40 mL) at rt, under Argon atmosphere. K2C03 (5.0 g, 36.4 mmol), followed by Boc cysteamine (6.4 g, 36.4mmol). The resulting mixture was left to stir at rt for 15 h then water (20 mL) and Et20 (30 ml) were added. The layers were separated and the aqueous layer was extracted with Et20 (30 mL). The combined organic extracts were dried (Na2SO4), filtered and evaporated under vacuum. Column chromatography on silica gel (hexane/EtOAc, 1:1, v/v) afforded compound 18d as a colorless oil in 70% yield (4.0 g, 12.6 mmol). ‘H NIVIR (500 IVIFIz, CDC13) ö (ppm)= 5.99-5.91 (m, 1H, CH), 5.35-5.27 (m, 2H, CH2), 4.97 (bs, 1H, CH), 4.44-4.34 (m, 2H,CH2), 3.98-3.94 (m, 1H, CH), 3.28-3.24 (m, 2H, CH2), 2.88 (dd, J= 4.7, 13.7 Hz, 1 x CH2),2.78 (dd, J= 5.2, 13.8 Hz, 1 x CH2), 2.74 (dd, J= 6.8, 13.7 Hz, 1 x CH2), 2.69-2.60 (m, 2H,CH2), 2.47 (dd, J= 2.4, 13.8 Hz, 1 x CH2), 1.39 (s, 9H, 3 x CH3). ‘3C NIVIR (125 MHz,CDC13) ö (ppm) = 164.3, 156.0, 132.4, 121.1, 79.7, 77.5, 57.0, 40.1, 37.8, 34.0, 33.0, 28.6.HRMS (ESI) m/z calcd for C14H25N204S [M+H] 317.1530, found 317.1562.

Reference： [1]Carosso, Serena; Liu, Rui; Miller, Patricia A.; Hecker, Scott J.; Glinka, Tomasz; Miller, Marvin J. [Journal of Medicinal Chemistry, 2017, vol. 60, # 21, p. 8933 - 8944]
[2]Current Patent Assignee: THE UNIVERSITY OF NOTRE DAME DU LAC - WO2019/70672, 2019, A1 Location in patent: Page/Page column 17; 18; 35

82
[ 67385-09-5 ]
[ 4986-89-4 ]
C₂₄H₃₅NO₁₀S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hexan-1-amine at 40℃; for 14h;	2.2 Example 2.2. Other Polymer Linkages The general Michael addition of thiols to acrylate linkages were used to prepare a host of pendant reactive groups, three of which are shown above. The functionalized acrylate was synthesized by reacting pentaerythritol tetraacrylate with the corresponding thiol in a 1:1 mol ratio via the thiol-Michael reaction. Pentaerythritol tetraacrylate (1.0 equiv., 3 g, 8.51 mmol), thiol (1.0 equiv., 8.51 mmol), and hexylamine (0.1 equiv. 0.112 mL, 0.85 mL) were added to a 20 mL scintillation vial, The reaction mixture became warm and homogeneous within two minutes and was stirred at 40° C. for 14 hours. Completion of the reaction was verified by 41 and 13C NMR and the products were used without further purification.

Reference： [1]Current Patent Assignee: CALIFORNIA INSTITUTE OF TECHNOLOGY - US2018/64747, 2018, A1 Location in patent: Paragraph 0033; 0184; 0185

83
[ 67385-09-5 ]
[ 29570-58-9 ]
C₄₂H₆₄N₂O₁₇S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	at 45℃;	2.1.2.1 Example 2.1.2.1. Preparation of Scaffolds Fabricated Via Two-Photon Lithography 2 mol of 2-(Boc-amino)ethanethiol and 1 mol of dipentaerythritol hexaacrylate were reacted via the thiol-Michael addition reaction described above. The structural form of one of the products is shown below in FIG. 12.

Reference： [1]Current Patent Assignee: CALIFORNIA INSTITUTE OF TECHNOLOGY - US2018/64747, 2018, A1 Location in patent: Paragraph 0036; 0175; 0177

84
[ 67385-09-5 ]
[ 72978-22-4 ]
C₂₁H₃₀N₂O₆S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium carbonate In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 12h; diastereoselective reaction;	General procedure A for the addition of thiols to 2,3-dehydroproline and 2,3-dehydropipecolic acid derivatives (Method A). General procedure: To a solution of 1 or 4 (0.5 mmol) and the corresponding thiol (5 mmol) in THF/DMF 5:1 (5 ml) under argon atmosphere an excess of K2CO3 (5 mmol) was added. The reaction mixture was stirred until complete by TLC at room temperature. Then, the resultant suspension was diluted with AcOEt (50 ml) and washed with water (5 x 25 ml). The organic phase was dried over anhydrous MgSO4, filtered off and evaporated to dryness. The crude of the reaction was purified by column chromatography on silica gel using as eluent a mixture of ethyl acetate/hexane (2:8).

Reference： [1]Gutiérrez, Alejandro; Osante, Iñaki; Cativiela, Carlos [Tetrahedron Letters, 2018, vol. 59, # 17, p. 1661 - 1665]

85
[ 698-70-4 ]
[ 67385-09-5 ]
C₁₀H₁₆N₂S [ No CAS ]

Reference： [1]ACS Chemical Neuroscience,2018,vol. 9,p. 800 - 808

86
[ 67385-09-5 ]
triphenyl(2-phenylpyridin-4-yl)phosphonium trifluoromethanesulfonate [ No CAS ]
tert-butyl (2-((2-phenylpyridin-4-yl)thio)ethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	Stage #1: 2-[(tert-butoxycarbonyl)amino]-1-ethanethiol With sodium hydride In tetrahydrofuran; mineral oil at 0℃; Inert atmosphere; Stage #2: triphenyl(2-phenylpyridin-4-yl)phosphonium trifluoromethanesulfonate In tetrahydrofuran; mineral oil at 0 - 20℃; for 3h; Inert atmosphere; chemoselective reaction;	6 4.2.2 General procedure for the thiol addition reaction to form heteroaryl thioethers 2a-2u General procedure: An oven dried 8 mL vial with a septa cap was charged with sodium hydride (60% dispersion in mineral oil, 1.1 equiv) and placed under a nitrogen atmosphere. THF (0.25 M) was added, the suspension was cooled to 0 °C and the thiol (1.1 equiv) was added dropwise over 5 min (if the thiol was a solid or viscous liquid, it was added as a 0.5 M solution in THF to an equivalent volume 0.5 M solution of NaH in THF). The resulting thick slurry was stirred for 30 min at 0 °C before the septa cap was briefly removed and the phosphonium salt (1.0 equiv) was added in one portion. The reaction was subjected to three rapid cycles of vacuum/nitrogen backfill, the ice bath removed and the reaction stirred for 3 h while warming to room temperature. The reaction was quenched with H2O, the aqueous layer was separated and extracted with CH2Cl2 (3×). The combined organic extracts were washed with a saturated aqueous solution of brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography under the stated conditions to provide the heteroaryl thioether product.

Reference： [1]Anderson, Ryan G.; Jett, Brianna M.; McNally, Andrew [Tetrahedron, 2018, vol. 74, # 25, p. 3129 - 3136]

87
[ 159014-14-9 ]
[ 67385-09-5 ]
tert-butyl (2-((4-cyano-1,2,5-oxadiazol-3-yl)thio)ethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With sodium hydroxide In tetrahydrofuran; water at 0 - 20℃; for 0.166667h;
	With water; sodium hydroxide In tetrahydrofuran at 0 - 20℃; for 0.166667h;	2 Step 2: ferf-Butyl (2-((4-cyano-1 ,2,5-oxadiazol-3-yl)thio)ethyl)carbamate (Int 100c) To a stirred solution of 4-nitro-1 ,2,5-oxadiazole-3-carbonitrile (Int 100b) (570 mg, 4.07 mmol) in THF (15 mL) at 0 °C was added A/-Boc-2-aminoethanethiol (1 .08 g, 6.1 1 mmol). 50% aqueous NaOH (2 mL) was added and the mixture was stirred at rt for 10 min. Water (15 mL) was added and the aqueous layer was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2S0 , filtered and concentrated to dryness. The residue was purified by column chromatography (PE:EtOAc = 10:1 ) to give the title compound as a white solid.

Reference： [1]Anderhub, Simon; Braun, Floriane; Hoffmann, Thomas; Hornberger, Martin; Kinzel, Olaf; Kleymann, Gerald; Morschhaeuser, Barbara; Pinto, Sheena; Steeneck, Christoph [ACS Medicinal Chemistry Letters, 2020]
[2]Current Patent Assignee: PHENEX DISCOVERY VERWALTUNGS GMBH - WO2018/83241, 2018, A1 Location in patent: Page/Page column 54-55

88
[ 67385-09-5 ]
tert-butyl N-(2-[3-[5-bromo-4-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)carbamate [ No CAS ]
tert-butyl N-[2-(3-[5-[(2-[[(tert-butoxy)carbonyl]amino]ethyl)sulfanyl]-4-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl)ethyl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; potassium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In tetrahydrofuran at 100℃;	13 Example 13 (General procedi (1179) (1180) N-(l -(2-aminoethyl)-3-(6-(difluoromethoxy)-3,4-dihydro-2H-benzo[] [ 1 ,4]thiazin-7-yl)- 1H- pyrazol-4-yl)pyrazolo[ 1 ,5-a]pyrimidine-3-carboxamide A degassed mixture of tert-butyl N-(2-[3-[5-bromo-4-chloro-2- (difluoromethoxy)phenyl]-4-[pyrazolo[ 1 ,5-a]pyrimidine-3-amido]- lH-pyrazol-1 - yl]ethyl)carbamate (300 mg, 0.479 mmol), tert-butyl N-(2-sulfanylethyl)carbamate (170 mg, 0.959 mmol), XantPhos (112 mg, 0.194 mmol), Pd2(dba)3 (96.0 mg, 0.262mmol) and potassium carbonate (133 mg, 0.962 mmol) in tetrahydrofuran (100 mL) was heated at 100 °C overnight. The reaction was allowed to cool to RT and concentrated under vacuum. The residue was purified by silica gel column eluting with ethyl acetate/petroleum ether (4/1). Appropriate fractions were combined and evaporated to give tert-butyl N-[2-(3-[5-[(2-[[(tert- butoxy)carbonyl] amino] ethyl) sulfanyl] -4-chloro-2-(difluoromethoxy)phenyl] -4- [pyrazolo[l,5-a]pyrimidine-3-amido]-lH-pyrazol-l-yl)ethyl]carbamate (310 mg, 90%) as a yellow solid. LC/MS (Method F, ESI): [M+H]+ = 723, RT = 1.05 min.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2018/122212, 2018, A1 Location in patent: Page/Page column 172; 173

Type	HazMat fee for 500 gram (Estimated)
Excepted Quantity	USD 0.00
Limited Quantity	USD 15-60
Inaccessible (Haz class 6.1), Domestic	USD 80+
Inaccessible (Haz class 6.1), International	USD 150+
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Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
{[ item.p_purity ]}	{[ item.pr_size ]}	{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]}	{[ getRatePrice(item.pr_usd, 1,1) ]}	Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]}	{[ item.pr_usastock ]}	Inquiry -	{[ item.pr_chinastock ]}	Inquiry -

CAS No. :	67385-09-5	MDL No. :	MFCD00274335
Formula :	C₇H₁₅NO₂S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GSJJCZSHYJNRPN-UHFFFAOYSA-N
M.W :	177.26	Pubchem ID :	3017761
Synonyms :		Chemical Name :	tert-Butyl (2-mercaptoethyl)carbamate

Num. heavy atoms :	11
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.86
Num. rotatable bonds :	5
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	48.21
TPSA :	77.13 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 :	No
Log Kp (skin permeation) :	-6.52 cm/s

[ CAS No. 67385-09-5 ] {[proInfo.proName]}

Quality Control of [ 67385-09-5 ]

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[ 67385-09-5 ] Synthesis Path-Downstream 1~88

Related Functional Groups of
[ 67385-09-5 ]

Aliphatic Chain Hydrocarbons

Amides

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Log Po/w (iLOGP) :	2.19
Log Po/w (XLOGP3) :	1.22
Log Po/w (WLOGP) :	1.44
Log Po/w (MLOGP) :	1.15
Log Po/w (SILICOS-IT) :	0.73
Consensus Log Po/w :	1.35

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

Log S (ESOL) :	-1.38
Solubility :	7.43 mg/ml ; 0.0419 mol/l
Class :	Very soluble
Log S (Ali) :	-2.44
Solubility :	0.648 mg/ml ; 0.00366 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.75
Solubility :	3.16 mg/ml ; 0.0178 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.1

Signal Word:	Danger	Class:	9
Precautionary Statements:	P260-P264-P270-P273-P280-P301+P312+P330-P304+P312-P305+P351+P338-P314-P337+P313-P391-P501	UN#:	3082
Hazard Statements:	H302-H319-H332-H372-H400	Packing Group:	Ⅲ
GHS Pictogram:

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P378
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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
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P413
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P422
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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. 67385-09-5 ] {[proInfo.proName]}

Quality Control of [ 67385-09-5 ]

Related Doc. of [ 67385-09-5 ]

Product Details of [ 67385-09-5 ]

Calculated chemistry of [ 67385-09-5 ]

Physicochemical Properties

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Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 67385-09-5 ]

Application In Synthesis of [ 67385-09-5 ]

[ 67385-09-5 ] Synthesis Path-Downstream 1~88

Related Functional Groups of [ 67385-09-5 ]

Aliphatic Chain Hydrocarbons

Amides

Amines

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Precautionary Statements-General

Prevention

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Related Functional Groups of
[ 67385-09-5 ]