Name: 927-58-2|4-Bromobutyryl chloride|95%
Brand: Ambeed
SKU: A708194
Price: 9.0 USD
Availability: InStock
Rating: 98 (26 reviews)

1
[ 2623-87-2 ]
[ 927-58-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 4h;	1 Step 1: Preparation of 4-bromobutanoyl chloride Into a 250-mL round-bottom flask, was placed 4-bromobutanoic acid (10.0 g, 59.88 mmol, 1.00 equiv), dichloromethane (100 mL), N,N-dimethylformamide (0.15 mL). This was followed by the addition of thionyl chloride (8.5 mL) dropwise with stirring at 0. The resulting solution was stirred for 4 h at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 11.08 g (100%) of 4-bromobutanoyl chloride as light yellow oil.
79%	With thionyl chloride at 70℃; for 3h; Heating;
	With thionyl chloride

	With pyridine; thionyl chloride In 1,2-dichloro-ethane
	With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran at 0℃; for 1h;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 16h;
	With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 40℃; for 1h;
	With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 3h;	4 SOCl2 (1.60 mL, 21.6 mmol) and a few drops of dry DMF were added to a solution of 4-bromobutyrric acid (3.00 g, 18.0 mmol) in dry CH2Cl2 (40 mL) , stirred under N2 at r.t. The stirring was continued for 3 h at r.t. The solution of the acyl chloride so obtained was slowly added to a stirred solution of salycilic aldehyde (1.73 mL, 14.4 mmol) and dry Pyridine (2.20 mL, 27.0 mmol) in dry CH2Cl2 (40 mL) , kept under N2, at 0 0C. The reaction was allowed to reach r.t. and was completed after 2 h. The mixture was washed with HCl 2M (3 x 30 mL) . The organic layer was dried with MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (PE/EtOAc 90/10 v/v) to give the title compound as pale yellow oil (3.54g) . Yield 80 %. TLC: Rf = 0.67 PE/EtOAc 80/20 v/v1H-NMR (CDCl3) δ 2.34-2.36 (2H, m) , 2.87-2.92 (2H, m) , 3.55-3.60 (2H, m) , 7.18 (IH, d, Arom ), 7.43 (IH, t, Arom ), 7.66 (IH, t, Arom ), 7.88 (IH, d, Arom ), 10.1 (IH, s br) . 13C-NMR (CDCl3) δ 27.4, 32.3, 32.5, 123.5, 126.5, 132.0, 134.8, 151.0, 171.0, 188.9. MS (CI) m/z 271/273 (M+l)+.
	With thionyl chloride at 20℃; for 1h;
	With oxalyl dichloride In dichloromethane at 20℃; for 1.75h;	1 Preparation of 4-bromobutyryl chlorideTo a solution of 4-bromobutyric acid (2.00 g, 12.0 mmol, 1.2 eq.) in DCM (40 mL) was added oxalyl chloride (2 M in dichloroethane, 36 mL, 18 mmol, 1.8 eq.) and catalytic DMF (20 μL). The mixture was stirred at room temperature for 1.75 hours and the solvent was removed via rotary evaporation to provide 4- bromobutyryl chloride (high vacuum was not used to dry the product due to its potential volatility). The crude material was used immediately in the next step without further purification.
	With oxalyl dichloride In dichloromethane at 20℃; for 4h;	4 Preparation of 2-(4-bromobutanamido)-7V-(4-fluorobenzyl)-4-methylthiazole-5- carboxamideTo a solution of 4-bromobutanoic acid (4.40 g, 26.0 mmol) in anhydrous dichloromethane (100 mL) was added two drops of λ/,iV'-dimethylformamide, followed by the addition of oxalyl chloride (4.99 g, 39.0 mmol) dropwise. The reaction was stirred at ambient temperature for 4 hours. The solvent was removed in vacuo to afford 4- bromobutanoyl chloride (4.87 g, 26.0 mmol) as a yellow oil, which was used in the next step without further purification.
	With thionyl chloride In dichloromethane at 20℃; for 2h;
	With thionyl chloride for 3h; Reflux;
	With oxalyl dichloride In dichloromethane at 20℃; for 5h;	41.1 Step 1 A solution of 4-bromobutanoic acid (25.0 g, 150 mmol), DMF (5 drops) and oxalyl chloride (17.0 mL, 195.0 mmol) in dichloromethane (250 mL) was stirred at room temperature for 5 hr. The reaction mixture was concentrated under reduced pressure, dichloromethane (200 mL) and ethanol (9.0 mL, 170 mmol) were added to the residue, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was washed with saturated aqueous sodium hydrogencarbonate and saturated brine, and the organic layer was dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (0 - 5% ethyl acetate/hexane) to give ethyl 4-bromobutanoate as a colorless oil (24.5 g, 84%).
	With thionyl chloride In chloroform at 20℃; for 24h;
	With oxalyl dichloride In dichloromethane at 25℃; Inert atmosphere;
	With thionyl chloride for 0.5h; Cooling with ice;
	With oxalyl dichloride at 20℃; for 0.75h; Inert atmosphere;	General procedure for the synthesis of ?-bromo-N-(4-bromophenyl)alkanamides (10a-e) General procedure: The appropriate ω-bromoalkanoic acid (1 mmol) was suspended in oxalyl chloride (ca. 2 mL), stirred at ambient temperature for 45 min, and the excess oxalyl chloride evaporated under reduced pressure. The residue was dissolved in CH2Cl2 (10 mL), cooled to -78 °C, and treated dropwise with a solution of 4-bromoaniline (1.1 mmol) and Et3N (1.1 mmol) in CH2Cl2 (11 mL). The mixture was warmed to ambient temperature, stirred for 1 h, and CH2Cl2 (50 mL) was added. The solution was washed with H2O (50 mL), 1 M aq. HCl (50 mL), sat. aq. Na2CO3 (50 mL), brine (50 mL), dried (MgSO4), and the solvent evaporated under reduced pressure to give crude amides 10a-10e.
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere;
	With thionyl chloride at 75℃; Inert atmosphere;	General procedure for preparation of bromoacyl esters (8c and 8d) through acid chlorides (7c, 7d: 5-bromovaleric acid (1 equiv) or 4-bromobutyric acid (1 equiv) was dissolved in thionyl chloride (4.5 equiv). The reaction mixture was then heated (75 C, oil bath) under a nitrogen atmosphere overnight. The excess thionyl chloride was removed by adding dichloromethane (25 mL) followed by rotary evaporation under aspirator vacuum. The addition of the dichloromethane and rotary evaporation was repeated (3 ) which yielded the crude acid chloride as an oil. The 5-bromobutyryl chloride 7c or the 4- bromovaleryl chloride 7d were used without further purification in the next step. Benzoin (1 equiv) was dissolved in pyridine (12 mL) followed by cooling the solution to 0 C (ice water bath). The acid chloride 7c, 7d (1 equiv) was then added dropwise to the stirred solution while cooling and stirring. The reaction flask was capped, and after 30 min, the cooling bath was removed. The reaction mixture was then stirred (4 h) at room temperature while monitoring by TLC. After the starting materials were consumed, the reaction mixture was then dissolved in dichloromethane (300 mL) and washed with 5% aqueous HCl (5 120 mL). The organic layer was then separated and dried over anhydrous sodium sulfate. Flash chromatography on silica gel (hexane/ethyl acetate, 6:1) afforded esters 8c (70%) and 8d (23%) as oils
	With thionyl chloride; N,N-dimethyl-formamide In dichloromethane
	With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1h;
	With thionyl chloride
	With phosphorus trichloride
	With thionyl chloride at 20℃; Further stages;
	With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 4h;	1.1. 3-(3-bromopropanamido)benzoic acid (3a) General procedure: In ice bath, 3-bromopropanoic acid (1a, 1.53 g,10 mmol) was dissolved in dichloromethane (30 ml), oxalyl chloride (1.71 ml, 20 mmol) and one drop of dimethylformamide were added. The solution was stirred for 4 h at room temperature. The solvent and excess oxalyl chloride was evaporated. Then, the produced 3-bromopropanoyl chloride was dissolved in 10 ml THF and dropped in the mixture of 3-aminobenzoic acid (2a,1.37 g, 10 mmol) and sodium bicarbonate (1.68 g, 20 mmol) in THF. After stirred for 8 h, the solvent was removed and the mixture was acidified with 1M HCl. The final product was purified by recrystallization with ethanol. Yield 66%, mp: 210-211 °C. 1H NMR (400 MHz, DMSO-d6) δ 12.93(s, 1H), 10.23 (s, 1H), 8.24 (t, J =1.6 Hz,1H), 7.81 (dt, J = 8.0 Hz, 1.6Hz, 1H), 7.63 (dt, J = 8.0 Hz, 1.6Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H),3.74 (t, J = 6.0 Hz, 2H), 2.97 (t, J = 6.0 Hz, 2H).
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 4 - 25℃;	1.4 General procedure for the preparation of compounds (2d-2o) General procedure: To a solution ofbromocarboxylicacids (0.2mol) in dichloromethane (200 mL) was addedoxalylchloride (0.4mol) at 4oC.N,N-dimethylformamide(2 mL) was then added cautiously, and the reaction was stirred for 4 h at 25oC.The solvent was removed by distillation under vacuum at 30-40oC.This concentrate was taken directly into the next stage.
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; Inert atmosphere;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane Inert atmosphere;
	With oxalyl dichloride In tetrahydrofuran at 20℃; for 1h;	Intermediate 19D.; 4-Bromo-N-[6-(3,5-dimethyl-pyrazol-1 -yl)-2-(5-methyl-furan-2- yl)-pyrimidin-4-yl]-butyramide EPO To 10 mL THF were added 3.Og (18mmol, 2eq) 4-bromobutyric acid, 2.5g (2.2eq) oxalyl chloride, followed by a few drops of DMF. The reaction mixture was stirred at r.t. for 1 hour. Solvent was removed by nitrogen flow and the residue was resuspended in 10 mL dichloromethane followed by of Intermediate 19C and 0.9 mL pyridine. The reaction mixture was stirred at r.t. for 2 hours. The reaction was quenched with 5OmL saturated sodium bicarbonate, extracted twice with 5OmL dichloromethane, the organic layers were combined, dried under sodium sulfate and concentrated to give Intermediate 19D. Intermediate 19D was used in the next step without further purification.
	With oxalyl dichloride at 20℃; for 4h; Inert atmosphere;
	With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 0℃; for 1h;	39 [0393] To a solution of 4-bromobutanoic acid (3.4 g, 21 mmol) in dichloromethane (30 mL) was added thionyl chloride (3.68 g, 30.9 mmol) and dimethyl formamide (75 mg, 1.0 mmol). The mixture was stirred for at 0°C 1 hour. The mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (10 mL). The resulting solution was added to a mixture of 3-04-2 and diisopropylethylamine (3.99 g, 30.9 mmol) in dichloromethane (30 mL). The mixture was stirred at 20°C for 30 min then concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1 - 3 : 1) to afford compound 3-04-3 (4.8 g, 87.47% yield) as a white solid.
	With thionyl chloride for 2h; Reflux;
	With thionyl chloride In N,N-dimethyl-formamide at 50℃; for 1h;	To a solution of 1-bromobutyric acid (16.7 parts by weight) and DMF (100 parts by weight), thionyl chloride (11.9 parts by weight) was added dropwise,The mixture was reacted at 50 ° C. for 1 hour, followed by addition of 3-isopropoxypropylamine (11.7 parts by weight), and reacted at 50 ° C. for 3 hours. After the reaction, unreacted thionyl chloride was distilled off. Subsequently, o-mercaptophenol (12.6 parts by weight) and potassium carbonate (30 parts by weight) were added, and the reaction was carried out at 50 ° C. for 5 hours. After the reaction, liquid separation was performed with ethyl acetate and 1N aqueous hydrochloric acid, and the organic layer was concentrated and purified by silica gel column chromatography to obtain compound A-124B.
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃;	11; 21 Synthesis of 11-1 To a solution of 4-bromobutyric acid (0.97 mmol, 161mg) in CH2C12 (3 mL) and DMF (0.01 mL) was added oxalyl chloride (3 eq, 2.91 mmol, 370 mg, 0. 25 mL) at RT. The mixture was stirred at RT overnight. The reaction mixture was then concentrated in vacuo. The residual liquid/solid (slightly yellow) was dissolved in 5 mL of CH2C12 and was added a solution of 8-2 (410 mg, 0.48 mmol), triethylamine (0.4 mL) and DMAP (2 mg) in CH2C12 (20 mL) at RT in 2 min. After addition, the resulting mixture was stirred at RT for 2.5 h. TLC (Hexane/ethyl acetate = 9: 1) showed two major spots. The reaction mixture was then concentrated at RT under reduced pressure. The residue was used for the next reaction without any purification.
	With thionyl chloride for 2h; Reflux; Inert atmosphere;
	With thionyl chloride at 75℃; for 2h; Sealed tube; Inert atmosphere;	4.2. General procedure for synthesis of 3a-d General procedure: The reaction vessel was capped and heated to 75 C for 2 h and thesolvent was removed by rotary evaporation. To the crude acidchloride was added isobutanol (10 mL), and the resulting mixturewas allowed to sit at 25 C for 12 h. The solvent was removed byrotary evaporation to provide the crude product which was sufficientlypure to carry forward.
	With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 23℃; for 1h;

Reference： [1]Current Patent Assignee: YALE UNIVERSITY; ARVINAS - WO2020/51564, 2020, A1 Location in patent: Paragraph 2301; 2302
[2]Incze, M.; Soti, F.; Szantay, Cs. [Acta Chimica Academiae Scientiarum Hungaricae, 1980, vol. 104, p. 267 - 272]
[3]Hyne,J.B.; Jensen,J.H. [Canadian Journal of Chemistry, 1965, vol. 43, p. 57 - 63] McElvain; Carney [Journal of the American Chemical Society, 1946, vol. 68, p. 2599] Hanasaki, Tomonori; Ueda, Mitsunori; Nakamura, Naotake [Molecular Crystals and Liquid Crystals Science and Technology, Section A: Molecular Crystals and Liquid Crystals, 1993, vol. 237, p. 329 - 336]
[4]Raevskii,K.S. et al. [Pharmaceutical Chemistry Journal, 1976, vol. 10, # 4, p. 471 - 474][Khimiko-Farmatsevticheskii Zhurnal, 1976, vol. 10, # 4, p. 55 - 58]
[5]Baba, Atsuo; Kawamura, Noriaki; Makino, Haruhiko; Ohta, Yoshikazu; Taketomi, Shigehisa; Sohda, Takashi [Journal of Medicinal Chemistry, 1996, vol. 39, # 26, p. 5176 - 5182]
[6]Tercel, Moana; Stribbling, Stephen M.; Sheppard, Hilary; Siim, Bronwyn G.; Wu, Kent; Pullen, Susan M.; Botting, K. Jane; Wilson, William R.; Denny, William A. [Journal of Medicinal Chemistry, 2003, vol. 46, # 11, p. 2132 - 2151]
[7]Cano, Montserrat; Ladlow, Mark; Balasubramanian, Shankar [Journal of Organic Chemistry, 2002, vol. 67, # 1, p. 129 - 135]
[8]Current Patent Assignee: NICOX S.A. - WO2007/60112, 2007, A1 Location in patent: Page/Page column 28
[9]Holzer, Marcel; Ziegler, Sigrid; Albrecht, Beatrice; Kronenberger, Bernd; Kaul, Artur; Bartenschlager, Ralf; Kattner, Lars; Klein, Christian D.; Hartmann, Rolf W. [Molecules, 2008, vol. 13, # 5, p. 1081 - 1110]
[10]Current Patent Assignee: ARETE THERAPEUTICS - WO2008/51873, 2008, A2 Location in patent: Page/Page column 62
[11]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2008/36715, 2008, A1 Location in patent: Page/Page column 48
[12]Lazzarato, Loretta; Donnola, Monica; Rolando, Barbara; Marini, Elisabetta; Cena, Clara; Coruzzi, Gabriella; Guaita, Elena; Morini, Giuseppina; Fruttero, Roberta; Gasco, Alberto; Biondi, Stefano; Ongini, Ennio [Journal of Medicinal Chemistry, 2008, vol. 51, # 6, p. 1894 - 1903]
[13]Location in patent: experimental part Sashida, Haruki; Nakayama, Akemi; Kaname, Mamoru [Synthesis, 2008, # 20, p. 3229 - 3236]
[14]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1953148, 2008, A1 Location in patent: Page/Page column 122
[15]Location in patent: experimental part Romanova; Shtil'; Serebrennikova [Russian Journal of Bioorganic Chemistry, 2008, vol. 34, # 6, p. 743 - 746] Location in patent: experimental part Romanova; Serebrennikova; Shtil [Russian Journal of Bioorganic Chemistry, 2009, vol. 35, # 5, p. 641 - 644]
[16]Ren, Hong; Wulff, William D. [Organic Letters, 2010, vol. 12, # 21, p. 4908 - 4911]
[17]Hu, Mingyu; Li, Lin; Wu, Hao; Su, Ying; Yang, Peng-Yu; Uttamchandani, Mahesh; Xu, Qing-Hua; Yao, Shao Q. [Journal of the American Chemical Society, 2011, vol. 133, # 31, p. 12009 - 12020]
[18]Beinat, Corinne; Banister, Samuel D.; Van Prehn, Saundra; Doddareddy, Munikumar Reddy; Hibbs, David; Sako, Michael; Chebib, Mary; Tran, Thao; Al-Muhtasib, Nour; Xiao, Yingxian; Kassiou, Michael [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 7, p. 2380 - 2384]
[19]Jayaraman, Muthusamy; Ansell, Steven M.; Mui, Barbara L.; Tam, Ying K.; Chen, Jianxin; Du, Xinyao; Butler, David; Eltepu, Laxman; Matsuda, Shigeo; Narayanannair, Jayaprakash K.; Rajeev, Kallanthottathil G.; Hafez, Ismail M.; Akinc, Akin; Maier, Martin A.; Tracy, Mark A.; Cullis, Pieter R.; Madden, Thomas D.; Manoharan, Muthiah; Hope, Michael J. [Angewandte Chemie - International Edition, 2012, vol. 51, # 34, p. 8529 - 8533]
[20]Loner, Catherine M.; Luzzio, Frederick A.; Demuth, Donald R. [Tetrahedron Letters, 2012, vol. 53, # 42, p. 5641 - 5644]
[21]Kutty, Samuel K.; Barraud, Nicolas; Pham, Amy; Iskander, George; Rice, Scott A.; Black, David Stc.; Kumar, Naresh [Journal of Medicinal Chemistry, 2013, vol. 56, # 23, p. 9517 - 9529]
[22]Hensle, Eva M.; Esfandiari, N. Melody; Lim, Sung-Gon; Blum, Suzanne A. [European Journal of Organic Chemistry, 2014, vol. 2014, # 16, p. 3347 - 3354]
[23]Valeev; Bikzhanov; Miftakhov [Russian Journal of Organic Chemistry, 2014, vol. 50, # 10, p. 1511 - 1519][Zh. Org. Khim., 2014, vol. 50, # 10, p. 1523 - 1531,9]
[24]Borzenkov, Mykola; Mitina, Natalia; Lobaz, Volodymyr; Hevus, Orest [Journal of Surfactants and Detergents, 2015, vol. 18, # 1, p. 133 - 144]
[25]Gorecka, Ewa; Vaupoti, Nataa; Zep, Anna; Pociecha, Damian; Yoshioka, Jun; Yamamoto, Jun; Takezoe, Hideo [Angewandte Chemie - International Edition, 2015, vol. 54, # 35, p. 10155 - 10159][Angew. Chem., 2015, vol. 127, p. 10293 - 10297,5]
[26]Fu, Huansheng; Han, Leiqiang; Hou, Xuben; Dun, Yanyan; Wang, Lei; Gong, Xiaowei; Fang, Hao [Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 5774 - 5781]
[27]Jiao, Peifu; Jin, Peng; Li, Chencan; Cui, Lechao; Dong, Lihua; Pan, Bin; Song, Wentong; Ma, Liang; Dong, Jinlong; Song, Lei; Jin, Xinjie; Li, Faming; Wan, Maosheng; Lv, Zhitao; Geng, Qiaohong [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 19, p. 4679 - 4683]
[28]Quéméner, Agnès; Maillasson, Mike; Arzel, Laurence; Sicard, Benoit; Vomiandry, Romy; Mortier, Erwan; Dubreuil, Didier; Jacques, Yannick; Lebreton, Jacques; Mathé-Allainmat, Monique [Journal of Medicinal Chemistry, 2017, vol. 60, # 14, p. 6249 - 6272]
[29]Zhao, Wei; Wurz, Ryan P.; Peters, Jonas C.; Fu, Gregory C. [Journal of the American Chemical Society, 2017, vol. 139, # 35, p. 12153 - 12156]
[30]Current Patent Assignee: ALMIRALL SA - WO2006/110884, 2006, A2 Location in patent: Page/Page column 102-103
[31]Nayak, Rashmi Ashwathama; Bhat, Sachin A.; Shanker; Rao, D. S. Shankar; Yelamaggad [New Journal of Chemistry, 2019, vol. 43, # 5, p. 2148 - 2162]
[32]Current Patent Assignee: CORNELL UNIVERSITY; TRI-INSTITUTIONAL THERAPEUTICS DISCOVERY INSTITUTE - WO2019/75259, 2019, A1 Location in patent: Paragraph 0393
[33]Huang, Fei; Zhang, Songlin [Organic Letters, 2019, vol. 21, # 18, p. 7430 - 7434]
[34]Current Patent Assignee: FUJIFILM HOLDINGS CORP. - JP5914379, 2016, B2 Location in patent: Paragraph 0135
[35]Current Patent Assignee: ACUITAS THERAPEUTICS INC - WO2020/146805, 2020, A1 Location in patent: Page/Page column 68; 69; 85
[36]Wang, Yiqiong; Huang, Fei; Zhang, Songlin [European Journal of Organic Chemistry, 2020, vol. 2020, # 32, p. 5178 - 5181]
[37]Baker, Hannah; Ferreira, Liam D.; Gayler, Kevin M.; Kane, Robert R.; Karunananthan, Johann W.; Kostyo, Jessica H.; Martin, Emil; Mattke, Jordan; Nguyen, Harold; Plunk, Michael A.; Quintana, Jeremy M.; Sharina, Iraida; Shuda, Mina; Stinchcomb, Alexandra L. [European Journal of Medicinal Chemistry, 2021, vol. 224]
[38]Zhang, Dapeng; Atochina-Vasserman, Elena N.; Maurya, Devendra S.; Liu, Matthew; Xiao, Qi; Lu, Juncheng; Lauri, George; Ona, Nathan; Reagan, Erin K.; Ni, Houping; Weissman, Drew; Percec, Virgil [Journal of the American Chemical Society, 2021, vol. 143, # 43, p. 17975 - 17982] Zhang, Dapeng; Atochina-Vasserman, Elena N.; Lu, Juncheng; Maurya, Devendra S.; Xiao, Qi; Liu, Matthew; Adamson, Jasper; Ona, Nathan; Reagan, Erin K.; Ni, Houping; Weissman, Drew; Percec, Virgil [Journal of the American Chemical Society, 2022, vol. 144, # 11, p. 4746 - 4753]

2
[ 462-06-6 ]
[ 927-58-2 ]
[ 40132-01-2 ]

Yield	Reaction Conditions	Operation in experiment
33%	Stage #1: 4-bromobutyroyl chloride With aluminum (III) chloride In dichloromethane at 0℃; for 0.166667h; Stage #2: fluorobenzene In dichloromethane at 0 - 20℃; for 1h;	20.22 (22) 4-Bromo-1-(4-fluorophenyl)butan-1-one AlCl3 (167 mg, 1.25 mmol) to DCM (5.20 mL) and then dissolved, 4-bromobutyryl chloride (145 , 1.25 mmol) was slowly added dropwise to a 0 in. After 10 minutes fluorobenzene then slowly added dropwise to the reaction solution at the same temperature for a (98.0 , 1.04 mmol), and stirred for one hour at room temperature. After checking the completion of the reaction by TLC, the reaction solution was diluted with DCM, it poured into ice water to 0 . Extract the mixture with saturated aqueous Na2CO3, the organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The concentrated filtrate was purified by column chromatography (Hex: EtOAc = 10: 1) Compound 186 was synthesized using the (83.8 mg, 33%, light yellow oil).
	With aluminium trichloride
	With aluminum (III) chloride In dichloromethane at 0 - 20℃; for 2h;

	With aluminum (III) chloride In dichloromethane at 0 - 20℃; Inert atmosphere;
	With aluminum (III) chloride In dichloromethane at 0 - 20℃; Inert atmosphere;

Reference： [1]Current Patent Assignee: KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY; UNIVERSITY OF ULSAN - KR101525019, 2015, B1 Location in patent: Paragraph 1142; 1232-1234
[2]Raevskii,K.S. et al. [Pharmaceutical Chemistry Journal, 1976, vol. 10, # 4, p. 471 - 474][Khimiko-Farmatsevticheskii Zhurnal, 1976, vol. 10, # 4, p. 55 - 58]
[3]Shim, Young Sun; Hwang, Hyun Sook; Nam, Ghilsoo; Choi, Kyung Il [Bulletin of the Korean Chemical Society, 2013, vol. 34, # 8, p. 2317 - 2320]
[4]Huang, Fei; Zhang, Songlin [Organic Letters, 2019, vol. 21, # 18, p. 7430 - 7434]
[5]Wang, Yiqiong; Huang, Fei; Zhang, Songlin [European Journal of Organic Chemistry, 2020, vol. 2020, # 32, p. 5178 - 5181]

3
[ 927-58-2 ]
[ 93-67-4 ]
[ 54585-19-2 ]

Yield	Reaction Conditions	Operation in experiment
67.3%	With pyridine In tetrahydrofuran Ambient temperature; stirred overnight;
	With sodium hydrogencarbonate In diethyl ether

Reference： [1]McKenzie [Journal of Heterocyclic Chemistry, 1980, vol. 17, # 4, p. 657 - 659]
[2]Nagarajan,K.; Shah,R.K. [Indian Journal of Chemistry, 1974, vol. 12, p. 263 - 269]

4
[ 3143-02-0 ]
[ 927-58-2 ]
[ 89276-32-4 ]

Yield	Reaction Conditions	Operation in experiment
83%	With pyridine In dichloromethane at 0℃; for 2h;
72%	With pyridine In dichloromethane at 0 - 20℃; for 16h;	2 Step 2: Preparation of (3-methyloxetan-3-yl)methyl 4-bromobutanoate Into a 250-mL round-bottom flask, was placed (3-methyloxetan-3-yl)methanol (6.14 g, 60.12 mmol, 1.00 equiv), dichloromethane (100 mL), pyridine (5.70 g, 72.06 mmol, 1.20 equiv). This was followed by the addition of a solution of 4-bromobutanoyl chloride (11.08 g, 59.75 mmol, 0.99 equiv) in dichloromethane (100 mL) dropwise with stirring at 0. The resulting solution was stirred for 16 h at room temperature. The resulting solution was extracted with dichloromethane (50 mL x 2) and the organic layers combined. The resulting mixture was washed with brine (10 mL x 2). The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/3). This resulted in 11.4 g (72%) of 5-bromo-1-[(3-methyloxetan-3-yl)methoxy]pentan-2-one as light yellow oil.
	With pyridine In dichloromethane at 0℃;

	With pyridine; 4 A molecular sieve In tetrahydrofuran at 0℃; for 1h;
	With pyridine In dichloromethane at 0℃;	1 3-Methyl-3-hydroxymethyloxetane (10.2 g, 0.1 mole) (Sigma-Aldrich Corporation, St. Louis, Mo.) was dissolved in anhydrous dichloromethane (200 ml). Pyridine (9.8 ml, 0.12 moles) was then added to the solution. Thereafter, the solution was cooled to 0° C. and 4-bromobutyryl chloride (18.5 g, 0.1 mole) (Sigma-Aldrich Corporation, St. Louis, Mo.) dissolved in anhydrous dichloromethane (50 ml) was added dropwise over 20 minutes. The mixture was stirred overnight under argon atmosphere. Next, the reaction mixture was washed with water and dried with anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. Yield 23.6 g. NMR (d6-DMSO): 1.26 ppm (s, 3H), 2.07 ppm (m, 2H), 2.51 ppm (t, 2H), 3.56 ppm (t, 2H), 4.14 ppm (s, 2H), 4.24 ppm (d, 2H), 4.38 ppm (d, 2H).
	With pyridine In tetrahydrofuran at 0℃; for 1h;
	With pyridine In tetrahydrofuran at 0℃; for 1h; Inert atmosphere;	2.1.1.1 Preparation of (3-methyloxetan-3-yl)methyl ω-bromoalkanoate (9a-d) General procedure: Pyridine (10.5 mmol) was dissolved into dry tetrahydrofuran (18 mL) and the solution cooled to 0 °C in an ice bath. 3-Methyl-3-oxetanemethanol (8.75 mmol) was added and then the appropriate ω-bromoalkanoyl chloride (9.75 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for an additional 1 h. The reaction mixture was poured into an ice-water mixture and then extracted with methylene chloride (5× 30 mL). The aqueous phase was concentrated under reduced pressure to remove remaining tetrahydrofuran and methylene chloride, and then extracted with methylene chloride (2× 100 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to afford the desired (3-methyloxetan-3-yl)methyl ω-bromoalkanoates (9a-d) in quantitative yields that were used without further purification at the next step.

Reference： [1]Jones, Raymond C. F.; Schofield, Julie [Journal of the Chemical Society. Perkin transactions I, 1990, # 2, p. 375 - 383]
[2]Current Patent Assignee: YALE UNIVERSITY; ARVINAS - WO2020/51564, 2020, A1 Location in patent: Paragraph 2303; 2304
[3]Corey, E. J.; Raju, Natarajan [Tetrahedron Letters, 1983, vol. 24, # 50, p. 5571 - 5574]
[4]Cano, Montserrat; Ladlow, Mark; Balasubramanian, Shankar [Journal of Organic Chemistry, 2002, vol. 67, # 1, p. 129 - 135]
[5]Current Patent Assignee: NEKTAR THERAPEUTICS - US2005/36978, 2005, A1 Location in patent: Page/Page column 22-23
[6]Champeil, Elise; Crean, Conor; Larraya, Carlos; Pescitelli, Gennaro; Proni, Gloria; Ghosez, Léon [Tetrahedron, 2008, vol. 64, # 45, p. 10319 - 10330]
[7]Saha, Pijus; Fortin, Sebastien; Leblanc, Valerie; Parent, Sophie; Asselin, Eric; Berube, Gervais [Steroids, 2012, vol. 77, # 11, p. 1113 - 1122]

5
[ 927-58-2 ]
[ 6414-58-0 ]
[ 101578-94-3 ]

Reference： [1]Bulletin de la Societe Chimique de France,1989,p. 650 - 656

6
[ 927-58-2 ]
[ 119-53-9 ]
2-oxo-1,2-diphenylethyl-4-bromobutanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With pyridine at 0 - 20℃; for 4.5h;	General procedure for preparation of bromoacyl esters (8c and 8d) through acid chlorides (7c, 7d General procedure: 5-bromovaleric acid (1 equiv) or 4-bromobutyric acid (1 equiv) was dissolved in thionyl chloride (4.5 equiv). The reaction mixture was then heated (75 C, oil bath) under a nitrogen atmosphere overnight. The excess thionyl chloride was removed by adding dichloromethane (25 mL) followed by rotary evaporation under aspirator vacuum. The addition of the dichloromethane and rotary evaporation was repeated (3 ) which yielded the crude acid chloride as an oil. The 5-bromobutyryl chloride 7c or the 4- bromovaleryl chloride 7d were used without further purification in the next step. Benzoin (1 equiv) was dissolved in pyridine (12 mL) followed by cooling the solution to 0 C (ice water bath). The acid chloride 7c, 7d (1 equiv) was then added dropwise to the stirred solution while cooling and stirring. The reaction flask was capped, and after 30 min, the cooling bath was removed. The reaction mixture was then stirred (4 h) at room temperature while monitoring by TLC. After the starting materials were consumed, the reaction mixture was then dissolved in dichloromethane (300 mL) and washed with 5% aqueous HCl (5 120 mL). The organic layer was then separated and dried over anhydrous sodium sulfate. Flash chromatography on silica gel (hexane/ethyl acetate, 6:1) afforded esters 8c (70%) and 8d (23%) as oils. 2-oxo-1,2-diphenylethyl-4-bromobutanoate (8c): Rf: 0.49 (hexane/ethylacetate, 4:1); FTIR: 3063.60, 1708.60, 1692.03, 1588.70, 1531.70 cm 1; 1H NMR (400 MHz, CDCl3) d: 2.21-2.23 (t,2H); 2.60-2.69 (m, 2H); 3.45-3.47 (t, 2H); 6.85 (s, 1H); 7.28-8.01 (m, 10H); 13C NMR (100 MHz, CDCl3) d: 193.66, 172.08, 134.56, 133.57, 128.70-129.43, 77.85, 32.55, 32.34, 27.83; FTIR: 3063.60, 1708.60, 1692.03, 1588.70, 1531.70 cm 1.
70%	With pyridine at 0℃;	General procedure: General Procedure for the preparation of the bromoacyl esters (37a, 37b): Benzoin (1 eq) was dissolved in pyridine (12 mL) followed by cooling the solution to 0 °C (ice water bath). The acid chloride 36a or 36b (1 eq) was then added dropwise to the stirred solution while cooling. The reaction flask was capped, and after 30 minutes, the cooling bath was removed. The reaction mixture was stirred (4 h) while monitoring by TLC. After the starting materials were consumed, the reaction mixture was then dissolved in dichloromethane (300 mL) and washed with 5% aqueous HC1 (5 x 120 mL). The organic layer was then separated and dried over anhydrous sodium sulfate. Flash chromatography on silica gel (hexane/ethyl acetate, 6:1) afforded esters 37a and 37b as oils in 70% and 23% yield respectively: 2-Oxo-l,2- diphenylethyl-4-bromobutanoate (37a): Rf: 0.49 (hexane/ethylacetate, 4:1); FTIR: 3063.60, 1708.60, 1692.03, 1588.70, 1531.70 cm'1; 1H NMR (400 MHz, CDC13) 8: 2.21-2.23 (t, 2H); 2.60-2.69 (m, 2H); 3.45-3.47 (t, 2H); 6.85 (s, 1H); 7.28-8.01 (m, 10H); 13C NMR (100 MHz, CDC13) 5: 193.66, 172.08, 134.56, 133.57, 128.70-129.43, 77.85, 32.55, 32.34, 27.83 2-oxo- l,2-diphenylethyl-5-bromopentanoate (37b): Rf: 0.47 (hexane/ethyl acetate, 4:1); FTIR: 1734.38, 1693.88, 1597.38, 1448.37 cm"1; 1H NMR (400MHz, CDC13) δ: 1.81-1.87 (m, 2H); 1.91-1.98 (m, 2H); 2.44-2.59 (m, 2H); 3.40-3.43 (t, 2H); 6.85 (s, 1H), 7.35-7.93 (m, 10H); 13C NMR (lOOMHz, CDC13) δ: 193.75, 172.63, 134.59, 133.49, 128.07-128.83, 60.25, 44.55, 33.09, 31.76, 23.38.
	With pyridine In dichloromethane 1.) from 0 deg C, to RT, 1.) RT, 1 h;

Reference： [1]Loner, Catherine M.; Luzzio, Frederick A.; Demuth, Donald R. [Tetrahedron Letters, 2012, vol. 53, # 42, p. 5641 - 5644]
[2]Current Patent Assignee: UNIVERSITY OF LOUISVILLE - WO2013/16206, 2013, A1 Location in patent: Page/Page column 36
[3]Meanwell; Rosenfeld; Trehan; Wright; Brassard; Buchanan; Federici; Fleming; Gamberdella; Zavoico; Seiler [Journal of Medicinal Chemistry, 1992, vol. 35, # 19, p. 3483 - 3497]

7
[ 927-58-2 ]
[ 100-51-6 ]
[ 126430-46-4 ]

Yield	Reaction Conditions	Operation in experiment
83%	With potassium carbonate; In dichloromethane; for 2h;	To a solution of 4-bromobutyryl chloride (Aldrich Chemical Company, Wisconsin), (10.27 g, 55.4 mmol) in 100 mL of dichloromethane was added benzyl alcohol (Aldrich Chemical Company, Wisconsin), (6.29 g, 58.1 mmol), followed by potassium carbonate (8.3 g, 60 mmol) in four portions. After 2 hours, water was added, and the layers were separated. The organic layer was washed with water, brine, and dried over magnesium sulfate. Evaporation of the solvent gave the title compound (11.87 g, 83% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) delta 7.36 (m, 5H), 5.14 (s, 2H), 3.46 (t, J=6.4 Hz, 2H), 2.56 (t, J=7.2 Hz, 2H), 2.20 (quin, J=6.6 Hz, 2H).
82%	With dmap; In dichloromethane; at 20℃; for 2h;	[00140] Benzyl alcohol (3.1 ml_, 30 mmol) was added to a solution of Compound 1 (3.47 ml_, 30 mmol) and 4-dimethylaminopyridine (732 mg, 6 mmol) in dichloromethane (100 ml_). The reaction was stirred for 2 hours at room temperature then quenched with 1 M HCI (100 ml_). The organic phase was washed once more with 1 M HCI (100 ml_), dried over MgS04, filtered, dried by rotary evaporation and was dried under vacuum to yield Compound 2 as a colorless oil (6.29 g, 24.5 mmol, 82%).
	With triethylamine; In dichloromethane; at 20℃; for 2h;	To a solution of benzyl alcohol (1 mL) and triethylamine (2.69 mL) in dichloromethane (15 mL) was added 4-bromobutyryl chloride (1.68 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 8/1) to give benzyl 4-bromobutyrate (2.45 g). To a solution of 3-(2,3,4,6-tetra-O-pivaloyl-beta-D-glucopyranosyloxy)-4-[2-(4-pivaloyloxyphenyl)ethyl]-1H-pyrazolo[3,4-b]pyridine (0.17 g) in acetone (3 mL) were added cesium carbonate (0.16 g), benzyl 4-bromobutyrate (0.1 g) and a catalytic amount of sodium iodide, and the mixture was stirred at room temperature for 2 days. The reactionmixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 10/1 - 3/1) to give 1-(3-benzyloxycarbonylpropyl)-3-(beta-D-glucopyranosyloxy)-4-[2-(4-pivaloyloxyphenyl)ethyl]-1H-pyrazolo[3,4-b]pyridine (0.14 g). This material was dissolved in tetrahydrofuran (5 mL) . To the solution was added 10% palladium-carbon powder (50 mg) , and the mixture was stirred at room temperature'under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 1/2 - dichloromethane/methanol = 15/1) to give the title compound (95 mg). 1H-NMR (CDCl3) delta ppm: 1.04 (9H, s), 1.13 (9H, s), 1.15 (9H, s), 1.17 (9H, s), 1.35 (9H, s), 2.15-2.3 (2H, m), 2.3-2.45 (2H, m), 2.8-3.4 (4H, m), 3.95-4.05 (1H, m), 4.05-4.15 (1H, m), 4.31 (1H, dd, J=12.2Hz, 1.7Hz), 4.35-4.55 (2H, m), 5.2-5.35 (1H, m), 5.35-5.45 (1H, m), 5.45-5.55 (1H, m), 6.03 (1H, d, J=8.1Hz), 6.7 (1H, d, J=4.9Hz), 6.9-7.0 (2H, m), 7.15-7.25 (2H, m), 8.27 (1H, d, J=4.9Hz)

Reference： [1]Patent: US2006/189603,2006,A1 .Location in patent: Page/Page column 57
[2]Patent: WO2016/86026,2016,A1 .Location in patent: Paragraph 00140
[3]Journal of Medicinal Chemistry,1996,vol. 39,p. 5176 - 5182
[4]Synthesis,2010,p. 953 - 958
[5]Patent: EP1724278,2006,A1 .Location in patent: Page/Page column 44-45

8
[ 927-58-2 ]
[ 108168-88-3 ]
N-tert-Butyl-2-cyano-2-[dihydro-furan-(2Z)-ylidene]-acetamide [ No CAS ]
N-tert-Butyl-2-cyano-2-[dihydro-furan-(2E)-ylidene]-acetamide [ No CAS ]

Reference： [1]Helvetica Chimica Acta,1998,vol. 81,p. 1319 - 1328

9
[ 927-58-2 ]
[ 6330-25-2 ]
2-Cyano-2-[dihydro-furan-(2Z)-ylidene]-N-methyl-acetamide [ No CAS ]

Reference： [1]Helvetica Chimica Acta,1998,vol. 81,p. 1319 - 1328

10
[ 927-58-2 ]
[ 6638-79-5 ]
[ 130250-57-6 ]

Yield	Reaction Conditions	Operation in experiment
80%	With triethylamine In dichloromethane at 0 - 20℃; for 3h;	4A 4A 4-Bromo-N-methoxy-N-methylbutanamide NEt3 (10.5 mL, 75.1 mmol) was added to a cooled (0 °C) suspension of N,O-dimethyl hydroxylamine hydrochloride (6.71 g, 68.8 mmol) in CH2Cl2 (130 mL), followed by dropwise addition of 4-bromobutanoyl chloride (7.24 mL, 62.6 mmol) and additional NEt3 (10.5 mL, 75.1 mmol). The reaction was stirred for 3 h at rt, the volatiles removed under reduced pressure. The residue was diluted with EtOAc (100 mL), washed successively with 1 M aq. HCl, sat. aq. NaHCO3 and brine (50 mL each), dried 5 (MgSO4) and concentrated under reduced pressure to afford a yellow oil (11 g, 80%) which was used without further purification. 1H NMR (500 MHz, CDCl3) δ 3.73 (s, 3H), 3.53 (t, J = 6.3 Hz, 2H), 3.20 (s, 3H), 2.64 (t, J = 7.1 Hz, 2H), 2.33 - 2.16 (m, 2H).
80%	With triethylamine In dichloromethane at 0 - 20℃; for 3h;	4A 4A 4-Bromo-N-methoxy-N-methylbutanamide NEt3 (10.5 mL, 75.1 mmol) was added to a cooled (0 °C) suspension of N,O-dimethyl hydroxylamine hydrochloride (6.71 g, 68.8 mmol) in CH2Cl2 (130 mL), followed by dropwise addition of 4-bromobutanoyl chloride (7.24 mL, 62.6 mmol) and additional NEt3 (10.5 mL, 75.1 mmol). The reaction was stirred for 3 h at rt, the volatiles removed under reduced pressure. The residue was diluted with EtOAc (100 mL), washed successively with 1 M aq. HCl, sat. aq. NaHCO3 and brine (50 mL each), dried 5 (MgSO4) and concentrated under reduced pressure to afford a yellow oil (11 g, 80%) which was used without further purification. 1H NMR (500 MHz, CDCl3) δ 3.73 (s, 3H), 3.53 (t, J = 6.3 Hz, 2H), 3.20 (s, 3H), 2.64 (t, J = 7.1 Hz, 2H), 2.33 - 2.16 (m, 2H).
40%	With pyridine In dichloromethane for 1h;

With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 16h;

4-Bromobutanoyl chloride (5.62 ml, 48.5 mmol) in DCM (64 ml) was added slowly to a solution of DIPEA (17.80 ml, 102 mmol) and N,O-dimethylhydroxylamine hydrochloride (4.97 g, 51.0 mmol) in DCM (32 ml) at 0° C. The mixture was stirred at room temperature for 16 hours then diluted with DCM (50 ml). The mixture was washed with 1M HCl(aq) (2×50 ml) and saturated NaHCO3(aq) (2×50 ml). The organic phase was passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 30% EtOAc/hexane afforded the title compound. [1892] 1H NMR (400 MHz, CDCl3) δ 3.69 (3H, s), 3.62 (2H, t), 3.49 (3H, s), 3.17 (3H, s), 2.61 (2H, t), 2.17 (2H, quint), 2.09 (2H, quint)

Reference： [1]Current Patent Assignee: PFIZER INC - WO2022/8912, 2022, A1 Location in patent: Page/Page column 28; 29
[2]Current Patent Assignee: PFIZER INC - WO2022/8912, 2022, A1 Location in patent: Page/Page column 28; 29
[3]Selvamurugan; Aidhen [Synthesis, 2001, # 15, p. 2239 - 2246]
[4]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2014/171417, 2014, A1 Location in patent: Paragraph 1891; 1892

11
[ 91-16-7 ]
[ 927-58-2 ]
[ 105174-48-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	With boron trifluoride diethyl etherate In dichloromethane for 0.166667h;
95%	With ethylaluminum dichloride In dichloromethane for 0.833333h;
75%	With aluminium trichloride In dichloromethane at 0℃; for 3h;

75%	With aluminium trichloride In dichloromethane at 0℃; for 3h;
	With aluminum (III) chloride In dichloromethane Reflux;
	With aluminum (III) chloride In dichloromethane at 0 - 20℃; Inert atmosphere;
	With aluminum (III) chloride In dichloromethane at 0 - 20℃; Inert atmosphere;

Reference： [1]Chaturvedi, Devdutt; Chaturvedi, Amit K.; Mishra, Nisha; Mishra, Virendra [Synlett, 2012, vol. 23, # 18, p. 2627 - 2630,4]
[2]Chaturvedi, Devdutt; Chaturvedi, Amit K.; Mishra, Nisha; Mishra, Virendra [Organic and biomolecular chemistry, 2012, vol. 10, # 46, p. 9148 - 9151,4]
[3]Voight, Eric A; Rein, Christian; Burke, Steven D [Journal of Organic Chemistry, 2002, vol. 67, # 24, p. 8489 - 8499]
[4]Burke, Steven D.; Voight, Eric A. [Organic Letters, 2001, vol. 3, # 2, p. 237 - 240]
[5]Hu, Huamin; Dyke, Jason Christopher; Bowman, Brett Allen; Ko, Ching-Chang; You, Wei [Langmuir, 2016, vol. 32, # 38, p. 9873 - 9882]
[6]Huang, Fei; Zhang, Songlin [Organic Letters, 2019, vol. 21, # 18, p. 7430 - 7434]
[7]Wang, Yiqiong; Huang, Fei; Zhang, Songlin [European Journal of Organic Chemistry, 2020, vol. 2020, # 32, p. 5178 - 5181]

12
[ 927-58-2 ]
[ 153-78-6 ]
4-bromo-N-(9H-fluoren-2-yl)-butyramide [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2003,vol. 125,p. 9588 - 9589
[2]Organic Letters,2006,vol. 8,p. 3821 - 3824

13
[ 927-58-2 ]
[ 525-03-1 ]
4-bromo-N-(9H-fluoren-9-yl)-butyramide [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2003,vol. 125,p. 9588 - 9589
[2]Proceedings of the National Academy of Sciences of the United States of America,2010,vol. 107,p. 4573 - 4578

14
[ 927-58-2 ]
[ 1771-18-2 ]
N-(4-bromobutyryl)-2-methoxyphenothiazine [ No CAS ]

Reference： [1]Il Farmaco,2003,vol. 58,p. 669 - 676

15
[ 50-24-8 ]
[ 927-58-2 ]
prednisolone 21-(4'-bromobutyrate) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With triethylamine In tetrahydrofuran at 20℃; for 4h;

Reference： [1]Baraldi, Pier Giovanni; Romagnoli, Romeo; Nuñez, Maria Del Carmen; Perretti, Mauro; Paul-Clark, Mark J.; Ferrario, Massimiliano; Govoni, Mirco; Benedini, Francesca; Ongini, Ennio [Journal of Medicinal Chemistry, 2004, vol. 47, # 3, p. 711 - 719]

16
[ 927-58-2 ]
[ 5900-59-4 ]
2-(4-bromo-butyrylamino)-4-chloro-benzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 4151 - 4154

17
[ 927-58-2 ]
[ 1885-32-1 ]
2-(4-bromo-butyrylamino)-3-methyl-benzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 4151 - 4154

18
[ 927-58-2 ]
[ 115643-59-9 ]
[ 437998-39-5 ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 4151 - 4154

19
[ 927-58-2 ]
[ 28144-70-9 ]
[ 437998-35-1 ]

Yield	Reaction Conditions	Operation in experiment
88%	With triethylamine In tetrahydrofuran at 0℃; for 1h; Inert atmosphere;	Synthesis of 2-(4-Bromo-butyrylamino)-benzamide (1) 1.00g (7.35 mol) of anthranilamide was dissolved in 15 mlof tetrahydrofuran, 1.03 ml (8.82 mol) of 4-bromobutyryl chloride and1.53 ml (11.03 mol) of triethylamine was added dropwise at 0°C, and the mixture was stirred under a nitrogen atmosphere for 1 hr. The reaction mixture was distilled under a reduced pressure to remove the solvent,and the residue was extracted with ethyl acetate and aqueous NaCl, and the separated organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under a reduced pressure. The product was purified by column chromatography (Hexane: Ethyl acetate= 1:1) to obtain1.84 g of the title compound (yield 88%) as a pale yellow color solid 1H NMR (300 MHz, CDCl3) δ 2.27 (m,2H), 2.62 (t, 2H), 2.50 (t, 2H), 3.52 (t, 2H), 7.09 (dd, J = 8.5 Hz, 7.8 Hz, 1H), 7.51 (dd, J = 8.7 Hz, 7.7 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H), 8.63 (d, J =8.5 Hz, 1H), 11.22 (brs, 1H)MS(EI)m/e 285[M]+
81.3%	With pyridine In dichloromethane at 0℃; for 1.5h;

Reference： [1]Le, Tuong Vy Thi; Suh, Jee Hee; Kim, Nakjeong; Park, Hyun-Ju [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 9, p. 2642 - 2646]
[2]Hattori, Kouji; Kido, Yoshiyuki; Yamamoto, Hirofumi; Ishida, Junya; Kamijo, Kazunori; Murano, Kenji; Ohkubo, Mitsuru; Kinoshita, Takayoshi; Iwashita, Akinori; Mihara, Kayoko; Yamazaki, Syunji; Matsuoka, Nobuya; Teramura, Yoshinori; Miyake, Hiroshi [Journal of Medicinal Chemistry, 2004, vol. 47, # 17, p. 4151 - 4154] Ishida, Junya; Yamamoto, Hirofumi; Kido, Yoshiyuki; Kamijo, Kazunori; Murano, Kenji; Miyake, Hiroshi; Ohkubo, Mitsuru; Kinoshita, Takayoshi; Warizaya, Masaichi; Iwashita, Akinori; Mihara, Kayoko; Matsuoka, Nobuya; Hattori, Kouji [Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 5, p. 1378 - 1390]

20
[ 927-58-2 ]
[ 57-88-5 ]
[ 86689-85-2 ]

Yield	Reaction Conditions	Operation in experiment
97%	With pyridine In dichloromethane for 2h; Inert atmosphere;
85%	With triethylamine In tetrahydrofuran at -15 - 20℃; for 48h; Inert atmosphere;	4 2.4 Synthesis of Chol-(CH₂)₃-Br Cholesterol (0.500 g, 1.29 mmol) was dissolved in anhydrous THF (50 mL) in a two-necked flask equipped with a magnetic stirrer and rubber septum under inert argon atmosphere. TEA (0.340 g, 3.36 mmol) was then added to the reaction vessel, which was cooled to - 15 °C using an ice-salt mixture. A mixture of 4-bromobutyrylchloride (0.32 g, 1.701 mmol) and THF (10 mL) was added dropwise to the reaction mixture for 20 min. The whole mixture was stirred at room temperature for 48 h, diluted with DCM (100 mL), and washed with 1 N HCl solution (2 * 50 mL). After the organic layers were combined and dried with MgSO4, the solvent was removed by a rotary evaporator and the compound was dried under reduced pressure at ambient temperature until a constant weight was obtained. Yield: 0.585 g (85%). mp: 64-67 °C; FTIR (ATR, cm- 1): 2940 and 2865 (C-H), 1724 (C=O), 1470 (C-H), 1235 ((C=O)-O), and 1045 (C-O-C); 1H NMR (500 MHz, CDCl3, δ, ppm): 5.36 (s, 1H, C=CH in Chol), 4.61 (m, 1 H, CH-O in Chol), 3.46 (t, 2 H, O(C=O)CH2CH2CH2Br), 2.47 (t, 2H, O(C=O)CH2CH2CH2Br), and 2.17 (m, 2 H, O(C=O)CH2CH2CH2Br); MS (ESI) (m/z): [M + 1]+ calculated for C31H51BrO2: 535.64; found: 536.42.
82%	With pyridine In tetrahydrofuran at 0 - 20℃; for 12h;

82%	With pyridine In tetrahydrofuran at 0 - 20℃;
79%	With triethylamine In toluene at 20℃; for 24h;
	With pyridine In tetrahydrofuran at 0 - 20℃; for 8h;
	With pyridine at 0 - 20℃;

Reference： [1]Mochizuki, Masahito; Sato, Shinichi; Asatyas, Syifa; Leśnikowski, Zbigniew J.; Hayashi, Tomohiro; Nakamura, Hiroyuki [RSC Advances, 2019, vol. 9, # 41, p. 23973 - 23978]
[2]Ilkar Erdagi, Sevinc; Doganci, Erdinc; Uyanik, Cavit; Yilmaz, Faruk [Reactive and functional polymers, 2016, vol. 99, p. 49 - 58]
[3]Nayak, Rashmi Ashwathama; Bhat, Sachin A.; Shanker; Rao, D. S. Shankar; Yelamaggad [New Journal of Chemistry, 2019, vol. 43, # 5, p. 2148 - 2162]
[4]Veerabhadraswamy; Bhat, Sachin A.; Hiremath, Uma S.; Yelamaggad, Channabasaveshwar V. [ChemPhysChem, 2019, vol. 20, # 21, p. 2836 - 2851]
[5]Gorecka, Ewa; Vaupoti, Nataa; Zep, Anna; Pociecha, Damian; Yoshioka, Jun; Yamamoto, Jun; Takezoe, Hideo [Angewandte Chemie - International Edition, 2015, vol. 54, # 35, p. 10155 - 10159][Angew. Chem., 2015, vol. 127, p. 10293 - 10297,5]
[6]Kinoshita, Hidetoshi; Hata, Masayuki; Achalkumar, Ammathnadu S.; Yelamaggad, Channabasaveswar V.; Akutsu, Hiroki; Yamada, Jun-Ichi; Nakatsuji, Shin'ichi [Tetrahedron Letters, 2005, vol. 46, # 39, p. 6701 - 6703]
[7]Achalkumar, Ammathnadu S.; Shankar Rao, Doddamane S.; Yelamaggad, Channnabasaveshwar V. [New Journal of Chemistry, 2014, vol. 38, # 9, p. 4235 - 4248]
[8]Shanker; Bindushree; Chaithra; Pratap; Gupta, Ravindra Kumar; Achalkumar; Yelamaggad [Journal of Molecular Liquids, 2019, vol. 275, p. 849 - 858]

21
[ 58401-43-7 ]
[ 927-58-2 ]
[ 949915-86-0 ]

Yield	Reaction Conditions	Operation in experiment
	In 1,2-dichloro-ethane; for 17h;Heating / reflux;	A solution of 4-chloroquinolin-3 -amine (3.70 g, 20.74 mmol) and 4-bromobutyryl chloride (11.54 g, 62.22 mmol) dissolved in 100 mL of 1 ,2-dichloroethane was heated to reflux. After 17 hours the reaction was cooled to room temperature, diluted with dichloromethane, washed with saturated aqueous K2CO3, H2O and brine, dried over Na2SO4, and concentrated under reduced pressure to give a brown solid. The solid was triturated with a mixture of hexane and ether, filtered and dried to give 4-bromo-iV-(4- chloroquinolin-3-yl)butanamide (3.65 g) as a brown solid.

Reference： [1]Patent: WO2007/106852,2007,A2 .Location in patent: Page/Page column 85

22
[ 546111-78-8 ]
[ 927-58-2 ]
(-)-N-{2-[3-(2,2-dimethylpropionyl)-5-(2-oxopyrrolidin-1-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl]ethyl}methanesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: N-{2-[5-amino-3-(2,2-dimethylpropionyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl]ethyl}methanesulfonamide; 4-bromobutyroyl chloride With pyridine In dichloromethane at 20℃; for 2h; Stage #2: With sodium acetate In dimethyl sulfoxide at 100℃; for 0.233333h;	17 The optically active N-{2-[5-amino-3-(2,2-dimethylpropionyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl]et hyl}methanesulfonamide (0.647 g, 1.68 mmol) obtained in Step 2 of Example 15 was dissolved in dichloromethane (25 mL), and pyridine (0.41 mL, 5.1 mmol) and 4-bromobutyryl chloride (0.49 mL, 4.2 mmol) were added, then the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water, and the mixture was extracted with chloroform. The organic layer was washed with 0.5 mol/L hydrochloric acid and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in dimethyl sulfoxide (DMSO, 6 mL), and sodium acetate (0.331 g, 4.04 mmol) was added, then the mixture was heated to 100°C over 14 minutes with stirring. After cooling, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (n-hexane/ethyl acetate = 3/1 -> 1/1), and recrystallized from acetone to give Compound c {(-)-N-{2-[3-(2,2-dimethylpropionyl)-5-(2-oxopyrrolidin-1-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl] ethyl}methanesulfonamide} (0.649 g, 85%). 1H NMR (270 MHz, CDCl3) δ (ppm): 1.34 (s, 9H), 2.23 (m, 2H), 2.56 (m, 2H), 2.61 (m, 1H), 2.97 (s, 3H), 3.27 (m, 1H), 3.40 (m, 1H), 3.63 (m, 1H), 3.98 (m, 2H), 4.01 (br t, J = 3.5 Hz, 1H), 7.20-7.37 (m, 5H). APCI-MS m/z: 453 (M+1)+. Melting point: 107.0-110.0°C. Specific rotation: A solution of the resulting compound in methanol gave a negative value as a specific rotation for sodium D line (wavelength: 589.3 nm) at 20°C.
85%	Stage #1: N-{2-[5-amino-3-(2,2-dimethylpropionyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl]ethyl}methanesulfonamide; 4-bromobutyroyl chloride With pyridine In dichloromethane at 20℃; for 2h; Stage #2: With sodium acetate In dimethyl sulfoxide at 100℃; for 0.233333h;	16 Compound c: (-)-N-{2-[3-(2,2-Dimethylpropionyl)-5-(2-oxopyrrolidin-1-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl]ethyl}methanesulfonamide Reference Example 16 Compound c: (-)-N-{2-[3-(2,2-Dimethylpropionyl)-5-(2-oxopyrrolidin-1-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl]ethyl}methanesulfonamide The optically active N-{2-[5-amino-3-(2,2-dimethylpropionyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl]ethyl}methanesulfonamide (0.647 g, 1.68 mmol) obtained in Step 2 of Reference Example 14 was dissolved in dichloromethane (25 mL), and pyridine (0.41 mL, 5.1 mmol) and 4-bromobutyryl chloride (0.49 mL, 4.2 mmol) were added, then the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water, and the mixture was extracted with chloroform. The organic layer was washed with 0.5 mol/L hydrochloric acid and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in dimethyl sulfoxide (DMSO, 6 mL), and sodium acetate (0.331 g, 4.04 mmol) was added, then the mixture was heated to 100°C over 14 minutes with stirring. After cooling, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (n-hexane/ethyl acetate = 3/1 -> 1/1), and recrystallized from acetone to give Compound c {(-)-N-{2-[3-(2,2-dimethylpropionyl)-5-(2-oxopyrrolidin-1-yl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl]ethyl}methanesulfonamide} (0.649 g, 85%). 1H NMR (270 MHz, CDCl3) δ (ppm): 1.34 (s, 9H), 2.23 (m, 2H), 2.56 (m, 2H), 2.61 (m, 1H), 2.97 (s, 3H), 3.27 (m, 1H), 3.40 (m, 1H), 3.63 (m, 1H), 3.98 (m, 2H), 4.01 (br t, J = 3.5 Hz, 1H), 7.20-7.37 (m, 5H). APCI-MS m/z: 453 (M+1)+. Melting point: 107.0-110.0°C. Specific rotation: A solution of the resulting compound in methanol gave a negative value as a specific rotation for sodium D line (wavelength: 589.3 nm) at 20°C.

Reference： [1]Current Patent Assignee: FUJIFILM HOLDINGS CORP.; KIRIN HOLDINGS CO., LTD.; Kyowa Kirin (in: Kirin Holdings) - EP1867640, 2007, A1 Location in patent: Page/Page column 36-37
[2]Current Patent Assignee: Kyowa Kirin (in: Kirin Holdings); FUJIFILM HOLDINGS CORP.; KIRIN HOLDINGS CO., LTD. - EP1870404, 2007, A1 Location in patent: Page/Page column 29

23
[ 546112-07-6 ]
[ 927-58-2 ]
(-)-N-{2-[5-(2-oxopyrrolidin-1-yl)-2-phenyl-3-propionyl-2,3-dihydro-1,3,4-thiadiazol-2-yl]ethyl}methanesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: N-[2-(5-amino-2-phenyl-3-propionyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethyl]methanesulfonamide; 4-bromobutyroyl chloride With pyridine In dichloromethane at 0 - 20℃; for 2h; Stage #2: With sodium acetate In dimethyl sulfoxide at 100℃; for 0.0833333h;	19 The optically active N- [2-(5-amino-2-phenyl-3-propionyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethyl]methanesu lfonamide (1.01 g, 2.83 mmol) obtained in Step 2 of Example 16 and pyridine (330 µL, 4.08 mmol) were dissolved in dichloromethane (40 mL), and 4-bromobutyryl chloride (390 µL, 3.40 mmol) was added at 0°C, then the mixture was stirred at room temperature for 2 hours. To the mixture was added 1 mol/L hydrochloric, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the residue were added DMSO (10 mL) and sodium acetate (560 mg, 6.83 mmol), and the mixture was stirred at 100°C for 5 minutes. After cooling, water and 1 mol/L hydrochloric acid were added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol = 20/1) to give Compound e {(-)-N-{2-[5-(2-oxopyrrolidin-1-yl)-2-phenyl-3-propionyl-2,3-dihydro-1,3,4-thiadiazol-2-yl]ethyl}methanesulfonamide} (878 mg, 73%). 1H NMR (270 MHz, CDCl3) δ (ppm): 1.15 (t, J = 6.6 Hz, 3H), 2.22 (m, 2H), 2.55-2.67 (m, 3H), 2.94 (s, 3H), 3.31-3.47 (m, 4H), 3.61 (m, 1H), 3.91-3.98 (m, 2H), 5.0 (br s, 1H), 7.20-7.35 (m, 5H). APCI-MS m/z: 423 (M-1)-. Melting point: 188.0-191.0°C. Specific rotation: A solution of the resulting compound in methanol gave a negative value as a specific rotation for sodium D line (wavelength: 589.3 nm) at 20°C.
73%	Stage #1: N-[2-(5-amino-2-phenyl-3-propionyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethyl]methanesulfonamide; 4-bromobutyroyl chloride With pyridine In dichloromethane at 0 - 20℃; for 2h; Stage #2: With sodium acetate In dimethyl sulfoxide at 100℃; for 0.0833333h;	18 Compound e:(-)-N-{2-[5-(2-Oxopyrrolidin-1-yl)-2-phenyl-3-propionyl-2,3-dihydro-1,3,4-thiadiazol-2-yl]ethyl}methanesulfonamide Reference Example 18 Compound e:(-)-N-{2-[5-(2-Oxopyrrolidin-1-yl)-2-phenyl-3-propionyl-2,3-dihydro-1,3,4-thiadiazol-2-yl]ethyl}methanesulfonamide The optically active N-[2-(5-amino-2-phenyl-3-propionyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethyl]methanesulfonamide (1.01 g, 2.83 mmol) obtained in Step 2 of Reference Example 15 and pyridine (330 μL, 4.08 mmol) were dissolved in dichloromethane (40 mL), and 4-bromobutyryl chloride (390 μL, 3.40 mmol) was added at 0°C, then the mixture was stirred at room temperature for 2 hours. To the mixture was added 1 mol/L hydrochloric, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the residue were added DMSO (10 mL) and sodium acetate (560 mg, 6.83 mmol), and the mixture was stirred at 100°C for 5 minutes. After cooling, water and 1 mol/L hydrochloric acid were added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol = 20/1) to give Compound e {(-)-N-{2-[5-(2-oxopyrrolidin-1-yl)-2-phenyl-3-propionyl-2,3-dihydro-1,3,4-thiadiazol-2-yl]ethyl}methanesulfonamide} (878 mg, 73%). 1H NMR (270 MHz, CDCl3) δ (ppm): 1.15 (t, J = 6.6 Hz, 3H), 2.22 (m, 2H), 2.55-2.67 (m, 3H), 2.94 (s, 3H), 3.31-3.47 (m, 4H), 3.61 (m, 1H), 3.91-3.98 (m, 2H), 5.0 (br s, 1H), 7.20-7.35 (m, 5H). APCI-MS m/z: 423 (M-1)-. Melting point: 188.0-191.0°C. Specific rotation: A solution of the resulting compound in methanol gave a negative value as a specific rotation for sodium D line (wavelength: 589.3 nm) at 20°C.

Reference： [1]Current Patent Assignee: FUJIFILM HOLDINGS CORP.; KIRIN HOLDINGS CO., LTD.; Kyowa Kirin (in: Kirin Holdings) - EP1867640, 2007, A1 Location in patent: Page/Page column 37
[2]Current Patent Assignee: Kyowa Kirin (in: Kirin Holdings); FUJIFILM HOLDINGS CORP.; KIRIN HOLDINGS CO., LTD. - EP1870404, 2007, A1 Location in patent: Page/Page column 30

24
[ 1011301-27-1 ]
[ 927-58-2 ]
4-bromo-N-{4-[3-(4-tert-butyl-benzoyl)-thioureido]-phenyl}-butyramide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With triethylamine; In dichloromethane; at 20℃; for 1.5h;	Thiourea 4 (200 mg, 0.61 mmol, 1 equiv.) was stirred in CH2Cl2 (10 mL) under N2 atmosphere. 4-Bromobutyryl chloride (169 mg, 0.92 mmol, 1.5 equiv.) was added, followed by triethylamine (85 muL, 0.61 mmol, 1 equiv.) . The orange solution was stirred at rt for 1.5 h and diluted with CH2Cl2 (10 mL) . The organic solution was washed with 1 M aqueous hydrochloric acid (1 x 10 mL) , 10% aqueous sodium hydroxide (1 x 50 mL) , and saturated brine (1 x 10 mL) . The organic phase was dried over MgSO4 and concentrated in vacuo. The resulting pale yellow foam was purified by flash chromatography on silica (50% ethyl acetate/petroleum ether) to give 4-bromo-N- {4- [3- (4-tert- butyl-benzoyl) -thioureido] -phenyl} -butyramide (138 mg, 48%) as a yellow oil. 1H NMR (CDCl3, 300 MHz) delta 1.35 (s, 9H, (CH3)3), 2.26 (m, 2H, CH2CH2Br), 2.57 (t, 2H, J = 7.0 Hz, CH2), 3.52 (t, 3H, J = 6.2 Hz, CH2), 7.60 (m, 6H, ArH), 7.82 (d, 2H, J = <n="40"/>8.7 Hz, ArH), 9.08 (s(br), IH, NH), 12.59 (s(br), IH, NH).
48%	With triethylamine; In dichloromethane; at 20℃; for 1.5h;Inert atmosphere;	Thiourea 5 (200 mg, 0.61 mmol) was stirred in CH2Cl2 (10 mL) under N2 atmosphere. 4-Bromobutyryl chloride (169 mg, 0.92 mmol) was added, followed by triethylamine (85 muL, 0.61 mmol). The orange solution was stirred at rt for 1.5 h and diluted with CH2Cl2 (10 mL). The organic solution was washed with 1 M aqueous hydrochloric acid (1 × 10 mL), 10% aqueous sodium hydroxide (1 × 50 mL), and saturated brine (1 × 10 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The resulting pale yellow foam was purified by flash chromatography on silica using hexanes/ethyl acetate (1:1) to give 4-bromo-N-{4-[3-(4-tert-butyl-benzoyl)-thioureido]-phenyl}-butyramide (138 mg, 0.29 mmol, 48%) as a yellow oil. 1H NMR (300 MHz, CDCl3) delta 12.59 (1H, br s, NH), 9.08 (1H, br s, NH), 7.82 (2H, d, J = 8.7 Hz, ArH), 7.60 (6H, m, ArH), 3.52 (2H, t, J = 6.2 Hz, CH2), 2.57 (2H, t, J = 7.0 Hz, CH2), 2.26 (2H, m, CH2), 1.35 (9H, s, (CH3)3). Treatment of the prepared bromo compound (138 mg, 0.29 mmol) with dimethylamine (3 mL) in H2O (7.5 mL) gave a crude mixture which was dissolved in a minimal amount of acetone and 2 M hydrochloric acid in ether solution was added dropwise until a precipitate appeared. The solid was filtered and the yellow solid which was recrystallised from isopropanol to give 8 (75 mg, 0.16 mmol, 55%) as a yellow solid.

Reference： [1]Patent: WO2008/29096,2008,A2 .Location in patent: Page/Page column 38-39
[2]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 1779 - 1793

25
[ 1013658-02-0 ]
[ 927-58-2 ]
[ 1013658-06-4 ]

Yield	Reaction Conditions	Operation in experiment
92%	With triethylamine In tetrahydrofuran; dichloromethane at 0 - 20℃; for 2h;	4 To a solution of 2-amino-λ/-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide (5.60 g, 22.0 mmol) and triethylamine (2.61 g, 26.0 mmol) in anhydrous tetrahydrofuran (250 mL) was added 4-bromobutanoyl chloride (4.99 g, 26.0 mmol) in anhydrous dichloromethane (10 mL) dropwise at 0 0C. The reaction mixture was stirred at ambient temperature for 2 hours, then diluted with dichloromethane (200 mL) and washed with saturated aqueous sodium bicarbonate solution (2 x 150 mL), and brine (150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrate in vacuo to afford the title compound as a yellow oil in 92% yield (8.00 g): 1H NMR (300 MHz, CDCl3) δ 8.61 (br s, IH), 7.32-7.22 (m, 2H), 7.05-6.94 (m, 2H), 6.14 (t, J= 5.6 Hz, IH), 4.53 (d, J= 5.6 Hz, 2H), 3.45 (t, J= 6.7 Hz, 2H), 2.65 (t, J= 6.7 Hz, 2H), 2.58 (s, 3H), 2.23 (quintet, J= 6.7 Hz, 2H); MS (ES+) m/z 413.1 (M + 1), 415.1 (M + 1).

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2008/36715, 2008, A1 Location in patent: Page/Page column 48

26
[ 3593-75-7 ]
[ 927-58-2 ]
[ 886138-28-9 ]

Yield	Reaction Conditions	Operation in experiment
80%	With aluminium trichloride In dichloromethane at 20℃;

Reference： [1]Sotgiu, Giovanna; Barbarella, Giovanna [Journal of Organic Chemistry, 2007, vol. 72, # 13, p. 4925 - 4931]

27
[ 927-58-2 ]
[ 1077-16-3 ]
C₁₆H₂₃BrO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With aluminium trichloride In dichloromethane at 20℃; for 2h;

Reference： [1]Arnold, Leggy A.; Kosinski, Aaron; Estébanez-Perpiñá, Eva; Fletterick, Robert J.; Guy, R. Kiplin [Journal of Medicinal Chemistry, 2007, vol. 50, # 22, p. 5269 - 5280]

28
[ 154590-35-9 ]
[ 927-58-2 ]
[ 1364441-94-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 2h;	Step 1: Cool in ice a solution of the product of Preparation 13, Step 3 (1.53 g, 5.2 mmol) and DIPEA (1.10 ml, 6.2 mmol) in THF (40 ml). Add dropwise 4-bromobutyryl chloride (1.01 g, 5.4 mmol). Stir 2 h and partition with ether and satd. NaHCO3. Dry (MgSO4) and concentrate to obtain the carbamate as a yellow solid
	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 2h;	Cool in ice a solution of the product of Preparation 17, Step 3 (1.53 g, 5.2 mmol) and DIPEA (1.10 ml, 6.2 mmol) in THF (40 ml). Add dropwise 4-bromobutyryl chloride (1.01 g, 5.4 mmol). Stir 2 h and partition with ether and satd. NaHCO3. Dry (MgSO4) and concentrate to obtain the carbamate as a yellow solid.

Reference： [1]Patent: US2004/220194,2004,A1 .Location in patent: Page 22
[2]Patent: US2005/239795,2005,A1 .Location in patent: Page/Page column 21

29
[ 927-58-2 ]
[ 134991-79-0 ]
[ 225942-06-3 ]

Yield	Reaction Conditions	Operation in experiment
66%	With triethylamine In tetrahydrofuran at 0 - 20℃; for 2h;	17 [00420] Triethylamine (206 mg, 2.04 mmol) was added to a THF (6 ml) solution of 3-amino-2,4-bis(methylthio)-6-methylpyridine (341 mg, 1.70 mmol), and 4-bromobutanoyl chloride (379 mg, 2.04 mmol) was then slowly added thereto dropwise while being cooled with ice. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 75 g, eluent-hexane:acetone=5:1→3:1) to obtain 390 mg (yield 66%) of 4-bromo-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]butanamide as a colorless crystal (melting point: 139 to 140° C.).

Reference： [1]Current Patent Assignee: KOWA COMPANY, LTD. - US6849647, 2005, B1 Location in patent: Page 112

30
[ 927-58-2 ]
[ 171228-49-2 ]
[ 221615-80-1 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; In dichloromethane; at 20℃;	Example 1 To a stirred mixture of 10 g (14 mmol) of the compound of formula IV (prepared in accordance with the procedure of Example 32 of WO 96/38443, published 5 December 1996) and 2.27 g, (1.3 eq) of the base, 4-(N,N-dimethylamino)pyridine ("DMAP") in 200 mL of methylene chloride, 4-bromobutyryl chloride (1.3 eq, 18.6 mmol, 3.44g) was added dropwise and the resulting reaction mixture was stirred at room temperature until the reaction was determined to be complete by thin layer chromatography ("TLC"). The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate("EtOAc"). The organic phase was separated, washed with water and dried over MgSO4. The organic solvent was removed and the so-formed residue was purified on a silica gel chromatography column using EtOAc as the eluent to provide 8.58 g of the bromide VI as a white solid

Reference： [1]Patent: EP1027349,2005,B1 .Location in patent: Page 8-9

31
[ 321-64-2 ]
[ 927-58-2 ]
[ 326850-55-9 ]

Yield	Reaction Conditions	Operation in experiment
	In DMF (N,N-dimethyl-formamide); chloroform at 20℃; for 6h;	11.a a) Preparation of 9-[4-bromo)butyroylamino]-1,2,3,4-tetrahydroacridine To a solution of tacrine (4 g, 20.17 mmoles) in chloroform (50 ml) and N,N-dimethylformamide (15 ml), 4-bromobutyroylchloride (3.5 ml, 30.25 mmoles) is added. The reaction mixture is maintained under stirring at room temperature for 6 hours and then diluted with chloroform and washed with water. The organic phase, anhydrified with sodium sulphate, is evaporated at reduced pressure. The crude product is purged by chromatography on silica gel, eluding with n-hexane/ethyl acetate 8/2 (ratio by volume). 9-[4-bromo)butyroylamino]-1,2,3,4-tetrahydroacridine is obtained.

Reference： [1]Current Patent Assignee: NICOX S.A. - EP1252133, 2005, B1 Location in patent: Page/Page column 14

32
[ 864063-30-9 ]
[ 927-58-2 ]
N-[5,6-dihydro-5-oxo-indeno[1,2-c]isoquinolin-9-yl]-4-bromobutyramide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With sodium hydrogencarbonate In water; ethyl acetate at 20℃; for 1h;	6.1.bb To a suspension of Compound 54a (1.5 g, 0.006 mol) in saturated NaHCO3 (150 ml) and ethyl acetate (100 ml) was added 4-bromobutyryl chloride (5 eq). The reaction mixture was stirred at room temperature for 1 hour. The resultant solid was isolated by filtration, washed with water and ethyl acetate, and dried under vacuum to provide Compound 55a (1.625 g, 68%). 1H-NMR (DMSO-d6): 8, 2.09-2. 13 (m, 2H), 2.47- 2.52 (m, 2H), 3.58 (t, J = 6. 6 Hz, 2H), 3.85 (s, 2H), 7.40 (t, J = 6. 3 Hz, 1H), 7.50 (d, J = 8. 4 Hz, 1H), 7.66-7. 71 (m, 2H), 7.86 (d, J = 8. 4 Hz, 1H), 7.92 (s, 1H), 8.20 (d, J = 8.1 Hz, 1H), 10.10 (s, 1H), 12.24 (s, 1H).
68%	With sodium hydrogencarbonate In water; ethyl acetate at 20℃; for 1h;	5.5.1.1-149bb 1-149bb) Preparation of N-[5,6-Dihydro-5-oxo-indeno[1,2-c]isoquinolin-9-yl]-4-bromo-butylamide (55a) To a suspension of Compound 54a (1.5 g, 0.006 mol) in saturated NaHCO3 (150 ml) and ethyl acetate (100 ml) was added 4-bromobutyryl chloride (5 eq). The reaction mixture was stirred at room temperature for 1 hour. The resultant solid was isolated by filtration, washed with water and ethyl acetate, and dried under vacuum to provide Compound 55a (1.625 g, 68%). 1H-NMR (DMSO-d6): δ, 2.09-2.13 (m, 2H), 2.47-2.52 (m, 2H), 3.58 (t, J=6.6 Hz, 2H), 3.85 (s, 2H), 7.40 (t, J=6.3 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.66-7.71 (m, 2H), 7.86 (d, J=8.4 Hz, 1H), 7.92 (s, 1H), 8.20 (d, J=8.1 Hz, 1H), 10.10 (s, 1H), 12.24 (s, 1H).
68%	With sodium hydrogencarbonate In water; ethyl acetate at 20℃; for 1h;	5.d d) Preparation of N-[5,6-Dihydro-5-oxo-indeno[1,2-c]isoquinolin-9-yl]-4-bromo-butylamide (55a); To a suspension of Compound 54a (1.5 g, 0.006 mol) in saturated NaHCO3 (150 ml) and ethyl acetate (100 ml) was added 4-bromobutyryl chloride (5 eq). The reaction mixture was stirred at room temperature for 1 hour. The resultant solid was isolated by filtration, washed with water and ethyl acetate, and dried under vacuum to provide Compound 55a (1.625 g, 68%). 1H-NMR (DMSO-d6): δ, 2.09-2.13 (m, 2H), 2.47-2.52 (m, 2H), 3.58 (t, J=6.6 Hz, 2H), 3.85 (s, 2H), 7.40 (t, J=6.3 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.66-7.71 (m, 2H), 7.86 (d, J=8.4 Hz, 1H), 7.92 (s, 1H), 8.20 (d, J=8.1 Hz, 1H), 10.10 (s, 1H), 12.24 (s, 1H).

Reference： [1]Current Patent Assignee: ROCKET PHARMACEUTICALS INC - WO2005/82368, 2005, A1 Location in patent: Page/Page column 95-96
[2]Current Patent Assignee: ROCKET PHARMACEUTICALS INC - US2006/19980, 2006, A1 Location in patent: Page/Page column 58
[3]Current Patent Assignee: ROCKET PHARMACEUTICALS INC - US2006/287313, 2006, A1 Location in patent: Page/Page column 31

33
[ 927-58-2 ]
1-[(4-methoxy-1-methyl-1H-imidazol-5-yl)methyl]pyrrolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%	Stage #1: 1-(4-methoxy-1-methyl-1H-imidazol-5-yl)methanamine With potassium hydroxide; molecular sieve; sodium sulfate In dichloromethane at 0℃; for 0.25h; Stage #2: 4-bromobutyroyl chloride In dichloromethane for 2h; Stage #3: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 20h;	31.2 In a 50 ml, three-necked flask fitted with a magnetic stirrer, under inert atmosphere, 1-(4-methoxy-1-methyl-1H-imidazol-5-yl)methanamine x94 (0.37 g, 2.62 mmol), Na2SO4 (0.37 g, 2.62 mmol) and powdered molecular sieves are stirred inCH2CI2 (25 ml) at 0 0C. At this temperature, powdered KOH (0.53 g, 9.44 mmol) and a solution of tetra-n-butyl ammonium bromide (48 mg, 0.13 mmol) in CH2CI2 (5 ml) are added. The mixture is stirred for 0.25 h at 0 0C and 4-bromobutanoyl chloride (366 μl, 3.14 mmol) is added dropwise. Stirring is continued for 2 h. The mixture is filtered on Celite and evaporated in vacuo. The residue is dissolved in DMF (25 ml) and NaH (60 % dispersion in oil, 0.12 g, 3.14 mmol) is added. The mixture is stirred at room temperature for 16 h. An additional portion of NaH (0.52 mmol) is added and the mixture is stirred for 4 more hours at room temperature. The mixture is then diluted with 30 ml of CH2CI2, filtered on Celite and concentrated to dryness. The residue is purified by chromatography EPO on silicagel (CH2Cl2/MeOH/NH4θH: 95/4.5/0.5 (v/v/v)) and recrystallized from diisopropyl ether to afford 150 mg of 1-[(4-methoxy-1-methyl-1 H-imidazol-5-yl)methyl]pyrrolidin-2-one 120.Yield: 27 %.LC-MS (MH+): 210.

Reference： [1]Current Patent Assignee: UCB - WO2006/128692, 2006, A2 Location in patent: Page/Page column 97; 98

34
[ 927-58-2 ]
[ 90-02-8 ]
[ 937808-67-8 ]

Yield	Reaction Conditions	Operation in experiment
80%	With pyridine In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 2h;	4 SOCl2 (1.60 mL, 21.6 mmol) and a few drops of dry DMF were added to a solution of 4-bromobutyrric acid (3.00 g, 18.0 mmol) in dry CH2Cl2 (40 mL) , stirred under N2 at r.t. The stirring was continued for 3 h at r.t. The solution of the acyl chloride so obtained was slowly added to a stirred solution of salycilic aldehyde (1.73 mL, 14.4 mmol) and dry Pyridine (2.20 mL, 27.0 mmol) in dry CH2Cl2 (40 mL) , kept under N2, at 0 0C. The reaction was allowed to reach r.t. and was completed after 2 h. The mixture was washed with HCl 2M (3 x 30 mL) . The organic layer was dried with MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (PE/EtOAc 90/10 v/v) to give the title compound as pale yellow oil (3.54g) . Yield 80 %. TLC: Rf = 0.67 PE/EtOAc 80/20 v/v1H-NMR (CDCl3) δ 2.34-2.36 (2H, m) , 2.87-2.92 (2H, m) , 3.55-3.60 (2H, m) , 7.18 (IH, d, Arom ), 7.43 (IH, t, Arom ), 7.66 (IH, t, Arom ), 7.88 (IH, d, Arom ), 10.1 (IH, s br) . 13C-NMR (CDCl3) δ 27.4, 32.3, 32.5, 123.5, 126.5, 132.0, 134.8, 151.0, 171.0, 188.9. MS (CI) m/z 271/273 (M+l)+.
	With pyridine In dichloromethane at 0 - 20℃;

Reference： [1]Current Patent Assignee: NICOX S.A. - WO2007/60112, 2007, A1 Location in patent: Page/Page column 28
[2]Lazzarato, Loretta; Donnola, Monica; Rolando, Barbara; Marini, Elisabetta; Cena, Clara; Coruzzi, Gabriella; Guaita, Elena; Morini, Giuseppina; Fruttero, Roberta; Gasco, Alberto; Biondi, Stefano; Ongini, Ennio [Journal of Medicinal Chemistry, 2008, vol. 51, # 6, p. 1894 - 1903]

35
[ 945863-63-8 ]
[ 927-58-2 ]
1-[2-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl]piperidin-3-yl 2-oxa-6-azatricyclo[3.3.1.1(3,7)]decane-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84.65%	Stage #1: 1-(4-amino-2-fluorophenyl)piperidin-3-yI 2-oxa-6-azatricyclo[3.3.1.1(3,7)]decane-6-carboxylate; 4-bromobutyroyl chloride With dmap In tetrahydrofuran at 20℃; for 1h; Stage #2: With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 2h;	51 To a mixture of l-(4-ammo-2-fluorophenyl)piperidin-3-yl 2-oxa-6- azatricyclo[3.3.1.1(3,7)]decane-6-carboxylate (20.0 mg, 0.0000533 mol) and 4- dimethylaminopyridine (9.762 mg, 7.991E-5 mol) in tetrahydrofuran (0.49 mL, 0.0060 mol) was added 4-bromobutanoyl chloride (0.00771 mL, 0.0000666 mol). The mixture was stirred at rt for 1 h, then treated with 1.00 M of potassium tert-butoxide in tetrahydrofuran (0.213 mL) at rt for 2 h, and then evaporated to dryness. The residue was neutralized with diluted HCl, then purified on RP-HPLC to give the product (20 mg, 84.65%). LCMS (M+H) 444.1. The product was believed to have 3S stereochemistry based on the starting material.

Reference： [1]Current Patent Assignee: INCYTE CORP - WO2007/89683, 2007, A1 Location in patent: Page/Page column 64

36
1-(4-amino-2-fluorophenyI)piperidin-3-yl-3-hydroxy-8-azabicydo[3.2.1]octane-8-carboxylate [ No CAS ]
[ 927-58-2 ]
1-[2-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl]piperidin-3-yl-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	Stage #1: 1-(4-amino-2-fluorophenyI)piperidin-3-yl-3-hydroxy-8-azabicydo[3.2.1]octane-8-carboxylate; 4-bromobutyroyl chloride With dmap In tetrahydrofuran at 20℃; for 1h; Stage #2: With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 2h;	11 To a mixture of l-(4-amino-2-fluorophenyl)piperidin-3-yl-3-hydroxy-8- azafaicyclo[3.2.1]octane-8-carboxylate (20.0 mg, 0.0000552 mol) and 4-dimethylaminopyridine (10.11 mg, 8.277E-5 mol) in tetrahydrofuran (0.51 mL, 0.0062 mol) was added 4-bromo-butanoyl chloride, (0.00798 mL, 0.0000690 mol). The mixture was stirred at rt for 1 h, then treated with 1 .00 M of potassium tert-butoxide in tetrahydrofuran (THF) (0.221 mL) at rt for 2 h, then evaporated to dryness. The residue was purified on RP-HPLC to give the product (20 mg, 83%). LCMS (M+H): 432.2. The product was believed to have 3S stereochemistry and 3-endo configuration based on the starting materials.

Reference： [1]Current Patent Assignee: INCYTE CORP - WO2007/89683, 2007, A1 Location in patent: Page/Page column 44

37
[ 927-58-2 ]
[ 538-93-2 ]
[ 1057648-40-4 ]

Yield	Reaction Conditions	Operation in experiment
81.5%	Stage #1: 4-bromobutyroyl chloride; 1-phenyl-2-methylpropane In dichloromethane at 20℃; for 0.25h; Stage #2: With tetrabutylammonium trifluoromethylsulfonate In dichloromethane for 12h; Reflux;	6 Example 6: Synthesis of 4-isobutylphenyl-4-bromobutanone 26.8 g (0.2 mol) of 4-isobutylbenzene were added to 150 mL of methylene chloride,40.8 g (0.22 mol) of 4-bromobutyryl chloride was added under stirring,Stirred at room temperature 15min, added tetrabutyl ammonium trifluoromethanesulfonate 7.8g (0.02mol) in portions,Heated to reflux 12h, stop the reaction. Cooled to room temperature, washed three times with water,Dry over anhydrous Na2SO4 overnight. Filter to remove anhydrous Na2SO4,The filtrate was evaporated under reduced pressure to give crude 4-isobutylphenyl-4-bromobutanone,Anhydrous ethanol was recrystallized to give 46.1g of white crystals, yield 81.5%.
	With aluminium trichloride In dichloromethane at 0℃; for 0.75h;

Reference： [1]Current Patent Assignee: BEIJING GUANGDA HENGXIN TECH DEV - CN106278840, 2017, A Location in patent: Paragraph 0031; 0032
[2]Holzer, Marcel; Ziegler, Sigrid; Albrecht, Beatrice; Kronenberger, Bernd; Kaul, Artur; Bartenschlager, Ralf; Kattner, Lars; Klein, Christian D.; Hartmann, Rolf W. [Molecules, 2008, vol. 13, # 5, p. 1081 - 1110]

38
[ 205180-05-8 ]
[ 927-58-2 ]
[ 1021853-39-3 ]

Yield	Reaction Conditions	Operation in experiment
93%	With triethylamine In dichloromethane at 0 - 20℃; for 18h;	J.1 Stage 1 - Cyclopentyl λ/-(4-bromobutanoyl)-L-leucinate; To a solution of Intermediate D (free base, 1.82g, 9.1 mmol) in DCM (25ml) at 00C was added Et3N (1.40ml, lO.Ommol) and 4-bromobutyryl chloride (1.10ml, 9.1mmol). The reaction mixture was allowed to warm to RT and stirred for a further 18 hours. The mixture was diluted with DCM, washed with water (2 x 20ml), brine (2 x 20ml), dried (MgSO4), and concentrated under reduced pressure. Purification by column chromatography (10-30 % EtOAc in heptane) afforded the title intermediate as a pale yellow oil (2.97g, 93%). 1H NMR (300 MHz, CDCI3) δ: 5.91 (1H, br d, J=7.8Hz), 5.24-5.20 (1H, m), 4.62-4.55 (1 H, m), 3.65- 3.59 (1H1 m), 3.54-3.47 (1 H, m), 2.43 (2H, t, J=7.1 Hz), 2.25-2.09 (2H, m), 1.92-1.55 (1OH, m), 1.01-0.93 (7H, m).

Reference： [1]Current Patent Assignee: CHROMA THERAPEUTICS LIMITED - WO2008/50078, 2008, A1 Location in patent: Page/Page column 27

39
[ 927-58-2 ]
[ 1006912-84-0 ]
[ 1034471-92-5 ]

Yield	Reaction Conditions	Operation in experiment
68%	With 2-chloropyridine In acetonitrile at 0 - 20℃; for 4.5h;	G.3 Step 3: [1 -[4-(Aminosulfonyl)-2-fluorophenyl]-5-(2,5-dimethylbenzyl)-1 HA ,2,4- trazol-3-yl]methyl λ/-(4-bromobutanoyl), L-Valinate (g-3); Amine g-2 (324 mg, 0.662 mmol), was dissolved in CH3CN (3.3 mL), and 2- chloropyridine (0.188 mL, 1 .99 mmol), and cooled to O0C. 4-Bromobutyryl chloride(0.230 mL, 1.99 mmol), was added and allowed to warm to ambient temperature. After 3h, more 4-bromobutyryl chloride (0.080 mL), was added and stirred for another 1.5 h. The reaction mixture was diluted with EtOAc (50 mL), and washed with H2O (2 x 30 mL), 1 N HCI (30 mL), and brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (35 - 80% EtOAc/hexanes), to obtain [1 -[4-(aminosulfonyl)-2-fluorophenyl]-5-(2,5- dimethylbenzyl)-1 H-1 ,2,4-triazol-3-yl]methyl λ/-(4-bromobutanoyl)-L-valinate (286 mg, 68% yield), as a white solid, which was used without further purification. 1H NMR (400 MHz, CHLOROFORM-c/), δ ppm 7.72 - 7.79 (m, 2 H), 7.37 - 7.43 (m, 1 H), 6.94 - 6.97 (m, 1 H), 6.88 - 6.93 (m, 1 H), 6.61 (s, 1 H), 6.09 (d, J=8.6 Hz, 1 H), 5.23 - 5.36 (m, 2 H), 5.02 (s, 2 H), 4.69 (dd, >8.8, 4.6 Hz, 1 H), 4.06 (s, 2 H), 3.41 - 3.54 (m, 2 H), 2.44 (t, J=6.8 Hz, 2 H), 2.17 - 2.30 (m, 3 H), 2.17 (s, 3 H), 2.05 (s, 3 H), 0.96 (d, J=IA Hz, 3 H), 0.91 (d, J=6.8 Hz, 3 H). LC/MS ESI m/z (M+H)+ 639.0.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2008/75152, 2008, A1 Location in patent: Page/Page column 52; 54-55

40
[ 927-58-2 ]
[ 103-90-2 ]
[ 410071-27-1 ]

Yield	Reaction Conditions	Operation in experiment
94%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 16h;	9 A suspension of p-hydroxyphenyl acetamide (1.95 g, 12.8 mmol) and di- isopropyl-ethylamine (2.45 ml_, 14.08 mmol) in 100 mL dry DCM at 0 0C was treated dropwise with a solution of 4-bromobutyryl chloride (1.49 mL, 12.8 mmol) in 20 mL dry DCM under inert atmosphere, and the reaction mixture was allowed to warm up to ambient temperature. After 16h water and DCM were added. The two layers were separated and the organic layer was dried (MgSO4), and evaporated to give the title compound as a white solid. Yield: 3.62 g (94%). LC-MS (Method 2): Rt 3.02min, m/z 301 [MH+].

Reference： [1]Current Patent Assignee: CHARLES RIVER LABORATORIES INTERNATIONAL INC - WO2008/96128, 2008, A1 Location in patent: Page/Page column 47

41
[ 927-58-2 ]
[ 1092938-42-5 ]
[ 1092938-40-3 ]

Yield	Reaction Conditions	Operation in experiment
63%	Stage #1: 4-bromobutyroyl chloride; 2,3-dimethyl-1',3',6,7-tetrahydro-3H-spiro[chromeno[7,8-d]imidazole-8,2'-inden]-5-amine With triethylamine In tetrahydrofuran at 10℃; for 2h; Stage #2: With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 18h;	10 4-Bromobutyryl chloride (54 μl, 0.47 mmol) was added carefully at 10 0C to a suspension of 2,3-di- methyl-1',3',6,7-tetrahydro-3/-/-spiro[chromeno[7,8-c/]imidazole-8,2'-inden]-5-amine (0.15 g, 0.47 mmol) and triethylamine (65 μl, 0.47 mmol) in tetrahydrofuran (5 ml). The suspension was stirred at 10 0C for 2 h, cooled to 0 0C, and a solution of potassium fert-butoxide in tetrahydrofuran (1.1 ml, 1 M) was added. The solution was stirred 1 h at 0 0C, further potassium fert-butoxide solution in tetrahydrofuran (2.2 ml, 1 M) was added in two portions, and stirring was continued for 18 h. Water (50 ml) was added and the aqueous mixture was extracted with dichloromethane. The combined organic phases were dried (MgSO4) and concentrated in vacuo. After crystallization using diisopropyl ether, the title compound resulted as a pale brown solid (0.12 g, 63 %). 1H-NMR (d6-DMSO): δ (ppm) 7.29-7.12 (m, 4 H), 6.96 (s, 1 H), 3.73 (t, 2 H), 3.62 (s, 3 H), 3.12 (dd, 4 H), 2.70 (t, 2 H), 2.56-2.33 (m, 5 H + DMSO), 2.21-2.01 (m, 4 H).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2008/151927, 2008, A2 Location in patent: Page/Page column 45

42
[ 927-58-2 ]
[ 1040165-35-2 ]
[ 1040165-50-1 ]

Yield	Reaction Conditions	Operation in experiment
63%	Stage #1: 4-bromobutyroyl chloride; 6-amino-1-(tert-butoxycarbonyl)-2-(di-tert-butoxycarbonyl)aminoindole-3-carboxamide In toluene at 60℃; for 3h; Stage #2: With caesium carbonate In acetonitrile at 20℃; for 6.5h;	4-Bromobutyryl chloride (0.13 mL, 1.1 mmol) was added to a solution of 6-amino-1-(tert-butoxycarbonyl)-2-(di-tert-butoxycarbonyl)aminoindole-3-carbox amide (Reference compound 6-1, 0.50 g, 1.0 mmol) in toluene (5.0 mL). The mixture was stirred at 60 °C for 3 hours. The reaction mixture was poured into water (20 mL), and the whole was extracted with ethyl acetate (30 mL). The organic layer was concentrated under reduced pressure. Acetonitrile (10 mL) and cesium carbonate (0.14 g, 0.44 mmol) were added to the resultant solid, and the mixture was stirred at room temperature for 6.5 hours. After the reaction mixture was concentrated under reduced pressure, water (50 mL) was added to the residue. The whole was extracted with ethyl acetate (50 mL). The organic layer was washed with water (50 mL) and brine (50 mL), and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography to give the title reference compound (0.35 g) as a colorless solid (yield 63 %). 1-(tert-Butoxycarbonyl)-2-(di-tert-butoxycarbonyl)amino -6-(2-oxopyrrolidin-1-yl)indole-3-carboxamide (Reference compound 12-1) [Show Image] 1H-NMR (400 MHz, DMSO-d6) δ 1.32 (s, 18H), 1.59 (s, 9H), 2.10 (m, 2H), 2.49-2.51 (m, 2H), 3.92 (t, J = 7.0 Hz, 2H), 7.27 (br s, 1H), 7.51 (br s, 1H), 7.60 (dd, J = 8.8, 2.0 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 8.53 (d, J = 2.0 Hz, 1H)

Reference： [1]Current Patent Assignee: SANTEN PHARMACEUTICAL CO LTD - EP2119703, 2009, A1 Location in patent: Page/Page column 25

43
[ 927-58-2 ]
[ 155206-00-1 ]
[ 1194047-71-6 ]

Yield	Reaction Conditions	Operation in experiment
6%	With dmap; In dichloromethane; at 0℃; for 72h;Inert atmosphere;	To a suspension of <strong>[155206-00-1]bimatoprost</strong> (Cayman Chemicals; 540 mg, 1.30 mmol) in anhydrous dichloromethane (5.2 ml_) at 0C was added DMAP (850 mg, 1.33 mmol) and 4-bromobutyryl chloride (0.154 ml, .32 mmol) and allowed to stir for 72h. The resultant mixture was filtered and solvent removed by nitrogen flow. The residue was redissolved in dichloromethane, washed with saturated NaHCO3 and brine, and dried over MgSO4 to give a crude mixture, which was submitted to preparative reverse phase HPLC to give as a major separable pure component, 11-bromoester h-1 as a colorless oil, 42 mgO).1H NMR (400 MHz, DMSO-d6) delta 7.70 (bs., 1 H), 7.22 - 7.32 (m, 2 H), 7.10 - 7.21 (m, 3 H), 5.37 - 5.54 (m, 3 H), 5.20 - 5.35 (m, 1 H), 4.72 - 4.86 (m, 2 H), 4.57 - 4.66 (m,1 H), 3.84 - 4.01 (m, 2 H), 3.51 (t, J=6.57 Hz, 2 H), 2.96 - 3.10 (m, 2 H), 2.54 - 2.66 (m,2 H)1 2.21 - 2.45 (m, 4 H), 2.05 - 2.21 (m, 1 H), 1.89 - 2.04 (m, 7 H), 1.57 - 1.73 (m, 2 H), 1.30 - 1.54 (m, 4 H), 0.98 (t, J=7.33 Hz, 3 H). <n="53"/>LCMS (ESI): m/z 588.2 (M+Na)+HRMS: Calcd for C29H42BrNO5Na [M+Na]+: 586.2138. Found: 586.2132.

Reference： [1]Patent: WO2009/136281,2009,A1 .Location in patent: Page/Page column 51-52

44
[ 580-15-4 ]
[ 927-58-2 ]
[ 1221278-16-5 ]

Yield	Reaction Conditions	Operation in experiment
86%		4-Bromo-/V-quinolin-6-yl-butyramide (Intermediate compound); A mixture of 5-bromobuturylchloride (5.00 g, 25.6 mmol) and dichloromethane (50 ml) was cooled to 0C. 6-Aminoquinoline (3.43 g, 23.3 mmol) was added in small portions during 15 minutes. The temperature was allowed to reach room-temperature and stir for 15 h. Aqueous sodium hydroxide (40 ml, 1 M) was added and the mixture was extracted with dichloromethane (60 ml). The mixture was evaporated and diethylether (5 ml) was added, the solid was filtered and washed with diethylether. Yield 5.9 g (86%).

Reference： [1]Patent: WO2010/40808,2010,A1 .Location in patent: Page/Page column 10

45
[ 927-58-2 ]
[ 2216-51-5 ]
[ 1092777-14-4 ]

Yield	Reaction Conditions	Operation in experiment
97%	With pyridine In dichloromethane at 20℃;	1 Preparation of 4-bromobutanoic acid l-menthyl ester Preparative Example 1 Preparation of 4-bromobutanoic acid l-menthyl ester 14.6 g of l-menthol and 14.8 ml of pyridine were dissolved in 150 ml of dichloromethane, a solution obtained by dissolving 17.0 g of 4-bromobutyryl chloride in 20 ml of dichloromethane was slowly added dropwise thereto, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with 100 ml of water, and the solvent was removed under a reduced pressure, to obtain 27 g (97%) of the title compound as an oil. 1H-NMR (DMSO-d6, ppm): δ 4.7 (m, 1H), 3.5 (t, 2H), 2.5 (t, 2H), 2.2 (m, 2H), 2.0 (m, 1H), 1.9 (m, 1H), 1.7 (m, 2H), 1.5 (m, 1H), 1.3 (m, 1H), 1.1 (m, 3H), 0.9 (d, 6H), 0.7 (d, 3H). IR (KBr, cm-1): 2956, 2928, 2870, 1729, 1456, 1370, 1251, 1205, 1177, 1129, 984.
97%	With pyridine In dichloromethane at 20℃; for 1h;	Synthesis of 4-Bromobutanoic Acid l-Menthyl Ester:Intermediate for (R/S)-Bepotastine l-Menthyl Ester (3) Menthol (146 g, 0.93 mol) and 148 mL of pyridine were dissolved in 1500 mL of dichloromethane, a solution obtained by dissolving 4-bromobutyryl chloride (172 g, 0.93 mol) in 200 mL of dichloromethane was slowly added to the reaction mixture and stirred at rt for 1 h. The reaction mixture was washed with 1000 mL of water, and the solvent was removed under reduced pressure. The product was obtained 270 g (97%) as an oil.

Reference： [1]Current Patent Assignee: HANMI SCIENCE CO LTD - US2010/168433, 2010, A1 Location in patent: Page/Page column 4
[2]Ha, Tae Hee; Suh, Kwee-Hyun; Lee, Gwan Sun [Bulletin of the Korean Chemical Society, 2013, vol. 34, # 2, p. 549 - 552]

46
[ 693-05-0 ]
[ 927-58-2 ]
[ 1236765-29-9 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; at 20℃; for 2.08333h;Cooling with ice;	Example 66a; 3-(Methylamino)propanenitrile (841 mg) and triethylamine (2.1 ml) were dissolved in tetrahydrofuran (20 ml), and 4-bromobutanoyl chloride (2.04 g) dissolved in tetrahydrofuran (10 ml) was added thereto dropwise over 5 minutes under ice cooling. The mixture was stirred for 2 hours at room temperature. Subsequently, diethyl ether (20 ml) was added to the reaction solution, and precipitates generated therefrom were filtered, and the filtrate was concentrated under reduced pressure, to obtain a brown crude product. This crude product was purified by chromatography, and thus a brown oily substance (1.13 g) was obtained.

Reference： [1]Patent: US2010/190747,2010,A1 .Location in patent: Page/Page column 74

47
[ 6278-73-5 ]
[ 927-58-2 ]
[ 1236771-85-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	With triethylamine In tetrahydrofuran at 0 - 20℃;

Reference： [1]Location in patent: experimental part Kamal, Ahmed; Reddy, K. Srinivasa; Khan, M. Naseer A.; Shetti, Rajesh V.C.R.N.C.; Ramaiah, M. Janaki; Pushpavalli; Srinivas, Chatla; Pal-Bhadra, Manika; Chourasia, Mukesh; Sastry, G. Narahari; Juvekar, Aarti; Zingde, Surekha; Barkume, Madan [Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 13, p. 4747 - 4761]

48
[ 927-58-2 ]
[ 1237587-87-9 ]
[ 1237587-44-8 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In tetrahydrofuran at 20℃;	33 Production Example 33; To a solution of 525 mg of a compound obtained in Reference Production Example 23 as described later and 121 mg of triethylamine in 4 mL of tetrahydrofuran was added dropwise 223 mg of 4-bromobutyryl chloride at room temperature, followed by stirring for 1 hour. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 699 mg of a crude compound represented by the following formula (hereinafter referred to as the present compound (33)) . Present compound (33)
	With triethylamine In tetrahydrofuran at 20℃; for 1h;	33 Production Example 33 A quantity of 525 mg of the tert-butyl N-{2-chloro-5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl}carbazate obtained by Reference Production Example 23 and 121 mg of triethylamine were dissolved in 4 mL of tetrahydrofuran, and 223 mg of 4-bromobutyryl chloride was added dropwise at room temperature and stirred for one hour. Water was added to the reaction mixture, and it was extracted by ethyl acetate. The organic layer was dried by anhydrous sodium sulfate and concentrated under reduced pressure, and 699 mg of crude tert-butyl N'-(4-bromobutyryl)-N-{2-chloro-5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl}carbazate (refer to as hydrazide compound (33) in this specification) was obtained.
	With triethylamine In tetrahydrofuran at 20℃; for 1h;	33 Production Example 33 Production Example 33 In 4 mL of tetrahydrofuran were dissolved 525 mg of the tert-butyl N-{2-chloro-5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl}carbazate obtained by Reference Production Example 23 and 121 mg of triethylamine, and 223 mg of 4-bromobutyryl chloride was added dropwise thereto at room temperature, and then the mixture was stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 699 mg of crude tert-butyl N'-(4-bromobutyryl)-N-{2-chloro-5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl}carbazate (herein referred to as the present hydrazide compound (33).).

	With triethylamine In tetrahydrofuran at 20℃; for 1h;	33 Production Example 33 Production Example 33 In 4 mL of tetrahydrofuran were dissolved 525 mg of the tert-butyl N-{2-chloro-5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl}carbazate obtained by Reference Production Example 23 and 121 mg of triethylamine, and 223 mg of 4-bromobutyryl chloride was added dropwise thereto at room temperature, and then the mixture was stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 699 mg of crude tert-butyl N'-(4-bromobutyryl)-N-{2-chloro-5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl}carbazate (herein referred to as the present hydrazide compound (33).).
	With triethylamine In tetrahydrofuran at 20℃; for 1h;	33 Production Example 33 Production Example 33 In 4 mL of tetrahydrofuran were dissolved 525 mg of the tert-butyl N-{2-chloro-5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl}carbazate obtained by Reference Production Example 23 and 121 mg of triethylamine, and 223 mg of 4-bromobutyryl chloride was added dropwise thereto at room temperature, and then the mixture was stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 699 mg of crude tert-butyl N'-(4-bromobutyryl)-N-{2-chloro-5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl}carbazate (herein referred to as the present hydrazide compound (33).).
	With triethylamine In tetrahydrofuran at 20℃; for 1h;	33 Production Example 33 Production Example 33 In 4 mL of tetrahydrofuran were dissolved 525 mg of the tert-butyl N-{2-chloro-5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl}carbazate obtained by Reference Production Example 23 and 121 mg of triethylamine, and 223 mg of 4-bromobutyryl chloride was added dropwise thereto at room temperature, and then the mixture was stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 699 mg of crude tert-butyl N'-(4-bromobutyryl)-N-{2-chloro-5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl}carbazate (herein referred to as the present hydrazide compound (33).).
699 mg	With triethylamine In tetrahydrofuran at 20℃; for 1h;	P.33 Production Example 33 Production Example 33 In 4 mL of tetrahydrofuran were dissolved 525 mg of the tert-butyl N-{2-chloro-5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl}carbazate obtained by Reference Production Example 23 and 121 mg of triethylamine, and 223 mg of 4-bromobutyryl chloride was added dropwise thereto at room temperature, and then the mixture was stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 699 mg of crude tert-butyl N'-(4-bromobutyryl)-N-{2-chloro-5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl}carbazate (herein referred to as the present hydrazide compound (33)).

Reference： [1]Current Patent Assignee: SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Chemical (w/o Dongwoo Fine-Chem) - WO2010/90344, 2010, A1 Location in patent: Page/Page column 110
[2]Current Patent Assignee: SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Chemical (w/o Dongwoo Fine-Chem) - US2012/35218, 2012, A1 Location in patent: Page/Page column 33
[3]Current Patent Assignee: SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Chemical (w/o Dongwoo Fine-Chem) - US2013/131115, 2013, A1 Location in patent: Paragraph 0699
[4]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - US2013/131117, 2013, A1 Location in patent: Paragraph 0741
[5]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - US2013/131116, 2013, A1 Location in patent: Paragraph 0904; 0905
[6]Current Patent Assignee: SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Chemical (w/o Dongwoo Fine-Chem) - US2013/131118, 2013, A1 Location in patent: Paragraph 0954; 0955; 0956
[7]Current Patent Assignee: SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Chemical (w/o Dongwoo Fine-Chem) - US2013/137682, 2013, A1 Location in patent: Paragraph 0775; 0776

49
[ 927-58-2 ]
[ 144243-24-3 ]
[ 1240315-22-3 ]

Yield	Reaction Conditions	Operation in experiment
57%	With triethylamine In dichloromethane at 22℃; Inert atmosphere;	1 Intermediate 1 1,1-Dimethylethyl 3-[(4-bromobutanoyl)amino]-1-piperidinecarboxylate (D1) To a solution of 3-amino-1-N-Boc-piperidine (1.5g, 7.49mmol) in dichloromethane (6OmL), cooled to O0C under argon, was added triethylamine (9.74mmol, 1.36ml_) followed by the dropwise addition of 4-bromobutyryl chloride (8.99mmol, 1.04ml_). The reaction was allowed to warm in temperature to 22 0C and stirred for 4 days and 5 hours. The reaction was diluted with dichloromethane (10OmL) and the solution washed with 1 N hydrochloric acid (10OmL), water (5OmL) and saturated sodium bicarbonate solution (5OmL). The organic layer was passed though a hydrophobic frit and reduced in vacuo to yield a colourless oil.The compound was purified by silica chromatography (Biotage SP4, eluting with 20% EtOAc in hexane (5 column volumes), 20-50% (over 10 column volumes)) to yield the title compound as a white solid (1.5Og, 57%)1H NMR (DMSO) δ 1.34 (1H, m), 1.38 (9H, s), 1.67 (1H, m), 1.76 (1H, m), 1.93 (2H, m), 2.22 (2H, m), 2.89 (2H, br s), 3.54 (2H, br s), 3.63 (2H, t, J=7Hz), 3.74 (2H, br s), 7.83 (1H, d, J=7Hz)

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2010/91721, 2010, A1 Location in patent: Page/Page column 14-15

50
[ 927-58-2 ]
[ 1633-22-3 ]
[ 1250265-63-4 ]

Yield	Reaction Conditions	Operation in experiment
79%	With aluminum (III) chloride In dichloromethane at -50 - -20℃; for 0.333333h;

Reference： [1]Location in patent: experimental part Skultety, Marika; Hübner, Harald; Löber, Stefan; Gmeiner, Peter [Journal of Medicinal Chemistry, 2010, vol. 53, # 19, p. 7219 - 7228]

51
[ 927-58-2 ]
[ 6038-19-3 ]
[ 1268997-97-2 ]

Yield	Reaction Conditions	Operation in experiment
25%	With sodium hydroxide; In water; ethyl acetate; at 0 - 20℃; for 1h;	Synthesis of conjugate (QS0108-Cip): (D,L)-4-bromo-N-(2-oxotetrahydrothiophen-3-yl) butanamide.; <strong>[6038-19-3]D,L-homocysteine thiolactone hydrochloride</strong> (5.2 g, 34 mmol) was dissolved in water and covered with ethyl acetate. The solution was cooled to 0 C. and the acid chloride (7.06, 38 mmol) was added dropwise. Subsequently 1 N NaOH was added dropwise (44.2 mmol). The mixture was stirred for 1 h during which the temperature of the reaction warmed to ambient temperature. No precipitate was observed, however, TLC analysis (10% MeOH/methylene chloride; v/v) indicated all the starting material (dissolved in saturated NaHCO3 before spotting the TLC) had been consumed. The reaction mixture was extracted several times with ethyl acetate. The ethyl acetate was dried over Na2SO4, filtered, and the solvent was removed in vacuo to give 2.24 g of an off-white solid (25% yield).

Reference： [1]Patent: US2011/53890,2011,A1 .Location in patent: Page/Page column 4

52
[ 927-58-2 ]
[ 148546-78-5 ]
[ 1325188-71-3 ]

Yield	Reaction Conditions	Operation in experiment
42.1%	Stage #1: 4-bromobutyroyl chloride; 4-methoxy-3-(4-methyl-1-piperazinyl)benzeneamine With disodium hydrogenphosphate In chloroform at 20℃; Stage #2: With sodium methylate In methanol for 16h;	Preparation of 5This protocol was performed according to conditions disclosed in Tetrahedron 2001, 57 (47), 9635.To a suspension of disodium phosphate (0.257 g, 1.808 mmol) in chloroform (4 ml) compound 4a (0.2 g, 0.904 mmol) was added and stirred followed by dropwise addition of 4-bromobutanoyl chloride (0.105 ml, 0.904 mmol) at rt. Reaction mixture was stirred at rt. for 16 h and filter through Celite plug, filtrate was concentrated in vacuo and directly used for next step. The crude product was added to a solution of sodium methoxide (0.090 ml, 2.166 mmol) in MeOH (2 ml) and the resulting mixture was stirred at rt. for 16 h. Solvents were evaporated and the crude product was added to a silica gel column and was eluted with 15 % MeOH in CHCh to obtain pure product 5a, 0.11 g (42.1 %).
42.1%	Stage #1: 4-bromobutyroyl chloride; 4-methoxy-3-(4-methyl-1-piperazinyl)benzeneamine With disodium hydrogenphosphate In chloroform at 20℃; for 16h; Stage #2: With sodium methylate In methanol at 20℃; for 16h;	Preparation of 5 [0565] Preparation of 5 [0566] This protocol was performed according to conditions disclosed in Tetrahedron 2001, 57 (47), 9635. [0567] To a suspension of disodium phosphate (0.257 g, 1.808 mmol) in chloroform (4 ml) compound 4a (0.2 g, 0.904 mmol) was added and stirred followed by dropwise addition of 4-bromobutanoyl chloride (0.105 ml, 0.904 mmol) at rt. Reaction mixture was stirred at rt. for 16 h and filter through Celite plug, filtrate was concentrated in vacuo and directly used for next step. The crude product was added to a solution of sodium methoxide (0.090 ml, 2.166 mmol) in MeOH (2 ml) and the resulting mixture was stirred at rt. for 16 h. Solvents were evaporated and the crude product was added to a silica gel column and was eluted with 15% MeOH in CHCl3 to obtain pure product 5a, 0.11 g (42.1%).

Reference： [1]Current Patent Assignee: UNIVERSITY OF CAMBRIDGE - WO2011/98776, 2011, A1 Location in patent: Page/Page column 58
[2]Current Patent Assignee: UNIVERSITY OF CAMBRIDGE - US2013/53372, 2013, A1 Location in patent: Paragraph 0565; 0566; 0567

53
[ 927-58-2 ]
[ 129791-92-0 ]
[ 947537-74-8 ]

Yield	Reaction Conditions	Operation in experiment
90%	With pyridine In dichloromethane at 0 - 20℃; for 16h;	21-O-(4-bromobutanoyl)-1',4-Didehydro-1-deoxy-1,4-dihydro-3'-hydroxy-5'-[4-(2-methylpropyl)-1-piperazinyl]-1-oxorifamycin VIII (79): 4-Bromobutyryl chloride (2.18 mL, 18.82 mmol) was added drop wise to a cooled (0° C.) solution of rifalzil (11.80 g, 12.55 mmol), pyridine (3.04 mL, 37.65 mmol) and DMAP (153 mg, 1.25 mmol) in dichloromethane (150 mL). After stirring for 16 h at ambient temperature, the reaction mixture was diluted with dichloromethane (800 mL) and washed successively with water (2×500 mL) and brine (2×500 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel chromatography with 60-100% ethyl acetate/hexanes and then 1-5% MeOH/CH2Cl2 to afford 79 (12.40 g, 90% yield). Mass calculated for C55H69BrN4O14: 1090. found: 1091 (M+H).

Reference： [1]Current Patent Assignee: MELINTA THERAPEUTICS INC. - US2011/263534, 2011, A1 Location in patent: Page/Page column 98

54
[ 927-58-2 ]
[ 141781-17-1 ]
[ 1338582-78-7 ]
[ 1338582-77-6 ]

Yield	Reaction Conditions	Operation in experiment
70%	With tetrabutylammomium bromide; sodium carbonate In dichloromethane; water at 20℃;	4.3.1. General procedure for the synthesis of 3-N-monocarbonyl TSAO-T derivatives (3-6) General procedure: TSAO-T (1 mmol), Na2CO3 (8 mmol) and Bu4NBr (0.1 mmol) were dissolved in a mixture of CH2Cl2 and water (1/2 V/V). Acylated reactant (1.2 mmol) was added to the mixture with vigorous stirring at room temperature until disappearance of the starting material (TLC monitoring). Water and CH2Cl2 were added; the organic phase was separated, washed with water (3 times), dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography followed by crystallization from water to give the final product.

Reference： [1]Location in patent: experimental part Moura, Marina; Josse, Solen; Van Nhien, Albert Nguyen; Fournier, Carole; Duverlie, Gilles; Castelain, Sandrine; Soriano, Elena; Marco-Contelles, José; Balzarini, Jan; Postel, Denis [European Journal of Medicinal Chemistry, 2011, vol. 46, # 10, p. 5046 - 5056]

55
[ 629-76-5 ]
[ 927-58-2 ]
[ 959258-35-6 ]

Yield	Reaction Conditions	Operation in experiment
88%	In dichloromethane at 0 - 20℃; for 4.5h; Inert atmosphere;	3 4-bromobutyl chloride (1 eq.) was dissolved in dichloromethane (50mL) and the reaction flask was cooled to about 0°C using an ice bath. To the above mixture, 1- pentadecanol (1 eq.) in dichloromethane (50mL) was added slowly using a pressure- equalizing addition funnel over a period of about 30 min. To the resulting above mixture, a catalytic amount (5 drops) of concentrated sulfuric acid was added. The reaction mixture was stirred at about 0°C for about 30 minutes and then stirred at room temperature for four hours. The reaction mixture was transferred to a separatory funnel and the organic layer was washed with saturated sodium bicarbonate (x3), water (x2), brine (xl). The organic layer was dried over sodium sulfate, filtered and concentrated to give the desired product, pentadecyl-4- bromobutanoate as colorless oil (88% yield).

Reference： [1]Current Patent Assignee: THERMO FISHER SCIENTIFIC INC - WO2012/68176, 2012, A1 Location in patent: Page/Page column 101

56
[ 866837-96-9 ]
[ 927-58-2 ]
C₁₆H₁₇N₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		5-(2-Oxo-pyrrolidin-1 -yl)-1 -phenyl-1 H-pyrazole-3-carboxylic acid; 700mg (3,0 mmol) of 5-Amino-1 -phenyl-1 H-pyrazole-3-carboxylic acid ethyl ester are dissolved in 20ml of dioxane and added to a suspension of NaH (266mg 60% suspension in mineral oil, 6,66mmol) in 10 ml of dioxane. After stirring for l Ominutes at RT 4-bromobutyryl chloride (617,5mg, 3,3mmol) is added and the resulting mixture is stirred overnight at RT. A MeOH/H20 mixture (10ml, 1 : 1 ) is added to destroy excess NaH and the solvent is removed in vacuo. The crude product is redissolved in 15 ml of EtOH and 8mmol of 1 M NaOH is added and the mixture is stirred overnight. The solvent is removed in vacuo and the residue subjected to HPLC chromatography: Yield: 554mg,. 68%
		5-(2-Oxo-pyrrolidin-1-yl)-1-phenyl-1H-pyrazole-3-carboxylic acid700 mg (3.0 mmol) of 5-Amino-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester are dissolved in 20 ml of dioxane and added to a suspension of NaH (266 mg 60% suspension in mineral oil, 6.66 mmol) in 10 ml of dioxane. After stirring for 10 minutes at RT 4-bromobutyryl chloride (617.5 mg, 3.3 mmol) is added and the resulting mixture is stirred overnight at RT. A MeOH/H2O mixture (10 ml, 1:1) is added to destroy excess NaH and the solvent is removed in vacuo. The crude product is redissolved in 15 ml of EtOH and 8 mmol of 1M NaOH is added and the mixture is stirred overnight. The solvent is removed in vacuo and the residue subjected to HPLC chromatography: Yield: 554 mg,. 68%

Reference： [1]Patent: WO2012/101199,2012,A1 .Location in patent: Page/Page column 86
[2]Patent: US2012/232112,2012,A1 .Location in patent: Page/Page column 29

57
[ 927-58-2 ]
[ 224436-97-9 ]
[ 1133000-40-4 ]

Yield	Reaction Conditions	Operation in experiment
72%	With pyridine In N,N-dimethyl-formamide; acetone at 0 - 20℃; for 1h;	12a Step 12a: 4-Bromo-N-(5-((5-tert-butyloxazol-2-yl)methylthio)thiazol-2-yl)- butanamide (Compound 0401-13)To a stirred mixture of compound 0108 (13.5g, 0.05 mol) and pyridine (5g) in dimethylformamide (100 ml) was added a solution of 4-bromobutanoyl chloride (14 g, 0.075 mol) in acetone (25 ml) over a period of 2-3 min, while maintaining at 0- 5°C. The resulting mixture was allowed to warm to r.t. and stirred for additional 1 h. To the mixture 1 M HCl (20 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (30 mLx4 ), dried and concentrated to afford the crude product compound 0401-13 as a yellow solid (15 g, 72 % yield). 1H NMR (DMSO-d6) δ 12.30 (s, IH), 7.38 (s, IH), 6.71 (s, IH), 4.05 (s, 2H), 3.56 (t, J= 6.6Hz, 2H), 2.58 (t, J= 6.6Hz, 2H), 2.08-2.13 (m, 2H), 1.18 (s, 9H). LC-MS: 419(M+l).

Reference： [1]Current Patent Assignee: CURIS INC - WO2009/36016, 2009, A1 Location in patent: Page/Page column 63

58
[ 927-58-2 ]
[ 626-01-7 ]
[ 1426918-48-0 ]

Yield	Reaction Conditions	Operation in experiment
64%	With triethylamine In dichloromethane at 20℃;	20.1 20.1: 4-Bromo-N-(3-iodo-phenyl)-butyramide 20.1: 4-Bromo-N-(3-iodo-phenyl)-butyramide To a solution of 3-iodoaniline (1.5 g, 6.85 mmol) and triethylamine (1.34 mL, 9.59 mmol) in dichloromethane (28 mL) at 0°C was added dropwise 4-bromobutyryl chloride (0.99 mL, 8.56 mmol). The reaction mixture was then stirred at room temperature overnight. The organic extract was washed with an aqueous 1 M HCl solution, aqueous 1M NaOH solution and brine, dried (Na2SO4), filtered, concentrated under vacuum. The crude residue was purified by silica gel column chromatography using a gradient of EtOAc (0-15%) in cyclohexane to yield a sticky solid. Trituration in a mixture of cyclohexane and ether and then filtration give the title compound as a solid (1.61 g, 64%). 1H NMR (400 MHz, CDCl3): δ 2.17-2.33 (m, 2H), 2.58 (t, 2H), 3.54 (t, 1H), 3.68 (t, 1H), 7.03-7.08 (m, 1H), 7.32-7.51 (m, 3H), 7.96 (s, 1H).
64%	With triethylamine In dichloromethane at 20℃;	20.1 20.1: 4-Bromo-N-(3-iodo-phenyl)-butyramide 20.1: 4-Bromo-N-(3-iodo-phenyl)-butyramide To a solution of 3-iodoaniline (1.5 g, 6.85 mmol) and triethylamine (1.34 mL, 9.59 mmol) in dichloromethane (28 mL) at 0° C. was added dropwise 4-bromobutyryl chloride (0.99 mL, 8.56 mmol). The reaction mixture was then stirred at room temperature overnight. The organic extract was washed with an aqueous 1M HCl solution, aqueous 1M NaOH solution and brine, dried (Na2SO4), filtered, concentrated under vacuum. The crude residue was purified by silica gel column chromatography using a gradient of EtOAc (0-15%) in cyclohexane to yield a sticky solid. Trituration in a mixture of cyclohexane and ether and then filtration give the title compound as a solid (1.61 g, 64%). 1H NMR (400 MHz, CDC3): δ 2.17-2.33 (m, 2H), 2.58 (t, 2H), 3.54 (t, 1H), 3.68 (t, 1H), 7.03-7.08 (m, 1H), 7.32-7.51 (m, 3H), 7.96 (s, 1H).
64%	With triethylamine In dichloromethane at 0 - 20℃;	20.1 20.1 : 4-Bromo-N-(3-iodo-phenyl)-butyramide 20.1 : 4-Bromo-N-(3-iodo-phenyl)-butyramide To a solution of 3-iodoaniline (1.5 g, 6.85 mmol) and triethylamine (1 .34 ml_,9.59 mmol) in dichloromethane (28 ml_) at 0°C was added dropwise 4-bromobutyryl chloride (0.99 ml_, 8.56 mmol). The reaction mixture was then stirred at room tem- perature overnight. The organic extract was washed with an aqueous 1 M HCI solution, aqueous 1 M NaOH solution and brine, dried (Na2S04), filtered, concentrated under vacuum. The crude residue was purified by silica gel column chromatography using a gradient of EtOAc (0-15%) in cyclohexane to yield a sticky solid. Trituration in a mixture of cyclohexane and ether and then filtration give the title compound as a solid (1 .61 g, 64%).1 H N MR (400 MHz, CDCI3): 5 2.17-2.33 (m, 2H), 2.58 (t, 2H), 3.54 (t, 1 H), 3.68 (t, 1 H), 7.03-7.08 (m, 1 H), 7.32-7.51 (m, 3H), 7.96 (s, 1 H).

Reference： [1]Current Patent Assignee: SANOFI - EP2567959, 2013, A1 Location in patent: Paragraph 0438; 0439
[2]Current Patent Assignee: SANOFI - US2013/65894, 2013, A1 Location in patent: Paragraph 0989; 0990
[3]Current Patent Assignee: SANOFI - WO2013/37390, 2013, A1 Location in patent: Page/Page column 191-192

59
[ 927-58-2 ]
[ 381676-95-5 ]
[ 1435516-37-2 ]

Yield	Reaction Conditions	Operation in experiment
53%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃;	Intermediate 28.5-(3-bromopropyl)-3-{4-[(tetrahydro-2H-pyran-2-yloxy)methyl]phenyl}-1 ,2,4- oxadiazole To a solution of /V-hydroxy-4-[(tetrahydro-2/-/-pyran-2-yloxy)methyl]benzene- carboximidamide (Intermediate 27; 21 1 mg, 0.84mmol) in DCM (3mL) was added DIEA (0.176mL, 1 .01 mmol). The mixture was cooled to 0°C and a solution of 4- bromobutanoyl chloride (0.108mL, 0.88mmol) in DCM (1 mL) was added dropwise. The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the crude obtained was purified by column chromatography with silica gel, eluting with a mixture of Hexane: ether give the title compound as a solid (198mg, 53%).LRMS (m/z): 382 (M+1 )+
53%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃;	Intermediate 28.5-(3-bromopropyl)-3-{4-[(tetrahydro-2H-pyran-2-yloxy)methyl]phenyl}-1 ,2,4- oxadiazole Intermediate 28.5-(3-bromopropyl)-3-{4-[(tetrahydro-2H-pyran-2-yloxy)methyl]phenyl}-1 ,2,4- oxadiazoleTo a solution of /V-hydroxy-4-[(tetrahydro-2/-/-pyran-2-yloxy)methyl]benzene- carboximidamide (Intermediate 27; 21 1 mg, 0.84mmol) in DCM (3mL) was added DIEA (0.176mL, 1 .01 mmol). The mixture was cooled to 0°C and a solution of 4- bromobutanoyl chloride (0.108mL, 0.88mmol) in DCM (1 mL) was added dropwise. The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the crude obtained was purified by column chromatography with silica gel, eluting with a mixture of Hexane: ether give the title compound as a solid (198mg, 53%).LRMS (m/z): 382 (M+1 )+

Reference： [1]Current Patent Assignee: ALMIRALL SA - WO2013/68552, 2013, A1 Location in patent: Page/Page column 50; 51
[2]Current Patent Assignee: ALMIRALL SA - WO2013/68554, 2013, A1 Location in patent: Page/Page column 60-61

60
[ 927-58-2 ]
[ 1351586-51-0 ]
[ 1351586-52-1 ]

Yield	Reaction Conditions	Operation in experiment
90%	In dichloromethane at 0 - 20℃; for 20h;	18 Synthesis of nonadeca-l,18-dien-10-yl 4-bromobutanoate (250) To a solution of the alcohol 249 (5.6 g, 20 mol) in anhydrous DCM (300 mL) was added slowly and carefully Bromobutryl chloride (20 mmol) at 0° C under inert atmosphere. The reaction mixture was warmed to room temperature, stirred for 20 h and monitored by TLC (silica gel, 10% ethyl acetate in hexanes). Upon completion of the reaction, mixture was diluted with water (400 mL) and organic layer was separated out. Organic phase was then washed with sat. solution of NaHC03 (1 x 400 mL) followed by brine (1 x 100 mL) and concentrated under vacuum. Crude product was then purified by silica gel (100-200mesh) column, eluted with 2-3% ethyl acetate in hexane solution to give 6 g (90%) of desired product 250 as colorless liquid. 1H NMR (400 MHz, CDC13) δ 5.80 (ddt, J = 16.9, 10.2, 6.7 Hz, 2H), 5.05 - 4.81 (m, 5H), 3.46 (t, J = 6.5 Hz, 2H), 2.48 (t, J = 7.2 Hz, 2H), 2.17 (p, J = 6.8 Hz, 2H), 2.11 - 1.93 (m, 4H), 1.65 - 1.44 (m, 4H), 1.43 - 1.17 (m, 19H). 13C NMR (101 MHz, cdcl3) δ 172.51, 139.37, 114.35, 77.54, 77.23, 76.91, 74.86, 34.31, 33.99, 33.01, 32.96, 29.65, 29.56, 29.24, 29.09, 28.11, 25.52.
90%	With sodium hydrogencarbonate In ethyl acetate at 0 - 20℃; for 20h; Inert atmosphere;	8 Synthesis of nonadeca-1,18-dien-10-yl 4-bromobutanoate (12) Synthesis of nonadeca-1,18-dien-10-yl 4-bromobutanoate (12) To a solution of the alcohol 11 (5.6 g, 20 mol) in anhydrous DCM (300 mL) was added slowly and carefully Bromobutryl chloride (20 mmol) at 0° C. under inert atmosphere. The reaction mixture was warmed to room temperature, stirred for 20 h and monitored by TLC (silica gel, 10% ethyl acetate in hexanes). Upon completion of the reaction, mixture was diluted with water (400 mL) and organic layer was separated out. Organic phase was then washed with sat. solution of NaHCO3 (1400 mL) followed by brine (1100 mL) and concentrated under vacuum. Crude product was then purified by silica gel (100-200 mesh) column, eluted with 2-3% ethyl acetate in hexane solution to give 6 g (90%) of desired product 12 as colorless liquid. 1H NMR (400 MHz, CDCl3) δ 5.80 (ddt, J=16.9, 10.2, 6.7 Hz, 2H), 5.05-4.81 (m, 5H), 3.46 (t, J=6.5 Hz, 2H), 2.48 (t, J=7.2 Hz, 2H), 2.17 (p, J=6.8 Hz, 2H), 2.11-1.93 (m, 4H), 1.65-1.44 (m, 4H), 1.43-1.17 (m, 19H). 13C NMR (101 MHz, cdcl3) δ 172.51, 139.37, 114.35, 77.54, 77.23, 76.91, 74.86, 34.31, 33.99, 33.01, 32.96, 29.65, 29.56, 29.24, 29.09, 28.11, 25.52.

Reference： [1]Current Patent Assignee: ALNYLAM PHARMACEUTICALS INC - WO2013/86354, 2013, A1 Location in patent: Page/Page column 164
[2]Current Patent Assignee: ALNYLAM PHARMACEUTICALS INC; VECTOR VITALE IP, LLC, - US2016/9637, 2016, A1 Location in patent: Paragraph 0469; 0471

61
[ 927-58-2 ]
[ 288318-08-1 ]
[ 1443522-08-4 ]

Yield	Reaction Conditions	Operation in experiment
66.7%	With dmap In dichloromethane at 20℃; for 14h;	27 Compound 522: To a stirred solution of 521 (10 g, 29.73 mmol) and DMAP (0.1 g, 0.82 mmol) in dry DCM (50 mL) was added 4-bromo butyryl chloride (6.56 g, 35.68 mmol) and stirred at room temperature for 14 h. 5 mL of saturated NaHC03 was added and the organic layer was separated and dried over anhydrous Na2S04. Concentration of the solvent gave the crude product which was purified by column chromatography (0- 10 % ethyl acetate in hexane) to yield compound 522 (9.6 g, 66.7 , Rf: 0.9, 5 % ethyl acetate in hexane).

Reference： [1]Current Patent Assignee: ALNYLAM PHARMACEUTICALS INC - WO2013/86354, 2013, A1 Location in patent: Page/Page column 184

62
[ 927-58-2 ]
[ 1433887-72-9 ]
[ 1433893-25-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With triethylamine In tetrahydrofuran at 20℃; for 0.5h;	92.A Step A: l-(3-Isopropyl-l,2,4-thiadiazol-5-yl)piperidin-4-amine hydrochloride (500 mg, 1.90 mmol) was suspended in THF (20 mL). Triethylamine (663 μ, 4.76 mmol) and 4-bromobutanoyl chloride (265 μ, 2.28 mmol) were added and stirred at ambient temperature for 30 minutes. The reaction was partitioned between water and EtOAc, dried over MgS04, filtered, and concentrated to afford 4-bromo-N-(l-(3-isopropyl-l,2,4-thiadiazol- 5-yl)piperidin-4-yl)butanamide (711 mg, 1.89 mmol, 99% yield) as a white solid.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2013/66869, 2013, A1 Location in patent: Paragraph 00530

63
[ 927-58-2 ]
[ 100-66-3 ]
1-(4-methoxyphenyl)-4-bromo-1-butanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: 4-bromobutyroyl chloride With aluminum (III) chloride In dichloromethane at 0℃; for 0.166667h; Stage #2: methoxybenzene In dichloromethane at 0 - 20℃; for 1h;	20.17 (17) 4-Bromo-1-(4-methoxyphenyl)butan-1-one AlCl3 (740 mg, 5.55 mmol) to DCM (23 mL) and then dissolved, 4-bromobutyryl chloride (643 , 5.55 mmol) was slowly added dropwise to a 0 in. After 10 minutes, then slowly added dropwise to the reaction solution at the same temperature for an anisole (503 , 4.63 mmol), and stirred for one hour at room temperature. After checking the completion of the reaction by TLC, the reaction solution was diluted with DCM, it poured into ice water to 0 . After extracting the mixture with a saturated Na2CO3 aqueous solution, and concentrated after drying the organic layer with anhydrous Na2SO4, the residue was filtered under reduced pressure, the concentrated filtrate was purified by column chromatography (Hex: EtOAc = 7: 1). Compound 181 by using a (1.03 g, 86% , it was synthesized lightyellow oil).
	With aluminum (III) chloride In dichloromethane at 0 - 20℃; for 2h;
	With aluminum (III) chloride In dichloromethane at 0 - 20℃; Inert atmosphere;

With aluminum (III) chloride In dichloromethane at 0 - 20℃; Inert atmosphere;

Reference： [1]Current Patent Assignee: KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY; UNIVERSITY OF ULSAN - KR101525019, 2015, B1 Location in patent: Paragraph 1142; 1212-1214
[2]Shim, Young Sun; Hwang, Hyun Sook; Nam, Ghilsoo; Choi, Kyung Il [Bulletin of the Korean Chemical Society, 2013, vol. 34, # 8, p. 2317 - 2320]
[3]Huang, Fei; Zhang, Songlin [Organic Letters, 2019, vol. 21, # 18, p. 7430 - 7434]
[4]Wang, Yiqiong; Huang, Fei; Zhang, Songlin [European Journal of Organic Chemistry, 2020, vol. 2020, # 32, p. 5178 - 5181]

64
[ 927-58-2 ]
[ 166176-45-0 ]
4-bromo-N-(6-chloroimidazo[1,2-b]pyridazin-3-yl)butanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With pyridine; In tetrahydrofuran; at 20℃; for 1.0h;	To 1.0 g (5.930 mmol) of <strong>[166176-45-0]6-chloroimidazo[1,2-b]pyridazin-3-amine</strong> dissolved in 15 ml of THFwas added 4-bromobutanoyl chloride (1.21 g, 6.52 mmol) and pyridine (0.96 ml, 11.86 mmol). Thismixture was stirred for 1 hr at rt, and then diluted with 30 ml EtOAc and quenched with aq. NaHC03.The organic layer was separated and washed with brine, dried over MgS04, and concentrated. The10 solid obtained (1.39 g, 7 4% yield) was pure enough to be used for the next step without furtherpurification.

Reference： [1]Patent: WO2013/134219,2013,A1 .Location in patent: Page/Page column 100

65
[ 927-58-2 ]
[ 168297-86-7 ]
(4S)-3-(4-bromo-1-oxobutyl)-4-isopropyl-5,5-dimethyl-1,3-oxazolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	Stage #1: (S)-4-isopropyl-5,5-dimethyloxazolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at -80℃; for 0.666667h; Inert atmosphere; Stage #2: 4-bromobutyroyl chloride In tetrahydrofuran; hexane at -80℃; for 2h; Inert atmosphere;	(4S)-3-(4-bromobutanoyl)-4-isopropyl-5,5-dimethyl-1,3-oxazolidin-2-one (9) A 2.0 M solution of n-butyllithium in hexane (3.2 ml, 6.37 mmol) was added to a stirred solution of oxazolidinone 8 (0.50 g, 3.18 mmol) in dry tetrahydrofuran (20 ml) under Ar at -80 °C, the mixture was stirred for 40 min, and a solution of 4-bromobutyryl chloride (0.77 g, 4.15 mmol) in tetrahydrofuran (5 ml) was added dropwise.The reaction mixture was stirred for 2 h at -80 °C and then allowed to warm to -60 °C, followed by addition of a solution of tetrahydrofuran-water (4:1, 20 ml). The mixture was allowed to reach room temperature and then was treated with a saturated solution of ammonium chloride. The organic phase was separated, the aqueous phase was extracted with ethyl acetate (2 × 30 ml), the extracts were combined with the organic phase and dried over MgSO4, filtered, and evaporated. Purification of the product by column chromatography (30% ethyl acetate/light petroleum) afforded product 9 (0.81 g, 84%) as a light yellow oil
81%	Stage #1: (S)-4-isopropyl-5,5-dimethyloxazolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at -80℃; for 0.25h; Stage #2: 4-bromobutyroyl chloride In tetrahydrofuran at -80 - -60℃; for 1h;

Reference： [1]Valeev, Ruslan F.; Bikzhanov, Radmir F.; Miftakhov, Mansur S. [Mendeleev Communications, 2014, vol. 24, # 6, p. 372 - 373]
[2]Valeev; Bikzhanov; Miftakhov [Russian Journal of Organic Chemistry, 2014, vol. 50, # 10, p. 1511 - 1519][Zh. Org. Khim., 2014, vol. 50, # 10, p. 1523 - 1531,9]

66
[ 927-58-2 ]
[ 19056-40-7 ]
1-(4-bromo-3-methoxyphenyl)pyrrolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71.8%	Stage #1: 4-bromobutyroyl chloride; 4-bromo-3-methoxyaniline With potassium hydroxide In dichloromethane at 0 - 20℃; for 1h; Inert atmosphere; Stage #2: With tetrabutylammomium bromide; potassium hydroxide In dichloromethane at 20℃; for 1h;	23.1 Step 1: 1 -(4-Bromo-3-methoxyphenyl)pyrrolidin-2-one Step 1: 1 -(4-Bromo-3-methoxyphenyl)pyrrolidin-2-one Under an atmosphere of nitrogen, in a 100 mL round-bottomed flask at 0 °C, 4-bromo-3- methoxyaniline (2 g, 9.9 mmol) and KOH (6.93 ml, 13.9 mmol) were combined with dichloromethane (30 ml) to give a light brown solution. Then 4-bromobutanoyl chloride (1.84 g, 1.15 ml, 9.9 mmol) was added. The reaction was stined for 1 h at RT. The reaction mixture was poured into 50 ml dichioromethane and extracted with water (3 x 20 ml). The organic layer was dried over Na2SO4 and concentrated in vacuo.The residue was dissolved in 30m1 dichloromethane. Then tetrabutylammonium bromide (63.8 mg, 198 imol) and KOH (50 %, 6 ml) were added. The reaction was stirred for 1 h at RT. The reaction mixture was poured into dichloromethane (50 ml) and extracted with water (3 x 20 ml).The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 50 g, 20 % to 50 % EtOAc in heptane). The title compound was obtained as a off-white crystalline (1.92 g, 71.8 %). MS (mle) = 272.1 [M+H].
71.8%	Stage #1: 4-bromobutyroyl chloride; 4-bromo-3-methoxyaniline With potassium hydroxide In dichloromethane at 0 - 20℃; for 1h; Inert atmosphere; Stage #2: With tetrabutylammomium bromide; potassium hydroxide In dichloromethane at 20℃; for 1h;	23.1 Step 1:1 -(4-l3romo-3-methoxyphenyl)pyrrolidin-2-one Under an atmosphere of nitrogen, in a 100 mL round-bottomed flask at 0° C., 4-bromo-3-methoxyaniline (2 g, 9.9 mmol) and KOH (6.93 ml, 13.9 mmol) were combined with dichloromethane (30 ml) to give a light brown solution. Then 4-bromobutanoyl chloride (1.84 g, 1.15 ml, 9.9 mmol) was added. The reaction was stirred for 1 h at RT. The reaction mixture was poured into 50 ml dichloromethane and extracted with water (320 ml). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in 30 ml dichloromethane. Then tetrabutylammonium bromide (63.8 mg, 198 μmol) and KOH (50%, 6 ml) were added. The reaction was stirred for 1 h at RT. The reaction mixture was poured into dichloromethane (50 ml) and extracted with water (320 ml). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 50 g, 20% to 50% EtOAc in heptane). The title compound was obtained as a off-white crystalline (1.92 g, 71.8%). MS (m/e)=272.1 [M+H]+.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2015/107053, 2015, A1 Location in patent: Page/Page column 38; 39
[2]Current Patent Assignee: ROCHE HOLDING AG - US2016/326150, 2016, A1 Location in patent: Paragraph 0243; 0244

67
[ 927-58-2 ]
[ 700-12-9 ]
4-bromo-1-(2,3,4,5,6-pentamethylphenyl)butan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With aluminum (III) chloride In dichloromethane at 0℃; for 3h;
86%	With aluminum (III) chloride In dichloromethane at 0℃; for 3.08333h; Schlenk technique; Inert atmosphere;	4-Bromo-1-(2,3,4,5,6-pentamethylphenyl)butan-1-one S1 To a solution of 4-bromobutyryl chloride (217 μL, 1.87 mmol) and pentamethylbenzene(222 mg, 1.50 mmol) in CH2Cl2 (15 mL) at 0 °C was added AlCl3 (250 mg, 1.87 mmol)portion-wise over 5 minutes. The reaction was stirred at 0 °C for 3 h, and then carefully pouredinto cold H2O (15 mL). The layers were separated and the organic layer washed with sat. aq.NaHCO3 (20 mL). The aqueous layers were extracted with CH2Cl2 (3 × 20 mL) and thecombined organics dried (MgSO4) and concentrated in vacuo. Purification by flash columnchromatography (SiO2, eluent load, Pentane:Et2O, 95:5) afforded ketone S1 (0.38 g, 86%) as acolourless solid.
86%	With aluminum (III) chloride In dichloromethane at 0℃; for 3h;	4-Bromo-1-(2,3,4,5,6-pentamethylphenyl)butan-1-one S20 To a solution of 4-bromobutyryl chloride (217 μL, 1.87 mmol), pentamethylbenzene (222 mg,1.50 mmol) in CH2Cl2 (15 mL) at 0 °C was added AlCl3 (250 mg, 1.87 mmol) portion-wise over 5 min. Following the addition, the reaction was stirred at 0 °C for 3 h, and then carefully pouredinto cold H2O (15 mL). The layers were separated and the organic layer washed with sat. aq. NaHCO3 (20 mL). The aqueous layers were extracted with CH2Cl2 (3 x 20 mL) and the combinedorganics dried (MgSO4), and concentrated in vacuo. Purification by column chromatography (SiO2, eluent load, Pentane:Et2O, 95:5) afforded ketone S20 (0.38 g, 86%) as a colourless solid. Rf = 0.29 (Pentane:Et2O, 95:5), [UV, KMnO4]. m.p. = 74-75 °C. IR (film) νmax/cm-1 2925, 1697, 1575, 1438, 1403, 1315, 1243, 1110. 1H NMR (CDCl3, 400 MHz) δ = 3.58 (2H, t, J = 6.4 Hz, C3H2), 2.88 (2H, t, J = 6.9 Hz, C1H2), 2.29 (2H, quint., J = 6.7 Hz, C2H2), 2.24 (3H, s, Ar-CH3), 2.19 (6H, s, 2 Ar-CH3), 2.11 (6H, s, 2 CH3). 13C NMR (CDCl3, 101 MHz) δ = 210.8 (C=O), 140.3 (Ar-C), 135.7 (Ar-C), 133.3 (2C, 2 Ar-C), 127.4 (2C, 2 Ar-C), 43.5 (C1H2), 33.5 (C3H2), 26.4 (C2H2), 17.3 (2C, 2 Ar-CH3), 16.8(Ar-CH3), 16.1 (2C, 2 Ar-CH3). HRMS (ESI+) Found [M+H]+ = 297.0850; C15H22O79Br requires 297.0849, Δ 0.56 ppm.

Reference： [1]Frost, James R.; Cheong, Choon Boon; Akhtar, Wasim M.; Caputo, Dimitri F. J.; Stevenson, Neil G.; Donohoe, Timothy J. [Journal of the American Chemical Society, 2015, vol. 137, # 50, p. 15664 - 15667]
[2]Cheong, Choon Boon; Frost, James R.; Donohoe, Timothy J. [Synlett, 2020, vol. 31, # 18, p. 1828 - 1832]
[3]Frost, James R.; Cheong, Choon Boon; Akhtar, Wasim M.; Caputo, Dimitri F.J.; Christensen, Kirsten E.; Stevenson, Neil G.; Donohoe, Timothy J. [Tetrahedron, 2021, vol. 86]

68
[ 927-58-2 ]
spinosyn A 17-pseudoaglycone [ No CAS ]
17-O-(4-bromobutyryl)spinosyn A 17-pseudoaglycone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With potassium carbonate In dichloromethane at 20℃; for 12h;	9 Example 9: preparation of 17-O-polybromide butyrate-multi-alexin A-17-Psa In 50 ml in shan Jingping, adding 1.10g (1.82mmol) 17-O-Psa multi-alexin A and 30 ml dichloromethane, weighing 0.50g (3.65mmol) potassium carbonate are added to a reaction system, the volume 423 μ L 4- bromine butyryl chloride (3.65mmol) are added to a reaction system, the reaction at room temperature under stirring 12h. Stop reaction, filtration to remove solid potassium carbonate, by adding 100 ml water, with dichloromethane (3×100 ml) extraction, combined with the phase, anhydrous sodium sulfate drying 4h. Rotary evaporation under reduced pressure to remove the solvent after the silica gel (200-300 mesh) column chromatography [eluant: V (petroleum ether): V (ethyl acetate) =4:1] the white solid obtained purified 0.62g, yield 46%.
46%	With potassium carbonate In dichloromethane at 20℃; for 12h;	Synthesis of 17-O-(4-bromobutyryl)-spinosyn A 17-Pseudoaglycone (7) To a solution of Spinosyn A 17-Pseudoaglycone (6, synthesized according to Graupner’s procedure: Graupner, P. R.; Martynow, J.; Anzeveno, P. B. J. Org. Chem. 2005, 70, 2154.) (1.10 g, 1.82 mmol) in 30 mL CH2Cl2 was added K2CO3 (0.50 g, 3.65 mmol) and 4-bromobutyryl choloride (423 μL, 3.65 mmol) successively and the resulting mixture was stirred at r.t. for 12 h. The mixture was pooled into 200 mL H2O, extracted with ethyl acetate (3 × 50 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residual was applied on a silica column chromatography, eluting with a mixture of petroleum ether and ethyl acetate (4:1) to afford 0.62 g 17-O-(4-bromobutyryl)-spinosyn A 17-Pseudoaglycone (7) as a white solid, yield 46%: mp 93-98 oC, 1H NMR (400 MHz, CDCl3) δ 6.81 (s, 1H), 5.89 (d, J = 9.8 Hz, 1H), 5.83-5.77 (m, 1H), 5.07-5.01 (m, 1H), 4.86 (s, 1H), 4.72-4.65 (m, 1H), 4.36-4.29 (m, 1H), 3.58-3.55 (m, 4H), 3.52-3.45 (m, 10H), 3.43-3.37 (m, 1H), 3.16-3.10 (m, 2H), 3.07-3.00 (m, 1H), 2.93-2.85 (m, 1H), 2.60-2.50 (m, 3H), 2.46-2.40 (m, 1H), 2.31-2.23 (m, 1H), 2.23-2.15 (m, 4H), 1.97-1.90 (m, 1H), 1.65-1.56 (m, 3H), 1.54-1.42 (m, 3H), 1.41-1.32 (m, 2H), 1.31-1.27 (m, 3H), 1.15-1.11 (m, 2H), 1.09-1.05 (m, 1H), 0.98-0.85 (m, 2H), 0.82 (t, J = 7.5 Hz, 3H)13C NMR (125 MHz, CDCl3) δ 201.14, 172.49, 171.96, 147.46, 144.03, 129.38, 128.73, 95.52, 82.27, 81.06, 77.68, 76.38, 76.16, 75.36, 67.94, 60.95, 59.00, 57.67, 49.52, 47.63, 46.06, 45.43, 41.51, 41.15, 37.42, 36.33, 34.17, 32.69, 32.59, 32.52, 30.12, 28.17, 27.71, 21.08, 17.80, 16.38, 9.37; HRMS (ESI) m/z [M + H]+ calcd. for C37H56BrO10 739.3057, found 739.30 84.

Reference： [1]Current Patent Assignee: CENTRAL SOUTH UNIVERSITY - CN105884844, 2016, A Location in patent: Paragraph 0071; 0072; 0073; 0074; 0075; 0076
[2]Ma, Da-You; Wang, Long-Long; Lai, Qin; Peng, Kun-Jian; Li, Xuan; Li, Zeng-Xia; Liu, Li-Jun; Luo, Zhi-Yong; Liu, Su-You [Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 20, p. 3346 - 3349]

69
[ 625-82-1 ]
[ 927-58-2 ]
[ 109-63-7 ]
5,5-difluoro-10-(3-hydroxypropyl)-1,3,7,9-tetramethyl-5H-4λ⁴,5λ⁴-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-4-ium-5-uide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	Stage #1: 2,4-dimethyl-1H-pyrrole; 4-bromobutyroyl chloride In dichloromethane for 8h; Inert atmosphere; Cooling with ice; Reflux; Stage #2: boron trifluoride diethyl etherate With triethylamine In dichloromethane; toluene at 20 - 50℃; Cooling with ice;	1 Example 1 A round bottom flask was charged with 2,4-dimethyl-1H-pyrrole(2.2 eq.), dissolved in anhydrous dichloromethane, nitrogen protection, ice bath, with a constant pressure low liquid funnel dropping 4-bromobutyryl chloride (1.0eq.). After completion of the dropwise addition, the reaction was refluxed for 8 hours, dried to dryness of methylene chloride. Add toluene and dichloromethane (toluene and methylene chloride volume ratio = 19: 1), ice bath, triethylamine (7.0 eq.) and the boron trifluoride-ether complex (7.0 eq.) was dropped by a constant pressure low - fluid funnel. After completion of the drop, remove the ice bath, room temperature reaction 10-20min, 50 °C heating reaction 3h. The reaction solution was cooled, poured into ice water, quenched, extracted with methylene chloride, dried over sodium sulfate, dried solvent, purified by column to obtain product, reddish brown solid, yield 30%.
30%	Stage #1: 2,4-dimethyl-1H-pyrrole; 4-bromobutyroyl chloride In dichloromethane at 50℃; for 8h; Inert atmosphere; Cooling with ice; Stage #2: boron trifluoride diethyl etherate With triethylamine In dichloromethane; toluene at 20 - 50℃; Cooling with ice;	1 The synthesis route is the same as Chinese Patent 201510418869.2 (application number).Add 2,4-Dimethyl-pyrrole (2.2eq.) into a round bottom flask, dissolved in anhydrous dichloromethane, protected by nitrogen, ice bath,Add 4-bromobutyryl chloride (1.0eq.) in a constant-pressure low-liquid funnel. After the addition is complete, heat and reflux for 8h.Spin to dry the dichloromethane, add toluene and dichloromethane (volume ratio of toluene to dichloromethane = 19:1),In an ice bath, add triethylamine (7.0eq.), add boron trifluoride-ether complex (7.0eq.) dropwise with a constant pressure low liquid funnel,After the addition is complete, remove the ice bath, react at room temperature for 10-20 minutes, and heat at 50°C for 3 hours.The reaction solution was cooled, poured into ice water for quenching, extracted with dichloromethane, dried over sodium sulfate, and spinned to dry the solvent.Purification by column to obtain product 3a, reddish brown solid, yield 30%,
30%	Stage #1: 2,4-dimethyl-1H-pyrrole; 4-bromobutyroyl chloride In dichloromethane at 50℃; for 8h; Cooling with ice; Inert atmosphere; Stage #2: boron trifluoride diethyl etherate With triethylamine In dichloromethane; toluene at 20 - 50℃; Cooling with ice; Inert atmosphere;	1 Example 1 Synthesis of compound 3a Add 2,4-Dimethyl-pyrrole (2.2eq.) into the round bottom flask, dissolve in anhydrous dichloromethane, nitrogen protection, ice bath, drop 4-bromobutyryl chloride (1.0eq. .), after the dropwise addition is completed, heat and reflux for 8h, spin off the dichloromethane, add toluene and dichloromethane (volume ratio of toluene to dichloromethane = 19:1), ice bath, add triethylamine (7.0eq.) , Use a constant-pressure low-liquid funnel to drop the boron trifluoride-ether complex (7.0eq.). After the addition is complete, remove the ice bath, react at room temperature for 10-20min, heat at 50°C for 3h, cool the reaction solution, and pour Quenched in ice water, extracted with dichloromethane, dried with sodium sulfate, spin-dried the solvent, and purified by column to obtain product 3a, a reddish brown solid, with a yield of 30%,

20.2%

Stage #1: 2,4-dimethyl-1H-pyrrole; 4-bromobutyroyl chloride In dichloromethane at 0 - 25℃; for 1h; Stage #2: With triethylamine In dichloromethane at 25℃; for 0.166667h; Cooling with ice; Stage #3: boron trifluoride diethyl etherate In dichloromethane at 25℃;

3.3 Synthesis of intermediate 5 Dimethylpyrrole (2.0 mL, 19 mmol) and 4-bromobutyryl chloride (1.0 mL, 8.8 mmol) were dissolved in 20ML in dichloromethane. The reaction was stirred at 0 ° C for 30 min and then at 25 ° C for 30 min. In the iceTriethylamine (3.7 mL, 26 mmol) was added dropwise and stirred at 25 & lt; 0 & gt; C for 10 min.Boron trifluoride diethyl ether (5.5 mL, 44 mmol) was added dropwise and the mixture was stirred overnight at 25 ° C. The solvent was distilled off under reduced pressure, and the intermediate was isolated by column chromatography5 (546 mg, 20.2%).

Reference： [1]Current Patent Assignee: CHINESE ACADEMY OF SCIENCES; Shanghai Institute of Materia Medica (in: CAS) - CN106349261, 2017, A Location in patent: Paragraph 0037; 0038; 0039
[2]Current Patent Assignee: Shanghai Institute of Materia Medica (in: CAS); CHINESE ACADEMY OF SCIENCES - CN111848657, 2020, A Location in patent: Paragraph 0050-0052
[3]Current Patent Assignee: Shanghai Institute of Materia Medica (in: CAS); CHINESE ACADEMY OF SCIENCES - CN112574240, 2021, A Location in patent: Paragraph 0034-0036
[4]Current Patent Assignee: DALIAN UNIVERSITY OF TECHNOLOGY - CN105503921, 2016, A Location in patent: Paragraph 0113; 0114; 0015

70
[ 927-58-2 ]
[ 1011-65-0 ]
methyl 3-(4-bromobutanoyl)indole-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	Stage #1: 4-bromobutyroyl chloride With aluminum (III) chloride In dichloromethane at 20℃; for 0.5h; Stage #2: 5-methoxycarbonylindole In dichloromethane for 3h;	7 4.1.7. Methyl 3-(4-bromobutanoyl)indole-5-carboxylate (14) A suspension of AlCl3 (2.24 g, 16.8 mmol) in dry CH2Cl2 (20 mL) was treated dropwise with 4-bromobutanoyl chloride (1.60 g, 8.63 mmol) and stirred at room temperature for 30 min. Then, a solution of methyl indole-5-carboxylate (1.00 g, 5.71 mmol) in dry CH2Cl2 (10 mL) was added dropwise and stirring was continued for 3 h. After work up as described for the synthesis of 8, the precipitated product was separated, washed with diethyl ether, and dried. Yield: 1.81 g, 98%; C14H14BrNO3 (324.2); mp 132-133 °C; 1H NMR (DMSO-d6): δ (ppm) 1.79 (quin, 2H, J = 7.2 Hz), 2.89 (t, 2H, J = 7.4 Hz), 3.45 (t, 2H, J = 6.5 Hz), 3.90 (s, 3H), 7.54 (d, 1H, J = 8.6 Hz), 7.82 (dd, 1H, J = 8.6 Hz und 2.0 Hz), 8.43 (d, 1H, J = 3.1 Hz), 8.87-8.88 (m, 1H), 12.22 (sbroad, 1H); MS (EI): m/z (%) 324 (3) [M]+, 202 (100).

Reference： [1]Arnsmann, Martina; Hanekamp, Walburga; Elfringhoff, Alwine Schulze; Lehr, Matthias [European Journal of Medicinal Chemistry, 2017, vol. 125, p. 1107 - 1114]

71
[ 15861-24-2 ]
[ 927-58-2 ]
3-(4-bromobutyryl)indole-5-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	Stage #1: 4-bromobutyroyl chloride With aluminum (III) chloride In 1,2-dichloro-ethane at 0℃; for 0.833333h; Stage #2: 1H-indole-5-carbonitrile In 1,2-dichloro-ethane at 0 - 20℃; for 2.5h;	2 Example 2: Preparation of 3- (4-bromo-butyryl) indole-5-carbonitrile At 0 , equipped with mechanical stirring three 1L flask was added 1,2-dichloroethane (200 mL) and anhydrous aluminum chloride (15.4g, 0.12moL). At the same temperature was added dropwise 4-bromo-butyryl chloride (25.0g, 0.13moL), about 20min addition was complete, stirring was continued for 30 min. Was then added 5-cyano-indole (14.0g, 0.096moL) in 1,2-dichloroethane (200mL), keeping the temperature at 0 ~ 5 . The addition was complete within 30min. The ice bath was removed, brought to room temperature and then stirring was continued for 2h. document.write(""); Subsequently, the reaction mixture was added to 100g of ice and 100mL of concentrated hydrochloric acid. The reaction was stirred at room temperature overnight. Filtered and dried under vacuum to give a brown solid 3- (4-bromo-butyryl) indole-5-carbonitrile 21.8g, 78% yield.

Reference： [1]Current Patent Assignee: JIANGSU NHWA PHARMACEUTICAL COMPANY LIMITED - CN103570698, 2016, B Location in patent: Paragraph 0070-0074

72
[ 927-58-2 ]
4-((2R,5S)-5-((4-aminophenoxy)methyl)-2-(trifluoromethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile [ No CAS ]
4-bromo-N-(4-(((2R,5S)-3-(4-cyano-3-(trifluoromethyl)phenyl)-2-(trifluoromethyl)oxazolidin-5-yl)methoxy)phenyl)butanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With pyridine In dichloromethane at 20℃; for 14h;	17.1 Step 1. Preparation of 4-bromo-N-(4-(((2R,5S)-3-(4-cyano-3-(trifluoromethyl)phenyl)-2-(trifluoromethyl)oxazolidin-5-yl)methoxy)phenyl)butanamide To a 10-ml flask, 60 mg (0.14 mmol) of the compound 4-((2R,5S)-5-((4-aminophenoxy)methyl)-2-(trifluoromethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile obtained in Example 14 was added, and 3 ml of dichloromethane was added, followed by stirring. 16.2 ul (0.14 mmol, 1 eq) of 4-bromobutyryl chloride and 14 ul (0.168 mmol, 1.2 eq) of pyridine were added, followed by stirring at room temperature for about 14 hours. After completion of the reaction, the reaction product was concentrated, and layers were separated with ethyl acetate (10 ml) and water (10 ml). Then, an organic layer was separated and washed with a saturated NaCl aqueous solution. The organic layer was dehydrated and dried over MgSO4 concentrated under reduced pressure, and separated by a column to obtain 80 mg (96%) of a title compound. Mass[M+H] : 580.06

Reference： [1]Current Patent Assignee: DONG-A ST CO., LTD. - EP3135669, 2017, A1 Location in patent: Paragraph 0197; 0198

73
[ 927-58-2 ]
[ 19171-19-8 ]
4-bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)butanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	In tetrahydrofuran; for 4h;Reflux;	To a solution of 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1, 1 mmol) in dry THF (4 mL) was added into 4-bromobutanoyl chloride (3 mmol). The reaction was heated toreflux for 4 h. The reaction mixture was concentrated and the residue was extracted with DCM. The organic layer was washed with saturated NaHCO3 and dried with anhydrous MgSO4. The residue was purified by chromatography (DCM/MeOH, 50:1) to give the light yellow solid 2a (0.24 g, 58% yield). MS (ESI) m/z[MNa] 444.1; mp 183e184 C. 1H NMR (400 MHz, DMSO-d6)d 11.16 (s, 1H), 9.82 (s, 1H), 8.40 (d, J 8.3 Hz, 1H), 7.84 (t,J 7.9 Hz, 1H), 7.62 (s, 1H), 5.15 (dd, J 12.7, 5.4 Hz, 1H), 3.62 (t,J 6.6 Hz, 2H), 2.90 (m, 2H), 2.63 (m, 4H), 2.15 (m, 2H). 13C NMR(101 MHz, DMSO-d6) d 173.21, 171.41, 170.24, 167.96, 167.14, 136.78,136.54, 132.03, 127.24, 119.02, 118.04, 49.45, 40.70, 35.34, 34.68,31.44, 28.47, 22.50.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 151,p. 237 - 247

74
[ 88497-27-2 ]
[ 927-58-2 ]
C₈H₈BrN₃O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With potassium carbonate; In acetonitrile; at 20℃; for 21h;	To Compound 196 (1.00 g, 5.75 mmol) in acetonitrile (20 mL) suspension were added 4-bromobutanoyl chloride(0.798 mL, 6.90 mmol) and potassium carbonate (1.99 g, 14.4 mmol), and the mixture was stirred at room temperaturefor 21 hours. After the insoluble material was removed by filtration, and the filtrate solution was concentrated underreduced pressure. The concentrated residue was dissolved in chloroform (50 mL), and washed with water (30 mL). Theaqueous layer was re-extracted with chloroform (50mL), the organic layer was dried over anhydrous magnesium sulfate.After concentration, the residue was purified by silica gel chromatography (chloroform - methanol), and obtained solidwas washed with hexane to obtain Compound 197 (990 mg, 71% yield) as a white solid.1H-NMR (CDCl3) delta: 2.22 (tt, J = 8.2, 7.2 Hz, 2H), 2.69 (t, J = 8.2 Hz, 2H), 4.22 (t, J = 7.2 Hz, 2H), 7.60 (d, J = 9.4 Hz,1H), 8.63 (d, J = 9.4 Hz, 1H).

Reference： [1]Patent: EP3305789,2018,A1 .Location in patent: Paragraph 0754; 0755

75
[ 110-66-7 ]
[ 927-58-2 ]
S-pentyl 4-bromobutanethioate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With dmap; triethylamine In dichloromethane at 20℃; Inert atmosphere;	1.DA S-Pentyl 4-bromobutanethioate DMAP (0.439 g, 3.60 mmol) was placed into a flask and dissolved in DCM(36 mL) under nitrogen. Triethylamine (5.1 mL, 36 mmol) and 1 -pentanethiol (2.2 mL, 18 mmol) were then added. 4-Bromobutanoyl chloride (3.1 mL, 27 mmol) was added rapidly drop-wise. The cloudy yellow solution was allowed to stir overnight at room temperature. The reaction was quenched with 50 mL of water. The organic layer was collected and the aqueous layer washed with DCM 2x. The combined organic layers were dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an orange oil. The crude was purified by ISCO silica flash chromatography (Hexanes: Ethyl Acetate 0-5%) to obtain S-pentyl 4- bromobutanethioate. Yield (4.0 g, 88%).1H NMR (400 MHz, CDCl3) δ: ppm 3.44 (t, 2H), 2.88 (t, 2H), δ.74 (t, 2H), 2.21 (m, 2H), 1.57 (m, 2H), 1.33 (m, 4H), 0.89 (m, 3H).

Reference： [1]Current Patent Assignee: MODERNA THERAPEUTICS INC - WO2018/232120, 2018, A1 Location in patent: Paragraph 00966

76
[ 927-58-2 ]
[ 32559-18-5 ]
methyl 1-(4-bromobutanoyl)piperidine-2-carboxylate [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2019,vol. 2019,p. 5230 - 5233

77
[ 2104-04-3 ]
[ 927-58-2 ]
4-bromo-N-(4-(4-methoxyphenyl)thiazol-2-yl)butanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃;	General procedure for the synthesis of (2-amino-4-phenylthiazole) amide derivatives (4a-4e) General procedure: Compounds 1, 2, and 3 (Ma et al. 2014) were obtainedaccording to the previously described method. Chloroacetylchloride (1.45 mmol) in CH2Cl2 (15 mL) wasadded dropwise to a cooled solution (0 °C) of 4-(4-methoxyphenyl)thiazol-2-amine 3 (1.21 mmol) and diisopropylethylamine(DIEA) (1.24 mmol) in CH2Cl2(25 mL). The completion of the reaction was assessed bythin-layer chromatography (TLC). The organic layer wasseparated, washed with saturated NaHCO3 solution(100 mL), water, and brine, the aqueous phase wasextracted with CH2Cl2 (60 mL), and the organic phaseswere collected, dried over anhydrous MgSO4, and evaporatedin vacuo. The product was separated and purifiedby column chromatography on silica gel using an ethylacetate/petroleum ether mixture (1/4) as the eluent toafford pure compound 4a (Scheme 1).

Reference： [1]Zhang, Xiao-Zhong; Xu, Yuan; Jian, Meng-Meng; Yang, Kan; Ma, Zheng-Yue [Medicinal Chemistry Research, 2019, vol. 28, # 10, p. 1683 - 1693]

78
[ 927-58-2 ]
2,5-bis(benzo[d]thiazol-2-yl)phenol [ No CAS ]
C₂₄H₁₇BrN₂O₂S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With triethylamine In dichloromethane at 0℃;	Synthesis and characterization of the fluorescent probe BTP-LB Compound BTP (36 mg, 0.1 mmol) was dissolved in 8 mL ofanhydrous dichloromethane, cooled the mixture to 0 C by anice-bath, then triethylamine (69 mL) and 4-bromobutyryl chloride(116 mL) were added slowly. After reaction completed by silicagel TLC plate, the solvent was evaporated under reduced pressureand the crude product was further puried by column chromatog-raphy (dichloromethane: Petroleum ether = 3:1, v/v) to obtaincompound BTP-LB (50 mg, 98%) as a yellow solid.1H NMR(400 MHz, DMSO) d 8.53 (d, J = 8.0 Hz, 1H), 8.24-8.13 (m, 6H),7.62 (t, J = 6.7 Hz, 2H), 7.55 (t, J = 7.1 Hz, 2H), 3.72 (t, J = 6.5 Hz,2H), 3.08 (t, J = 7.1 Hz, 2H), 2.34-2.27 (m, 2H).13C NMR(100 MHz, DMSO d 6 ) d 171.38, 165.68, 161.47, 153.94, 152.83,148.88, 136.20, 135.37, 135.32, 131.14, 130.17, 128.04, 127.51,127.44, 126.60, 125.87, 123.70, 123.12, 122.74, 34.46, 33.20, 27.84. HRMS: m/z calcd for C 24 H 18 BrN 2 O 2 S 2 [M+H]+, 508.9988;found 508.9989.

Reference： [1]Li, Meng; Chen, Hui; Liu, Xiang; Wang, Yanlan; Zhang, Nuonuo; Zheng, Kaibo [Tetrahedron Letters, 2019, vol. 60, # 45]

79
[ 927-58-2 ]
[ 131929-68-5 ]
17-O-(4-bromobutyryl)-spinosyn A [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With potassium carbonate In dichloromethane at 20℃; for 12h;	1.1.4 Synthesis of 17-O-(4-bromo)butyryl-spinosyn A 17-Pseudoaglycone (10) To a solution of Spinosyn A 17-Pseudoaglycone (9)24 (1.10 g, 1.82 mmol) in 30 mL CH2Cl2 was added K2CO3 (0.50 g, 3.65 mmol) and 4-bromobutyryl choloride (423 μL, 3.65 mmol) successively and the resulting mixture was stirred at r.t. for 12 h. The mixture was pooled into 200 mL H2O, extracted with ethyl acetate (3 × 50 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residual was applied on a silica column chromatography, eluting with a mixture of petroleum ether and ethyl acetate (4:1) to afford 0.62 g 17-O-(4-bromo)butyryl-spinosyn A 17-Pseudoaglycone (10) as a white solid, yield 46%: mp 93-98 oC, 1H NMR (400 MHz, CDCl3) δ 6.81 (s, 1H), 5.89 (d, J = 9.8 Hz, 1H), 5.83-5.77 (m, 1H), 5.07-5.01 (m, 1H), 4.86 (s, 1H), 4.72-4.65 (m, 1H), 4.36-4.29 (m, 1H), 3.58-3.55 (m, 4H), 3.52-3.45 (m, 10H), 3.43-3.37 (m, 1H), 3.16-3.10 (m, 2H), 3.07-3.00 (m, 1H), 2.93-2.85 (m, 1H), 2.60-2.50 (m, 3H), 2.46-2.40 (m, 1H), 2.31-2.23 (m, 1H), 2.23-2.15 (m, 4H), 1.97-1.90 (m, 1H), 1.65-1.56 (m, 3H), 1.54-1.42 (m, 3H), 1.41-1.32 (m, 2H), 1.31-1.27 (m, 3H), 1.15-1.11 (m, 2H), 1.09-1.05 (m, 1H), 0.98-0.85 (m, 2H), 0.82 (t, J = 7.5 Hz, 3H)13C NMR (125 MHz, CDCl3) δ 201.14, 172.49, 171.96, 147.46, 144.03, 129.38, 128.73, 95.52, 82.27, 81.06, 77.68, 76.38, 76.16, 75.36, 67.94, 60.95, 59.00, 57.67, 49.52, 47.63, 46.06, 45.43, 41.51, 41.15, 37.42, 36.33, 34.17, 32.69, 32.59, 32.52, 30.12, 28.17, 27.71, 21.08, 17.80, 16.38, 9.37; HRMS (ESI) m/z [M + H]+ calcd. for C37H56BrO10 : 739.3057, found 739.30 84.

Reference： [1]Lai, Qin; Li, Zeng-Xia; Liu, Li-Jun; Liu, Su-You; Luo, Zhi-Yong; Ma, Da-You; Peng, Kun-Jian; Wang, Long-Long [Bioorganic and medicinal chemistry letters, 2020]

80
[ 927-58-2 ]
[ 82820-87-9 ]

Yield	Reaction Conditions	Operation in experiment
60%	With N-Bromosuccinimide; hydrogen bromide In 1,2-dichloro-ethane at 80℃; for 1.5h;	9 Example 9Preparation of 2,4-dibromobutyryl chloride 12.8 g of 4-bromobutyryl chloride was dissolved in 28 mL of 1,2-dichloroethane, and 14.7 g of N-bromosuccinimide and hydrobromic acid (7 drops) were added. Heat to 80°C and stir for 1.5 hours. Cool, concentrate under reduced pressure until no liquid is evaporated. After filtering, washing with 10 mL of dichloromethane twice, the filtrate was concentrated under reduced pressure, and then distilled under reduced pressure to obtain 10.9 g of light yellow liquid with a yield of 60%.

Reference： [1]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - CN111471058, 2020, A Location in patent: Paragraph 0055-0058

81
[ 927-58-2 ]
[ 6294-52-6 ]
C₁₃H₁₅BrN₂O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; dmap; In tetrahydrofuran; for 3h;Cooling with ice; Reflux;	General procedure: 4-Bromobutyryl chloride (0.05 mol) was added dropwise to an ice cold solution of 5,6-disubstituted 2-aminobenzo[d]thiazoles 1a-h and dimethylaminopyridine(0.075 mol) in pyridine (100 ml). The reaction mixture was refluxed for 3 hrs. After completion of reaction, the solvent was evaporated. The residue was extracted with CH2Cl2 and washed with 10% HCl. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to yield a crude oil. The oily residue was purified by silica gel chromatography column to afford a sticky pale yellow mass of the 2a-h.

Reference： [1]Medicinal Chemistry,2020,vol. 16,p. 812 - 825

82
[ 927-58-2 ]
[ 261761-95-9 ]
1-deoxy-2,3,5-tri-O-benzyl-1-[2-(tert-butoxycarbony)-6-oxohexahydropyridazine-1-yl]-L-xylitol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	Stage #1: 4-bromobutyroyl chloride; 1-(2-tert-Butyloxycarbonyl)hydrazino-1-deoxy-2,3,5-tri-O-benzyl-L-xylitol With triethylamine In dichloromethane at 0℃; for 0.333333h; Inert atmosphere; Stage #2: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 3.03333h; Inert atmosphere;	1-Deoxy-2,3,5-tri-O-benzyl-1-[2-(tert-butoxycarbony)-6-oxohexahydropyridazine-1-yl]-l-xylitol (34) To a solution of hydrazide 21 (1.65 g, 3.07 mmol, 1.0 equiv) and NEt3 (0.51 mL, 3.68 mmol, 1,2 equiv) in CH2Cl2 (33 mL) was added dropwise 4-bromobutyryl chloride (0.37 mL, 3.23 mmol, 1.05 equiv) at 0 °C under an argon atmosphere. The resulting reaction mixture was kept stirring at 0 °C for 20 min. After this time, sat. aq NaHCO3 (20 mL) was added and the phases were separated. The aqueous layer was extracted with CH2Cl2 (20 mL) and the combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was dissolved in toluene (3 20 mL) and concentrated under reduced pressure. Then, the residue was dissolved in DMF (20 mL) under an argon atmosphere and NaH (60% dispersion in mineral oil, 368.4 mg, 9.21 mmol, 3.0 equiv) was added. The resulting mixture was kept stirring at 0 °C for 20 min and then at RT for 2.7 h before the dropwise addition of H2O (20 mL) at 0 °C. Then, the phases were separated and the aqueous layer was extracted with EtOAc (2 20 mL). The combined organic extracts were concentrated under reduced pressure and the concentrate underwent purification by silica gel flash column chromatography (PE-EtOAc, 7:3 → 13:7) to obtain the target compound 34 as a colorless syrup; yield: 1.27 g (68%); Rf = 0.33 (PE-EtOAc, 1:1); []D 28 +11(c 0.75, EtOAc). Very complicated NMR spectra due to rotamers. 1H NMR (CDCl3, 400.13 MHz): = 7.37-7.28 (m, 15 H), 4.79-4.44 (m, 7 H), 4.07-3.95 (m, 3 H), 3.71 (dd, J = 3.0, 5.4 Hz, 1H), 3.48-3.47 (m, 3 H), 3.10-3.29 (m, 1H), 2.34-2.14 (m, 5 H), 1.48 (s, 9 H). 13C NMR (CD3OD, 100.61 MHz): = 172.6, 155.6 138.1, 138.0, 128.4- 127.7, 82.3, 76.2, 74.5, 73.3, 72.5, 71.9, 71.3, 69.3, 68.9, 47.9, 45.9, 44.0, 30.0, 28.2, 21.4. HRMS (ESI): m/z [M + H]+ calcd for C35H45N2O7: 605.3221; found: 605.3211.

Reference： [1]Evangelista, Tereza C. Santos; Ferreira, Sabrina Baptista; Sydnes, Magne O.; Fernández-Bolaños, José G.; Lindbäck, Emil; Lopéz, Óscar [Synthesis, 2019, vol. 51, # 21, p. 4066 - 4077]

83
[ 927-58-2 ]
C₂₃H₂₇N₃O [ No CAS ]
(E)-2-(2-(3-(dicyanomethylene)-5,5-dimethylcyclohex-1-en-1-yl)vinyl)-5-(diethylamino)phenyl 4-bromobutyric acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere;	1.1-1.5 (1) Under the protection of nitrogen, mix DHDM (1.0g, 2.8mmol), triethylamine (1.0mL) and anhydrous dichloromethane (50mL) and add them to a 100mL three-necked flask, and use an ice bath to cool to 0 °C .(2) Under ice bath conditions, then 4-bromobutyryl chloride (0.62 mg, 3.3 mmol) was slowly added dropwise to the three-neck flask containing the mixture of step (1), and stirred at room temperature for 10-12 hours. During the reaction, thin layer chromatography (TLC) was used to monitor the progress of the reaction.(3) After the completion of the reaction, the mixture was poured into 50 mL of ice water at 0° C., stirred and mixed, and dichloromethane was added for extraction 3 times, each time 10 mL. After drying with 5.0 g of anhydrous sodium sulfate, the organic phase was concentrated to an oily substance.(4) Prepare the eluent with n-hexane and ethyl acetate in a volume ratio of 3:1 and purify the crude product by column chromatography.Obtain 1.03g of purple black solid (E)-2-(2-(3-(dicyanomethylene)-5,5-dimethylcyclohex-1-en-1-yl)vinyl)-5 -(Diethylamino)phenyl 4-bromobutyric acid DCDB, the yield was 72%.

Reference： [1]Current Patent Assignee: ANHUI AGRICULTURAL UNIVERSITY - CN111807993, 2020, A Location in patent: Paragraph 0071-0085

84
[ 927-58-2 ]
γ-telluride butyrolactone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69.7%	With sodium hydrogen telluride; tetrabutylammomium bromide In water at 25℃;
69.7%	With sodiumhydrogen telluride; tetrabutylammomium bromide In water; toluene at 20℃; for 12h;	7.1-12.1 (1) Synthesis of γ-telluride butyrolactone molecule Add 2.00 g of tellurium powder (15.67 mmol) and 1.3 g of sodium borohydride (34.36 mmol) into a 250 mL round bottom flask, and slowly drop 30 mL of degassed pure water into it under ice-water bath conditions. After the reaction system stops producing gas, Seal with a rubber stopper, and pour nitrogen into the system for 10 minutes to remove the air in the reaction device. React for 4 hours at 90°C to obtain a light purple transparent NaHTe aqueous solution, which is returned to room temperature for later use. 0.20 g of tetrabutylammonium bromide (0.62 mmol) and 3.00 g of 4-bromobutyryl chloride (16.18 mmol) were dissolved in 40 mL of toluene to obtain solution A. Under stirring conditions, use a constant pressure dropping funnel to inject the prepared solution A dropwise into the sodium telluride (NaHTe) solution system, and react at room temperature for 12 h (the reaction equation is shown below). After the reaction, the reaction system was separated, the aqueous phase was washed with dichloromethane to be colorless, the organic phases were combined, the organic phase was washed with saturated aqueous sodium bicarbonate solution, the washing liquid was extracted with dichloromethane to be colorless, and the organic phases were combined , Add anhydrous sodium sulfate for drying, filter to remove anhydrous sodium sulfate, remove toluene and dichloromethane by rotary evaporation, use silica gel column for column chromatography of the obtained crude product, eluent ratio: petroleum ether: ethyl acetate Ester=20:1. The solvent was removed by rotary evaporation again to obtain a light yellow transparent oily liquid, which is the synthesized γ-tellurobutyrolactone, with a yield of 69.7%. The obtained compound was characterized by hydrogen nuclear magnetic resonance spectroscopy, carbon nuclear magnetic resonance spectroscopy, tellurium nuclear magnetic resonance spectroscopy and mass spectrometry. The molecular structure characterization is shown in Figure 1.

Reference： [1]Liu, Cheng; Zhang, Zhiheng; Fan, Zhiyuan; He, Chaowei; Tan, Yizheng; Xu, Huaping [Chemistry - An Asian Journal, 2020, vol. 15, # 24, p. 4321 - 4326]
[2]Current Patent Assignee: TSINGHUA UNIVERSITY (CHINA) - CN112110891, 2020, A Location in patent: Page/Page column 10-12

85
[ 927-58-2 ]
2-(2-(4-hydroxystyryl)-4H-chromene-4-ylidene)malononitrile [ No CAS ]
C₂₄H₁₇BrN₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With triethylamine In dichloromethane at 20℃; for 12.3h; Cooling with ice;	1.1.5 1.5. Synthesis of the fifth compound Combine the fourth compound (1g, 3.18mmol) with4-bromobutyryl chloride (700mg, 3.8mmol) dissolved in dichloromethane,Under the catalysis of triethylamine, ice bath for 20min,React at room temperature for 12h, spin dry to obtain the crude product,The crude product was purified by column chromatography to obtain the fifth compound as a yellow-brown powdery solid (yield rate of 70%);

Reference： [1]Current Patent Assignee: NANJING UNIVERSITY OF SCIENCE AND TECHNOLOGY - CN112679459, 2021, A Location in patent: Paragraph 0042; 0049; 0058; 0059

86
[ 927-58-2 ]
C₄₄H₈₇NO₄ [ No CAS ]
C₄₈H₉₂BrNO₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 1h;	13.1 Step 1: Preparation of Intermediate 13-1 To a solution of 11-2 (200 mg, 0.29 mmol, 1.0 eq) in CH 2Cl 2 (20 mL) was added DIPEA (120 mg, 0.87 mmol, 3.0 eq) and 4-bromobutanoyl chloride (107 mg, 0.58 mmol, 2.0 eq) . The reaction was stirred at 0 for 1 hour. The reaction mixture was poured into water (50 ml) and extracted with CH 2Cl 2 (3*50 mL) . The combined organic layer was washed with brine, dried over anhydrous Na 2SO 4 and concentrated in vacuo to provide 13-1 as yellow oil (191 mg, yield: 78 %) .

Reference： [1]Current Patent Assignee: SUZHOU ABOGEN BIOSCIENCES - WO2021/204175, 2021, A1 Location in patent: Paragraph 00419

87
[ 927-58-2 ]
C₂₈H₂₃NO₄ [ No CAS ]
C₃₂H₂₈BrNO₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With triethylamine In dichloromethane at 20℃; for 1.5h;	Synthesis of compound NDRO-8 The intermediateNDR(70 mg) was dissolved in 25 mL dichloromethane, about 75 mg of 4-bromobutyryl chloride was added, and then 3-4 drops of triethylamine were added. After stirring at room temperature for 30 min, 35 mg of 4-bromobutyryl chloride was added,after stirred for 1hthe reaction was stopped and quenched with water. Extracted the liquid, and washed the organic layer with water three times, then evaporated the dichloromethane. The reaction mixture was separated by column chromatography (dichloromethane: methanol = 80:1), and the red solid compoundNDRO-8was obtained 43 mg with a yield of 46%.1H NMR (500 MHz, CDCl3)δ8.63 (d,J= 9.1 Hz, 1H), 8.05 (d,J= 7.1 Hz, 1H), 7.68 - 7.58 (m, 2H), 7.54 (d,J= 2.2 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.16 (d,J= 7.2 Hz, 1H), 6.78 (d,J= 8.7 Hz, 1H), 6.69 - 6.60 (m, 2H), 6.43 (d,J= 8.6 Hz, 1H), 3.58 (t,J= 6.4 Hz, 2H), 3.41 (q,J= 7.0 Hz, 4H), 2.85 (t,J= 7.2 Hz, 2H), 2.39 - 2.30 (m, 2H), 1.22 (t,J= 7.1 Hz, 6H).13C NMR (100 MHz, CDCl3)δ168.54, 167.22, 151.13, 149.88, 147.25,144.95, 132.42, 132.41, 127.04, 126.43, 124.47, 122.66, 122.39, 121.68, 121.55, 120.06, 119.47, 118.77, 115.97, 110.30, 106.50, 81.79, 50.93, 42.05, 30.09, 30.00, 25.06, 10.02. HRMS (ESI positive)theoreticalvalue[M+H]+586.1151measuredvalue586.1219.

Reference： [1]He, Shengui; Zhang, Shufang; Zhao, Xin; Zhu, Xinyue; Chen, Lisen; Cui, Jingnan [Chinese Chemical Letters, 2022, vol. 33, # 9, p. 4233 - 4237]

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+
Accessible (Haz class 3, 4, 5 or 8), International	USD 200+

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
{[ item.p_purity ]}	{[ item.pr_size ]}	{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]}	{[ getRatePrice(item.pr_usd, 1,1) ]}	Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]}	{[ item.pr_usastock ]}	Inquiry -	{[ item.pr_chinastock ]}	Inquiry -

CAS No. :	927-58-2	MDL No. :	MFCD00000753
Formula :	C₄H₆BrClO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LRTRXDSAJLSRTG-UHFFFAOYSA-N
M.W :	185.45	Pubchem ID :	70225
Synonyms :

Num. heavy atoms :	7
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.75
Num. rotatable bonds :	3
Num. H-bond acceptors :	1.0
Num. H-bond donors :	0.0
Molar Refractivity :	34.21
TPSA :	17.07 Å²

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.14 cm/s

[ CAS No. 927-58-2 ] {[proInfo.proName]}

Quality Control of [ 927-58-2 ]

Related Doc. of [ 927-58-2 ]

Product Details of [ 927-58-2 ]

Calculated chemistry of [ 927-58-2 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 927-58-2 ]

Application In Synthesis of [ 927-58-2 ]

[ 927-58-2 ] Synthesis Path-Upstream 1~3

[ 927-58-2 ] Synthesis Path-Downstream 1~87

Related Functional Groups of
[ 927-58-2 ]

Bromides

Acyl Chlorides

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Log Po/w (iLOGP) :	1.78
Log Po/w (XLOGP3) :	1.82
Log Po/w (WLOGP) :	1.93
Log Po/w (MLOGP) :	1.57
Log Po/w (SILICOS-IT) :	1.95
Consensus Log Po/w :	1.81

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	3.0
Bioavailability Score :	0.55

Log S (ESOL) :	-1.94
Solubility :	2.14 mg/ml ; 0.0115 mol/l
Class :	Very soluble
Log S (Ali) :	-1.8
Solubility :	2.95 mg/ml ; 0.0159 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.51
Solubility :	0.57 mg/ml ; 0.00308 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.18

Signal Word:	Danger	Class:	8
Precautionary Statements:	P210-P261-P264-P271-P280-P301+P330+P331-P303+P361+P353-P304+P340+P310-P305+P351+P338+P310-P363-P370+P378-P403+P233-P403+P235-P405-P501	UN#:	3265
Hazard Statements:	H227-H314-H335	Packing Group:	Ⅱ
GHS Pictogram:

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

[ CAS No. 927-58-2 ] {[proInfo.proName]}

Quality Control of [ 927-58-2 ]

Related Doc. of [ 927-58-2 ]

Product Details of [ 927-58-2 ]

Calculated chemistry of [ 927-58-2 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 927-58-2 ]

Application In Synthesis of [ 927-58-2 ]

[ 927-58-2 ] Synthesis Path-Upstream 1~3

[ 927-58-2 ] Synthesis Path-Downstream 1~87

Related Functional Groups of [ 927-58-2 ]

Bromides

Acyl Chlorides

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 927-58-2 ]