Name: 18143-30-1|(2-Mercaptoethyl)trimethylsilane|95%
Brand: Ambeed
SKU: A496395
Rating: 90 (40 reviews)

1
[ 18269-56-2 ]
[ 18143-30-1 ]

Yield	Reaction Conditions	Operation in experiment
99.7%	With potassium carbonate In methanol; diethyl ether; water at 20℃; for 3.5h;
	With sodium hydroxide
	With potassium hydroxide In ethanol Heating;

Reference： [1]Schwan, Adrian L.; Brillon, Denis; Dufault, Robert [Canadian Journal of Chemistry, 1994, vol. 72, # 2, p. 325 - 333]
[2]Mironow; Pogonkina [Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1959, p. 85,88;engl.Ausg.S.76,78]
[3]Ito,T.I.; Weber,W.P. [Journal of Organic Chemistry, 1974, vol. 39, p. 1694 - 1697]

2
[ 18143-30-1 ]
[ 637-59-2 ]
[ 114764-11-3 ]

Yield	Reaction Conditions	Operation in experiment
90%	With dmap; dicyclohexyl-carbodiimide In dichloromethane
68%	Stage #1: 2-trimethylsilylethanethiol With sodium hydride In tetrahydrofuran at 20℃; for 0.5h; Stage #2: 1-Bromo-3-phenylpropane In tetrahydrofuran at 20℃; for 15h; Further stages.;

Reference： [1]Anderson, M.B.; Ranasinghe, M.G.; Palmer, J.T.; Fuchs, P.L. [Journal of Organic Chemistry, 1988, vol. 53, # 13, p. 3125 - 3127]
[2]Chambert, Stephane; Thomasson, Francois; Decout, Jean-Luc [Journal of Organic Chemistry, 2002, vol. 67, # 6, p. 1898 - 1904]

3
[ 18143-30-1 ]
[ 130220-12-1 ]
[ 130220-22-3 ]

Yield	Reaction Conditions	Operation in experiment
87%	With sodium hydride In tetrahydrofuran 1.) 0 deg C, 2.) RT, 5 min;

Reference： [1]Scarpetti, David; Fuchs, Philip L. [Journal of the American Chemical Society, 1990, vol. 112, # 22, p. 8084 - 8090]

4
[ 18143-30-1 ]
[ 3031-68-3 ]
[ 172495-34-0 ]

Yield	Reaction Conditions	Operation in experiment
87%	With potassium hydroxide In N,N-dimethyl-formamide for 2h; Ambient temperature;
87%	With potassium hydroxide In water; ethyl acetate; N,N-dimethyl-formamide	1 (Z,Z)-2,5-Bis[β-(trimethylsilyl)ethylthio]-2,4-hexadiene-1,6-diol (13) STR10 EXAMPLE 1 (Z,Z)-2,5-Bis[β-(trimethylsilyl)ethylthio]-2,4-hexadiene-1,6-diol (13) STR10 2-(Trimethylsilyl)ethanethiol (336 μL, 2.10 mmol) was added to a suspension of 300 mg of KOH in 3 mL of DMF. After stirring at room temperature for 20 minutes, 110 mg of 1,6-dihydroxy-2,4-hexadyne (12) (1.00 mmol) was added to the mixture. The resulting mixture, which turned immediately brownish, was stirred at room temperature for 3 hours, upon which time it was poured into 40 mL of a 1:1 water/ether mixture. The ether layer was separated and the aqueous layer was extracted again with 20 mL of ether. The combined ether layers were washed first with water (25 mL) and then with brine (30 mL) and dried over anhydrous MgSO4. The crude reaction mixture obtained by removal of the solvent by rotary evaporation was purified by silica gel flash column chromatography using 3:1 ethyl acetate/hexanes as the eluent, affording 328 mg of the bis-thiol adduct 13 (87%) as a white solid: mp 64.5°- 65.0° C. (hexanes); Rf 0.59 (1:3 ethyl acetate/hexanes); 1 H NMR (360 MHz, CDCl3) δ0.01 (s,18H), 0.82-0.87 (4H) and 2.75-2.80 (4H) (two sets of identical AA'XX' spin systems), 1.90 (s,2H), 4.27 (s,4H), 6.89 (s, 2H); 13 C NMR (90 MHz, CDCl3) δ-1.81 (q, 6C), 18.06 (t, 2C), 27.80 (t, 2C), 65.87 (t, 2C), 127.78 (d, 2C), 138.73 (s,2C); IR (KBr) 3349 (s), 3026 (w), 1612 (w), 1559 (w), 1414 (m), 1249 (s), 1031 (s) 859 (s) cm-1. Anal. Calcd for C16 H34 O2 S2 Si2: C, 50.74; H, 9.05. Found: C, 50.47; H, 8.91.

Reference： [1]Koreeda, Masato; Yang, Wu [Journal of the American Chemical Society, 1994, vol. 116, # 23, p. 10793 - 10794]
[2]Current Patent Assignee: UNIVERSITY OF MICHIGAN - US5453500, 1995, A

5
[ 18143-30-1 ]
[ 3736-77-4 ]
[ 260366-23-2 ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 3h;

Reference： [1]Chambert, Stephane; Gautier-Luneau, Isabelle; Fontecave, Marc; Decout, Jean-Luc [Journal of Organic Chemistry, 2000, vol. 65, # 1, p. 249 - 253]

6
[ 18143-30-1 ]
[ 14985-44-5 ]
[ 260366-30-1 ]

Yield	Reaction Conditions	Operation in experiment
95%	With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 8h;
79%

Reference： [1]Chambert, Stephane; Gautier-Luneau, Isabelle; Fontecave, Marc; Decout, Jean-Luc [Journal of Organic Chemistry, 2000, vol. 65, # 1, p. 249 - 253]
[2]Location in patent: scheme or table Miyata, Ken-ichi; Tamamushi, Ryuji; Tsunoda, Hirosuke; Ohkubo, Akihiro; Seio, Kohji; Sekine, Mitsuo [Organic Letters, 2009, vol. 11, # 3, p. 605 - 608]

7
[ 18143-30-1 ]
[ 93372-52-2 ]
[ 410080-32-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 15h;

Reference： [1]Chambert, Stephane; Thomasson, Francois; Decout, Jean-Luc [Journal of Organic Chemistry, 2002, vol. 67, # 6, p. 1898 - 1904]

8
[ 18143-30-1 ]
[ 5135-30-8 ]
5'-deoxy-5'-(2-(trimethylsilyl)ethyl)adenosine [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2002,vol. 67,p. 1898 - 1904

9
[ 18143-30-1 ]
[ 13389-03-2 ]
[ 794574-97-3 ]

Yield	Reaction Conditions	Operation in experiment
63%	With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 36h;

Reference： [1]Hamm, Michelle L.; Cholera, Rushina; Hoey, Courtney L.; Gill, Timothy J. [Organic Letters, 2004, vol. 6, # 21, p. 3817 - 3820]

10
[ 863997-47-1 ]
[ 18143-30-1 ]
5-bromo-2'-(2-trimethylsilanylethylsulfanyl)-[2,5']bipyrimidinyl [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With 2.9-dimethyl-1,10-phenanthroline; sodium t-butanolate In toluene at 110℃; for 24h;

Reference： [1]Morales, Gustavo M.; Jiang, Ping; Yuan, Shenwen; Lee, Youngu; Sanchez, Arturo; You, Wei; Yu, Luping [Journal of the American Chemical Society, 2005, vol. 127, # 30, p. 10456 - 10457]

11
[ 18143-30-1 ]
[ 182872-01-1 ]
[ 793724-83-1 ]

Yield	Reaction Conditions	Operation in experiment
47%	Stage #1: 2-trimethylsilylethanethiol; 5'-trimethylsilyl-3,4'-dimethyl-2,2'-dithiophene With neoproine; sodium t-butanolate In toluene at 110℃; for 24h; Stage #2: With trifluoroacetic acid In dichloromethane at 20℃; for 3h;

Reference： [1]Jiang, Ping; Morales, Gustavo M.; You, Wei; Yu, Luping [Angewandte Chemie - International Edition, 2004, vol. 43, # 34, p. 4471 - 4475]

12
[ 18143-30-1 ]
[ 783321-44-8 ]
[ 894773-46-7 ]

Yield	Reaction Conditions	Operation in experiment
84%	With zinc(II) iodide In dichloromethane at 20℃; for 2h;

Reference： [1]Kobayashi, Kenji; Shimaoka, Reishi; Kawahata, Masatoshi; Yamanaka, Masamichi; Yamaguchi, Kentaro [Organic Letters, 2006, vol. 8, # 11, p. 2385 - 2388]

13
1-((12-bromododecyl)oxy)-4-iodobenzene [ No CAS ]
[ 18143-30-1 ]
[ 915021-85-1 ]

Yield	Reaction Conditions	Operation in experiment
87%	With lithium hexamethyldisilazane In tetrahydrofuran at 20℃;
87%	Stage #1: 2-trimethylsilylethanethiol With lithium hexamethyldisilazane Stage #2: 1-((12-bromododecyl)oxy)-4-iodobenzene

Reference： [1]Shirai, Yasuhiro; Cheng, Long; Chen, Bo; Tour, James M. [Journal of the American Chemical Society, 2006, vol. 128, # 41, p. 13479 - 13489]
[2]Location in patent: scheme or table Shirai, Yasuhiro; Guerrero, Jason M.; Sasaki, Takashi; He, Tao; Ding, Huanjun; Vives, Guillaume; Yu, Byung-Chan; Cheng, Long; Flatt, Austen K.; Taylor, Priscilla G.; Gao, Yongli; Tour, James M. [Journal of Organic Chemistry, 2009, vol. 74, # 20, p. 7885 - 7897]

14
[ 18143-30-1 ]
[ 5925-76-8 ]
[ 307000-62-0 ]

Yield	Reaction Conditions	Operation in experiment
82%	Stage #1: 2-trimethylsilylethanethiol With trimethylaluminum In toluene at -78℃; for 1h; Stage #2: selenobenzoic acid O-methyl ester In toluene at 20℃; for 3h; Further stages.;

Reference： [1]Mural; Kamoto; Kato [Journal of the American Chemical Society, 2000, vol. 122, # 40, p. 9850 - 9851]

15
[ 18143-30-1 ]
[ 52630-09-8 ]
[ 307000-64-2 ]

Yield	Reaction Conditions	Operation in experiment
87%	Stage #1: 2-trimethylsilylethanethiol With trimethylaluminum In toluene at -78℃; Stage #2: 4-Methyl-monoselenobenzoesaeure-O-methylester In toluene at 20℃; Further stages.;

Reference： [1]Mural; Kamoto; Kato [Journal of the American Chemical Society, 2000, vol. 122, # 40, p. 9850 - 9851]

16
[ 18143-30-1 ]
2-methylselenobenzoic acid O-methyl ester [ No CAS ]
[ 307000-63-1 ]

Yield	Reaction Conditions	Operation in experiment
92%	With trimethylaluminum In toluene

Reference： [1]Mural; Kamoto; Kato [Journal of the American Chemical Society, 2000, vol. 122, # 40, p. 9850 - 9851]

17
[ 18143-30-1 ]
[ 49617-83-6 ]
[2-(3-iodo-benzylsulfanyl)-ethyl]-trimethyl-silane [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2006,vol. 128,p. 13479 - 13489
[2]Journal of Organic Chemistry,2009,vol. 74,p. 7885 - 7897

18
2,2'-anhydrothymidine [ No CAS ]
[ 18143-30-1 ]
[ 947322-23-8 ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 3h;

Reference： [1]Gerland, Beatrice; Desire, Jerome; Lepoivre, Michel; Decout, Jean-Luc [Organic Letters, 2007, vol. 9, # 16, p. 3021 - 3023]

19
[ 18143-30-1 ]
[ 1026090-01-6 ]
[ 1026089-22-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 95 - 100℃; for 20h;	7.1 Step 1 (S)-3-[4-(2-Trimethylsilanyl-ethylsulfanyl)-phenyl]-pyrrolidine-l-carboxylic acid tert-butyl ester; 2-(Trimethylsilyl)ethane thiol (0.33 mL, 2.1 mmol), Pd2(dba)3 (183.9 mg), Xantphos (231.4 mg) and DIPEA (0.296 mL) were added to a solution of (S)-3-(4-bromo-phenyl)- pyrrolidine-1-carboxylic acid tert-butyl ester (528 mg, 1.618 mmol) in 1,4-dioxane (7 mL) under nitrogen atmosphere. The reaction mixture was heated at 95-1000C for 20 hours. After cooling to room temperature, a solution of 10% KHSOVNa2SO4WaS added and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified via flash chromatography (hexane/EtOAc, 94/6) to give 616 mg (quantitative yield) EPO of (S)-3-[4-(2-trimethylsilanyl-ethylsulfanyl)-phenyl]-pyrrolidine-l-carboxylic acid tert- butyl ester.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2008/55847, 2008, A1 Location in patent: Page/Page column 64-65

20
[ 18143-30-1 ]
[ 170236-36-9 ]
C₃₅H₄₂N₂O₆SSi [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride In N,N-dimethyl-formamide at 90℃; for 24h;
	Stage #1: 2-trimethylsilylethanethiol With sodium hydride In N,N-dimethyl-formamide Inert atmosphere; Stage #2: 5'-O-(4,4'-dimethoxytrityl)-2,3'-anhydro-2'-deoxyuridine In N,N-dimethyl-formamide at 90℃; for 24h; Inert atmosphere;	2',3'-Dideoxy-3'-(2-(trimethylsilyl)ethyl)thiouridine; A solution of 2-(trimethylsilyl)ethanethiol (980 μl, 7.02 mmol) in DMF (8 ml) is added to a suspension of a sodium hydride (60%, 234 mg, 7.02 mmol) in anhydrous DMF (8 ml). This mixture is left stirring and under argon for 15 min and then the derivative 51 (3 g, 5.85 mmol) is added. After 24 h under argon at 90° C., the unreacted sodium hydride is neutralized with 3 ml of methanol and the solvents are evaporated under reduced pressure. The residue is subsequently taken up in dichloromethane (100 ml) and the solution is neutralized with a NaH2PO4 solution (10%, 10 ml), washed with water (100 ml) and dried over sodium sulfate before being evaporated to dryness. The residue is taken up in dichloromethane in order to be chromatographed on silica gel with a dichloromethane-ethyl acetate (8:2) mixture comprising 1% of triethylamine and to give the sulfide in the form of a yellow foam.

Reference： [1]Gerland, Beatrice; Desire, Jerome; Balzarini, Jan; Decout, Jean-Luc [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 14, p. 6824 - 6831]
[2]Current Patent Assignee: JOSEPH FOURIER UNIVERSITY - US2009/264637, 2009, A1 Location in patent: Page/Page column 26

21
[ 18143-30-1 ]
tert-butyl [2-[4-(bromoethyl)benzoyl]amino}-4-(2-thienyl)phenyl]carbamate [ No CAS ]
[ 1112416-20-2 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 4h;	1.I λL[2-amino-5-(2-thienyl)phenyl]-4-([2-(trimethylsilyl)ethyl]thio}methyl)benzamide. To a solution of terf-butyl[2-[4-(bromoethyl)benzoyl]amino}-4-(2-thienyl)phenyl]carbamate (0.200 g, 0.410 mmol) in DCM was added DIPEA (0.071 mL, 0.742 mmol) and 2-trimethylsilyl)ethanethiol (0.065 mL, 0.410 mmol). The reaction was allowed to stir at room temperature for 4 h. The reaction was washed with sat'd NaHCC>3 and extracted with DCM, dried (MgSO4), filtered and concentrated in vacuo. The filtrate was purified by MPLC (0-100% DCM/EtOAc) to give tert-butyl (4-(2-thienyl)-2-[4-([2- trimethylsilyl)ethyl]thio}methyl)benzoyl]amino}phenyl)carbamate. MS: cal'd 563 (MNa+), exp 563 (MNa+).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2009/20589, 2009, A1 Location in patent: Page/Page column 73

22
[ 18143-30-1 ]
[ 123492-60-4 ]
3-(3-(2-(trimethylsilyl)ethylthio)butanoyl)oxazolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With C₄₃H₃₆F₆N₄OS In chloroform at -20℃; for 72h; optical yield given as %ee; enantioselective reaction;

Reference： [1]Liu, Yan; Sun, Bingfeng; Wang, Baomin; Wakem, Matthew; Deng, Li [Journal of the American Chemical Society, 2009, vol. 131, # 2, p. 418 - 419]

23
[ 22423-26-3 ]
[ 18143-30-1 ]
[ 947322-23-8 ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 3h; Inert atmosphere;	46 2'-Deoxy-2'-(2-(trimethylsilyl)ethyl)thiothymidine 46; 2-(trimethylsilyl)ethanethiol (3.5 g, 26 mmol) is added to a suspension of 2,2'-anhydrothymidine (5 g, 22 mmol) and anhydrous potassium carbonate (11 g, 79 mmol) in DMF (110 ml). The solution is left stirring and under argon at 120° C. for 3 h. After filtering off and rinsing the inorganic salts with dichloromethane, the solvents are evaporated under reduced pressure to give a yellow oil. This residue is chromatographed on silica gel in a dichloromethane-methanol (95:5) mixture. The sulfide 46 is obtained in the form of a white solid (6.9 g, 19 mmol, 88%).M.p.: 58-60° C.1H NMR (400 MHz, CDCl3) δ 8.73 (1H, s, NH), 7.25 (1H, d, J=8.0 Hz, 6-H), 5.46 (1H, d, J=9.2 Hz, 1'-H), 4.36 (1H, m, 3'-H), 4.24 (1H, m, 4'-H), 3.99 (2H, m, 2'H+5'-H), 3.81 (1H, m, 5'-H), 2.60 (2H, m, S-CH2), 1.96 (3H, s, 5-CH3), 0.85 (2H, m, CH2Si), -0.02 (9H, s, Si(CH3)3).13C NMR (100 MHz, CDCl3) δ 163.4 (C2), 150.5 (C4), 138.87 (C6), 111.4 (C5), 93.3 (C1'), 86.6 (C4'), 71.5 (C3'), 63.1 (5'-CH2), 52.8 (C2'), 28.4 (S-CH2), 18.1 (CH2-Si), 12.4 (CH3), -1.8 (Si (CH3)3)MS (DCI, NH3-isobutane) m/z 375 [M+H]+, 392 [M+H+NH3]+.
88%	In N,N-dimethyl-formamide at 20℃;

Reference： [1]Current Patent Assignee: JOSEPH FOURIER UNIVERSITY - US2009/264637, 2009, A1 Location in patent: Page/Page column 27
[2]Oliveira, Maralise P.; Franco, Lucas L.; Lima, Maria C.A.; Simões, Cláudia M.O.; Galdino, Suely L.; Pitta, Ivan R.; Décout, Jean-Luc; Alves, Ricardo J. [Journal of the Brazilian Chemical Society, 2015, vol. 26, # 4, p. 816 - 821]

24
[ 22423-26-3 ]
[ 18143-30-1 ]
[ 953792-21-7 ]

Yield	Reaction Conditions	Operation in experiment
79%	Stage #1: O-2,2'-cyclo-5-methyluridine With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; Stage #2: 2-trimethylsilylethanethiol In N,N-dimethyl-formamide at 20℃; Inert atmosphere; Stage #3: With water; ammonium chloride In N,N-dimethyl-formamide at 0℃;	52 1-(3'-(2-(trimethylsilyl)ethylthio)-β-D-xylofuranos-1'-yl)thymine 52; Sodium hydride (65%, 1.10 g, 29.9 mmol) is added at 0° C. to a suspension of 2,2'-anhydrothymidine (0.6 g, 2.49 mmol) in anhydrous DMF (15 ml) followed, after 3 h at ambient temperature under argon and with stirring, by 2-(trimethylsilyl)ethanethiol (0.75 ml, 3.96 mmol). The solution is left stirring under argon at ambient temperature for 3 h. The reaction mixture is subsequently placed at 0° C. and an aqueous ammonium chloride solution (10%, 10 ml) is added. The solvents are evaporated under reduced pressure and the residue obtained is taken up in dichloromethane (100 ml) in order to be washed twice with water (50 ml). The organic phases are combined and dried over magnesium sulfate before being evaporated to dryness. The yellow residue obtained is chromatographed on silica gel in a dichloromethane-methanol (95:5) mixture. The sulfide 52 is obtained in a form of a white solid (0.734 g, 1.96 mmol, 79%).1H NMR (400 MHz, CDCl3) δ 10.34 (1H, s, NH), 7.66 (1H, s, 6-H), 5.68 (1H, bd, J=4.2 Hz, 1'-H), 5.78 (1H, d, J=8.0 Hz, 5-H), 4.55 (1H, m, 4'-H), 4.38 (1H, m, 2'-H), 3.91-3.87 (2H, m, 5'-H), 2.67 (2H, m, S-CH2), 0.85 (2H, m, CH2Si), -0.01 (9H, s, Si(CH3)3).13C NMR (100 MHz, CDCl3) δ 164.3 (C2), 151.3 (C4), 136.5 (C6), 110.4 (C5), 91.2 (C1'), 80.6 (C4'), 80.9 (C2'), 62.8 (5'-CH2), 50.5 (C3'), 28.6 (S-CH2), 16.2 (CH2-Si), -1.8 (Si(CH3)3).MS (DCI, NH3/isobutane) m/z 375 [M+H]+.

Reference： [1]Current Patent Assignee: JOSEPH FOURIER UNIVERSITY - US2009/264637, 2009, A1 Location in patent: Page/Page column 29

25
[ 18143-30-1 ]
[ 1395416-68-8 ]
[ 1395416-67-7 ]

Yield	Reaction Conditions	Operation in experiment
77%	With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 120℃; for 4h; Inert atmosphere; Sealed tube;	216.b A solution of 3-bromo-N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-N-methyl-5-(trifluoromethyl)benzamide (0.135 g, 279 μmol) and 2-(trimethylsilyl)ethanethiol (37.5 mg, 44.1 μL, 279 μmol) in dioxane (2 mL) was stirred under argon for 5 minutes in a sealed tube. To the clear light yellow solution were added tris(dibenzylideneacetone)dipalladium(0) (6.4 mg, 6.98 μmol, CAS RN 52409-22-0) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8.08 mg, 14.0 μmol, CAS RN 161265-03-8) and DIPEA (72.2 mg, 97.6 μL, 559 μmol) and the reaction mixture was stirred at 120° C. After stirring for 4 hours in a sealed tube, heating was stopped. The reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 20 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless solid (0.116 g; 77%). MS (ESI): m/z=537.17 [M+H]+.
77%	With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 120℃; for 4h; Inert atmosphere; sealed tube;	216.b A solution of 3-bromo-N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-N-methyl-5- (trifluoromethyl)benzamide (0.135 g, 279 μιηο) and 2-(trimethylsilyl)ethanethiol (37.5 mg, 44.1 μ, 279 μιηο) in dioxane (2 mL) was stirred under argon for 5 minutes in a sealed tube. To the clear light yellow solution were added tris(dibenzylideneacetone)dipalladium(0) (6.4 mg, 6.98 μιηο, CAS RN 52409-22-0) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8.08 mg, 14.0 μιηο, CAS RN 161265-03-8) and DIPEA (72.2 mg, 97.6 μ,, 559 μιηο) and the reaction mixture was stirred at 120 °C. After stirring for 4 hours in a sealed tube, heating was stopped. The reaction mixture was poured on saturated aqueous NH4C1 solution and EtOAc and the layers were separated. The aqueos layer was extracted twice with EtOAc. The organic layers were dried over MgS04, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 20 g column using an MPLC system eluting with a gradient of n- heptane : EtOAc (100 : 0 to 0 : 100). Colorless solid (0.116 g; 77%). MS (ESI): m/z = 537.17 [M+H]+.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2012/232051, 2012, A1 Location in patent: Page/Page column 114
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2012/117000, 2012, A1 Location in patent: Page/Page column 252; 253

26
[ 18143-30-1 ]
[ 1066-54-2 ]
selenothioacetic acid S-(2-trimethylsilyl)ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	Stage #1: trimethylsilylacetylene With n-butyllithium In diethyl ether at 0℃; for 0.166667h; Stage #2: With selenium In diethyl ether at 20℃; for 0.333333h; Stage #3: 2-trimethylsilylethanethiol In tetrahydrofuran at 0℃; for 0.5h;	Synthetic procedure of selenothioacetic acid S-(2-trimethylsilyl)ethyl ester (2a) In a 300 mL three-necked flask, BuLi (12.8 mL, 20.0 mmol) was added to an Et2O (200 mL) solution of (trimethylsilyl)acetylene (2.8 mL, 20.0 mmol) at 0 °C. After the stirring at 0 °C for 10 min, powder selenium (1.58 g, 20.0 mmol) was added to the resulting mixture at 20 °C, and it was stirred for 20 min. To this was added 2-(trimethylsilyl)ethanethiol (3.2 mL 20.0 mmol) at 0 °C, and the mixture was stirred for 30 min. The reaction mixture was poured into water, and extracted with Et2O. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel using hexane as an eluent to give 2.68 g of 2a (56%) as a purple oil; IR (neat) 2953, 2902, 1654, 1560, 1418, 1357, 1249, 1166, 1136, 1107, 1009, 1008, 824 cm-1; 1H NMR (CDCl3) δ 0.06 (s, 9H, SiMe3), 1.00 (m, 2H, CH2Si), 2.55 (s, 3H, CH3), 3.20 (m, 2H, SCH2); 13C NMR (CDCl3) δ -1.8, 14.4, 44.9, 38.2 (SCH2), 44.9 (CH3), 237.8 (C=Se, 1JC-Se=222.3 Hz); 77Se NMR (CDCl3, Me2Se) δ 1501.9; MS (EI) m/z 240. Anal. Calcd for C7H16SSeSi; C, 35.13; H, 6.74. Found: C, 35.35; H, 7.03.

Reference： [1]Murai, Toshiaki; Nonoyama, Takamasa [Tetrahedron, 2012, vol. 68, # 51, p. 10489 - 10495,7] Murai, Toshiaki; Nonoyama, Takamasa [Tetrahedron, 2012, vol. 68, # 51, p. 10489 - 10495]

27
3-bromo-5-trifluoromethylbenzoic acid methyl ester [ No CAS ]
[ 18143-30-1 ]
[ 1466574-67-3 ]

Yield	Reaction Conditions	Operation in experiment
82%	Stage #1: 3-bromo-5-trifluoromethylbenzoic acid methyl ester; 2-trimethylsilylethanethiol In 1,4-dioxane for 0.0833333h; Inert atmosphere; Stage #2: With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 20 - 120℃; for 22h; Inert atmosphere; Sealed tube;	9.f f) 3-Trifluoromethyl-5-(2-trimethylsilanyl-ethylsulfanyl)-benzoic acid methyl ester A solution of 3-bromo-5-trifluoromethyl-benzoic acid methyl ester (600 mg, 2.12 mmol, CAS RN 187331-46-0) in dioxane (6 mL) and 2-(trimethylsilyl)ethanethiol (285 mg, 335 μL, 2.12 mmol, CAS RN 18143-30-1) was stirred under argon for 5 min., treated with tris(dibenzylideneacetone)dipalladium (0) (48.5 mg, 53.0 μmol, CAS RN 52522-40-4), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (61.3 mg, 106 μmol, xantphos, CAS RN 161265-03-8) and N,N-diisopropylethylamine (548 mg, 740 μL, 4.24 mmol) and stirred at 120° C. in a sealed tube for 4 h. Stirring was continued at room temperature for another 18 hours. The reaction mixture was poured on saturated aqueous ammonium chloride solution and ethyl acetate and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 80:20). Yellow liquid (587 mg, 82%). MS (EI): m/z=336 ([M]).
82%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 20 - 120℃; for 22h;	9.f 3-Trifluoromethyl-5-(2-trimethylsilanyl-ethylsulfanyl)-benzoic acid methyl ester A solution of 3-bromo-5-trifluoromethyl-benzoic acid methyl ester (600 mg, 2.12 mmol, CAS R 187331-46-0) in dioxane (6 mL) and 2-(trimethylsilyl)ethanethiol (285 mg, 335 μ,, 2.12 mmol, CAS RN 18143-30-1) was stirred under argon for 5 min., treated with tris(dibenzylideneacetone)dipalladium (0) (48.5 mg, 53.0 μιηο, CAS RN 52522-40-4), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (61.3 mg, 106 μιηο, xantphos, CAS RN 161265- 03-8) and N,N-diisopropylethylamine (548 mg, 740 μ, 4.24 mmol) and stirred at 120 °C in a sealed tube for 4 h. Stirring was continued at room temperature for another 18 hours. The reaction mixture was poured on saturated aqueous ammonium chloride solution and ethyl acetate and the layers were separated. The aqueos layer was extracted twice with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane : ethyl acetate (100 : 0 to 80 : 20). Yellow liquid (587 mg, 82%). MS (EI): m/z = 336 ([M]).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2013/267519, 2013, A1 Location in patent: Paragraph 0251
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2013/149977, 2013, A1 Location in patent: Page/Page column 56

28
[ 18143-30-1 ]
[ 1194341-42-8 ]
4-amino-2-((2-(trimethylsilyl)ethyl)thio)nicotinonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 50℃; Inert atmosphere;	2.A Step A: 4-Amino-2-((2-(trimethylsilyl)ethyl)thio)nicotinonitrile To the resulting DMSO solution was added 2-(trimethylsilyl)ethanethiol (4200 mg, 31 mmol) and potassium carbonate (5400 mg, 39 mmol). The mixture was purged three times was nitrogen, and heated to 50°C overnight. LC showed the reaction was very clean. The reaction was diluted with water, and extracted with EtOAc. The extraction was dried over sodium sulfate, filtered and concentrated, and the resulting yellow oil was used in the next step without further purification. LC/MS [M+H]+: 252.
	With potassium carbonate In dimethyl sulfoxide at 50℃; Inert atmosphere;	2.A Step A: 4-Amino-2-((2-(trimethylsilyl)ethyl)thio)nicotinonitrile To the resulting DMSO solution was added 2-(trimethylsilyl)ethanethiol (4200 mg, 31 mmol) and potassium carbonate (5400 mg, 39 mmol). The mixture was purged three times was nitrogen, and heated to 50° C. overnight. LC showed the reaction was very clean. The reaction was diluted with water, and extracted with EtOAc. The extraction was dried over sodium sulfate, filtered and concentrated, and the resulting yellow oil was used in the next step without further purification. LC/MS [M+H]+: 252.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2015/112441, 2015, A1 Location in patent: Page/Page column 41
[2]Current Patent Assignee: MERCK & CO INC - US2016/333021, 2016, A1 Location in patent: Paragraph 0296

29
[ 175204-08-7 ]
[ 18143-30-1 ]
2-(p-tolyloxy)-6-((2-(trimethylsilyl)ethyl)thio)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 20℃;	179.A Step A: 2-(p-tolyloxy)-6-((2-(trimethylsilyl)ethyl)thio)benzonitrile To a solution of 2-fluoro-6-(p-tolyloxy)benzonitrile (0.5 g, 2.2 mmol) and potassium carbonate (0.608 g, 4.40 mmol) in DMF (30 mL) was added 2- (trimethylsilyl)ethanethiol (0.355 g, 2.64 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered. The filtrate was diluted with EtOAc, and washed with water and brine. The organic layer was dried over anhydrous MgS04, filtered, and concentrated. The residue was purified by silica gel column chromatography using 0-30% EtOAc/Hexanes as mobile phase to afford the title compound. LC-MS (IE, m/z): 342.18 [M+l]+.
	With potassium carbonate In N,N-dimethyl-formamide at 20℃;	179.A Step A: 2-(p-tolyloxy)-6-((2-(trimethylsilyl)ethyl)thio)benzonitrile Step A: 2-(p-tolyloxy)-6-((2-(trimethylsilyl)ethyl)thio)benzonitrile (0615) To a solution of 2-fluoro-6-(p-tolyloxy)benzonitrile (0.5 g, 2.2 mmol) and potassium carbonate (0.608 g, 4.40 mmol) in DMF (30 mL) was added 2-(trimethylsilyl)ethanethiol (0.355 g, 2.64 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered. The filtrate was diluted with EtOAc, and washed with water and brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using 0-30% EtOAc/Hexanes as mobile phase to afford the title compound. LC-MS (IE, m/z): 342.18 [M+1]+

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2015/112441, 2015, A1 Location in patent: Page/Page column 160; 161
[2]Current Patent Assignee: MERCK & CO INC - US2016/333021, 2016, A1 Location in patent: Paragraph 0615

30
[ 18143-30-1 ]
2-chloro-4-(4-(hydroxymethyl)phenyl)nicotinonitrile [ No CAS ]
4-(4-(hydroxymethyl)phenyl)-2-((2-(trimethylsilyl)ethyl)thio)nicotinonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 16h;	181.B Step B : 4-(4-(Hydroxymethyl)phenyl)-2-((2-(trimethylsilyl)ethyl)thio)nicotinonitrile To a flask charged with 2-chloro-4-(4-(hydroxymethyl)phenyl)nicotinonitrile (400 mg, 1.64 mmol) and a stir bar was added 2-(trimethylsilyl)ethanethiol (329 mg, 2.45 mmol), K2C03 (452 mg, 3.27 mmol), and DMF (20 ml). The mixture was heated to 50°C for 16 hours. LC showed complete and clean reaction. The reaction was diluted with EtOAc, washed with water and brine, and separated. The crude solution was dried over sodium sulfate, filtered and concentrated to give 4-(4-(hydroxymethyl)phenyl)-2-((2-(trimethylsilyl)ethyl)thio)nicotinonitrile as a light yellow solid which was used in the next step without further purification. LC/MS [M+H]+: 343.
	With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 16h;	181.B Step B: 4-(4-(Hydroxymethyl)phenyl)-2-((2-(trimethylsilyl)ethyl)thio)nicotinonitrile Step B: 4-(4-(Hydroxymethyl)phenyl)-2-((2-(trimethylsilyl)ethyl)thio)nicotinonitrile (0625) To a flask charged with 2-chloro-4-(4-(hydroxymethyl)phenyl)nicotinonitrile (400 mg, 1.64 mmol) and a stir bar was added 2-(trimethylsilyl)ethanethiol (329 mg, 2.45 mmol), K2CO3 (452 mg, 3.27 mmol), and DMF (20 ml). The mixture was heated to 50° C. for 16 hours. LC showed complete and clean reaction. The reaction was diluted with EtOAc, washed with water and brine, and separated. The crude solution was dried over sodium sulfate, filtered and concentrated to give 4-(4-(hydroxymethyl)phenyl)-2-((2-(trimethylsilyl)ethyl)thio)nicotinonitrile as a light yellow solid which was used in the next step without further purification. LC/MS [M+H]+: 343.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2015/112441, 2015, A1 Location in patent: Page/Page column 163
[2]Current Patent Assignee: MERCK & CO INC - US2016/333021, 2016, A1 Location in patent: Paragraph 0625

31
[ 18143-30-1 ]
[ 1644384-66-6 ]
methyl 4-(3-cyano-2-((2-(trimethylsilyl)ethyl)thio)pyridin-4-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 20℃;	182.B Step B: Methyl 4-(3-cyano-2-((2-(trimethylsilyl)ethyl)thio)pyridin-4-yl)benzoate A mixture of methyl 4-(2-chloro-3-cyanopyridin-4-yl)benzoate (600 mg, 2.2 mmol), 2-(trimethylsilyl)-ethanethiol (380 mg, 2.9 mmol), and K2CO3 (460 mg, 3.3 mmol) in DMF (10 ml) was allowed to stir at RT overnight. TLC and LC showed a clean reaction. The reaction was diluted with EtOAc (50 mL), washed with water and brine, and separated. The crude solution was dried over sodium sulfate, filtered and concentrated to give methyl 4-(3- cyano-2-((2-(trimethylsilyl)ethyl)thio)pyridin-4-yl)benzoate as a yellow oil. The material was used in the next step without purification. LC/MS [M+H]+: 371.
	With potassium carbonate In N,N-dimethyl-formamide at 20℃;	182.B Step B: Methyl 4-(3-cyano-2-((2-(trimethylsilyl)ethyl)thio)pyridin-4-yl)benzoate Step B: Methyl 4-(3-cyano-2-((2-(trimethylsilyl)ethyl)thio)pyridin-4-yl)benzoate (0631) A mixture of methyl 4-(2-chloro-3-cyanopyridin-4-yl)benzoate (600 mg, 2.2 mmol), 2-(trimethylsilyl)-ethanethiol (380 mg, 2.9 mmol), and K2CO3 (460 mg, 3.3 mmol) in DMF (10 ml) was allowed to stir at RT overnight. TLC and LC showed a clean reaction. The reaction was diluted with EtOAc (50 mL), washed with water and brine, and separated. The crude solution was dried over sodium sulfate, filtered and concentrated to give methyl 4-(3-cyano-2-((2-(trimethylsilyl)ethyl)thio)pyridin-4-yl)benzoate as a yellow oil. The material was used in the next step without purification. LC/MS [M+H]+: 371

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2015/112441, 2015, A1 Location in patent: Page/Page column 165
[2]Current Patent Assignee: MERCK & CO INC - US2016/333021, 2016, A1 Location in patent: Paragraph 0631

32
[ 18143-30-1 ]
[ 1171919-75-7 ]
2-chloro-4-((2-(trimethylsilyl)ethyl)thio)nicotinonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere;	To a solution of <strong>[1171919-75-7]2-chloro-4-iodonicotinonitrile</strong> (2.0 g, 7.6 mmol) and K2CO3 (1.57 g, 1 1.34 mmol) in DMF (7 mL) was added 2-(trimethylsilyl)ethanethiol (1.21 mL, 7.56 mmol) under dry 2 atmosphere at room temperature. The mixture was stirred at the room temperature for 16 hours. The crude UPLC did not show the desired peak but the TLC indicated complete consumption of starting material. The reaction mixture was concentrated under vacuo. The crude was adsorbed onto silica gel, and loaded onto silica gel column and eluted with hexane and ethyl acetate to give 2-chloro-4-((2-(trimethylsilyl)ethyl)thio)nicotinonitrile. LC/MS [M+H]+: 271.
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere;	Step A: 2-Chloro-4-((2-(trimethylsilyl)ethyl)thio)nicotinonitrile (0649) To a solution of <strong>[1171919-75-7]2-chloro-4-iodonicotinonitrile</strong> (2.0 g, 7.6 mmol) and K2CO3 (1.57 g, 11.34 mmol) in DMF (7 mL) was added 2-(trimethylsilyl)ethanethiol (1.21 mL, 7.56 mmol) under dry N2 atmosphere at room temperature. The mixture was stirred at the room temperature for 16 hours. The crude UPLC did not show the desired peak but the TLC indicated complete consumption of starting material. The reaction mixture was concentrated under vacuo. The crude was adsorbed onto silica gel, and loaded onto silica gel column and eluted with hexane and ethyl acetate to give 2-chloro-4-((2-(trimethylsilyl)ethyl)thio)nicotinonitrile. LC/MS [M+H]+: 271.

Reference： [1]Patent: WO2015/112441,2015,A1 .Location in patent: Page/Page column 169
[2]Patent: US2016/333021,2016,A1 .Location in patent: Paragraph 0649

33
[ 18143-30-1 ]
3-chloro-5-(4-(hydroxymethyl)phenyl)isonicotinonitrile [ No CAS ]
3-(4-(hydroxymethyl)phenyl)-5-((2-(trimethylsilyl)ethyl)thio)isonicotinonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere;	189.B Step B : 3 -(4-(Hydroxymethyl)phenyl)-5-((2-(trimethylsilyl)ethyl)thio)isonicotinonitrile To a solution of 3-chloro-5-(4-(hydroxymethyl)phenyl)isonicotinonitrile (1.1 g, 4.50 mmol) and potassium carbonate (0.746 g, 5.39 mmol) in DMF (25 mL) was added 2- (trimethylsilyl)ethanethiol (1.1 mL, 6.87 mmol) at room temperature under N2. The reaction mixture was stirred for 3 hours. The crude UPLC indicated starting material still remained. The mixture was allowed to stir for a total of 24 hours. The crude UPLC indicated complete consumption of starting material. The reaction was diluted with EtOAc and washed with H20. The organic layer was concentrated under vacuum and purified on a silica gel column eluted with hexane and ethyl acetate to give 3-(4-(hydroxymethyl)phenyl)-5-((2- (trimethylsilyl)ethyl)thio)isonicotinonitrile. LC/MS [M+H]+: 343.
	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 3h; Inert atmosphere;	189.B Step B: 3-(4-(Hydroxymethyl)phenyl)-5-((2-(trimethylsilyl)ethyl)thio)isonicotinonitrile Step B: 3-(4-(Hydroxymethyl)phenyl)-5-((2-(trimethylsilyl)ethyl)thio)isonicotinonitrile (0656) To a solution of 3-chloro-5-(4-(hydroxymethyl)phenyl)isonicotinonitrile (1.1 g, 4.50 mmol) and potassium carbonate (0.746 g, 5.39 mmol) in DMF (25 mL) was added 2-(trimethylsilyl)ethanethiol (1.1 mL, 6.87 mmol) at room temperature under N2. The reaction mixture was stirred for 3 hours. The crude UPLC indicated starting material still remained. The mixture was allowed to stir for a total of 24 hours. The crude UPLC indicated complete consumption of starting material. The reaction was diluted with EtOAc and washed with H2O. The organic layer was concentrated under vacuum and purified on a silica gel column eluted with hexane and ethyl acetate to give 3-(4-(hydroxymethyl)phenyl)-5-((2-(trimethylsilyl)ethyl)thio)isonicotinonitrile. LC/MS [M+H]+: 343.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2015/112441, 2015, A1 Location in patent: Page/Page column 171
[2]Current Patent Assignee: MERCK & CO INC - US2016/333021, 2016, A1 Location in patent: Paragraph 0656

34
[ 18143-30-1 ]
2-chloro-4-(p-tolyl)nicotinonitrile [ No CAS ]
4-(p-tolyl)-2-((2-(trimethylsilyl)ethyl)thio)nicotinonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 60h; Inert atmosphere;	190.B Step B : 4-(p-Tolyl)-2-((2-(trimethylsilyl)ethyl)thio)nicotinonitrile To a solution of 2-chloro-4-(p-tolyl)nicotinonitrile (907 mg, 3.97 mmol) and potassium carbonate (l . lg, 7.93 mmol) in DMF (10 mL) was added 2-(trimethylsilyl)ethanethiol (0.57 ml, 3.57 mmol) at room temperature under dry N2. The mixture was stirred for 60 hours. The reaction mixture was poured into a separatory funnel containing H2O and the organic layer was extracted with EtOAc (3x). The combined extracts were dried over Na2S04, filtered and the solution was evaporated to dryness under reduced pressure. The crude 1H-NMR showed 4-(p- tolyl)-2-((2-(trimethylsilyl)ethyl)thio)nicotinonitrile with small amount of impurities so the crude product was used without further purification in the next step. LC/MS [M+H]+: 327.
	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 60h; Inert atmosphere;	190.B Step B: 4-(p-Tolyl)-2-((2-(trimethylsilyl)ethyl)thio)nicotinonitrile Step B: 4-(p-Tolyl)-2-((2-(trimethylsilyl)ethyl)thio)nicotinonitrile (0662) To a solution of 2-chloro-4-(p-tolyl)nicotinonitrile (907 mg, 3.97 mmol) and potassium carbonate (1.1 g, 7.93 mmol) in DMF (10 mL) was added 2-(trimethylsilyl)ethanethiol (0.57 ml, 3.57 mmol) at room temperature under dry N2. The mixture was stirred for 60 hours. The reaction mixture was poured into a separatory funnel containing H2O and the organic layer was extracted with EtOAc (3×). The combined extracts were dried over Na2SO4, filtered and the solution was evaporated to dryness under reduced pressure. The crude 1H-NMR showed 4-(p-tolyl)-2-((2-(trimethylsilyl)ethyl)thio)nicotinonitrile with small amount of impurities so the crude product was used without further purification in the next step. LC/MS [M+H]+: 327.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2015/112441, 2015, A1 Location in patent: Page/Page column 173
[2]Current Patent Assignee: MERCK & CO INC - US2016/333021, 2016, A1 Location in patent: Paragraph 0662

35
[ 18143-30-1 ]
[ 133116-83-3 ]
2-(trifluoromethyl)-6-((2-(trimethylsilyl)ethyl)thio)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h;	To a solution of <strong>[133116-83-3]2-fluoro-6-(trifluoromethyl)benzonitrile</strong> (1.0 g, 5.29 mmol) and K2C03 (1.46 g, 10.58 mmol) in DMF (5 mL) was added 2-(trimethylsilyl)ethanethiol (1.01 ml, 6.35 mmol). The mixture was stirred at room temperature for 4 hours. The TLC indicated complete consumption of starting material. The mixture was filtered and evaporated to dryness in vacuo. The crude was adsorbed onto silica gel, and purified by hexane and ethyl acetate to afford the desired compound. LC/MS [M+H]+:304.
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h;	Step A: 2-(Trifluoromethyl)-6-((2-(trimethylsilyl)ethyl)thio)benzonitrile (0711) To a solution of <strong>[133116-83-3]2-fluoro-6-(trifluoromethyl)benzonitrile</strong> (1.0 g, 5.29 mmol) and K2CO3 (1.46 g, 10.58 mmol) in DMF (5 mL) was added 2-(trimethylsilyl)ethanethiol (1.01 ml, 6.35 mmol). The mixture was stirred at room temperature for 4 hours. The TLC indicated complete consumption of starting material. The mixture was filtered and evaporated to dryness in vacuo. The crude was adsorbed onto silica gel, and purified by hexane and ethyl acetate to afford the desired compound. LC/MS [M+H]+:304

Reference： [1]Patent: WO2015/112441,2015,A1 .Location in patent: Page/Page column 194
[2]Patent: US2016/333021,2016,A1 .Location in patent: Paragraph 0711

36
[ 18143-30-1 ]
[ 94088-46-7 ]
2-methoxy-6-((2-(trimethylsilyl)ethyl)thio)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h;	To a solution of <strong>[94088-46-7]2-fluoro-6-methoxybenzonitrile</strong> (1.0 g, 6.62 mmol) and potassium carbonate (1.83 g, 13.23 mmol) in DMF (5 ml) was added 2- (trimethylsilyl)ethanethiol (1.27 ml, 7.94 mmol). The mixture was stirred at room temprature for 4 hours. The TLC indicated complete consumption of starting material. The mixture was filtered and the filtrate was concentrated under vacuum. The crude was adsorbed onto silica gel, and purified by silica gel column with hexane and ethyl acetate to give 2-methoxy-6-((2- (trimethylsilyl)ethyl)thio)benzonitrile. LC/MS [M+H]+:266.
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h;	Step A: 2-Methoxy-6-((2-(trimethylsilyl)ethyl)thio)benzonitrile (0716) To a solution of <strong>[94088-46-7]2-fluoro-6-methoxybenzonitrile</strong> (1.0 g, 6.62 mmol) and potassium carbonate (1.83 g, 13.23 mmol) in DMF (5 ml) was added 2-(trimethylsilyl)ethanethiol (1.27 ml, 7.94 mmol). The mixture was stirred at room temperature for 4 hours. The TLC indicated complete consumption of starting material. The mixture was filtered and the filtrate was concentrated under vacuum. The crude was adsorbed onto silica gel, and purified by silica gel column with hexane and ethyl acetate to give 2-methoxy-6-((2-(trimethylsilyl)ethyl)thio)benzonitrile. LC/MS [M+H]+:266.

Reference： [1]Patent: WO2015/112441,2015,A1 .Location in patent: Page/Page column 195
[2]Patent: US2016/333021,2016,A1 .Location in patent: Paragraph 0716

37
[ 18143-30-1 ]
tert-butyl 4-(4′-bromo-2′-cyano-3′-fluoro-[1,1′-biphenyl]-4-yl)piperidine-1-carboxylate [ No CAS ]
tert-butyl 4-(4′-bromo-2′-cyano-3′-((2-(trimethylsilyl)ethyl)thio)-[1,1′-biphenyl]-4-yl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29.1%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 7h;	259.B Step B: tert-Butyl 4-(4'-bromo-2'-cyano-3'-((2-(trimethylsilyl)ethyl)thio)-[l, l'-biphenyl]- 4-yl)piperidine- 1 -carboxylate To a round bottom containing tert-butyl 4-(4'-bromo-2'-cyano-3'-fluoro-[l,r- biphenyl]-4-yl)piperidine-l -carboxylate (1.41 g, 3.07 mmol) was added potassium carbonate (0.636 g, 4.60 mmol), followed by a solution of 2-(trimethylsilyl)ethanethiol (0.309 g, 2.302 mmol) in DMF (15 ml). The reaction stirred at room temp for 7 hr. The reaction was diluted with ethyl acetate and washed with water and brine (3 times). The organic was extracted out and concentrated. The residue was purified by normal phase ISCO on a 40g column eluted with 0% to 30% ethyl acetate in hexane. The pure fractions were concentrated to afford tert-butyl 4-(4'- bromo-2'-cyano-3 '-((2-(trimethylsilyl)ethyl)thio)-[ 1 , 1 '-biphenyl]-4-yl)piperidine- 1 -carboxylate (540 mg, 29.1%). LC-MS: calculated for CzsHsvBr zOzSSi 572.2 observed m/e (M+H)+: 573.5.
29.1%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 7h;	259.B Step B: tert-Butyl 4-(4′-bromo-2′-cyano-3′-((2-(trimethylsilyl)ethyl)thio)-[1,1′-biphenyl]-4-yl)piperidine-1-carboxylate Step B: tert-Butyl 4-(4′-bromo-2′-cyano-3′-((2-(trimethylsilyl)ethyl)thio)-[1,1′-biphenyl]-4-yl)piperidine-1-carboxylate (0725) To a round bottom containing tert-butyl 4-(4′-bromo-2′-cyano-3′-fluoro-[1,1′-biphenyl]-4-yl)piperidine-1-carboxylate (1.41 g, 3.07 mmol) was added potassium carbonate (0.636 g, 4.60 mmol), followed by a solution of 2-(trimethylsilyl)ethanethiol (0.309 g, 2.302 mmol) in DMF (15 ml). The reaction stirred at room temp for 7 hr. The reaction was diluted with ethyl acetate and washed with water and brine (3 times). The organic was extracted out and concentrated. The residue was purified by normal phase ISCO on a 40 g column eluted with 0% to 30% ethyl acetate in hexane. The pure fractions were concentrated to afford tert-butyl 4-(4′-bromo-2′-cyano-3′-((2-(trimethylsilyl)ethyl)thio)-[1,1′-biphenyl]-4-yl)piperidine-1-carboxylate (540 mg, 29.1%). LC-MS: calculated for C28H37BrN2O2SSi 572.2 observed m/e (M+H)+: 573.5

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2015/112441, 2015, A1 Location in patent: Page/Page column 198
[2]Current Patent Assignee: MERCK & CO INC - US2016/333021, 2016, A1 Location in patent: Paragraph 0725

38
[ 18143-30-1 ]
3-chloro-2-fluoro-6-iodobenzonitrile [ No CAS ]
3-chloro-6-iodo-2-((2-(trimethylsilyl)ethyl)thio)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 20℃;	263.A Step A: 3-chloro-6-iodo-2-((2-(trimethylsilyl)ethyl)thio)benzonitrile To a solution of 3-chloro-2-fluoro-6-iodobenzonitrile (0.500 g, 1.78 mmol) and K2C03 (0.491 g, 3.55 mmol) in DMF (3 mL) was added 2-(trimethylsilyl)ethanethiol (0.341 mL, 2.13 mmol), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered, the filtrate was diluted with EtOAc and washed with water (twice) and then with brine. The organic layer was dried over anhydrous MgS04, filtered, concentrated and purified by silica gel column chromatography using (0-15)% EtOAc/Hexanes as mobile phase to afford the title compound.
	With potassium carbonate In N,N-dimethyl-formamide at 20℃;	263.A Step A: 3-chloro-6-iodo-2-((2-(trimethylsilyl)ethyl)thio)benzonitrile Step A: 3-chloro-6-iodo-2-((2-(trimethylsilyl)ethyl)thio)benzonitrile (0736) To a solution of 3-chloro-2-fluoro-6-iodobenzonitrile (0.500 g, 1.78 mmol) and K2CO3 (0.491 g, 3.55 mmol) in DMF (3 mL) was added 2-(trimethylsilyl)ethanethiol (0.341 mL, 2.13 mmol), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered, the filtrate was diluted with EtOAc and washed with water (twice) and then with brine. The organic layer was dried over anhydrous MgSO4, filtered, concentrated and purified by silica gel column chromatography using (0-15)% EtOAc/Hexanes as mobile phase to afford the title compound.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2015/112441, 2015, A1 Location in patent: Page/Page column 202
[2]Current Patent Assignee: MERCK & CO INC - US2016/333021, 2016, A1 Location in patent: Paragraph 0736

39
[ 18143-30-1 ]
5-(4-bromophenyl)-3-chloropyridazine-4-carbonitrile [ No CAS ]
5-(4-bromophenyl)-3-((2-(trimethylsilyl)ethyl)thio)pyridazine-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 20℃;	277.C Step C: 5-(4-Bromophenyl)-3-((2-(trimethylsilyl)ethyl)thio)pyridazine-4-carbonitrile 5-(4-Bromophenyl)-3-chloropyridazine-4-carbonitrile (2.50 g, 8.49 mmol) was dissolved in DMF (42.4 mL). K2C03 (2.346 g, 16.98 mmol) and 2-(trimethylsilyl)ethanethiol (1.03 g, 7.64 mmol) were added and the reaction was stirrred overnight at rt. The reaction was diluted with EtOAc and water. The organic phase was washed with water (x2) and brine, then dried over anhydrous a2S04, filtered, and concentrated. The residue was purified by MPLC on a 40g silica column eluting with 0% to 35% EtOAc in Hexane to afford 5-(4-bromophenyl)-3- ((2-(trimethylsilyl)ethyl)thio)pyridazine-4-carbonitrile. LC-MS: calculated for C^HisBr sSSi 393.0; observed m/e (M+H)+: 394.2. 'H NMR δ (ppm) (MeOH): 9.09 (s, 1H), 7.67 (d, 2H), 7.57 (d, 2H), 3.42-3.37 (m, 2H), 1.04-0.99 (m, 2H), 0.00 (s, 9H).
	With potassium carbonate In N,N-dimethyl-formamide at 20℃;	277.C Step C: 5-(4-Bromophenyl)-3-((2-(trimethylsilyl)ethyl)thio)pyridazine-4-carbonitrile Step C: 5-(4-Bromophenyl)-3-((2-(trimethylsilyl)ethyl)thio)pyridazine-4-carbonitrile (0763) 5-(4-Bromophenyl)-3-chloropyridazine-4-carbonitrile (2.50 g, 8.49 mmol) was dissolved in DMF (42.4 mL). K2CO3 (2.346 g, 16.98 mmol) and 2-(trimethylsilyl)ethanethiol (1.03 g, 7.64 mmol) were added and the reaction was stirred overnight at rt. The reaction was diluted with EtOAc and water. The organic phase was washed with water (×2) and brine, then dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by MPLC on a 40 g silica column eluting with 0% to 35% EtOAc in Hexane to afford 5-(4-bromophenyl)-3-((2-(trimethylsilyl)ethyl)thio)pyridazine-4-carbonitrile. LC-MS: calculated for C16H18BrN3SSi 393.0; observed m/e (M+H)+: 394.2. 1H NMR δ (ppm) (MeOH): 9.09 (s, 1H), 7.67 (d, 2H), 7.57 (d, 2H), 3.42-3.37 (m, 2H), 1.04-0.99 (m, 2H), 0.00 (s, 9H).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2015/112441, 2015, A1 Location in patent: Page/Page column 211; 212
[2]Current Patent Assignee: MERCK & CO INC - US2016/333021, 2016, A1 Location in patent: Paragraph 0763

40
[ 18143-30-1 ]
[ 103408-15-7 ]
2-((2-(trimethylsilyl)ethyl)thio)-1-naphthonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	399.A Step A: 2-((2-(trimethylsilyl)ethyl)thio)-l-naphthonitrile A solution of n-butyllithium (2.5M in Hexane) (2.74 ml, 6.8 mmol) was added drop wise to a solution of 2,2,6,6-tetramethylpiperidine (1.15 ml, 6.8 mmol) in THF (5mL) while maintaining the temperature at 0°C. After 30 minutes of stirring, the reaction mixture was cooled to -78°C and a solution of 1-naphthonitrile (1 g, 6.53 mmol) in THF (3 mL) was added drop wise. The resulting dark solution was maintained at -78°C and stirred for 2 hours. A solution of iodine (1.74 g, 6.8 mmol) in THF (3 mL) was added drop wise and stirred at -78°C for 2 hours, then allowed to warm to room temperature overnight. The reaction mixtue was quenched with 0 and resulting mixture was extracted with EtOAc. The combined organic extracts were dried over Na2S04, filtered and concentrated. The resulting crude, 2-iodo-l- naphthonitrile (1.7 g, 6.1 mmol) and potassium carbonate (1.01 g, 7.3 mmol) were dissolved in DMF (10 ml). To that mixture, 2-(trimethylsilyl)ethanethiol (1.46 ml, 9.1 mmol) was added and stirred at room temperature under 2 overnight. The reaction mixture was washed with water and organic was extracted with EtOAc. The combined organic layer was dried over Na2S04, filtered and concentrated under vacuum. The crude was purfied by MPLC with hexanes and EtOAc to give desired compound. NMR (MeOD): δ 0.1 lppm (s, 9H), 1.03ppm (m, 2H), 3.28ppm (m, 2H), 7.61ppm (dd, J= 8.2 Hz, 1H), 7.64ppm (d, J= 8.8 Hz, 1H), 7.73ppm (d, J = 7.1 Hz, 1H), 7.98ppm (d, J= 8.2Hz, 1H), 8.03ppm (d, J= 8.8Hz, 1H), 8.09ppm, (d, J= 8.5Hz, 1H).
	With potassium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	399.A Step A: 2-((2-(trimethylsilyl)ethyl)thio)-1-naphthonitrile The resulting crude, 2-iodo-1-naphthonitrile (1.7 g, 6.1 mmol) and potassium carbonate (1.01 g, 7.3 mmol) were dissolved in DMF (10 ml). To that mixture, 2-(trimethylsilyl)ethanethiol (1.46 ml, 9.1 mmol) was added and stirred at room temperature under N2 overnight. The reaction mixture was washed with water and organic was extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude was purified by MPLC with hexanes and EtOAc to give desired compound. 1H NMR (MeOD): δ 0.11 ppm (s, 9H), 1.03 ppm (m, 2H), 3.28 ppm (m, 2H), 7.61 ppm (dd, J=8.2 Hz, 1H), 7.64 ppm (d, J=8.8 Hz, 1H), 7.73 ppm (d, J=7.1 Hz, 1H), 7.98 ppm (d, J=8.2 Hz, 1H), 8.03 ppm (d, J=8.8 Hz, 1H), 8.09 ppm, (d, J=8.5 Hz, 1H).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2015/112441, 2015, A1 Location in patent: Page/Page column 257
[2]Current Patent Assignee: MERCK & CO INC - US2016/333021, 2016, A1 Location in patent: Paragraph 0857

41
[ 18143-30-1 ]
8-benzyloxy-5-bromo-7-chloro-quinoline [ No CAS ]
2-[(8-benzyloxy-7-chloro-5-quinolyl)sulfanyl]ethyl-trimethyl-silane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 90℃; Inert atmosphere; Sealed tube;
76%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 90℃; for 2h; Inert atmosphere;	9.1 Stepi: 2- j(8-benzyloxy-7-chloro-5-quinolyl)sulfanylj ethyl-trimethyl-silane 101251 To a stirring solution of 8-benzyloxy-5 -bromo-7-chloro-quinoline (5. 9g, 16.92mmol) in dioxane (100 mL), 2-trimethylsilylethanethiol (3.57 mL, 25.39 mmol) tris(dba)dipalladium (774.88 mg, 0.8500 mmol) Xantphos (489.62 mg, 0.8500 mmol) cesium carbonate (16.54 g, 50.77 mmol) were added. Nitrogen was bubbled in for 3 mm. The solution was heated at 90 °C for two hours. The solution was cooled to room temperature. Water (50 ml) was added. The solution was extracted with ethyl acetate (80X 2 ml), brine (50 ml), dried over sodium sulfate. The organic solution was filtered and concentrated. The residue was purified over ISCO eluted with ethyl acetate/hexane (0-30%) to give 2-[(8-benzyloxy-7-chloro-5- quinolyl)sulfanyl]ethyl-trimethyl-silane (6.459 g,12.853 mmol, 76% yield) the slightly colored oil. MS (ES+) m/z 402.0 [M+H].’H NIVIR (CDC13) ö: 8.99 - 9.04 (m, 1H), 8.66 - 8.73 (m, 1H), 7.61 - 7.69 (m, 2H), 7.54 - 7.59 (m, 1H), 7.47 - 7.52 (m, 1H), 7.33 - 7.44 (m, 3H), 5.45 - 5.52 (m, 2H), 2.94 - 3.04 (m, 2H), 0.91 - 1.01 (m, 2H), 0.03 - 0.09 (m, 9H).

Reference： [1]Buchler, Ingrid; Akuma, Daniel; Au, Vinh; Carr, Gregory; De León, Pablo; Depasquale, Michael; Ernst, Glen; Huang, Yifang; Kimos, Martha; Kolobova, Anna; Poslusney, Michael; Wei, Huijun; Swinnen, Dominique; Montel, Florian; Moureau, Florence; Jigorel, Emilie; Schulze, Monika-Sarah E. D.; Wood, Martyn; Barrow, James C. [Journal of Medicinal Chemistry, 2018, vol. 61, # 21, p. 9647 - 9665]
[2]Current Patent Assignee: LIEBER INSTITUTE FOR BRAIN DEVELOPMENT - WO2016/123577, 2016, A1 Location in patent: Paragraph 0125

42
[ 18143-30-1 ]
6-bromo-3-iodo-N,N-bis[(4-methoxyphenyl)methyl]-2-[2-[(4-methoxyphenyl)methyl]-2H-1,2,3,4-tetrazol-5-yl]benzene-1-sulfonamide [ No CAS ]
3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-(2-(trimethylsilyl)ethylthio)benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In N,N-dimethyl-formamide at 20℃;	13.A Step A: 3 -iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H- tetrazol-5 -yl)-6-((2-(trimethylsilyl)ethyl)thio)benzenesulfonamide A suspension of 6-bromo-3 -iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4- methoxybenzyl)-2H-tetrazol-5 -yl)benzenesulfonamide (10 g, 12.65 mmol), cesium carbonate (8.24 g, 25.3 mmol) and 2-(trimethylsilyl)ethanethiol (6.08 ml, 38.0 mmol) in DMF (100 ml) was stirred at rt overnight. The mixture was diluted with ether, washed with brine. The organic layer was dried (Mg504), and concentrated to give crude 3-iodo-N,N-bis(4-methoxybenzyl)-2- (2-(4-methoxybenzyl)-2H-tetrazol-5 -yl)-6-((2 -(trimethylsilyl)ethyl)thio)benzenesulfonamide which was used directly in the next step. LCMS [M+1]: 844.63.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2016/206101, 2016, A1 Location in patent: Page/Page column 54

43
[ 18143-30-1 ]
[ 105309-59-9 ]
tetrakis{4-[2-(trimethylsilyl)ethylsulfanyl]phenyl}methane [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2017,vol. 56,p. 8290 - 8294
Angew. Chem.,2017,vol. 129,p. 8405 - 8410,6

44
[ 18143-30-1 ]
ethyl 2-((benzyl(pivaloyloxy)amino)methyl)acrylate [ No CAS ]
ethyl 1-benzyl-2-(((2-(trimethylsilyl)ethyl)thio)methyl)aziridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	Stage #1: 2-trimethylsilylethanethiol With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.833333h; Stage #2: ethyl 2-((benzyl(pivaloyloxy)amino)methyl)acrylate In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 18h; diastereoselective reaction;	General procedure I (GPI) General procedure: A 2-necked flask (10 mL) equipped with a magnetic stirring bar (ellipsoidal), an Ar-inlet and a rubber septumwas charged with DMF (2 mL) and solid NaH in oil (23 mg, 0.52 mmol, 1.10 eq). The mixture was cooled in icebath and selected nucleophile (0.49 mmol, 1.05 eq) was added. The reaction mixture was stirred for 30 min atlow temperature, then 10 min at room temperature. After this time, the reaction mixture was cooled in ice bathand a solution of starting material (150 mg, 0.47 mmol, 1.0 eq) in DMF (2 mL) was added dropwise by means ofa syringe. The ice bath was removed and stirring was continued overnight at room temperature.Work-up: The reaction mixture was cooled in ice bath. Saturated NH4Cl(aq.) (10 mL) was added first dropwise,then in one portion (pH after quenching 8-9). The resulting mixture was extracted with diethyl ether (3 x 25 mL).Combined organic extracts were washed with water (2 x 30 mL), saturated NaHCO3(aq.) (10 mL), dried overNa2SO4(anhydr.), filtered and evaporated to dryness (bath temperature 35 °C). The crude product was purifiedby chromatographic separation on Rf-machine yielding the corresponding product as a colourless to yellow oil.

Reference： [1]Pietrasiak, Ewa; Schade, Grit; Baalouch, Myriam; Emery, Daniel; Beaudegnies, Renaud [Synlett, 2017, vol. 28, # 16, p. 2115 - 2120]

45
[ 18143-30-1 ]
6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1-sulfonamide [ No CAS ]
rac-tert-butyl (cis-3-fluoropiperidin-4-yl)carbamate [ No CAS ]
[ 824-94-2 ]
[ 853944-08-8 ]
tert-butyl (cis-1-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(N-((R)-3-((tert-butoxycarbonyl)amino)-2-hydroxypropyl)sulfamoyl)-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)phenyl)-3-fluoropiperidin-4-yl)carbamate [ No CAS ]
tert-butyl (cis-1-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(N-((R)-3-((tert-butoxycarbonyl)amino)-2-hydroxypropyl)sulfamoyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenyl)-3-fluoropiperidin-4-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1-sulfonamide; p-methoxybenzyl chloride With tetrabutyl-ammonium chloride; potassium carbonate; sodium iodide In chloroform; water at 50℃; Stage #2: 2-trimethylsilylethanethiol With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 5h; Stage #3: rac-tert-butyl (cis-3-fluoropiperidin-4-yl)carbamate; (2S)-N-tert-butoxycarbonyl-2-hydroxy-1,3-diaminopropane Further stages;	36.I; 37.A; 37.B; 1.A; 1.B; 1.C Step C: tert-butyl (cis-1-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(N-((R)-3-((tert- butoxycarbonyl)amino)-2-hydroxypropyl)sulfamoyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5- yl)phenyl)-3-fluoropiperidin-4-yl)carbamate and tert-butyl (cis-1-(3-(N,N-bis(4- methoxybenzyl)sulfamoyl)-4-(N-((R)-3-((tert-butoxycarbonyl)amino)-2- hydroxypropyl)sulfamoyl)-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)phenyl)-3-fluoropiperidin- 4-yl)carbamate. Into a 3000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1- sulfonamide (105 g, 244.17 mmol, 1.00 equiv), chloroform (1050 mL), potassium carbonate (168.9 g, 1.22 mol, 5.00 equiv), water (525 mL), NaI (11 g, 0.30 equiv), tetrabutyl(chloro)amine (20.4 g, 73.40 mmol, 0.30 equiv), 1-(chloromethyl)-4-methoxybenzene (230 g, 1.47 mol, 6.00 equiv). The resulting solution was stirred overnight at 50°C in an oil bath. The reaction mixture was cooled to RT. The resulting solution was extracted with 2x1000 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compounds. LC-MS: (ES, m/z): 790 [M+H]+ ; H-NMR: (300MHz, CDCl3, ppm): δ 7.956-7.928 (m, 0.5H), 7.852-7.824 (m, 1H), 7.656-7.612 (m, 1.5H), 7.323- 7.282 (m, 1.5H), 7.195-7.224 (m, 2H), 6.944-6.908 (m, 6H), 6.822-6.760 (m, 9H), 5.791 (m, 1H), 5.570-5.521 (m, 1H), 5.149-5.100 (m, 1H), 4.769-4.718 (m, 2H), 4.232-4.221 (m, 2H), 3.900-3.848 (m, 2H), 3.789-3.742 (m, 14H). 6-bromo-3-iodo-N,N-bis[(4-methoxyphenyl)methyl]-2-[1-[(4- methoxyphenyl)methyl]-1H-1,2,3,4-tetrazol-5-yl]benzene-1-sulfonamide, 6-bromo-3-iodo-N,N- bis[(4-methoxyphenyl)methyl]-2-[2-[(4-methoxyphenyl)methyl]-2H-1,2,3,4-tetrazol-5- yl]benzene-1-sulfonamide (500 mg, 0.633 mmol), 2-(trimethylsilyl)ethanethiol (170 mg, 1.265 mmol) and Cs2CO3 (618 mg, 1.898 mmol) were combined in DMF (1.5 mL). Then the mixture was stirred at RT for 5 hours. Then the mixture was poured onto ether (100 mL) with the organic layer collected and concentrated under vacuum to give the title compounds: LCMS [M + H]+: 844; 1H NMR (300 MHz, CDCl3): δ 4.71-4.40 (m, 1H), 4.13-4.00 (m, 1H), 3.83-3.67 (m, 1H), 2.81-2.72 (m, 1H), 2.32-2.21 (m, 2H), 2.08-1.74 (m, 2H), 1.44 (s, 9H). 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6- ((2-(trimethylsilyl)ethyl)thio)benzenesulfonamide (480 mg, 0.569 mmol) and m-CPBA (491 mg, 2.84 mmol) were combined in dichloromethane (2 mL). The mixture was stirred at RT for 4 hours. The resulting mixture was poured onto ether (200 mL) and washed with brine (150 mL). The organic layers were collected, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was applied on a silica gel column with EA/PE (1/3) to give the title compounds: LCMS [M + H]+: 876; 1H NMR (300 MHz, CDCl3): δ 8.62 (d, J = 8.7 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 7.90-7.88 (m, 1H), 7.69-7.68 (m, 0.5H), 7.56-7.53 (m, 0.5H), 7.27-7.20 (m, 2H), 6.91-6.79 (m, 12H), 5.44-5.39 (m, 1H), 5.20-5.15 (m, 1H), 4.58-4.53 (m, 2H), 3.98-3.79 (m, 2H), 3.75-3.66 (m, 9H), 2.50-2.48 (m, 2H), 1.19-1.03 (m, 1H), 0.83-0.82 (m, 1H), 0.01 (s, 9H). A flask was charged with 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4- methoxybenzyl)-2H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide and 3-iodo-N,N-bis(4-methoxybenzyl)-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-6-((2- (trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide (REFERENCE EXAMPLE 37) (400 mg, 0.457 mmol), racemic tert-butyl (cis-3-fluoropiperidin-4-yl)carbamate (498 mg, 2.283 mmol) and DABCO (256 mg, 2.283 mmol). The vial was sealed, degassed with N2, and filled with DMSO (3.1 mL). The resulting mixture was heated overnight at 110 °C. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography using (0- 100)% EtOAc/hexane as mobile phase to afford the title compound. LC/MS [M+H]+: 966.96. To a solution of tert-butyl (cis-1-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-(2- (4-methoxybenzyl)-2H-tetrazol-5-yl)-4-((2-(trimethylsilyl)ethyl)sulfonyl)phenyl)-3- fluoropiperidin-4-yl)carbamate and tert-butyl (cis-1-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2- (1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-4-((2-(trimethylsilyl)ethyl)sulfonyl)phenyl)-3- fluoropiperidin-4-yl)carbamate (0.36 g, 0.373 mmol) in THF (3.73 mL) was added tetrabutylammonium fluoride (0.820 ml, 0.820 mmol) (1.0 M in THF) dropwise at 0 °C. The reaction mixture was stirred at RT under N2 for 0.5 hours. The reaction mixture was diluted with EtOAc, washed four times with sat’d aqeous KHSO4, twice with brine, dried over MgSO4, and concentrated to afford the title compound. LC/MS [M+H]+: 866.73. To a solution of 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(cis-4-((tert- butoxycarbonyl)amino)-3-fluoropiperidin-1-yl)-3-(2-(4-methoxybenzyl)-2H-tetrazol-5- yl)benzenesulfinic acid and 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(cis-4-((tert- butoxycarbonyl)amino)-3-fluoropiperidin-1-yl)-3-(1-(4-methoxybenzyl)-1H-tetrazol-5- yl)benzenesulfinic acid (0.32 g, 0.370 mmol) in THF (2.58 mL) were added (S)-tert-butyl (3- amino-2-hydroxypropyl)carbamate (0.141 g, 0.739 mmol), TEA (0.103 mL, 0.739 mmol), and NCS (0.099 g, 0.739 mmol) in sequence at 0 °C under nitrogen. The mixture was stirred at the same temperature for 30 minutes. The reaction mixture was diluted with EtOAc, washed with NaHCO3 solution and brine. The organic layer was dried over MgSO4, evaporated, and the crude product was purified by silica gel column chromatography eluting with 0-100% EtOAc/hexanes to give the title compound. LC/MS [M+H]+: 1054.87.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2019/18186, 2019, A1 Location in patent: Page/Page column 62-63; 88-89

46
[ 18143-30-1 ]
6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1-sulfonamide [ No CAS ]
rac-tert-butyl (cis-3-fluoropiperidin-4-yl)carbamate [ No CAS ]
[ 824-94-2 ]
[ 853944-08-8 ]
N<SUP>1</SUP>-((R)-3-amino-2-hydroxypropyl)-4-(cis-4-amino-3-fluoropiperidin-1-yl)-3-(2H-tetrazol-5-yl)benzene-1,2-disulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1-sulfonamide; p-methoxybenzyl chloride With tetrabutyl-ammonium chloride; potassium carbonate; sodium iodide In chloroform; water at 50℃; Stage #2: 2-trimethylsilylethanethiol With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 5h; Stage #3: rac-tert-butyl (cis-3-fluoropiperidin-4-yl)carbamate; (2S)-N-tert-butoxycarbonyl-2-hydroxy-1,3-diaminopropane Further stages;	36.I; 37.A; 37.B; 1.A; 1.B; 1.C; 1.D Step D: N¹-((R)-3-amino-2-hydroxypropyl)-4-(cis-4-amino-3-fluoropiperidin-1-yl)-3-(2H- tetrazol-5-yl)benzene-1,2-disulfonamide Into a 3000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1- sulfonamide (105 g, 244.17 mmol, 1.00 equiv), chloroform (1050 mL), potassium carbonate (168.9 g, 1.22 mol, 5.00 equiv), water (525 mL), NaI (11 g, 0.30 equiv), tetrabutyl(chloro)amine (20.4 g, 73.40 mmol, 0.30 equiv), 1-(chloromethyl)-4-methoxybenzene (230 g, 1.47 mol, 6.00 equiv). The resulting solution was stirred overnight at 50°C in an oil bath. The reaction mixture was cooled to RT. The resulting solution was extracted with 2x1000 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compounds. LC-MS: (ES, m/z): 790 [M+H]+ ; H-NMR: (300MHz, CDCl3, ppm): δ 7.956-7.928 (m, 0.5H), 7.852-7.824 (m, 1H), 7.656-7.612 (m, 1.5H), 7.323- 7.282 (m, 1.5H), 7.195-7.224 (m, 2H), 6.944-6.908 (m, 6H), 6.822-6.760 (m, 9H), 5.791 (m, 1H), 5.570-5.521 (m, 1H), 5.149-5.100 (m, 1H), 4.769-4.718 (m, 2H), 4.232-4.221 (m, 2H), 3.900-3.848 (m, 2H), 3.789-3.742 (m, 14H). 6-bromo-3-iodo-N,N-bis[(4-methoxyphenyl)methyl]-2-[1-[(4- methoxyphenyl)methyl]-1H-1,2,3,4-tetrazol-5-yl]benzene-1-sulfonamide, 6-bromo-3-iodo-N,N- bis[(4-methoxyphenyl)methyl]-2-[2-[(4-methoxyphenyl)methyl]-2H-1,2,3,4-tetrazol-5- yl]benzene-1-sulfonamide (500 mg, 0.633 mmol), 2-(trimethylsilyl)ethanethiol (170 mg, 1.265 mmol) and Cs2CO3 (618 mg, 1.898 mmol) were combined in DMF (1.5 mL). Then the mixture was stirred at RT for 5 hours. Then the mixture was poured onto ether (100 mL) with the organic layer collected and concentrated under vacuum to give the title compounds: LCMS [M + H]+: 844; 1H NMR (300 MHz, CDCl3): δ 4.71-4.40 (m, 1H), 4.13-4.00 (m, 1H), 3.83-3.67 (m, 1H), 2.81-2.72 (m, 1H), 2.32-2.21 (m, 2H), 2.08-1.74 (m, 2H), 1.44 (s, 9H). 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6- ((2-(trimethylsilyl)ethyl)thio)benzenesulfonamide (480 mg, 0.569 mmol) and m-CPBA (491 mg, 2.84 mmol) were combined in dichloromethane (2 mL). The mixture was stirred at RT for 4 hours. The resulting mixture was poured onto ether (200 mL) and washed with brine (150 mL). The organic layers were collected, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was applied on a silica gel column with EA/PE (1/3) to give the title compounds: LCMS [M + H]+: 876; 1H NMR (300 MHz, CDCl3): δ 8.62 (d, J = 8.7 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 7.90-7.88 (m, 1H), 7.69-7.68 (m, 0.5H), 7.56-7.53 (m, 0.5H), 7.27-7.20 (m, 2H), 6.91-6.79 (m, 12H), 5.44-5.39 (m, 1H), 5.20-5.15 (m, 1H), 4.58-4.53 (m, 2H), 3.98-3.79 (m, 2H), 3.75-3.66 (m, 9H), 2.50-2.48 (m, 2H), 1.19-1.03 (m, 1H), 0.83-0.82 (m, 1H), 0.01 (s, 9H). A flask was charged with 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4- methoxybenzyl)-2H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide and 3-iodo-N,N-bis(4-methoxybenzyl)-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-6-((2- (trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide (REFERENCE EXAMPLE 37) (400 mg, 0.457 mmol), racemic tert-butyl (cis-3-fluoropiperidin-4-yl)carbamate (498 mg, 2.283 mmol) and DABCO (256 mg, 2.283 mmol). The vial was sealed, degassed with N2, and filled with DMSO (3.1 mL). The resulting mixture was heated overnight at 110 °C. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography using (0- 100)% EtOAc/hexane as mobile phase to afford the title compound. LC/MS [M+H]+: 966.96. To a solution of tert-butyl (cis-1-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-(2- (4-methoxybenzyl)-2H-tetrazol-5-yl)-4-((2-(trimethylsilyl)ethyl)sulfonyl)phenyl)-3- fluoropiperidin-4-yl)carbamate and tert-butyl (cis-1-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2- (1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-4-((2-(trimethylsilyl)ethyl)sulfonyl)phenyl)-3- fluoropiperidin-4-yl)carbamate (0.36 g, 0.373 mmol) in THF (3.73 mL) was added tetrabutylammonium fluoride (0.820 ml, 0.820 mmol) (1.0 M in THF) dropwise at 0 °C. The reaction mixture was stirred at RT under N2 for 0.5 hours. The reaction mixture was diluted with EtOAc, washed four times with sat’d aqeous KHSO4, twice with brine, dried over MgSO4, and concentrated to afford the title compound. LC/MS [M+H]+: 866.73. To a solution of 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(cis-4-((tert- butoxycarbonyl)amino)-3-fluoropiperidin-1-yl)-3-(2-(4-methoxybenzyl)-2H-tetrazol-5- yl)benzenesulfinic acid and 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(cis-4-((tert- butoxycarbonyl)amino)-3-fluoropiperidin-1-yl)-3-(1-(4-methoxybenzyl)-1H-tetrazol-5- yl)benzenesulfinic acid (0.32 g, 0.370 mmol) in THF (2.58 mL) were added (S)-tert-butyl (3- amino-2-hydroxypropyl)carbamate (0.141 g, 0.739 mmol), TEA (0.103 mL, 0.739 mmol), and NCS (0.099 g, 0.739 mmol) in sequence at 0 °C under nitrogen. The mixture was stirred at the same temperature for 30 minutes. The reaction mixture was diluted with EtOAc, washed with NaHCO3 solution and brine. The organic layer was dried over MgSO4, evaporated, and the crude product was purified by silica gel column chromatography eluting with 0-100% EtOAc/hexanes to give the title compound. LC/MS [M+H]+: 1054.87. To the solution of tert-butyl (cis-1-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4- (N-((R)-3-((tert-butoxycarbonyl)amino)-2-hydroxypropyl)sulfamoyl)-2-(2-(4-methoxybenzyl)- 2H-tetrazol-5-yl)phenyl)-3-fluoropiperidin-4-yl)carbamate and tert-butyl (cis-1-(3-(N,N-bis(4- methoxybenzyl)sulfamoyl)-4-(N-((R)-3-((tert-butoxycarbonyl)amino)-2- hydroxypropyl)sulfamoyl)-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)phenyl)-3-fluoropiperidin- 4-yl)carbamate (360 mg, 0.341 mmol) in DCM (2.5 mL) was added anisole (0.371 mL, 3.41 mmol) and TFA (2.63 mL, 34.1 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes. After removing the volatile, the residue was dissolved in TFA (5.26 mL, 68.2 mmol). The resulting mixture was stirred at 80 °C for 1.0 hour. After removing the volatile, the residue was purified by reverse phase HPLC (1-25% MeCN/water, 0.1% NH4OH as additive) to give the title compound. LC/MS [M+H]+: 494.41.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2019/18186, 2019, A1 Location in patent: Page/Page column 62-63; 88-90

47
[ 18143-30-1 ]
6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1-sulfonamide [ No CAS ]
[ 824-94-2 ]
3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-(2-(trimethylsilyl)ethylthio)benzenesulfonamide [ No CAS ]
3-iodo-N,N-bis(4-methoxybenzyl)-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)thio)benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1-sulfonamide; p-methoxybenzyl chloride With tetrabutyl-ammonium chloride; potassium carbonate; sodium iodide In chloroform; water at 50℃; Stage #2: 2-trimethylsilylethanethiol With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 5h;	36.I; 37.A Step A: 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-(2- (trimethylsilyl)ethylthio)benzenesulfonamide and 3-iodo-N,N-bis(4-methoxybenzyl)-2-(1-(4- methoxybenzyl)-1H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)thio)benzenesulfonamide Into a 3000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1- sulfonamide (105 g, 244.17 mmol, 1.00 equiv), chloroform (1050 mL), potassium carbonate (168.9 g, 1.22 mol, 5.00 equiv), water (525 mL), NaI (11 g, 0.30 equiv), tetrabutyl(chloro)amine (20.4 g, 73.40 mmol, 0.30 equiv), 1-(chloromethyl)-4-methoxybenzene (230 g, 1.47 mol, 6.00 equiv). The resulting solution was stirred overnight at 50°C in an oil bath. The reaction mixture was cooled to RT. The resulting solution was extracted with 2x1000 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compounds. LC-MS: (ES, m/z): 790 [M+H]+ ; H-NMR: (300MHz, CDCl3, ppm): δ 7.956-7.928 (m, 0.5H), 7.852-7.824 (m, 1H), 7.656-7.612 (m, 1.5H), 7.323- 7.282 (m, 1.5H), 7.195-7.224 (m, 2H), 6.944-6.908 (m, 6H), 6.822-6.760 (m, 9H), 5.791 (m, 1H), 5.570-5.521 (m, 1H), 5.149-5.100 (m, 1H), 4.769-4.718 (m, 2H), 4.232-4.221 (m, 2H), 3.900-3.848 (m, 2H), 3.789-3.742 (m, 14H). 6-bromo-3-iodo-N,N-bis[(4-methoxyphenyl)methyl]-2-[1-[(4- methoxyphenyl)methyl]-1H-1,2,3,4-tetrazol-5-yl]benzene-1-sulfonamide, 6-bromo-3-iodo-N,N- bis[(4-methoxyphenyl)methyl]-2-[2-[(4-methoxyphenyl)methyl]-2H-1,2,3,4-tetrazol-5- yl]benzene-1-sulfonamide (500 mg, 0.633 mmol), 2-(trimethylsilyl)ethanethiol (170 mg, 1.265 mmol) and Cs2CO3 (618 mg, 1.898 mmol) were combined in DMF (1.5 mL). Then the mixture was stirred at RT for 5 hours. Then the mixture was poured onto ether (100 mL) with the organic layer collected and concentrated under vacuum to give the title compounds: LCMS [M + H]+: 844; 1H NMR (300 MHz, CDCl3): δ 4.71-4.40 (m, 1H), 4.13-4.00 (m, 1H), 3.83-3.67 (m, 1H), 2.81-2.72 (m, 1H), 2.32-2.21 (m, 2H), 2.08-1.74 (m, 2H), 1.44 (s, 9H).
	Stage #1: 6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1-sulfonamide; p-methoxybenzyl chloride With tetrabutyl-ammonium chloride; potassium carbonate; sodium iodide In chloroform; water at 50℃; Inert atmosphere; Stage #2: 2-trimethylsilylethanethiol With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 5h;	2.A Step A: 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-(2- (trimethylsilyl)ethylthio)benzenesulfonamide and 3-iodo-N,N-bis(4-methoxybenzyl)-2-(1-(4- methoxybenzyl)-1H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)thio)benzenesulfonamide 6-bromo-3-iodo-N,N-bis[(4-methoxyphenyl)methyl]-2-[1-[(4- methoxyphenyl)methyl]-1H-1,2,3,4-tetrazol-5-yl]benzene-1-sulfonamide, 6-bromo-3-iodo-N,N- bis[(4-methoxyphenyl)methyl]-2-[2-[(4-methoxyphenyl)methyl]-2H-1,2,3,4-tetrazol-5- yl]benzene-1-sulfonamide (500 mg, 0.633 mmol), 2-(trimethylsilyl)ethanethiol (170 mg, 1.265 mmol) and Cs2CO3 (618 mg, 1.898 mmol) were combined in DMF (1.5 mL). Then the mixture was stirred at RT for 5 hr. The mixture was poured onto ether (100 mL) with the organic layer collected and concentrated under vacuum to give the title compounds: LCMS (ESI) calc’d for C36H42IN5O5S2Si [M + H]+: 844, found 844; 1H NMR (300 MHz, CDCl3): δ 4.71-4.40 (m, 1H), 4.13-4.00 (m, 1H), 3.83-3.67 (m, 1H), 2.81-2.72 (m, 1H), 2.32-2.21 (m, 2H), 2.08-1.74 (m, 2H), 1.44 (s, 9H).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2019/18186, 2019, A1 Location in patent: Page/Page column 62-63
[2]Current Patent Assignee: MERCK & CO INC - WO2019/135920, 2019, A1 Location in patent: Page/Page column 34-35

48
[ 18143-30-1 ]
6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1-sulfonamide [ No CAS ]
[ 824-94-2 ]
3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-(2-(trimethylsilyl)ethylsulfonyl)benzenesulfonamide [ No CAS ]
3-iodo-N,N-bis(4-methoxybenzyl)-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1-sulfonamide; p-methoxybenzyl chloride With tetrabutyl-ammonium chloride; potassium carbonate; sodium iodide In chloroform; water at 50℃; Stage #2: 2-trimethylsilylethanethiol With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 5h; Stage #3: With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 4h;	36.I; 37.A; 37.B Step B: 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-(2- (trimethylsilyl)ethylsulfonyl)benzenesulfonamide and 3-iodo-N,N-bis(4-methoxybenzyl)-2-(1- (4-methoxybenzyl)-1H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide Into a 3000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1- sulfonamide (105 g, 244.17 mmol, 1.00 equiv), chloroform (1050 mL), potassium carbonate (168.9 g, 1.22 mol, 5.00 equiv), water (525 mL), NaI (11 g, 0.30 equiv), tetrabutyl(chloro)amine (20.4 g, 73.40 mmol, 0.30 equiv), 1-(chloromethyl)-4-methoxybenzene (230 g, 1.47 mol, 6.00 equiv). The resulting solution was stirred overnight at 50°C in an oil bath. The reaction mixture was cooled to RT. The resulting solution was extracted with 2x1000 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compounds. LC-MS: (ES, m/z): 790 [M+H]+ ; H-NMR: (300MHz, CDCl3, ppm): δ 7.956-7.928 (m, 0.5H), 7.852-7.824 (m, 1H), 7.656-7.612 (m, 1.5H), 7.323- 7.282 (m, 1.5H), 7.195-7.224 (m, 2H), 6.944-6.908 (m, 6H), 6.822-6.760 (m, 9H), 5.791 (m, 1H), 5.570-5.521 (m, 1H), 5.149-5.100 (m, 1H), 4.769-4.718 (m, 2H), 4.232-4.221 (m, 2H), 3.900-3.848 (m, 2H), 3.789-3.742 (m, 14H). 6-bromo-3-iodo-N,N-bis[(4-methoxyphenyl)methyl]-2-[1-[(4- methoxyphenyl)methyl]-1H-1,2,3,4-tetrazol-5-yl]benzene-1-sulfonamide, 6-bromo-3-iodo-N,N- bis[(4-methoxyphenyl)methyl]-2-[2-[(4-methoxyphenyl)methyl]-2H-1,2,3,4-tetrazol-5- yl]benzene-1-sulfonamide (500 mg, 0.633 mmol), 2-(trimethylsilyl)ethanethiol (170 mg, 1.265 mmol) and Cs2CO3 (618 mg, 1.898 mmol) were combined in DMF (1.5 mL). Then the mixture was stirred at RT for 5 hours. Then the mixture was poured onto ether (100 mL) with the organic layer collected and concentrated under vacuum to give the title compounds: LCMS [M + H]+: 844; 1H NMR (300 MHz, CDCl3): δ 4.71-4.40 (m, 1H), 4.13-4.00 (m, 1H), 3.83-3.67 (m, 1H), 2.81-2.72 (m, 1H), 2.32-2.21 (m, 2H), 2.08-1.74 (m, 2H), 1.44 (s, 9H). 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6- ((2-(trimethylsilyl)ethyl)thio)benzenesulfonamide (480 mg, 0.569 mmol) and m-CPBA (491 mg, 2.84 mmol) were combined in dichloromethane (2 mL). The mixture was stirred at RT for 4 hours. The resulting mixture was poured onto ether (200 mL) and washed with brine (150 mL). The organic layers were collected, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was applied on a silica gel column with EA/PE (1/3) to give the title compounds: LCMS [M + H]+: 876; 1H NMR (300 MHz, CDCl3): δ 8.62 (d, J = 8.7 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 7.90-7.88 (m, 1H), 7.69-7.68 (m, 0.5H), 7.56-7.53 (m, 0.5H), 7.27-7.20 (m, 2H), 6.91-6.79 (m, 12H), 5.44-5.39 (m, 1H), 5.20-5.15 (m, 1H), 4.58-4.53 (m, 2H), 3.98-3.79 (m, 2H), 3.75-3.66 (m, 9H), 2.50-2.48 (m, 2H), 1.19-1.03 (m, 1H), 0.83-0.82 (m, 1H), 0.01 (s, 9H).
	Stage #1: 6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1-sulfonamide; p-methoxybenzyl chloride With tetrabutyl-ammonium chloride; potassium carbonate; sodium iodide In chloroform; water at 50℃; Inert atmosphere; Stage #2: 2-trimethylsilylethanethiol With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 5h; Stage #3: With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 4h;	2.B Step B: 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6- (2-(trimethylsilyl)ethylsulfonyl)benzenesulfonamide and 3-iodo-N,N-bis(4-methoxybenzyl)-2- (1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6- ((2-(trimethylsilyl)ethyl)thio)benzenesulfonamide (480 mg, 0.569 mmol) and m-CPBA (491 mg, 2.84 mmol) were combined in dichloromethane (2 mL). Then the mixture was stirred at RT for 4 hr. The resulting mixture was poured onto ether(200 mL). Then the mixture was washed with brine (150 mL). The organic layers were collected, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was then applied on a silica gel column with EA/PE (1/3) to give the title compounds: LCMS (ESI) calc’d for C36H42IN5O7S2Si [M + H]+: 876, found 876; 1H NMR (300 MHz, CDCl3): δ 8.62 (d, J = 8.7 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 7.90-7.88 (m, 1H), 7.69-7.68 (m, 0.5H), 7.56-7.53 (m, 0.5H), 7.27-7.20 (m, 2H), 6.91-6.79 (m, 12H), 5.44- 5.39 (m, 1H), 5.20-5.15 (m, 1H), 4.58-4.53 (m, 2H), 3.98-3.79 (m, 2H), 3.75-3.66 (m, 9H), 2.50- 2.48 (m, 2H), 1.19-1.03 (m, 1H), 0.83-0.82 (m, 1H), 0.01 (s, 9H).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2019/18186, 2019, A1 Location in patent: Page/Page column 62-63
[2]Current Patent Assignee: MERCK & CO INC - WO2019/135920, 2019, A1 Location in patent: Page/Page column 35

49
[ 18143-30-1 ]
6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1-sulfonamide [ No CAS ]
[ 824-94-2 ]
2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfinic acid [ No CAS ]
2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfinic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1-sulfonamide; p-methoxybenzyl chloride With tetrabutyl-ammonium chloride; potassium carbonate; sodium iodide In chloroform; water at 50℃; Stage #2: 2-trimethylsilylethanethiol With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 5h; Further stages;	36.I; 37.A-37.B; 38 REFERENCE EXAMPLE 38 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5- yl)benzenesulfinic acid and 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4- methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfinic acid Into a 3000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1- sulfonamide (105 g, 244.17 mmol, 1.00 equiv), chloroform (1050 mL), potassium carbonate (168.9 g, 1.22 mol, 5.00 equiv), water (525 mL), NaI (11 g, 0.30 equiv), tetrabutyl(chloro)amine (20.4 g, 73.40 mmol, 0.30 equiv), 1-(chloromethyl)-4-methoxybenzene (230 g, 1.47 mol, 6.00 equiv). The resulting solution was stirred overnight at 50°C in an oil bath. The reaction mixture was cooled to RT. The resulting solution was extracted with 2x1000 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compounds. LC-MS: (ES, m/z): 790 [M+H]+ ; H-NMR: (300MHz, CDCl3, ppm): δ 7.956-7.928 (m, 0.5H), 7.852-7.824 (m, 1H), 7.656-7.612 (m, 1.5H), 7.323- 7.282 (m, 1.5H), 7.195-7.224 (m, 2H), 6.944-6.908 (m, 6H), 6.822-6.760 (m, 9H), 5.791 (m, 1H), 5.570-5.521 (m, 1H), 5.149-5.100 (m, 1H), 4.769-4.718 (m, 2H), 4.232-4.221 (m, 2H), 3.900-3.848 (m, 2H), 3.789-3.742 (m, 14H). 6-bromo-3-iodo-N,N-bis[(4-methoxyphenyl)methyl]-2-[1-[(4- methoxyphenyl)methyl]-1H-1,2,3,4-tetrazol-5-yl]benzene-1-sulfonamide, 6-bromo-3-iodo-N,N- bis[(4-methoxyphenyl)methyl]-2-[2-[(4-methoxyphenyl)methyl]-2H-1,2,3,4-tetrazol-5- yl]benzene-1-sulfonamide (500 mg, 0.633 mmol), 2-(trimethylsilyl)ethanethiol (170 mg, 1.265 mmol) and Cs2CO3 (618 mg, 1.898 mmol) were combined in DMF (1.5 mL). Then the mixture was stirred at RT for 5 hours. Then the mixture was poured onto ether (100 mL) with the organic layer collected and concentrated under vacuum to give the title compounds: LCMS [M + H]+: 844; 1H NMR (300 MHz, CDCl3): δ 4.71-4.40 (m, 1H), 4.13-4.00 (m, 1H), 3.83-3.67 (m, 1H), 2.81-2.72 (m, 1H), 2.32-2.21 (m, 2H), 2.08-1.74 (m, 2H), 1.44 (s, 9H). 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6- ((2-(trimethylsilyl)ethyl)thio)benzenesulfonamide (480 mg, 0.569 mmol) and m-CPBA (491 mg, 2.84 mmol) were combined in dichloromethane (2 mL). The mixture was stirred at RT for 4 hours. The resulting mixture was poured onto ether (200 mL) and washed with brine (150 mL). The organic layers were collected, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was applied on a silica gel column with EA/PE (1/3) to give the title compounds: LCMS [M + H]+: 876; 1H NMR (300 MHz, CDCl3): δ 8.62 (d, J = 8.7 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 7.90-7.88 (m, 1H), 7.69-7.68 (m, 0.5H), 7.56-7.53 (m, 0.5H), 7.27-7.20 (m, 2H), 6.91-6.79 (m, 12H), 5.44-5.39 (m, 1H), 5.20-5.15 (m, 1H), 4.58-4.53 (m, 2H), 3.98-3.79 (m, 2H), 3.75-3.66 (m, 9H), 2.50-2.48 (m, 2H), 1.19-1.03 (m, 1H), 0.83-0.82 (m, 1H), 0.01 (s, 9H). A solution of 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H- tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide (1.0 g, 1.14 mmol) in tetrahydrofuran (10 mL) was stirred with tetrabutylammonium fluoride (1.194 g, 4.57 mmol) at RT under N2 for 0.5 hour. The mixture was diluted with ethyl acetate, washed with sat’d KHSO4 aqueous, dried over MgSO4, and concentrated under vacuum to get the crude product as a solid. The crude material was used directly for the next step: LCMS [M + H]+: 776; 1H NMR (300 MHz, CDCl3): δ 4.87-4.60 (bs, 1H), 4.36-4.21 (bs, 1H), 3.96-3.90 (m, 1H), 2.87-2.83 (m, 1H), 2.46-2.29 (m, 2H), 2.27 (d, J = 1.2 Hz, 3H), 1.95-1.91 (m, 1H), 1.43 (s, 9H).
	Stage #1: 6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1-sulfonamide; p-methoxybenzyl chloride With tetrabutyl-ammonium chloride; potassium carbonate; sodium iodide In chloroform; water at 50℃; Inert atmosphere; Stage #2: 2-trimethylsilylethanethiol With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 5h; Further stages;	3 REFERENCE EXAMPLE 3 (0215) 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5- yl)benzenesulfinic acid and 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4- methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfinic acid A solution of 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H- tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide (1.0 g, 1.14 mmol) in tetrahydrofuran (10 mL) was stirred with tetrabutylammonium fluoride (1.194 g, 4.57 mmol) at room temperature under N2 for 0.5 hr. LCMS showed the desired mass of 776. The mixture was diluted with ethyl acetate, washed with saturated KHSO4 aqueous, dried over MgSO4, and concentrated under vacuum to provide the crude product. The crude material was used directly for the next step: LCMS (ESI) calc’d for C31H30IN5O7S2 [M + H]+: 776, found 776; 1 NMR (300 MHz, CDCl3): δ 4.87-4.60 (bs, 1H), 4.36-4.21 (bs, 1H), 3.96-3.90 (m, 1H), 2.87-2.83 (m, 1H), 2.46-2.29 (m, 2H), 2.27 (d, J = 1.2 Hz, 3H), 1.95-1.91 (m, 1H), 1.43 (s, 9H).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2019/18186, 2019, A1 Location in patent: Page/Page column 62-64
[2]Current Patent Assignee: MERCK & CO INC - WO2019/135920, 2019, A1 Location in patent: Page/Page column 35

50
[ 18143-30-1 ]
6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1-sulfonamide [ No CAS ]
[ 824-94-2 ]
2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfonyl chloride [ No CAS ]
2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonyl chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1-sulfonamide; p-methoxybenzyl chloride With tetrabutyl-ammonium chloride; potassium carbonate; sodium iodide In chloroform; water at 50℃; Stage #2: 2-trimethylsilylethanethiol With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 5h; Further stages;	36.I; 37.A-37.B; 38-39 REFERENCE EXAMPLE 39 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5- yl)benzenesulfonyl chloride and 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4- methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonyl chloride Into a 3000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1- sulfonamide (105 g, 244.17 mmol, 1.00 equiv), chloroform (1050 mL), potassium carbonate (168.9 g, 1.22 mol, 5.00 equiv), water (525 mL), NaI (11 g, 0.30 equiv), tetrabutyl(chloro)amine (20.4 g, 73.40 mmol, 0.30 equiv), 1-(chloromethyl)-4-methoxybenzene (230 g, 1.47 mol, 6.00 equiv). The resulting solution was stirred overnight at 50°C in an oil bath. The reaction mixture was cooled to RT. The resulting solution was extracted with 2x1000 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compounds. LC-MS: (ES, m/z): 790 [M+H]+ ; H-NMR: (300MHz, CDCl3, ppm): δ 7.956-7.928 (m, 0.5H), 7.852-7.824 (m, 1H), 7.656-7.612 (m, 1.5H), 7.323- 7.282 (m, 1.5H), 7.195-7.224 (m, 2H), 6.944-6.908 (m, 6H), 6.822-6.760 (m, 9H), 5.791 (m, 1H), 5.570-5.521 (m, 1H), 5.149-5.100 (m, 1H), 4.769-4.718 (m, 2H), 4.232-4.221 (m, 2H), 3.900-3.848 (m, 2H), 3.789-3.742 (m, 14H). 6-bromo-3-iodo-N,N-bis[(4-methoxyphenyl)methyl]-2-[1-[(4- methoxyphenyl)methyl]-1H-1,2,3,4-tetrazol-5-yl]benzene-1-sulfonamide, 6-bromo-3-iodo-N,N- bis[(4-methoxyphenyl)methyl]-2-[2-[(4-methoxyphenyl)methyl]-2H-1,2,3,4-tetrazol-5- yl]benzene-1-sulfonamide (500 mg, 0.633 mmol), 2-(trimethylsilyl)ethanethiol (170 mg, 1.265 mmol) and Cs2CO3 (618 mg, 1.898 mmol) were combined in DMF (1.5 mL). Then the mixture was stirred at RT for 5 hours. Then the mixture was poured onto ether (100 mL) with the organic layer collected and concentrated under vacuum to give the title compounds: LCMS [M + H]+: 844; 1H NMR (300 MHz, CDCl3): δ 4.71-4.40 (m, 1H), 4.13-4.00 (m, 1H), 3.83-3.67 (m, 1H), 2.81-2.72 (m, 1H), 2.32-2.21 (m, 2H), 2.08-1.74 (m, 2H), 1.44 (s, 9H). 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6- ((2-(trimethylsilyl)ethyl)thio)benzenesulfonamide (480 mg, 0.569 mmol) and m-CPBA (491 mg, 2.84 mmol) were combined in dichloromethane (2 mL). The mixture was stirred at RT for 4 hours. The resulting mixture was poured onto ether (200 mL) and washed with brine (150 mL). The organic layers were collected, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was applied on a silica gel column with EA/PE (1/3) to give the title compounds: LCMS [M + H]+: 876; 1H NMR (300 MHz, CDCl3): δ 8.62 (d, J = 8.7 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 7.90-7.88 (m, 1H), 7.69-7.68 (m, 0.5H), 7.56-7.53 (m, 0.5H), 7.27-7.20 (m, 2H), 6.91-6.79 (m, 12H), 5.44-5.39 (m, 1H), 5.20-5.15 (m, 1H), 4.58-4.53 (m, 2H), 3.98-3.79 (m, 2H), 3.75-3.66 (m, 9H), 2.50-2.48 (m, 2H), 1.19-1.03 (m, 1H), 0.83-0.82 (m, 1H), 0.01 (s, 9H). A solution of 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H- tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide (1.0 g, 1.14 mmol) in tetrahydrofuran (10 mL) was stirred with tetrabutylammonium fluoride (1.194 g, 4.57 mmol) at RT under N2 for 0.5 hour. The mixture was diluted with ethyl acetate, washed with sat’d KHSO4 aqueous, dried over MgSO4, and concentrated under vacuum to get the crude product as a solid. The crude material was used directly for the next step: LCMS [M + H]+: 776; 1H NMR (300 MHz, CDCl3): δ 4.87-4.60 (bs, 1H), 4.36-4.21 (bs, 1H), 3.96-3.90 (m, 1H), 2.87-2.83 (m, 1H), 2.46-2.29 (m, 2H), 2.27 (d, J = 1.2 Hz, 3H), 1.95-1.91 (m, 1H), 1.43 (s, 9H). 2-(N, N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H- tetrazol-5-yl)benzenesulfinic acid (800 mg, 1.031 mmol) in tetrahydrofuran (10 mL) was cooled to 0°C. 1-chloropyrrolidine-2,5-dione (275 mg, 2.063 mmol) in tetrahydrofuran (2 mL) was added over 5 minutes. The mixture was stirred at the same temperature for 30 minutes, then diluted with ethyl acetate, washed with sat’d NaHCO3 and brine, dried over MgSO4, and concentrated to get the crude product: LCMS [M + H]+: 810.
	Stage #1: 6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1-sulfonamide; p-methoxybenzyl chloride With tetrabutyl-ammonium chloride; potassium carbonate; sodium iodide In chloroform; water at 50℃; Inert atmosphere; Stage #2: 2-trimethylsilylethanethiol With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 5h; Further stages;	4 REFERENCE EXAMPLE 4 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5- yl)benzenesulfonyl chloride and 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4- methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonyl chloride 2-(N, N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H- tetrazol-5-yl)benzenesulfinic acid (800 mg, 1.031 mmol) in tetrahydrofuran (10 mL) was cooled to 0oC. 1-chloropyrrolidine-2,5-dione (275 mg, 2.063 mmol) in tetrahydrofuran (2 mL) was added over 5 min. The mixture was stirred at the same temperature for 30 min, and monitored by LCMS (a small amount SM is still shown), then diluted with ethyl acetate, washed with saturated NaHCO3 and brine, dried over MgSO4, and concentrated to get the crude product: LCMS (ESI) calc’d for C31H29ClIN5O7S2 [M + H]+: 810, found 810.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2019/18186, 2019, A1 Location in patent: Page/Page column 62-64
[2]Current Patent Assignee: MERCK & CO INC - WO2019/135920, 2019, A1 Location in patent: Page/Page column 35-36

51
[ 18143-30-1 ]
N,N-dibenzyl-3-bromo-6-fluoro-2-(2H-tetrazol-5-yl)benzenesulfonamide [ No CAS ]
N,N-dibenzyl-3-bromo-2-(2H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)thio)benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-trimethylsilylethanethiol With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: N,N-dibenzyl-3-bromo-6-fluoro-2-(2H-tetrazol-5-yl)benzenesulfonamide In N,N-dimethyl-formamide; mineral oil at 20℃; for 1h;	51.A Step A: N,N-dibenzyl-3-bromo-2-(2H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)thio)benzenesulfonamide To a mixture of NaH (10.75 g, 0.27 mol, 60% in mineral oil) in DMF (500 mL) was added 2-(trimethylsilyl)ethanethiol (30.10 g, 0.22 mol) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 0.5 hours under nitrogen. Then N,N-dibenzyl-3-bromo-6-fluoro-2-(2H- tetrazol-5-yl)benzenesulfonamide (REFERENCE EXAMPLE 50- Step F) (45.0 g, 0.09 mol) was added slowly into the resulting mixture at RT. The reaction mixture was stirred at RT for 1 hour. The resulting mixture was used in the next step without further purification: LCMS [M + H]+: 616, 618.
	Stage #1: 2-trimethylsilylethanethiol With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: N,N-dibenzyl-3-bromo-6-fluoro-2-(2H-tetrazol-5-yl)benzenesulfonamide In N,N-dimethyl-formamide; mineral oil at 20℃; for 1h;	10.A Step A: N,N-dibenzyl-3-bromo-2- etrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)thio) benzenesulfonamide To a mixture of NaH (10.75 g, 0.27 mol, 60% in mineral oil) in DMF (500 mL) was added 2-(trimethylsilyl)ethanethiol (30.10 g, 0.22 mol) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 0.5 h under nitrogen. Then N,N-dibenzyl-3-bromo-6-fluoro-2-(2H- tetrazol-5-yl)benzenesulfonamide (Reference example 8 Step F) (45.0 g, 0.09 mol) was added slowly into the resulting mixture at room temperature. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was used in the next step directly without further purification: LCMS (ESI) calc’d for C26H30BrN5O2S2Si [M + H]+: 616, 618, found 616, 618.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2019/18186, 2019, A1 Location in patent: Page/Page column 76
[2]Current Patent Assignee: MERCK & CO INC - WO2019/135920, 2019, A1 Location in patent: Page/Page column 41-42

52
[ 18143-30-1 ]
3-bromo-6-fluoro-N,N-bis(4-methoxybenzyl)-2-(2H-tetrazol-5-yl)benzenesulfonamide [ No CAS ]
3-bromo-N,N-bis(4-methoxybenzyl)-2-(2H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)thio)benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In 1-methyl-pyrrolidin-2-one at 20℃; for 36h;	61.C Step C: 3-bromo-N,N-bis(4-methoxybenzyl)-2-(2H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl) thio)benzenesulfonamide To a flask were added 3-bromo-6-fluoro-N,N-bis(4-methoxybenzyl)-2-(2H- tetrazol-5-yl)benzenesulfonamide (14.2 g, 25.2 mmol), cesium carbonate (16.45 g, 50.5 mmol) and NMP (71 ml) followed by 2-(trimethylsilyl)ethanethiol (6.06 ml, 37.9 mmol). The reaction mixture was stirred at RT for 36 hours. The reaction was poured into a mixture of 300ml EtOAc, 100 ml 2N HOAc and 100 ml water. The organic layer was separated and washed sequentially with 2 x 100 ml 10% aq. LiCl, followed by brine then dried over Na2SO4, filtered and concentrated. The crude material was chromatographed on silica (gradient elution 0 to 100% EtOAc in hexanes) to provide the title compound.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2019/18186, 2019, A1 Location in patent: Page/Page column 84; 85

53
[ 233278-56-3 ]
[ 18143-30-1 ]
6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1-sulfonamide [ No CAS ]
[ 824-94-2 ]
[ 147081-49-0 ]
tert-butyl (R)-3-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(5,6-dihydro[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenyl)sulfonamido)pyrrolidine-1-carboxylate [ No CAS ]
tert-butyl (R)-3-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(5,6-dihydro[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-3-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)phenyl)sulfonamido)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A flask was charged with tert-butyl (R)-3-((2-(N,N-bis(4- methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4-methoxybenzyl)-1H-tetrazol-5- yl)phenyl)sulfonamido)pyrrolidine-1-carboxylate and tert-butyl (R)-3-((2-(N,N-bis(4- methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5- yl)phenyl)sulfonamido)pyrrolidine-1-carboxylate (REFERENCE EXAMPLE 5) (0.15 g, 0.156 mmol), <strong>[233278-56-3]5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine</strong> (0.039 g, 0.313 mmol), Cs2CO3 (0.153 g, 0.469 mmol) and rac-BINAP-Pd-G3 precatalyst (0.031 g, 0.031 mmol). The vial was sealed, degassed with N2, and filled with DME (1.6 mL). The resulting mixture was heated overnight at 80 C. The reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated and the residue was purified by silica gel column chromatography using (0-10%) MeOH/DCM as the mobile phase to afford the title compound. LC/MS [M+H]+: 956.81.

Reference： [1]Patent: WO2019/135920,2019,A1 .Location in patent: Page/Page column 48

54
[ 233278-56-3 ]
[ 18143-30-1 ]
6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1-sulfonamide [ No CAS ]
[ 824-94-2 ]
[ 147081-49-0 ]
(R)-4-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-N₁-(pyrrolidin-3-yl)-3-(2H-tetrazol-5-yl)benzene-1,2-disulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To the solution of tert-butyl (R)-3-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4- (5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-3-(2-(4-methoxybenzyl)-2H-tetrazol-5- yl)phenyl)sulfonamido)pyrrolidine-1-carboxylate and tert-butyl (R)-3-((2-(N,N-bis(4- methoxybenzyl)sulfamoyl)-4-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-3-(1-(4- methoxybenzyl)-1H-tetrazol-5-yl)phenyl)sulfonamido)pyrrolidine-1-carboxylate (70 mg, 0.073 mmol) in DCM (2.5 mL) was added anisole (0.080 mL, 0.732 mmol) and TFA (0.56 mL, 7.32 mmol) at 0 C. The reaction mixture was stirred at 0 C for 30 min. After removing the volatiles under vacuum, the residue was dissolved in TFA (2.24 mL, 29.3 mmol). The resulting mixture was stirred at 80 C for 1.0 h. After removing the volatiles under vacuum the residue was purified by reverse phase HPLC (gradient 3-30% MeCN/water as eluent, 0.1% NH4OH as additive) to give title compound. LC/MS [M+H]+: 496.50.

Reference： [1]Patent: WO2019/135920,2019,A1 .Location in patent: Page/Page column 48

55
[ 297172-19-1 ]
[ 18143-30-1 ]
6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1-sulfonamide [ No CAS ]
[ 824-94-2 ]
[ 147081-49-0 ]
tert-butyl (R)-3-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenyl)sulfonamido)pyrrolidine-1-carboxylate [ No CAS ]
tert-butyl (R)-3-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)-3-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)phenyl)sulfonamido)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A flask was charged with tert-butyl (R)-3-((2-(N,N-bis(4- methoxybenzyl)sulfamoyl)-4-iodo-3-(1-(4-methoxybenzyl)-1H-tetrazol-5- yl)phenyl)sulfonamido)pyrrolidine-1-carboxylate and tert-butyl (R)-3-((2-(N,N-bis(4- methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5- yl)phenyl)sulfonamido)pyrrolidine-1-carboxylate (REFERENCE EXAMPLE 5) (0.15 g, 0.156 mmol), <strong>[297172-19-1]5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine</strong> (0.038 g, 0.313 mmol), Cs2CO3 (0.153 g, 0.469 mmol) and Pd(dppf)Cl2 (0.023 g, 0.031 mmol). The vial was sealed, degassed with N2, and filled with DME (1.56 mL). The resulting mixture was heated overnight at 80 C. The reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated and the residue purified by silica gel column chromatography using (gradient 0-10%) MeOH in DCM as the mobile phase to afford the title compound. LC/MS [M+H]+: 955.82.

Reference： [1]Patent: WO2019/135920,2019,A1 .Location in patent: Page/Page column 49

56
[ 18143-30-1 ]
[ 130575-43-8 ]
(S)-N,N-dibenzyl-3-((2-(trimethylsilyl)ethyl)thio)butanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With C₁₀₂H₁₅₈N₂P₂ In ethyl acetate at 20℃; for 24h; enantioselective reaction;

Reference： [1]Dixon, Darren J.; Formica, Michele; Hamlin, Trevor A.; Rozsar, Daniel; Yamazaki, Ken [Journal of the American Chemical Society, 2022, vol. 144, # 2, p. 1006 - 1015]

57
[ 18143-30-1 ]
[ 1268338-99-3 ]
3,6-dicarboxy-2-((2-(trimethylsilyl)ethyl)thio)pyridine 1-oxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66.2%	With sodium methoxide In methanol at 68℃; for 3.5h; Inert atmosphere;	2 3,6-Dicarboxy-2-((2-(trimethylsilyl)ethyl)thio)pyridine l-oxide 9. 3,6-Dicarboxy-2- chloropyridine 1-oxide 8 (500 mg, 2.30 mmol) was dried overnight in a 100 mL flask equipped with a condenser and stir bar. Methanol (20 mL) was added to form a solution, and 2- (trimethylsilyl)ethanethiol (460 pL, 2.87 mmol) was added via syringe under an inert atmosphere. Sodium methoxide (30% by weight in methanol, 1.66 mL, 9.2 mmol) was added, and the solution was heated at 68 °C for 3.5 hr. Solvents were removed under reduced pressure, and the residue was dried overnight in vacuo. The residue was dissolved in 20 mL water, and IN HC1 (ca. 10 mL) was added to form a precipitate. The precipitate was filtered, washed with water (ca. 20 mL) and dried in vacuo to provide compound 9 (480 mg, 66.2%) as a dusty powder. HRMS-pESI: Calc, for C HieNOsSSi (M-H)’, 314.0524; found, 314.0524.

Reference： [1]Current Patent Assignee: LUMIPHORE INC - WO2022/87317, 2022, A1 Location in patent: Paragraph 00143; 00144

58
[ 18143-30-1 ]
[ 94781-88-1 ]
2-carboxy-6-((2-(trimethylsilyl)ethyl)thio)pyridine 1-oxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92.7%	With sodium methoxide In methanol at 68℃; for 4.5h; Inert atmosphere;	1 2-Carboxy-6-((2-(trimethylsilyl)ethyl)thio)pyridine l-oxide 2. 2-Bromo-6- carb oxy pyridine 1 -oxide 1 (500 mg, 2.29 mmol) was dried overnight in a 100 mL flask equipped with a condenser and stir bar. Methanol (20 mL) was added to form a solution, and 2- (trimethylsilyl)ethanethiol (459 pL, 2.86 mmol) was added via syringe under an inert atmosphere. Sodium methoxide (30% by weight in methanol, 1.24 mL, 6.87 mmol) was added, and the solution was heated at 68 °C for 4.5 hr. Solvents were removed under reduced pressure, and the residue was dried overnight in vacuo. The residue was dissolved in 20 mL water, and IN HC1 (ca. 10 mL) was added to form a precipitate. The precipitate was filtered, washed with water (ca. 10 mL) and dried in vacuo to provide compound 2 (576 mg, 92.7%) as a dusty powder. HRMS-pESI: Calc, for CnHieNChSSi (M-H); 270.0626; found, 270.0626.

Reference： [1]Current Patent Assignee: LUMIPHORE INC - WO2022/87317, 2022, A1 Location in patent: Paragraph 00137; 00138

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+
Accessible (Haz class 3, 4, 5 or 8), Domestic	USD 100+
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{[ 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. :	18143-30-1	MDL No. :	MFCD00077888
Formula :	C₅H₁₄SSi	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BCOLNMGFOWHFNI-UHFFFAOYSA-N
M.W :	134.32	Pubchem ID :	205521
Synonyms :

Signal Word:	Danger	Class:	3
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Hazard Statements:	H225-H315-H319-H335	Packing Group:	Ⅲ
GHS Pictogram:

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[ CAS No. 18143-30-1 ] {[proInfo.proName]}

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[ 18143-30-1 ] Synthesis Path-Downstream 1~58

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