Name: 99-66-1|2-Propylpentanoic acid|98%
Brand: Ambeed
SKU: A143794
Price: 5.0 USD
Availability: InStock
Rating: 96 (40 reviews)

1
[ 76002-02-3 ]
[ 99-66-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide
3.1 g	With sodium hydroxide In water at 80℃; for 20h;	1.1 Synthesis of Compound 3 0.06 moles of TBABr were added to a solution of 8 g (0.2 moles) of NaOH in 30 ml H2O and the resulting mixture was heated at about 80 °C till complete dissolution. After cooling to 60 °C, 6.1.5 g (0.5 moles) of n-propyl bromide 2 and 6.5 g (0.05 moles) of ethyl acetoacetate 1 were simultaneously added to the mixture. The resulting bi-phasic system, was kept under vigorous stirring for 39 hours at 71 X. 30.7 g (0,249 moles) of n-propyl bromide and a solution of 2.2 g (0.057) moles of NaOH in 5 ml of H2O was added and the resulting mixture was left to react under the aforesaid conditions for further 6 hours. The excess propyl bromide was distilled off and recovered, thus giving bi phasic reaction mixture whose organic phase consisted of ethyl 2,2-dipropyl acetoacetate which was directly used in the subsequent reaction. To this mixture comprising of the ethyl 2,2-dipropyl acetoacetate, a solution of NaOH 8 g (0.2 moles) in 10 ml of H2O was added and the resulting mixture left to react at 80°C for 20 hours. This end mixture was diluted with water and extracted with D M. Following the separation of layers the water phae was acidified to PH=1 with 33% HCl and extracted three times with ethy acetate. The ethyl acetate layer was dried over Na2SO4} and concentrated to dryness yeilding 3.1 g of compound 3.

Reference： [1]Burton [American Chemical Journal, 1881, vol. 3, p. 390]
[2]Current Patent Assignee: CELLIXBIO PRIVATE LTD - JP2015/533114, 2015, A Location in patent: Paragraph 0197; 0198; 0199

2
[ 13310-75-3 ]
[ 99-66-1 ]

Yield	Reaction Conditions	Operation in experiment
82.5%	With sodium perborate at 240℃; for 1h;
74%	With benzene-1,2-dicarboxylic acid at 240℃; for 1h;
	With sodium hydroxide

2 Preparation of sodium di-n-propyl acetate EXAMPLE 2 Preparation of sodium di-n-propyl acetate First of all, the crude di-n-propyl acetic acid was prepared from 8 g of di-n-propyl acetonitrile by the method described in Example 1.

Reference： [1]Chemat, Farid; Poux, Martine; Berlan, Jacques [Journal of the Chemical Society. Perkin Transactions 2 (2001), 1996, vol. 8, p. 1781 - 1784]
[2]Chemat, Farid; Poux, Martine; Berlan, Jacques [Journal of the Chemical Society. Perkin transactions II, 1994, # 12, p. 2597 - 2602]
[3]Keil [Hoppe-Seyler's Zeitschrift fur Physiologische Chemie, 1947, vol. 282, p. 139]
[4]Current Patent Assignee: SANOFI - US4127604, 1978, A

3
[ 99-66-1 ]
[ 2936-08-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With thionyl chloride In toluene Heating;
94%	With thionyl chloride at 10 - 20℃; for 4h;	1 Thionly chloride (39.6g, 332 mmol) was added slowly to Valproic acid (1, 16.0g, 110 mmol) while maintaining the internal tempeture at 10°C. The resulting mixture was allowed to warm to room temperature (RT) and stirred for about 4.0 hoars. The excess thionyl chloride was recovered by concentration under vacuum to obtain the Valproyl chloride (2) as a pale yellow liquid (16.8g, Yield: 94%).
93.6%	With thionyl chloride In N,N-dimethyl-formamide Reflux;

90%	With thionyl chloride at 10 - 80℃;
90%	With thionyl chloride In N,N-dimethyl-formamide at -5℃; for 2h; Reflux;
	With thionyl chloride
	With thionyl chloride
	With oxalyl dichloride
	With thionyl chloride Heating;
	With oxalyl dichloride In N,N-dimethyl-formamide; benzene for 2h; Ambient temperature;
	With thionyl chloride In benzene
	With thionyl chloride
	With thionyl chloride for 2h; Heating;
	With thionyl chloride Heating;
	With thionyl chloride for 1h; Heating;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 1h;
	With thionyl chloride In dichloromethane at 25℃; for 10h;
	With thionyl chloride; calcium(II) chloride In sodium hydroxide at 20℃;
	With oxalyl dichloride In dichloromethane for 1h;	1 2-Propylpentanoic acid (2,4-diphenylthiazol-5-yl)amide (1x).A stirred solution of 2-propylpentanoic acid (218 μL, 200 mg, 1 .39 mmol) in DCM (3 mL) was treated with oxalyl chloride (122 μL, 177 mg, 1 .39 mmol) and DMF-DCM (1 :4, 20 μL). After stirring for 1 h, the reaction mixture was evaporated to dryness and further dried under high vacuum to yield the crude acid chloride. 1d (70 mg, 0.28 mmol) in pyridine (3 mL) was added, followed by DMAP (10 mg), and the solution stirred at ambient temperature for 18 h. All volatiles were removed under reduced pressure and the residue taken up in DCM (40 mL). This solution was washed thoroughly with 1 M HCI (3 x 40 mL) then sat. NaHCO3 (3 x 40 mL) and evaporated. Purification by flash column chromatography on silica gel, eluted with 40-50% DCM-hexane, afforded the bis-amide product, 2,4-Diphenyl-5-[λ/,λ/-bis(2-propylpentanoyl)amino]thiazole (57 mg, 41 %), which crystallised as a pale orange solid on scratching. A portion of this material (47 mg) was suspended in 2-propanol (2.0 mL), then tetraethylammonium hydroxide, 20% w/v aqueous solution (146 μL, 2.0 mmol) was added. Dissolution of the starting material was observed as hydrolysis took place. After 2.5 hours the mixture was diluted with 1 M HCI (50 mL) and DCM (50 mL). The organic layer was separated, dried over MgSO4, filtered and evaporated. Purification by flash column chromatography on silica gel, eluted with 50-65% DCM-hexane, yielded 1x as a white, crystalline solid (26 mg, 74%). m/z (ES), 379 ([M+H]+); HRMS, found 379.1841 (C23H27N2OS, [M+H]+, requires 379.1844).
	With thionyl chloride	1 Preparation of l-(2-propyl-pentanoyl)-urea (Compound 6, VPU):Compound 6 (VPU)Valproyl chloride (0.057 mol), prepared by coupling of thionylchloride and valproic acid according to a published method [24], was dissolved in dry acetonitrile (50 ml), and the resulting solution was slowly added to a boiling solution of urea (0.14 mole) in dry acetonitrile (100 ml) and allowed to reflux for 2 hours. Thereafter the organic solvent was evaporated under reduced pressure and the product was dissolved in ethyl acetate (100 ml) and washed three times with 20 ml of distilled water. The organic fraction was dried over MgSO4, filtered and evaporated under reduced pressure. The products were purified by crystallization from ethyl acetate.Compound 6 was obtained in an overall yield of 83 % as white crystals which exhibited a melting point of 217-220 °C, the chemical structure thereof was confirmed by spectroscopic methods (NMR and GC-MS), and its purity established by elemental analysis.MS-EI, m/z: 144, 129, 115, 72, 61.1H NMR (300 MHz, CDCl3 δ TMS): 0.86-0.94 (t, J =0.05, 6H), 1.2-1.74 (m, 8H), 2.24-2.4 (m, IH), 5.62 (s, IH), 8.4 (s, IH), 9.42 (s, IH).Elemental analysis (C, H, N): C9H18N2O2.
	With thionyl chloride at 20℃;
	With oxalyl dichloride; N,N-dimethyl-formamide for 4h;
	With thionyl chloride In dichloromethane Cooling with ice; Reflux;
	With thionyl chloride
	With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide for 2h; Reflux;
	With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 2.33333h; Inert atmosphere;	4 Step-i: Synthesis of Compound 3 To a stirred solution of valproic acid i (20 g, 0.i38dichioromethane (200 mE) (i -2 drops of DMF) wasoxallyl chloride (i8.8 mE, 0.208 mol, i.5 eq.) dropthrough a dropping funnel at 00 C. under N2 atmospheremm. Removed the ice bath and allowed to room temperature. Then the reaction mixture was stirred for another 2Afier completion of the reaction (by TEC) volatilesconcentrated under N2 atmosphere. The obtained crudechloride-2 was added to a stirred mixture of acetaldehydemE, 0.4i59 mol, 3 eq.) and sodium iodide (52 g,mol, 2.5 eq.) in acetonitrile (220 mE) at 00 C. Afterstirred for 2 h at 0-5° C., it was poured in to ice waterextracted with hexane (2x200 mE). The combinedextracts were washed with 5% aqueous sodiumthiosulfate solution (2xiOO ml) followed by 5% sodium bicarbonate solution (50 mE) and finally washed with brine solution (2x50 ml). The combined organic layer was dried oversodium sulphate, filtered, evaporated under reducedpressure gave compound 3 as an oil 30 g (7 i%Yield).
	With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 2h; Inert atmosphere;	2.1 Dichloromethane (200mL) valproic acid 1 (20g, 0.138mol) of (1-2 drops of DMF) in the cause solution to the additional oxallyl chloride (18.8mL, 0.208mol, 1.5eq .) was, fall wisely by dropping funnel at 0oC under 20 minutes N2 atmosphere) to remove the ice bath, was allowed to room temperature.Thereafter, the reaction mixture was stirred between the RT for another 2h. After the reaction (by TLC) volatIles of completion, it has been centralized under N2 atmosphere. Obtained leave of acid chloride of 2, acetaldehyde(21.36mL, 0.4159mol, 3eq.) in acetonitrile (220mL) at 0°C And sodium iodide (52g, 0.3446mol, 2.5 equivalent It was added to a stirred mixture of the object). After 0°C was stirred between 2h at 0-5°C, it is extracted with hexane (2 × 200 mL), it was poured into ice water (200 mL).The combined organic extracts, the water of the sodium thiosulfate solution (2x100ml) is washed with 5% which was followed by a 5% sodium bicarbonate solution (50mL), it was washed at the end with an aqueous salt solution (2x50ml).Combined organic layers are filtered and dried over anhydrous sodium sulfate, and the synthesis product 3 as oil evaporated under lowered pressure to give 30 g (71% yield).
	With oxalyl dichloride at 0℃; for 8h;
	With thionyl chloride at 86℃; for 2h;	1.1 Step A: 2L reaction flask by adding 1.4L of thionyl chloride, dropping 700g of valproic acid, dropping, heating to 86 ° C reflux 2h, steaming to remove excess thionyl chloride, the residue was spare.
	With thionyl chloride In acetonitrile at 20℃; for 24h;
	With oxalyl dichloride In dichloromethane for 12h; Cooling with ice;	1.1.1; 1.1.2 (1) Preparation of 2-Propylvaleryl Chloride (Compound 1) 1. Reaction: Take a dry and clean 100 mL eggplant flask.Dissolve 10 mmol 2-propylvaleric acid in 20 mL of dichloromethane.Then 12 mmol of oxalyl chloride was added to the reaction system with a spatula.The mixture was stirred in an ice bath for 12 hours.The reaction was stopped after no raw material was detected in the TLC test system (developed system: dichloromethane:methanol=20:1,Volume ratio);2. Purification:Rotary drying using a rotary evaporator directly gave the crude product, which was purified to give 2-propylvaleryl chloride (Compound 1).
	With oxalyl dichloride Cooling with acetone-dry ice;	N-(heptan-4-yl)-5-(piperidin-1-yl)-2-(2-propylpentanamido)benzamide (5Pip) 290 of 2 (0.84 mmol) was suspended in ethylacetate with 60 mg Pd/C (10%) in a 50 mL round bottom flaske quipped with a magnetic stir bar. The mixture was stirred overnight under a hydrogen atmosphere at room temperature. The completion of the reduction led to a color change from yellow to colorless and appearance of blue fluorescence, which was monitored using TLC.The catalyst on the support was filtered out and the ethyl acetate was removed in vacuo. The solid was resuspended in 1,2-drichloroethane(5 mL), blanked with continuous flow of Ar and placed in a dryice/acetone bath. Concurrently, 2-propylpentanoic acid (160 uL, 1mmol) was converted to its acyl chloride form by treatment with oxalyl chloride in a flask immersed in dry ice/acetone bath. The thus obtained 2-propylpentanoyl chloride was added to the amine solution dropwise followed by a dropwise addition of triethylamine (1 mL, 7.2 mmol). The reaction mixture was allowed to warm up toroom temperature and was stirred overnight at 60°C. The solution was diluted with 25 mL of DCM, and washed with 5% HCL (2 ×100 mL) and with brine (100 mL). The organic layer was collected, dried over Na2SO4, and concentrated in vacuo. The product was purified using flash chromatography (column, 1” internal diameter,was packed with silica gel in hexanes, 6” to 8” height of the packed stationary phase). The purification (stationary phase: silica gel: eluent gradient: from 100% hexanes to 100% ethyl acetate) afforded 110mg (0.25 mmol, 30% yield) of 5Pip. 1H NMR (600 MHz, CDCl3) δ/ppm: 10.45 (1 H, s), 8.36 (1 H, d, J = 9.2 Hz), 7.02 (2 H, m), 5.0(1 H, J = 9.2 Hz), 4.09 (1 H, m), 3.04 (4 H, m), 2.22 (1 H, dt, J =9.2, 4.6 Hz), 1.71 (4 H, dt, J = 11, 5.8 Hz), 1.63 (2 H, m), 1.53 (4 H,m), 1.34 (12 H, m), 0.9 (6 H, p, J = 7.2 Hz), 0.86 (6H, m). 13C NMR(150 MHz, CDCl3) δ/ppm: 174.70, 168.83, 147.45, 131.84, 123.04,122.77, 120.72, 115.54, 51.91, 49.22, 49.00, 37.50, 35.40, 25.66,23.82, 20.74, 19.20, 14.08, 13.97. HRMS (m/z, ESI-TOF): calcd. for C27H46N3O2+, 444.3590 [M + H]+; found, 444.3692.
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 4h;	1 Synthesis of 2-propylpentanoyl chloride (2): To an ice cold stirred solution of 2- propylpentanoic acid (1, 40.0 g, 0.277 mol) in dichloromethane (400 mL) was added oxalyl chloride (70.41 g, 0.555 mol) followed by the addition of DMF (7.0 mL, 0.083 mmol). The resulting reaction mixture was stirred at room temperature for next 4h. After completion of reaction (TLC monitoring, by quenching a portion in MeOH), solvent was evaporated under reduced pressure under nitrogen atmosphere to get 2 as light yellow liquid. The crude was directly used for next step without recording any data. Yield: 40.0 g, 89%.
	With chlorinating agent In dichloromethane at 0℃;
	With thionyl chloride for 2h;
	With oxalyl dichloride at 20℃; for 4h;
	With thionyl chloride In dichloromethane at 25 - 45℃;	1.A Part- A: Preparation of 2-Propylpentanoyl Chloride (Valproic acid chloride): To a stirring solution of Valproic acid in DCM, slowly added SOC12 at 25-30°C for l-2hr, slowly raise the temperature of the reaction mass to 40-45°C and maintain for lhr. Distill off DCM atmospherically at 40-45°C and apply vacuum to remove traces of DCM & thionyl chloride to afford the desired product.
	With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 4h;	1 Preparation of 2-propylpentanoyl chloride(KSM-I): To an ice cold stirred solution of 2-propylpentanoic acid (1.40g, 0.277 mol) in dicloromethane (400 mL) was added oxalyl chloride (70.41 g, 0.555 mol) followed by the addition of DMF(7.0 mL,0.083 mmol). The resulting reaction mixture was stirred at room temperature for next 4 h. After completion of the reaction, solvent was evaporated under reduced pressure under nitrogen atmosphere to get the desired compound 2- propylpentanoyl chloride as light yellow liquid. The crude is used directly for the next condensation step. (Yield: 40.0g, 89%)
	With thionyl chloride In dichloromethane at 25 - 45℃;	1.A Part- A: Preparation of 2-Propylpentanoyl Chloride (Valproic acid chloride): To a stirring solution of Valproic acid in DCM, slowly added SOC12 at 25-30°C for l-2hr, slowly raise the temperature of the reaction mass to 40-45°C and maintain for lhr. Distill off DCM atmospherically at 40-45°C and apply vacuum to remove traces of DCM & thionyl chloride to afford the desired product.

Reference： [1]Drag, Marcin; Grembecka, Jolanta; Pawelczak, Malgorzata; Kafarski, Pawel [European Journal of Medicinal Chemistry, 2005, vol. 40, # 8, p. 764 - 771]
[2]Current Patent Assignee: NEONC TECHNOLOGIES INC - WO2018/195149, 2018, A1 Location in patent: Page/Page column 36-38
[3]Bian, Haiyong; Feng, Jinhong; Xu, Wenfang [Medicinal Chemistry Research, 2013, vol. 22, # 1, p. 175 - 185]
[4]Bechar, Elly; Astroug, Henri [Archiv der Pharmazie, 1997, vol. 330, # 9-10, p. 273 - 276]
[5]El-Latef, S. A. Ahd; Ragab; El-Eraky; Abo-Ghalia [Egyptian Journal of Chemistry, 2010, vol. 53, # 2, p. 301 - 314]
[6]Leroide [Annales de Chimie (Cachan, France), 1921, vol. <9> 16, p. 365]
[7]Benoit-Guyod,J.-L. et al. [Bulletin de la Societe Chimique de France, 1965, p. 1660 - 1661]
[8]Winn, Martin; Von Geldern, Thomas W.; Opgenorth, Terry J.; Jae, Hwan-Soo; Tasker, Andrew S.; Boyd, Steven A.; Kester, Jeffrey A.; Mantei, Robert A.; Bal, Radhika; Sorensen, Bryan K.; Wu-Wong, Jinshyun R.; Chiou, William J.; Dixon, Douglas B.; Novosad, Eugene I.; Hernandez, Lisa; Marsh, Kennan C. [Journal of Medicinal Chemistry, 1996, vol. 39, # 5, p. 1039 - 1048]
[9]Rekatas, George V.; Tani, Ekaterini; Demopoulos, Vassilis J.; Kourounakis, Panos N. [Archiv der Pharmazie, 1996, vol. 329, # 8-9, p. 393 - 398]
[10]Girard, Pierre; Guillot, Nadine; Motherwell, William B.; Hay-Motherwell, Robyn S.; Potier, Pierre [Tetrahedron, 1999, vol. 55, # 12, p. 3573 - 3584]
[11]Supuran, Claudiu T.; Popescu, Angela; Banciu, Mircea D. [Revue Roumaine de Chimie, 1992, vol. 37, # 2, p. 289 - 298]
[12]Kehler, Jan; Hansen, Henrik I.; Sanchez, Connie [Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 22, p. 2547 - 2548]
[13]Chazalette, Celine; Masereel, Bernard; Rolin, Stéphanie; Thiry, Anne; Scozzafava, Andrea; Innocenti, Alessio; Supuran, Claudiu T. [Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 23, p. 5781 - 5786]
[14]Deng, Jianping; Tabei, Junichi; Shiotsuki, Masashi; Sanda, Fumio; Masuda, Toshio [Macromolecules, 2004, vol. 37, # 14, p. 5149 - 5154]
[15]Thiry, Anne; Ledecq, Marie; Cecchi, Alessandro; Dogné, Jean-Michel; Wouters, Johan; Supuran, Claudiu T.; Masereel, Bernard [Journal of Medicinal Chemistry, 2006, vol. 49, # 9, p. 2743 - 2749]
[16]Heal, William; Thompson, Mark J.; Mutter, Roger; Cope, Hannah; Louth, Jenny C.; Chen, Beining [Journal of Medicinal Chemistry, 2007, vol. 50, # 6, p. 1347 - 1353]
[17]Shimshoni, Jakob Avi; Bialer, Meir; Wlodarczyk, Bogdan; Finnell, Richard H.; Yagen, Boris [Journal of Medicinal Chemistry, 2007, vol. 50, # 25, p. 6419 - 6427]
[18]Siafaka-Kapadai, Athanassia; Patiris, Marinis; Bowden, Charles; Javors, Martin [Biochemical Pharmacology, 1998, vol. 56, # 2, p. 207 - 212]
[19]Current Patent Assignee: UNIVERSITY OF SHEFFIELD - WO2008/90382, 2008, A1 Location in patent: Page/Page column 45
[20]Current Patent Assignee: Yissum Research & Development (in: Hebrew University); HEBREW UNIVERSITY OF JERUSALEM - WO2009/1356, 2008, A2 Location in patent: Page/Page column 43-44
[21]Location in patent: experimental part Yokoyama, Akihiro; Inagaki, Yuko; Ono, Tomomi; Yokozawa, Tsutomu [Journal of Polymer Science, Part A: Polymer Chemistry, 2011, vol. 49, # 6, p. 1387 - 1395]
[22]Location in patent: experimental part Diao, Lei; Polli, James E. [Journal of Pharmaceutical Sciences, 2011, vol. 100, # 9, p. 3802 - 3816]
[23]Location in patent: experimental part Peura, Lauri; Malmioja, Kalle; Laine, Krista; Leppaenen, Jukka; Gynther, Mikko; Isotalo, Antti; Rautio, Jarkko [Molecular Pharmaceutics, 2011, vol. 8, # 5, p. 1857 - 1866]
[24]El-Faham, Ayman; Farooq, Muhammad; Khattab, Sherine Nabil; Elkayal, Ahmed Mohamed; Ibrahim, Mahmoud Fawzy; Abutaha, Nael; Wadaan, Mohammad Ahmad; Hamed, Ezzat Awad [Chemical and Pharmaceutical Bulletin, 2014, vol. 62, # 6, p. 591 - 599]
[25]Ylikangas, Henna; Malmioja, Kalle; Peura, Lauri; Gynther, Mikko; Nwachukwu, Emmanuel O.; Leppänen, Jukka; Laine, Krista; Rautio, Jarkko; Lahtela-Kakkonen, Maija; Huttunen, Kristiina M.; Poso, Antti [ChemMedChem, 2014, vol. 9, # 12, p. 2699 - 2707]
[26]Current Patent Assignee: CELLIXBIO PRIVATE LTD - US2016/122282, 2016, A1 Location in patent: Paragraph 0112; 0113
[27]Current Patent Assignee: CELLIXBIO PRIVATE LTD - JP2015/533114, 2015, A Location in patent: Paragraph 0208; 0209; 0210
[28]Prestegui-Martel, Berenice; Bermúdez-Lugo, Jorge Antonio; Chávez-Blanco, Alma; Dueñas-González, Alfonso; García-Sánchez, José Rubén; Pérez-González, Oscar Alberto; Padilla-Martínez, Itzia Irene; Fragoso-Vázquez, Manuel Jonathan; Mendieta-Wejebe, Jessica Elena; Correa-Basurto, Ana María; Méndez-Luna, David; Trujillo-Ferrara, José; Correa-Basurto, José [Journal of Enzyme Inhibition and Medicinal Chemistry, 2016, vol. 31, p. 140 - 149]
[29]Current Patent Assignee: JIANGSU NHWA PHARMACEUTICAL COMPANY LIMITED - CN104230981, 2016, B Location in patent: Paragraph 0020; 0024-0025
[30]Alpuche-García, Andrea; Dávila-González, Xochitl; Arregui, Leticia; Beltrán, Hiram I. [RSC Advances, 2017, vol. 7, # 20, p. 12391 - 12399]
[31]Current Patent Assignee: FUZHOU UNIVERSITY - CN107540528, 2018, A Location in patent: Paragraph 0012
[32]Espinoza, Eli M.; Clark, John A.; Soliman, Joey; Derr, James B.; Morales, Maryann; Vullev, Valentine I. [Journal of the Electrochemical Society, 2019, vol. 166, # 5, p. H3175 - H3187]
[33]Current Patent Assignee: CELLIX BIO PROVATE; CELLIXBIO PRIVATE LTD - WO2020/26054, 2020, A1 Location in patent: Paragraph 00135-00136
[34]Tng, Jiahui; Lim, Junxian; Wu, Kai-Chen; Lucke, Andrew J.; Xu, Weijun; Reid, Robert C.; Fairlie, David P. [Journal of Medicinal Chemistry, 2020, vol. 63, # 11, p. 5956 - 5971]
[35]Fragoso-Vázquez; Méndez-Luna; Rosales-Hernández; Luna-Palencia; Estrada-Pérez; Fromager, Benedicte; Vásquez-Moctezuma; Correa-Basurto [Molecular Diversity, 2021, vol. 25, # 2, p. 1077 - 1089]
[36]Chamorro-Cevallos, Germán; Correa-Basurto, José; Cristóbal-Luna, José Melesio; Mendoza-Figueroa, Humberto L. [Toxicology and Applied Pharmacology, 2020, vol. 399]
[37]Current Patent Assignee: CELLIXBIO PRIVATE LTD - WO2021/245503, 2021, A1 Location in patent: Paragraph 0054-0056
[38]Current Patent Assignee: CELLIXBIO PRIVATE LTD - WO2022/49462, 2022, A1 Location in patent: Paragraph 0052-0053
[39]Current Patent Assignee: CELLIXBIO PRIVATE LTD - WO2021/245503, 2021, A1 Location in patent: Paragraph 0054-0056

4
[ 1636-27-7 ]
[ 99-66-1 ]

Yield	Reaction Conditions	Operation in experiment
97.7%	In acetonitrile at 90 - 100℃; for 12 - 15h;	1 Example 1:; To the stirred solution of 2,2-di-n-propyl malonic acid (1.0 kg, 5.313 moles) in acetonitrile (3.0 lit) was added copper (I) oxide (38.1g, 0.266 moles) at room temperature. Brown slurry thus obtained was gradually heated to reflux (oil bath temperature of 90-100 °C). The reaction mixture was allowed to stir continuously at reflux temperature for 12-15 hrs. Progress of the reaction was monitored by TLC and GC. After 12 hours of heating acetonitrile was distilled off at atmospheric pressure. Traces of remaining solvent from the crude mass were removed under vacuum at 50 0C. Crude reaction mixture obtained after drying for 30 minutes was cooled to 25 °C and water was added (1.5 lit), followed by 3.0 N aqueous hydrochloric acid (1.0 lit). Reaction mixture was allowed to stir for 30 minutes. It was then extracted with ethyl acetate (3 x 1.0 lit). The combined organic layers were washed with water (1.0 lit) and saturated brine solution (1.0 lit). Ethyl acetate layer was dried over anhydrous sodium sulphate. Solvent was distilled off under reduced pressure. Crude product thus obtained was dried under high vacuum at 50 °C for 2 hrs to obtain crude golden yellow liquid (800.0g). Finally the above product was fractional distilled under high vacuum (2 mbar) and at oil bath temp of 120-130 °C. Yield of the distilled product = 748.2 g (97.7%, colorless liquid). G.C. Purity = > 99.5%. Spectroscopic data of Valproic acid: 1H NMR in CDCl3: δ 11.13 (brd. s, IH), 2.43-2.34 (m, IH), 1.66-1.59 & 1.51-1.32 (2 x m, 8H), 0.94 (t, 6H).13C NMR in CDCl3: δ 183.43, 45.24, 34.43, 20.65, 14.06. GC-MS: 145 (M+H)+, 115. IR (Neat): 3037.89, 2962.66-2872.01, 2671.41, 1695.43, 1465.90, 1415.75, 1381.03, 1342.46, 1278.81, 1251.80, 1209.37, 1151.50, 1107.14, 943.19 cm-1.
88%	With poly-4-vinylpyridine In N,N-dimethyl-formamide for 0.05h; microwave irradiation;
	at 180 - 200℃;

	In butan-1-ol at 80 - 100℃; for 12 - 15h; Heating / reflux;	2 Example 2; Process as describe in Example 1 was used with different solvents, catalysts and different concentration of catalysts. The results are tabulated below:Table- 1 shows results of decarboxylation of di-n-propoylmalonic acid using different solvents in the presence of copper (I) oxide as a metal catalyst. The process as carried out at 80 °C to 100 °C using the procedure as described in the Example.Table-l• The % conversion was determined by derivatization using bis- (trimethylsilyl)trifluoroacetamide, followed by GC analysisThe results show highest conversion with DMF followed by ethanol. This shows that organic polar solvents provide the desired result of formation of valproic acid.
	In N,N-dimethyl-formamide at 80 - 100℃; for 12 - 15h; Heating / reflux;	2 Example 2; Process as describe in Example 1 was used with different solvents, catalysts and different concentration of catalysts. The results are tabulated below:Table- 1 shows results of decarboxylation of di-n-propoylmalonic acid using different solvents in the presence of copper (I) oxide as a metal catalyst. The process as carried out at 80 °C to 100 °C using the procedure as described in the Example.Table-l• The % conversion was determined by derivatization using bis- (trimethylsilyl)trifluoroacetamide, followed by GC analysisThe results show highest conversion with DMF followed by ethanol. This shows that organic polar solvents provide the desired result of formation of valproic acid.
	In water; acetonitrile at 80 - 100℃; for 12 - 15h; Heating / reflux;	2 Example 2; Process as describe in Example 1 was used with different solvents, catalysts and different concentration of catalysts. The results are tabulated below:Table- 1 shows results of decarboxylation of di-n-propoylmalonic acid using different solvents in the presence of copper (I) oxide as a metal catalyst. The process as carried out at 80 °C to 100 °C using the procedure as described in the Example.Table-l• The % conversion was determined by derivatization using bis- (trimethylsilyl)trifluoroacetamide, followed by GC analysisThe results show highest conversion with DMF followed by ethanol. This shows that organic polar solvents provide the desired result of formation of valproic acid.
	In ethanol at 80 - 100℃; for 12 - 15h; Heating / reflux;	2 Example 2; Process as describe in Example 1 was used with different solvents, catalysts and different concentration of catalysts. The results are tabulated below:Table- 1 shows results of decarboxylation of di-n-propoylmalonic acid using different solvents in the presence of copper (I) oxide as a metal catalyst. The process as carried out at 80 °C to 100 °C using the procedure as described in the Example.Table-l• The % conversion was determined by derivatization using bis- (trimethylsilyl)trifluoroacetamide, followed by GC analysisThe results show highest conversion with DMF followed by ethanol. This shows that organic polar solvents provide the desired result of formation of valproic acid.
	In water at 80 - 100℃; for 12 - 15h; Heating / reflux;	2 Example 2; Process as describe in Example 1 was used with different solvents, catalysts and different concentration of catalysts. The results are tabulated below:Table- 1 shows results of decarboxylation of di-n-propoylmalonic acid using different solvents in the presence of copper (I) oxide as a metal catalyst. The process as carried out at 80 °C to 100 °C using the procedure as described in the Example.Table-l• The % conversion was determined by derivatization using bis- (trimethylsilyl)trifluoroacetamide, followed by GC analysisThe results show highest conversion with DMF followed by ethanol. This shows that organic polar solvents provide the desired result of formation of valproic acid.
	In acetonitrile at 90 - 100℃; for 12 - 15h; Heating / reflux;	2 Example 2; Process as describe in Example 1 was used with different solvents, catalysts and different concentration of catalysts. The results are tabulated below:Table- 1 shows results of decarboxylation of di-n-propoylmalonic acid using different solvents in the presence of copper (I) oxide as a metal catalyst. The process as carried out at 80 °C to 100 °C using the procedure as described in the Example.Table-l• The % conversion was determined by derivatization using bis- (trimethylsilyl)trifluoroacetamide, followed by GC analysisThe results show highest conversion with DMF followed by ethanol. This shows that organic polar solvents provide the desired result of formation of valproic acid.Table-2 shows results of the decarboxylation of di-n-propylmalonic acid carried out using the metal catalysts other than copper (I) oxide. Table-2• The % conversion was determined by derivatization t using bis- (trimethylsilyl)trifluoroacetamide, followed by GC analysisThus it is evident that the salts do not provide desired conversion as copper oxide.
	In acetonitrile at 90 - 100℃; for 12 - 15h; Heating / reflux;	2 Example 2; Process as describe in Example 1 was used with different solvents, catalysts and different concentration of catalysts. The results are tabulated below:Table- 1 shows results of decarboxylation of di-n-propoylmalonic acid using different solvents in the presence of copper (I) oxide as a metal catalyst. The process as carried out at 80 °C to 100 °C using the procedure as described in the Example.Table-l• The % conversion was determined by derivatization using bis- (trimethylsilyl)trifluoroacetamide, followed by GC analysisThe results show highest conversion with DMF followed by ethanol. This shows that organic polar solvents provide the desired result of formation of valproic acid.Table-2 shows results of the decarboxylation of di-n-propylmalonic acid carried out using the metal catalysts other than copper (I) oxide. Table-2• The % conversion was determined by derivatization t using bis- (trimethylsilyl)trifluoroacetamide, followed by GC analysisThus it is evident that the salts do not provide desired conversion as copper oxide.
	In acetonitrile at 90 - 100℃; for 12 - 15h; Heating / reflux;	2 Example 2; Process as describe in Example 1 was used with different solvents, catalysts and different concentration of catalysts. The results are tabulated below:Table- 1 shows results of decarboxylation of di-n-propoylmalonic acid using different solvents in the presence of copper (I) oxide as a metal catalyst. The process as carried out at 80 °C to 100 °C using the procedure as described in the Example.Table-l• The % conversion was determined by derivatization using bis- (trimethylsilyl)trifluoroacetamide, followed by GC analysisThe results show highest conversion with DMF followed by ethanol. This shows that organic polar solvents provide the desired result of formation of valproic acid.Table-2 shows results of the decarboxylation of di-n-propylmalonic acid carried out using the metal catalysts other than copper (I) oxide. Table-2• The % conversion was determined by derivatization t using bis- (trimethylsilyl)trifluoroacetamide, followed by GC analysisThus it is evident that the salts do not provide desired conversion as copper oxide.
	at 170℃;	step 1 Decarboxylation: The obtained solid is heated at 170°C until no gas is released, 6.5 g of brown-black liquid is obtained, which is 3-propyl-n-pentanoic acid with the structural formula (8a) (equivalent to R2 in the structural formula (8) is propyl).
14.5 kg	In tert-butyl methyl ether for 1h; Large scale;	1-8 Pump 1000 kg of acid water after centrifugal separation of 2,2-dipropylmalonic acid into a 2000L reactor, add 250 kg of tert-butyl methyl ether with stirring, continue stirring for 1 hour, and stand still for layering. Dry with anhydrous magnesium sulfate, filter, and put the filtrate into a clean and dry esterification kettle, concentrate to dryness, add 400kg of anhydrous ethanol and 5kg of concentrated sulfuric acid to react, after the reaction is complete, post-treatment to obtain diethyl 2-propylmalonate. Then add 1.0kg sodium hydride to catalyze propylation, hydrolysis, acidification and decarboxylation. 14.5kg of valproic acid was obtained. The content (GC) is 99.8%.

Reference： [1]Current Patent Assignee: CALYX CHEMICALS AND PHARMACEUT - WO2008/62471, 2008, A2 Location in patent: Page/Page column 10
[2]Helavi; Solabannavar; Desai; Mane [Journal of Chemical Research - Part S, 2003, # 3, p. 174 - 175]
[3]Fuerth [Monatshefte fur Chemie, 1888, vol. 9, p. 310]
[4]Current Patent Assignee: CALYX CHEMICALS AND PHARMACEUT - WO2008/62471, 2008, A2 Location in patent: Page/Page column 10-11
[5]Current Patent Assignee: CALYX CHEMICALS AND PHARMACEUT - WO2008/62471, 2008, A2 Location in patent: Page/Page column 10-11
[6]Current Patent Assignee: CALYX CHEMICALS AND PHARMACEUT - WO2008/62471, 2008, A2 Location in patent: Page/Page column 10-11
[7]Current Patent Assignee: CALYX CHEMICALS AND PHARMACEUT - WO2008/62471, 2008, A2 Location in patent: Page/Page column 10-11
[8]Current Patent Assignee: CALYX CHEMICALS AND PHARMACEUT - WO2008/62471, 2008, A2 Location in patent: Page/Page column 10-11
[9]Current Patent Assignee: CALYX CHEMICALS AND PHARMACEUT - WO2008/62471, 2008, A2 Location in patent: Page/Page column 10-12
[10]Current Patent Assignee: CALYX CHEMICALS AND PHARMACEUT - WO2008/62471, 2008, A2 Location in patent: Page/Page column 10-12
[11]Current Patent Assignee: CALYX CHEMICALS AND PHARMACEUT - WO2008/62471, 2008, A2 Location in patent: Page/Page column 10-12
[12]Current Patent Assignee: Song Wei - CN112047964, 2020, A Location in patent: Paragraph 0053; 0056; 0057
[13]Current Patent Assignee: HUNAN PROVINCE XIANGZHONG PHARMACEUTICAL - CN112142588, 2020, A Location in patent: Paragraph 0015-0030

5
[ 99-66-1 ]
[ 51660-44-7 ]

Yield	Reaction Conditions	Operation in experiment
97%	With triethylamine; chlorophosphoric acid diphenyl ester In dichloromethane at 20℃;
82%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20 - 25℃;
80%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	Valproic anhydride was prepared by the addition of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (0.77 g, 5 mmol) to a solutionof VPA (1.44 g, 10 mmol) in 15 mL dichloromethane and stirringthe reaction overnight at room temperature. The solution was washedwith 3% citric acid (2 × 30 mL), 3% NaHCO3 (2 × 30 mL) and 3% NaCl(2 × 30 mL). The organic phase was dried over sodium sulfate, filteredand evaporated to yield the desired compound as a colorless liquid.Yield: 80%, 860 mg.

80%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	2.1 2.2.2. [Pt(DACH) (OH)(VPA)(ox)] (II) Valproic anhydride was prepared by the addition of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (0.77 g, 5 mmol) to a solutionof VPA (1.44 g, 10 mmol) in 15 mL dichloromethane and stirringthe reaction overnight at room temperature. The solution was washedwith 3% citric acid (2 × 30 mL), 3% NaHCO3 (2 × 30 mL) and 3% NaCl(2 × 30 mL). The organic phase was dried over sodium sulfate, filteredand evaporated to yield the desired compound as a colorless liquid.Yield: 80%, 860 mg.
	Multistep reaction;
	Multi-step reaction with 2 steps 1: thionyl chloride / 2 h / 86 °C 2: triethylamine / tetrahydrofuran / 4 h / 10 °C / Industrial scale
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;

Reference： [1]Tai, Akihiro; Kawasaki, Daisuke; Sasaki, Kenji; Gohda, Eiichi; Yamamoto, Itaru [Chemical and Pharmaceutical Bulletin, 2003, vol. 51, # 2, p. 175 - 180]
[2]Qu, Shen; Greenhalgh, Mark D.; Smith, Andrew D. [Chemistry - A European Journal, 2019, vol. 25, # 11, p. 2816 - 2823]
[3]Novohradsky, Vojtech; Zerzankova, Lenka; Stepankova, Jana; Vrana, Oldrich; Raveendran, Raji; Gibson, Dan; Kasparkova, Jana; Brabec, Viktor [Journal of Inorganic Biochemistry, 2014, vol. 140, p. 72 - 79]
[4]Novohradsky, Vojtech; Zerzankova, Lenka; Stepankova, Jana; Vrana, Oldrich; Raveendran, Raji; Gibson, Dan; Kasparkova, Jana; Brabec, Viktor [Journal of Inorganic Biochemistry, 2014, vol. 140, p. 72 - 79]
[5]Nicolaus,B.J.R. et al. [Helvetica Chimica Acta, 1962, vol. 45, p. 717 - 728]
[6]Current Patent Assignee: JIANGSU NHWA PHARMACEUTICAL COMPANY LIMITED - CN104230981, 2016, B
[7]Li, Yang; Shi, Shan; Zhang, Shurong; Gan, Zongjie; Wang, Xin; Zhao, Xudong; Zhu, Yijian; Cao, Meiting; Wang, Xiaoyue; Li, Wei [Dalton Transactions, 2021, vol. 50, # 32, p. 11180 - 11188]

6
[ 99-66-1 ]
[ 67-63-0 ]
[ 60498-67-1 ]

Yield	Reaction Conditions	Operation in experiment
	With trifluoroacetic anhydride In benzene

Reference： [1]Smith,G.G. et al. [Journal of Organic Chemistry, 1977, vol. 42, # 1, p. 44 - 47]

7
[ 2430-27-5 ]
[ 99-66-1 ]

Reference： [1]Tetrahedron Letters,2000,vol. 41,p. 3855 - 3857
[2]Pharmazie,1984,vol. 39,p. 865 - 865

8
[ 99-66-1 ]
[ 58175-57-8 ]

Yield	Reaction Conditions	Operation in experiment
89%	With hydrogen In 1,2-dimethoxyethane at 150℃; for 16h;
	Multi-step reaction with 2 steps 1: HCl 2: sodium; ethanol / 100 - 110 °C
	With lithium aluminium tetrahydride In dichloromethane for 24h; Reflux;

79 %Chromat.	With aluminium(III) triflate; tin(II) trifluoromethanesulfonate; hydrogen; [2-((diphenylphospino)methyl)-2-methyl-1,3-propanediyl]bis[diphenylphosphine] In water; toluene at 160℃; for 24h; Autoclave;
	Multi-step reaction with 2 steps 1.1: thionyl chloride / 2 h / 60 °C 1.2: 1 h / Reflux 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 0.5 h / 0 °C

Reference： [1]He, De-Hua; Wakasa, Noriko; Fuchikami, Takamasa [Tetrahedron Letters, 1995, vol. 36, # 7, p. 1059 - 1062]
[2]Koller; Kandler [Monatshefte fur Chemie, 1931, vol. 58, p. 234]
[3]Location in patent: experimental part Hen, Naama; Bialer, Meir; Yagen, Boris [Journal of Medicinal Chemistry, 2012, vol. 55, # 6, p. 2835 - 2845]
[4]Cui, Xinjiang; Li, Yuehui; Topf, Christoph; Junge, Kathrin; Beller, Matthias [Angewandte Chemie - International Edition, 2015, vol. 54, # 36, p. 10596 - 10599][Angew. Chem., 2015, vol. 127, p. 10742 - 10745,4]
[5]Current Patent Assignee: Song Wei - CN112047964, 2020, A

9
[ 29331-92-8 ]
[ 99-66-1 ]
10-[(2-propyl)pentanoyloxy]-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 2582 - 2587

10
[ 99-66-1 ]
[ 53297-68-0 ]
2-propyl-pentanoic acid (2-chloro-4-sulfamoyl-phenyl)-amide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 312 - 320

11
[ 99-66-1 ]
[ 35418-07-6 ]
[ 1026819-81-7 ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 467 - 474

12
[ 99-66-1 ]
[ 94512-73-9 ]
2-propyl-pentanoic acid 2-(4'-bromo-biphenyl-4-yl)-2-oxo-ethyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3521 - 3523

13
[ 99-66-1 ]
[ 30095-47-7 ]
2-propyl-pentanoic acid 2-(4-<i>tert</i>-butyl-phenyl)-2-oxo-ethyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3521 - 3523

14
[ 67-56-1 ]
[ 99-66-1 ]
[ 22632-59-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid Reflux;
	With sulfuric acid for 12h; Reflux;	Synthesis of Valproic Hydrazide 8 Valproic acid (0.01 mol) was dissolved in 50 mL of methanol, and 3-4 drops of conc. sulphuric acid was added. The reaction mixture was refluxed for 12-14 h on water bath. The progress of the reaction was checked by TLC using hexane-ethyl acetate (4 : 6) as a mobile phase. After the reaction was completed, excess of methanol was removed under reduced pressure and the crude product was dissolved in ethyl acetate (30 mL), washed with 5% sodium bicarbonate solution (20 mL×2), water (20 mL×2), dried over anhydrous sodium sulphate, filtered, and then the solvent was removed under reduced pressure to afford the product as a viscous liquid in 90% yield.34) The crude product was used for the next step. Hydrazine hydrate (15 mL) was added to a solution of methyl valproate (0.01 mol) in methanol (20 mL) and the reaction mixture was refluxed for 12-14 h. The reaction mixture was cooled to r.t. to give the hydrazide 8 as a white colored shining fluffy product,in yield 85%, mp 123-124°C.
14.4 g	Stage #1: valproic acid With thionyl chloride at 60℃; for 2h; Stage #2: methanol for 1h; Reflux;	step 2 Esterification: Put 14.8 g of 3-propyl n-valeric acid with the structural formula 8(a) in the flask, add 13.4 g of thionyl chloride dropwise and stir and gradually raise the temperature to 60°C. After 2 hours, 9 g of methanol was added dropwise, and the temperature was raised to reflux for 1 hour. The reaction system was lowered to room temperature, 60ml of water was added, extracted with 40mlx3 methyl tert-butyl ether, washed with 30ml of saturated sodium carbonate solution, dried with anhydrous sodium sulfate, and concentrated to obtain 14.4g of oily liquid.

With sulfuric acid at 60 - 70℃;

Reference： [1]Werstuck, Geoff H.; Kim, Anna J.; Brenstrum, Timothy; Ohnmacht, Stephan A.; Panna, Ella; Capretta, Alfredo [Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 22, p. 5465 - 5467]
[2]Location in patent: scheme or table Fass, Daniel M.; Shah, Rishita; Ghosh, Balaram; Hennig, Krista; Norton, Stephanie; Zhao, Wen-Ning; Reis, Surya A.; Klein, Peter S.; Mazitschek, Ralph; Maglathlin, Rebecca L.; Lewis, Timothy A.; Haggarty, Stephen J. [ACS Medicinal Chemistry Letters, 2011, vol. 2, # 1, p. 39 - 42]
[3]El-Faham, Ayman; Farooq, Muhammad; Khattab, Sherine Nabil; Elkayal, Ahmed Mohamed; Ibrahim, Mahmoud Fawzy; Abutaha, Nael; Wadaan, Mohammad Ahmad; Hamed, Ezzat Awad [Chemical and Pharmaceutical Bulletin, 2014, vol. 62, # 6, p. 591 - 599]
[4]Current Patent Assignee: Song Wei - CN112047964, 2020, A Location in patent: Paragraph 0058; 0059
[5]Dong, Lei; Fang, Ling; Dai, Xinxiang; Zhang, Jia; Wang, Jia; Xu, Pei [Drug Development Research, 2022, vol. 83, # 1, p. 131 - 141]

15
[ 99-66-1 ]
[ 530-62-1 ]
C₁₁H₁₈N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: valproic acid; 1,1'-carbonyldiimidazole With chloro-trimethyl-silane In acetonitrile for 2.5h; Stage #2: Stage #3: In pyridine; acetonitrile at 0 - 45℃;	Dissolve 2',2'-difluoro-2'-deoxycytidine (10.0 g, 38.0 mmol) in anhydrous pyridine (100 mL) and cool to O0C while stirring under nitrogen. Add chlorotrimethylsilane (24.0 mL, 190.0 mmol) dropwise, maintaining an internal temperature < 50C. Continue stirring at O0C for 2 hours. In a separate flask, dissolve 2- propylpentanoic acid (6.0 g, 41.8 mmol) in anhydrous acetonitrile (100 mL). Add 1,1- carbonyldiimidazole (6.8 g, 41.8 mmol) in small portions over 30 minutes and stir for 2 hours. Add this acetonitrile solution dropwise to the pyridine solution at O0C and allow the reaction to come to ambient temperature. Heat the reaction at 450C overnight then cool to 30-350C and add 100 mL absolute ethanol and heat at 450C for 30 minutes. Add 50 mL water and heat at 450C for 5 hours then cool to ambient temperature and concentrate in vacuo. Partition the crude residue between ethyl acetate and water. Acidify to pH ~2 with phosphoric acid and separate the organic layer. Back extract the aqueous layer with additional ethyl acetate. Combine the organic solutions and wash with saturated sodium bicarbonate solution and saturated sodium chloride solution, dry over magnesium sulfate and concentrate in vacuo. Purify by silica gel chromatography (120 g) eluting with a gradient of 30% to 60% ethyl acetate in methylene chloride. Isolate desired product as a white crushable foam (11.2 g, 77% yield). MS (ES): m/z 390.3 = [M+H]+ MS (ES): m/z 388.3 = [M-H]+1HNMR (400 MHz, DMSO-J6) δ 0.83 (t, 6H), 1.15-1.36 (m, 6H), 1.46-1.55 (m, 2H), 2.60 (dddd, IH, J=14.4, 9.6, 5.6, 5.6 Hz), (ddd, IH, J=12.6, 6.2, 3.6 Hz), 3,77-3.81 (m, IH), 3,87 (dt, IH, J=8.4, 3.0 Hz), 4.12-4.22 (m, IH), 5.27 (t, IH, J=5.6 Hz), 6.15 (t, IH, J=7.4 Hz), 6.29 (d, IH, J=6.4 Hz), 7.31 (d, IH, J=7.2 Hz), 8.23 (d, IH, J=8.0 Hz), 11.03 (s, IH).

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2007/149891, 2007, A2 Location in patent: Page/Page column 6

16
C₁₈H₁₅Cl₃N₂ [ No CAS ]
[ 99-66-1 ]
C₂₆H₂₉Cl₃N₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h;	4 Carboxylic acids of formula (III) are dissolved in DMF to a concentration of 0.25 M in the presence of 3 equivalents of DIPEA. 120 μl of these solutions are placed in each 2 ml well and 120 ml of a solution of TBTU in DMF at a concentration of 0.25 M are added. 300 μl of a solution containing the methylamine of formula (II) in DMF at a concentration of 0.1 M and 3 equivalents of DIPEA are added to each well. The plates are shaken at RT for 16 hours and then evaporated. The products formed in each well are dissolved with 500 μl of EtOAc, 400 PI of 0.1 M Na2CO3 are then added and the plates are shaken. After separation of the phases by settling, 430 μl of aqueous phase are discarded, 300 μl of 5% NaCl are then added and the plates are shaken. 350 μl of aqueous phase are then discarded, 20 μl are taken for LC/UV/MS analysis and the rest is evaporated under vacuum to give the expected compound.

Reference： [1]Current Patent Assignee: SANOFI - US2008/15245, 2008, A1 Location in patent: Page/Page column 8

17
[ 898907-19-2 ]
[ 99-66-1 ]
N-[[4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-thienyl]methyl]-2-propylpentanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In DCM at 20℃; for 48h;	1 N-[[4-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-2-thienyl]methyl]-2-propylpentanamide A mixture of 0.35 g of the compound obtained in Preparation 8.1, 0.125 g of 2-propylpentanoic acid, 0.36 ml of triethylamine and 0.3 g of TBTU in 30 ml of DCM is kept stirred for 48 hours at RT. The reaction mixture is concentrated under vacuum, the residue is taken up in water, extracted with AcOEt, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluding with the gradient of the heptane/AcOEt mixture from (100/1; v/v) to (90/10; v/v). 0.25 g of the expected compound is obtained.

Reference： [1]Current Patent Assignee: SANOFI - US2008/9543, 2008, A1 Location in patent: Page/Page column 11

18
[ 898907-20-5 ]
[ 99-66-1 ]
N-[[4-(4-bromophenyl)-5-(2,4-dichlorophenyl)-2-thienyl]methyl]-2-propylpentanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In DCM at 20℃; for 15h;	3 N-[[4-(4-Bromophenyl)-5-(2,4-dichlorophenyl)-2-thienyl]methyl]-4-propylpentanamide A mixture of 0.47 g of the compound obtained in Preparation 8.2, 0.19 ml of 2-propylpentanoic acid, 0.6 ml of triethylamine and 0.4 g of TBTU in 10 ml of DCM is kept stirred for 15 hours at RT. The reaction mixture is concentrated under vacuum, the residue it taken up in water, extracted with ether, the organic phase is washed with water, dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluding with the heptane/AcOEt mixture (50/50; v/v). 0.3 g of the expected compound is obtained after crystallization from pentane.

Reference： [1]Current Patent Assignee: SANOFI - US2008/9543, 2008, A1 Location in patent: Page/Page column 11

19
1-(6-(4-methoxyphenyl)-5-(2,4-dichlorophenyl)-2-methylpyridin-3-yl)methanamine [ No CAS ]
[ 99-66-1 ]
C₂₈H₃₂Cl₂N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In ethyl acetate; N,N-dimethyl-formamide at 20℃; for 16h; Combinatorial reaction / High throughput screening (HTS);	5 EXAMPLE 5 EXAMPLE 5 The compounds of formula (IA) 15 to 50 and (IB) 60 to 88 in which Z represents N(R1)XR2 and -X-=-CO- or SO2 are prepared by combinatorial chemistry according to the process described below: A carboxylic acid of formula (III) or, respectively, a sulfonyl halide of formula (IV) is dissolved in DMF to a concentration of 0.25M in the presence of 3 equivalents of DIPEA. 120 μl of this solution and 120 μl of a solution of TBTU in DMF at a concentration of 0.25M are placed in each 2 ml well. 300 μl of a solution containing the corresponding compound of formula (II) in DMF at a concentration of 0.1M and 3 equivalents of DIPEA is added to each well. The plates are shaken at RT for 16 hours and then evaporated. The products formed are dissolved in each well with 500 μl of EtOAc, 400 μl of 0.1M Na2CO3 are added and the plates are shaken. After separation of the phases by settling, 430 μl of aqueous phase are discharged and 300 μl of 5% NaCl are then added and the plates are shaken. 350 μl of aqueous phase are then discarded and the residues are analyzed by LC/UV/MS.

Reference： [1]Current Patent Assignee: SANOFI - US2008/21070, 2008, A1 Location in patent: Page/Page column 11; 13-14

20
[ 906540-73-6 ]
[ 99-66-1 ]
5-(4-Bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N'-(2-propylpentanoyl)-1H-pyrazole-3-carbohydrazide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine In dichloromethane at 20℃;	3.14 Preparation 3.14 5-(4-Bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N'-(2-propylpentanoyl)-1H-pyrazole-3-carbohydrazide A mixture of 0.7 g of the compound obtained in Preparation 2.3, 0.23 g of 2-propylpentanoic acid, 0.54 ml of triethylamine and 0.96 g of PyBOP in 20 ml of DCM is left stirring overnight at AT. The reaction mixture is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water, with a 1N HCl solution, with water and with a 10% NaHCO3 solution and dried over MgSO4, and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, elution being carried out with heptane and then with a heptane/AcOEt (80/20; v/v) mixture. 0.88 g of the expected compound is obtained, which compound is crystallized from an isopropyl ether/pentane mixture.

Reference： [1]Current Patent Assignee: SANOFI - US2008/39510, 2008, A1 Location in patent: Page/Page column 14

21
[ 99-66-1 ]
[ 1069-66-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydroxide; In water;Product distribution / selectivity;	Example 1 Preparation of Divalproex Sodium In a 3-L round-bottomed flask was placed valproic acid (144 g, 1 mole) and 40% NaOH aqueous solution (50 g, 0.5 mole). The resulting solution was then put on a rotavaper, applied vacuum, and heated up slowly (e.g., water bath temperature from room temperature to 95 C.) to remove the water. Upon completion of the water removals the reaction mixture was allowed to cool down to room temperature to obtain divalproex sodium (154 g, 100%).
100%	With sodium hydroxide; In water; at 20℃;	A solution of vpCO2H (270 mg, 1.87 mmol) in H2O (2 mL) was treated with 1.00 M NaOH (1.80mL, 1.80 mmol) and stirred at room temperature for 30?. Volatiles were then removed undervacuum and the residue was suspended in Et2O. The suspension was filtered and the resultingcolorless solid was washed with Et2O and dried under vacuum. The compound was subsequentlyused for coordination to Ruthenium, otherwise stored under N2 (hygroscopic). Yield: quantitative.
97.7%	With sodium hydroxide; In toluene;	Through boiling with NaOH and back titration, acid and ester were determined to total 2.381 moles. This reaction solution was mixed with 324 g of an aqueous 29.4 wt. % NaOH solution (2.381 moles NaOH) and refluxed for 3 hours. The residual alkali content was found to be 0.08%, or 0.58 g NaOH. Neutralization was carried out by the addition of 2 g dipropylacetic acid. Ethanol was distilled off and water was then discharged azeotropically with 450 ml toluene. The content of the flask was then evaporated on a rotary evaporator, first in a water-jet vacuum and then in an oil-pump vacuum, to dryness. After drying at 80 C. and 20 millibars over CaCl2, 388 g sodium dipropyl acetate representing a 97.7% yield was obtained. The dipropylacetic acid liberated after acidification with concentrated HCl had a purity of 99.47%. The remaining 0.53% was made up of dipropylmalonic acid (0.016), valeric acid (0.28), dipropylacetic ester (0.047) and three unknown compounds.

With sodium hydroxide;

Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. Chemically it is sodium hydrogen bis(2- propylpentanoate). Divalproex sodium is known and its preparation and therapeutic use as an anticonvulsive drug is described in U. S. Patent Nos. 4,988,731 and 5,212326. Divalproex sodium is available commercially as DEPAKOTE and DEPAKOTE ER (Abbott) in 125,250 and 500 mg dosages.

Reference： [1]Patent: US2011/40122,2011,A1 .Location in patent: Page/Page column 2
[2]Journal of Organometallic Chemistry,2018,vol. 869,p. 201 - 211
[3]Patent: US4417073,1983,A
[4]Patent: WO2005/120523,2005,A1 .Location in patent: Page/Page column 45

22
[ 99-66-1 ]
[ 68076-36-8 ]
[ 868566-95-4 ]

Yield	Reaction Conditions	Operation in experiment
92%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide)	1 Valproic acid [1] and Boc-diaminobutane [2] were condensed using PyBOP (benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate) and DIEA (N, N-diisopropylethylamine) in DMF (dimethyl formamide) to afford compound [3]. The crude product was purified by column chromatography to yield a white solid, 5.7 g, 92%.

Reference： [1]Current Patent Assignee: CEPTOR - WO2005/108353, 2005, A2 Location in patent: Page/Page column 19

23
[ 99-66-1 ]
[ 892128-60-8 ]

Yield	Reaction Conditions	Operation in experiment
77%	Stage #1: gemcitabine With pyridine; chloro-trimethyl-silane at 0 - 5℃; for 2h; Stage #2: valproic acid With 1,1'-carbonyldiimidazole In acetonitrile at 20 - 45℃; Stage #3: With ethanol; phosphoric acid; water more than 3 stages;	1 Dissolve 2',2'-difluoro-2'-deoxycytidine (10.0 g, 38.0 mmol) in anhydrous pyridine (100 mL) and cool to 00C while stirring under nitrogen. Add chlorotrimethylsilane (24.0 mL, 190.0 mmol) dropwise, maintaining an internal temperature < 5°C. Continue stirring at 0°C for 2 hours. In a separate flask, dissolve 2- propylpentanoic acid (6.0 g, 41.8 mmol) in anhydrous acetonitrile (100 mL). Add 1,1- carbonyldiimidazole (6.8 g, 41.8 mmol) in small portions over 30 minutes and stir for 2 hours. Add this acetonitrile solution dropwise to the pyridine solution at 0°C and allow the reaction to come to ambient temperature. Heat the reaction at 45°C overnight then cool to 30-35°C and add 100 mL absolute ethanol and heat at 45°C for 30 minutes. Add 50 mL water and heat at 45°C for 5 hours then cool to ambient temperature and concentrate in vacuo. Partition the crude residue between ethyl acetate and water. Acidify to pH ~2 with phosphoric acid and separate the organic layer. Back extract the aqueous layer with additional ethyl acetate. Combine the organic solutions and wash with saturated sodium bicarbonate solution and saturated sodium chloride solution, dry over magnesium sulfate and concentrate in vacuo. Purify by silica gel chromatography (120 g) eluting with a gradient of 30% to 60% ethyl acetate in methylene chloride. Isolate desired product as a white crushable foam (11.2 g, 77% yield). MS (ES): m/z 390.3 = [M+H]+ MS (ES): m/z 388.3 - [M-H]+1HNMR (400 MHz, δ 0.83 (t, 6H), 1.15-1.36 (m, 6H), 1.46-1.55 (m, 2H), 2.60 (dddd, IH, J=14.4, 9.6, 5.6, 5.6 Hz), (ddd, IH, J=12.6, 6.2, 3.6 Hz), 3,77-3.81 (m, IH), 3,87 (dt, IH, J=8.4, 3.0 Hz), 4.12-4.22 (m, IH), 5.27 (t, IH, J=5.6 Hz), 6.15 (t, IH, J=7.4 Hz), 6.29 (d, IH, J=6.4 Hz), 7.31 (d, IH, J=7.2 Hz), 8.23 (d, IH, J=8.0 Hz), 11.03 (s, IH).

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2006/65525, 2006, A1 Location in patent: Page/Page column 5

24
[ 99-66-1 ]
[ 107-06-2 ]
[ 99174-91-1 ]

Yield	Reaction Conditions	Operation in experiment
96.5%	With thionyl chloride; bromine In ethanol; water; N,N-dimethyl-formamide	1.a a) a) Preparation of ethyl 2-bromo-2-propylpentanoate 144 g of 2-propylpentanoic acid and 0.5 g of N,N-dimethylformamide are introduced under a nitrogen atmosphere into a Grignard reactor. The mixture is heated to 65° C., and 128.4 g of thionyl chloride are added in the course of 8 h while the temperature of the medium is maintained at between 65° and 70° C. When the addition is complete, the medium is heated to 95° C. and this temperature is maintained for one hour. 40 g of 1,2-dichloroethane are then introduced, the mixture is heated to 100° C., and 164 g of bromine are added in the course of 8 h. The temperature of the medium is maintained at 110°-115° C. for one hour after the addition is complete, the reaction mixture is cooled to 80°-85° C., and 74 g of absolute ethanol are then added in the course of 2 h 30 min. The mixture is heated to reflux for one hour and then cooled to 20° C. before adding 40 g of water. Settling is allowed to take place, the organic phase is concentrated and the oily residue is distilled [B.p.: 117°-119° C. (20 mmHg)]. In this manner, 242 9 of ethyl 2-bromo-2-propylpentanoate are obtained. Yield: 96.5%.

Reference： [1]Current Patent Assignee: SANOFI - US5262561, 1993, A

25
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD·HCl) [ No CAS ]
methanol-THF [ No CAS ]
N-benzyloxycarbonyl-(L)-isoleucyl-(L)-tryptophanol [ No CAS ]
[ 99-66-1 ]
[ 161708-73-2 ]

Yield	Reaction Conditions	Operation in experiment
84.8%	In dichloromethane; ethyl acetate; N,N-dimethyl-formamide	13 EXAMPLE 13 EXAMPLE 13 A mixture of N-benzyloxycarbonyl-(L)-isoleucyl-(L)-tryptophanol(2.14 g), palladium-carbon (5%, 50% wet, 1.0 g) and methanol-THF (5:1, 30 ml) was subjected to catalytic hydrogenation at room temperature and atomospheric pressure. After the catalyst was filtered off, the filterate was concentrated under reduced pressure to yield an oily substance. The oil and valproic acid (0.71 g) were dissolved in N,N-dimethylformamide (20 ml), and 1-hydroxybenzotriazole (HOBt) (0.82 g) and a solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD·HCl)(1.13 g) in dichloromethane (20 ml) were added thereto at 0° C. After stirring at 0° C. for 1 hour and at room temperature for 15 hours, the reaction mixture was concentrated under reduced pressure and the residue was suspended in ethyl acetate (120 ml). The mixture was successively washed with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate and brine, and dried (MgSO4). The organic solvent was evaporated off to yield N-valproyl-(L)-isoleucyl-(L)-tryptophanol (1.78 g, 84.8%) as crystals. Recrystallization from ethyl acetate-hexane gave colorless needles. Melting point: 190°-191° C. [α]D =-60.8° (c 0.50, CH3 OH) Elemental analysis (for C25 H39 N3 O3) Calculated: C,69.90; H,9.15; N,9.78 Found: C,69.69; H,9.14; N,9.50

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US5498728, 1996, A

26
[ 164645-70-9 ]
[ 99-66-1 ]
[ 164646-70-2 ]

Yield	Reaction Conditions	Operation in experiment
65%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In tetrahydrofuran	74.a a a (R)-N5 -[Amino(nitroimino)methyl]-N-[(4-hydroxyphenyl)methyl]-N2 -(1-oxo-2-propylpentyl)-ornithinamide Prepared analogously to Example 5d), but using tetrahydrofuran instead of acetonitrile, from (R)-N5 -[amino(nitroimino)methyl]-N-[(4-hydroxyphenyl)methyl]-ornithinamide, 2-propyl-pentanoic acid and TBTU in a yield of 65% of theory. Colourless crystalline substance which was further processed without purification.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US5616620, 1997, A

27
[ 18591-87-2 ]
[ 99-66-1 ]
[ 910553-33-2 ]

Yield	Reaction Conditions	Operation in experiment
13%		Example 186.; Preparation of 3-(4-chloro-2-morpholin-4-yl-thiazol-5-yl)-2,6-dimethyl-8-(1-propyl- butyl)-imidazo[1,2-b]pyridazine.; A. 6-Methyl-4-(1-propyl-butyl)-pyridazin-3-ylamine.; 6-Methyl-4-(1-propyl-butyl)-pyridazin-3-ylamine can be made using chemistry described in J. Heterocylic Chem. 1991, 28, 583. A 250 mL three neck round bottom flask is charged with <strong>[18591-87-2]3-amino-6-methyl pyridazine</strong> (2.5 g, 0.229 moles, 1.0 equiv), water (70 mL), and acetonitrile (50 mL). Concentrated sulfuric acid (3.51 g, 1.91 mL, 0.0344 moles, 1.5 equiv), silver nitrate (3.87 g, 0.0229 moles, 1.0 equiv), and valproic acid (7.21 g, 7.95 mL, 0.050 moles, 2.2 equiv) are added to the reaction mixture. The reaction is heated to 75 C. As the reaction mixture is heating, a solution of (NELO2S2O8 (7.85 g, 0.0344 moles, 1.5 equiv) in 40 mL of water is slowly added via an addition funnel over a period of 30 minutes. The reaction mixture is heated at 70-80 C for two more hours. The reaction mixture is cooled and dichoromethane is added. The reaction is made basic with a 30% aqueous NaOH solution and filtered through a short Celite plug. The organic layer is separated, and the aqueous layer is extracted two more times with dichoromethane. The combined organic extracts are dried over Na2SO4. The solvent is evaporated and the crude material is purified using silica gel chromatography with a 2.0 N solution Of NH3 in MeOH and methylene chloride as eluent. Yield = 0.61 g (13%). MS (APCI): 208 (M+l).

Reference： [1]Patent: WO2006/102194,2006,A1 .Location in patent: Page/Page column 140

28
[ 99-66-1 ]
2-propyl pentanoic acid anhydride [ No CAS ]
[ 51660-44-7 ]

Yield	Reaction Conditions	Operation in experiment
89%	With acetic anhydride In 5,5-dimethyl-1,3-cyclohexadiene	II Preparation of valproic acid anhydride with the above formula 2. (R3 =R4 =n-Pr) EXAMPLE II Preparation of valproic acid anhydride with the above formula 2. (R3 =R4 =n-Pr) 288 g (2 mol) of 2-propyl pentanoic acid was added to a three neck round bottom flask of 1 liter, which was provided with a vigreux column with distillation unit. Then 330 ml of freshly distilled xylene and 120 ml acetic acid anhydride were added. The obtained mixture was refluxed during 5 hours whereupon the formed acetic acid was slowly distilled. After cooling the solution was filtrated and distilled under reduced pressure. The 2-propyl pentanoic acid anhydride was obtained at 155°-156° C. (14 mm Hg, 1,9 kPa) in a yield of 89% and with a molecular weight of 270.42 g/mol. The thus obtained valproic acid anhydride should be considered as a prodrug of valproic acid. Valproic acid possesses anti-epileptic properties, but has a side effect gastro-intestinal complaints, such as nausea, vomica and indigestion.

Reference： [1]Current Patent Assignee: N V GANTAX PHARMACEUTICA - US4863965, 1989, A

29
[ 99-66-1 ]
[ 584-08-7 ]
[ 2695-47-8 ]
7-carboxy-7-propyl-1-decene [ No CAS ]
[ 13319-71-6 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; LiAlH4; NaH; diisopropylamine; In tetrahydrofuran; water;	EXAMPLE 1A Preparation of 7-Carboxy-7-propyl-1-decene by the Alkylation of Valproic Acid with 6-Bromo-1-hexene Under an argon blanket, sodium hydride (1 g, 50% oil, 0.022 mole) was washed twice with hexane and the washings decanted. To the washed NaH was added 50 ml of THF (freshly distilled from LiAlH4) and followed by the dropwise addition of valproic acid (2.88 g, 0.02 mole) in 20 ml of THF. The rate of addition was adjusted according to the amount of hydrogen evolved. The sodium salt was cooled in a salt ice bath to 0 and then diisopropylamine (2 g, 0.02 mole, distilled over CaH2) was added. The mixture was heated to 55 for 15 minutes, and then cooled to room temperature in two hours. The solution was then cooled to -1 and n-butyllithium (10 ml, 0.02 mole) was added while keeping the temperature between about 0-5. After 15 minutes, the reaction mixture was warmed to 35 for 33 minutes and again cooled to 0. To the cold reaction mixture was added dropwise cold (0-2) 6-bromo-1-hexene (3.2 g, 0.02 mole) in 20 ml of THF. The resulting solution was cooled in an ice bath for 30 minutes, then maintained at 33 for an hour. NaBr precipitated and the reaction mixture was allowed to stir overnight at room temperature. A sample of the solution was taken and shaken with D2 O; nmr showed no tertiary hydrogen present. The reaction mixture was then cooled in an ice bath, 25 ml of water was added and the mixture was extracted with 50 ml of ether. The ethereal solution had 50 ml of 5% K2 CO3 added to it and then was extracted with 250 ml of hexane. The basic aqueous solution in an ice bath was acidified with concentrated HCl to pH 1, saturated with salt, and then extracted with 250 ml of ether. The ethereal solution was washed with 3*10 ml of brine, dried (MgSO4) and concentrated to give 2.9 g of an oil. Tlc on silica (10% methanol in chloroform) gave a Rf 0.76 visualized by bromocresol green stain.

Reference： [1]Patent: US4238389,1980,A

30
[ 99-66-1 ]
divalproex sodium [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96.65%	With sodium hydroxide In di-isopropyl ether at 20 - 50℃; for 1h;	IV Example IV:To a solution of Valproic acid (10Og) in diisopropyl ether(200ml) at 20-300C, powdered caustic (13g ; half molar) is added & the reaction mixture is stirred at 40-500C for 1 hr to get clear solution. Then acetonitrile (800ml) is added to it inorder to crystallize the product. The solid, thus obtained, is further stirred at 0-50C for 2-3 hr followed by filtration. The product was dried at 40-450C for 10-12 hr. (104g; 96.65%)
94.79%	With sodium hydroxide In tert-butyl methyl ether at 20 - 50℃; for 1h;	V Example V:To a solution of Valproic acid (10Og) in methyl tertiary butyl ether(200ml) at 20- 300C, powdered caustic (13g ; half molar) is added & the reaction mixture is stirred at 40-500C for 1 hr to get clear solution. Then acetonitrile (800ml) is added to it inorder to crystallize the product. The solid, thus obtained, is further stirred at 0-50C for 2-3 hr followed by filtration. The product was dried at 40-450C for 10-12 hr. (102g;94.79%)
93%	With sodium hydroxide In dichloromethane at 20 - 40℃; for 1h;	III Example III:To a solution of Valproic acid (10Og) in dichloromethane (200ml) at 20-300C, powdered caustic (13g ; half molar) is added & the reaction mixture is stirred at 30- 400C for 1 hr to get clear solution. Then acetonitrile (600ml) is added to it inorder to crystallize the product. The solid, thus obtained, is further stirred at 0-50C for 2-3 hr followed by filtration. The product was dried at 40-450C for 10-12 hr. (10Og; 93%)

93.87%	With sodium hydroxide In toluene at 20 - 50℃; for 1h;	VI Example VI:To a solution of Valproic acid (10Og) in toluene (200ml) at 20-300C, powdered caustic (13g ; half molar) is added & the reaction mixture is stirred at 40-500C for 1 hr to get clear solution. Then acetonitrile (800ml) is added to it inorder to crystallize the product. The solid, thus obtained, is further stirred at 0-50C for 2-3 hr followed by filtration. The product was dried at 40-450C for 10-12 hr. (101g; 93.87%)
51.11%	With sodium hydroxide at 20 - 50℃; for 1h;	I; II Example I:; To lOOg of Valproic acid with stirring at 20-300C, powdered NaOH ( 13g; half molar) is added & the resulting reaction mixture is stirred at 40-500C for 1 hr. Then acetonitrile(600ml) is added to obtain clear solution at 40-500C and the solution is charcoalized at 40-500C followed by filtration at 40-500C through hyflo-bed. The resultant reaction mixture was stirred at 10-200C for 2-3 hr. The solid , thus obtained, was filtered and product was dried at 40-450C for 10-12 hr. (102.25g, 95%); Example II; To lOOg of Valproic acid with stirring at 20-300C, powdered NaOH (13g; half molar) is added & the resulting reaction mixture is stirred at 30-400C for 1 hr. Then acetone (600ml) is added to obtain clear solution at 30-400C and the material is charcoalized at 30-400C followed by filtration through hyflo-bed. The resultant reaction solution was stirred at -5°C to -1O0C for 2-3 hr. The solid , thus obtained, was filtered and product was dried at 40-450C for 10-12 hr. ( 55g, 51.11%)
51%	With sodium hydroxide In ethanol at 20 - 30℃; for 1h;	X; XI Example X:To a solution of valproic acid (10Og) in ethanol (200ml) at 20-300C, caustic (13g; half molar) is added & the reaction mixture is stirred at 20-300C for 1 hr. Then the ethanol was recovered at reduced pressure and acetonitrile (600ml) is added to it with stirring.The reaction mixture was further stirred at 0-50C for 2-3 hr. The solid, thus obtained, is filtered, washed with acetonitrile (100ml) and product was dried at 40-450C for 10-12 hr.(101g; ~ 93.87%); Example XI: EPO To a solution of valproic acid (10Og) in ethanol (200ml) at 20-30°C, caustic (13g; half molar) is added & the reaction mixture is stirred at 20-300C for 1 hr. Then the ethanol was recovered at reduced pressure and acetone (600ml) is added to it with stirring. The reaction mixture was further stirred at -5°C to -100C for 2-3 hr. The solid, thus obtained, is filtered, washed with chilled acetone (100ml) and product was dried at 40-450C for 10-12 hr.(55g; ~ 51%)
50.11%	With sodium hydroxide In methanol at 20 - 30℃; for 1h;	VIII; IX Example VIII;To a solution of valproic acid (10Og) in methanol (200ml) at 20-300C5 caustic (13g; half molar) is added & the reaction mixture is stirred at 20-300C for 1 hr. Then the methanol was recovered at reduced pressure and acetonitrile (600ml) is added to it with stirring. The reaction mixture was further stirred at 0-50C for 2-3 hr. The solid, thus obtained, is filtered, washed with acetonitrile (100ml) and product was dried at 40-45°C for 10-12 hr.(102g; ~ 95%); Example IX:To a solution of valproic acid (10Og) in methanol (200ml) at 20-300C, caustic (13g; half molar) is added & the reaction mixture is stirred at 20-300C for 1 hr. Then the methanol was recovered at reduced pressure and acetone (600ml) is added to it with stirring. The reaction mixture was further stirred at -5°C to -1O0C for 2-3 hr. The solid, thus obtained, is filtered, washed with chilled acetone (100ml) and product was dried at 40-450C for 10-12 hr.(54g; ~ 50.11%)

Reference： [1]Current Patent Assignee: MOREPEN LAB - WO2007/4238, 2007, A2 Location in patent: Page/Page column 8
[2]Current Patent Assignee: MOREPEN LAB - WO2007/4238, 2007, A2 Location in patent: Page/Page column 8
[3]Current Patent Assignee: MOREPEN LAB - WO2007/4238, 2007, A2 Location in patent: Page/Page column 8
[4]Current Patent Assignee: MOREPEN LAB - WO2007/4238, 2007, A2 Location in patent: Page/Page column 8
[5]Current Patent Assignee: MOREPEN LAB - WO2007/4238, 2007, A2 Location in patent: Page/Page column 7
[6]Current Patent Assignee: MOREPEN LAB - WO2007/4238, 2007, A2 Location in patent: Page/Page column 9-10
[7]Current Patent Assignee: MOREPEN LAB - WO2007/4238, 2007, A2 Location in patent: Page/Page column 9

31
[ 99-66-1 ]
[ 1069-66-5 ]
divalproex sodium [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93.75%	In acetonitrile;Heating / reflux;Product distribution / selectivity;	Example VII: EPO <DP n="10"/>A mixture of <strong>[1069-66-5]sodium valproate</strong> (6Og) and valproic acid (52.04g) was taken in acetonitrile (800ml) and heated at reflux to obtain a clear solution, which was filtered through hyflo-bed to remove suspended particles. Then the solution was stirred at 10- 200C for 2-3 hr. The solid, thus obtained, was filtered and washed with acetonitrile (100ml). The product was dried at 40-450C for 10-12 hr. (105g ; 93.75%)

Reference： [1]Patent: WO2007/4238,2007,A2 .Location in patent: Page/Page column 8-9
[2]Canadian Journal of Chemistry,2014,vol. 92,p. 9 - 15

32
[ 99-66-1 ]
[ 77-86-1 ]
[ 923953-12-2 ]

Yield	Reaction Conditions	Operation in experiment
97%	In methanol at 20℃; for 0.5h;	EXAMPLE[0024] Valproic acid (5.6 g, 40 mmol, 100 mol %) was added to methanol (50 mL) and stirred until the valproic acid was substantially dissolved Tris(hydroxymethyl)amιnomethane (4.8 g, 40 mmol, 100 mol %) was then added and the resulting mixture was stirred for 30 minutes at room temperature. The methanol was removed under vacuum at 180 mbar at 60°C. The isolated product is crystalline, and has a melting point of about 65°C to about 660C. The product (10.1 g, 97 % yield) was determined to be TRIS-valproate.[0025] The product was characterized by PXRD, which was consistent with that shown in Fig 1 , byDSC, which was consistent with Fig 2, and by FT-IR, which was consistent with Fig. 3. Elemental Analysis[0026] The calculated and empirically determined elemental analyses for the anhydrous tromethamine salt of valproic acid are as follows and as in Table 2:[0027] Empirical formula = C12H17NO5[0028] Molecular weight = 265 35 EPO .,>

Reference： [1]Current Patent Assignee: AVANTOR PERFORMANCE MATERIALS INC - WO2007/15724, 2007, A1 Location in patent: Page/Page column 4-5

33
[ 99-66-1 ]
magnesium valproate hydrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With magnesium ethylate In ethanol at 20℃; for 0.5 - 1h;	6; 9.C; 10.D EXAMPLE 6 Preparation of Magnesium Valproate Hydrate of the Present Invention A solution of magnesium valproate in absolute ethanol was obtained in the following manner. To a magnetically stirred, clear, colorless solution of valproic acid (3.17 g; 0.022 mol; Sigma Aldrich Chemical Co.) in 25 mL of absolute ethanol was added 1.14 g (0.01 mol) of magnesium ethoxide solid; residual solid was rinsed in with 1 mL of absolute ethanol. Within 60 minutes, a clear, pale yellow solution was obtained; no heating was observed. One milliliter portions of the solution were aliquoted into test tubes, and a second solvent or solution was added in portions. The results of the additions are summarized in Table 2. A 15 mL portion of acetonitrile was added to an equal volume of the ethanol solution of magnesium valproate. A white precipitate formed, which was isolated by filtration, washed with a fresh portion of acetonitrile, and dried to constant mass. The product, magnesium valproate hydrate, was obtained in 89% yield as a white solid, which exhibited an elemental composition identical to that calculated for magnesium valproate hydrate. The product did not melt at temperatures as high as 300° C. The product was not hygroscopic or deliquescent. The theoretical valproate content (weight %) of magnesium valproate hydrate is 88.6%; the valproate content found by HPLC analysis was 88.5%. TABLE 2 Solvents or Solutions Tested Volume Solvent or Solution Added Added Observation Saturated NaCl solution 1 mL Copious white precipitate (brine) Ethyl acetate 1 mL Clear solution Acetonitrile 1 mL Copious white precipitate Methyl t-butyl ether 1 mL Clear solution Tetrahydrofuran 1 mL Clear solution Dimethoxyethane 1 mL Clear solution Water 1 mL Cloudiness and some precipitate Acetone 5 mL Clear solution Saturated NaCl solution 4 drops Copious white precipitate (brine)Saturated NaHCO3 solution 4 drops Copious white precipitate Hexanes 3 mL Clear solution; EXAMPLE 9 Preparation of Magnesium Valproate Hydrate of the Present Invention Method C A solution of magnesium valproate in absolute ethanol was obtained in the following manner. To a magnetically stirred, clear, colorless solution of valproic acid (31.7 g; 0.22 mol; Sigma Aldrich Chemical Co.) in 200 mL of absolute ethanol was added 11.4 g (0.1 mol) of magnesium ethoxide solid; residual solid was rinsed in with 1 mL of absolute ethanol. Within 30 minutes, a clear, pale yellow solution was obtained; no increase in reaction temperature was observed. Acetonitrile (150 mL) was added to the ethanol solution in portions, and when the addition was complete a white precipitate formed. The reaction mixture was cold to the touch. The slurry was stirred for 15 minutes. The product, magnesium valproate hydrate, was isolated by filtration, washed with fresh acetonitrile, and dried to constant weight. The product, magnesium valproate hydrate, was obtained in 79.8% yield as a white solid, which exhibited an elemental composition identical to that calculated for magnesium valproate hydrate. The product did not melt at temperatures as high as 300° C. The product was not hygroscopic or deliquescent and was stable during storage under ambient conditions. The theoretical valproate content (weight %) of magnesium valproate hydrate is 88.6%; the valproate content found by HPLC analysis was 88.2%.; EXAMPLE 10 Preparation of Magnesium Valproate Hydrate of the Present Invention Method D Unless magnesium ethoxide is freshly generated in situ by reaction of magnesium metal with ethanol, the magnesium ethoxide solids that are obtained commercially frequently contain colored by-products that are potential contaminants of the desired product, magnesium valproate hydrate. To demonstrate the purification of an alcohol solution containing magnesium valproate and colored contaminants, a solution of magnesium valproate in absolute ethanol was obtained in the following manner. To a magnetically stirred, clear, colorless solution of valproic acid (15.12 g; 0.105 mol; Sigma Aldrich Chemical Co.) in 90 mL of absolute ethanol was added 5.7 g (0.05 mol) of magnesium ethoxide solid (Sigma Aldrich Chemical Co.). Within 30 minutes, a clear, pale yellow solution was obtained; no increase in reaction temperature was observed. The pale yellow solution was treated with decolorizing carbon. After filtration with the aid of Celite to facilitate carbon removal, a nearly colorless filtrate solution was obtained. Acetonitrile (45 mL) was added to the ethanol solution in portions, and when the addition was complete, a white precipitate formed. The reaction mixture was cold to the touch. The slurry was stirred for 15 minutes. The product, magnesium valproate hydrate, was isolated by filtration, washed with fresh acetonitrile, and dried to constant weight. The product, magnesium valproate hydrate, was obtained in 77% yield as a white solid, which exhibited an elemental composition identical to that calculated for magnesium valproate hydrate (Table 4). The product did not melt at temperatures as high as 300° C. The product was not hygroscopic or deliquescent and was stable during storage under ambient conditions. X-ray diffraction analysis showed that magnesium valproate hydrate of the present invention is a polymorph having both crystalline and amorphous structural features. The theoretical valproate content (weight %) of magnesium valproate hydrate is 88.6%; the valproate content found by HPLC analysis was 88.5%. TABLE 4 Percent by weight elemental composition of magnesium valproate hydrate C H O Mg Theoretical 59.4 9.8 23.3 7.5 Found 59.33 9.81 Not det'd 7.5
0%	With magnesium methanolate In methanol; isopropyl alcohol	3; 7.A; 11 EXAMPLE 3 Attempted Preparation of Microcrystalline Magnesium Valproate Attempts were made to prepare microcrystalline magnesium valproate in the following manner. To a magnetically stirred, clear, colorless solution of valproic acid (2.88 g; 0.02 mol; Sigma Aldrich Chemical Co.) in 20 mL of 2-propanol was added 10 mL (0.01 mol) of magnesium methoxide solution in methanol (Sigma Aldrich Chemical Co.). A clear, pale yellow solution was obtained. Acetone was added to the alcohol solution in portions; after 100 mL had been added, a clear and colorless solution was obtained; no precipitate formed. The reaction temperature did not change during the addition of acetone.; EXAMPLE 7 Preparation of Magnesium Valproate Hydrate of the Present Invention Method A A solution of magnesium valproate was obtained in the following manner. To a magnetically stirred, clear, colorless solution of valproic acid (2.88 g; 0.02 mol; Sigma Aldrich Chemical Co.) in 20 mL of 2-propanol was added 10 mL (0.01 mol) of magnesium methoxide solution in methanol (Sigma Aldrich Chemical Co.). A clear, pale yellow solution was obtained. Acetonitrile was added to the alcohol solution in portions, and after 100 mL had been added, a white precipitate formed. The reaction mixture was cold to the touch. The slurry was stirred for 15 minutes. The product, magnesium valproate hydrate, was isolated by filtration, washed with fresh acetonitrile, and dried to constant weight. The product, magnesium valproate hydrate, was obtained in 70% yield as a white solid, which exhibited an elemental composition identical to that calculated for magnesium valproate hydrate. The product did not melt at temperatures as high as 300° C. The product was not hygroscopic or deliquescent and was stable during storage under ambient conditions. The theoretical valproate content (weight %) of magnesium valproate hydrate is 88.6%; the valproate content found by HPLC analysis was 88.5%.; EXAMPLE 11 Attempted Preparation of Magnesium Valproate To a magnetically stirred, clear, colorless solution of valproic acid (3.17 g; 0.022 mol; Sigma Aldrich Chemical Co.) in 20 mL of 2-propanol was added 10 mL (0.01 mol) of magnesium methoxide in methanol solution. A clear, colorless solution was obtained; no increase in reaction temperature was observed. 2-Propanol (45 mL) was added in portions, and when the addition was completed, a white precipitate formed. The white solid contained valproate but did not have a composition corresponding to that of magnesium valproate (Table 5). The theoretical valproate content (weight %) of magnesium valproate hydrate is 88.6%; the valproate content found by HPLC analysis was 41.9%. TABLE 5 Percent by weight elemental composition of magnesium valproate C H O Mg Theoretical 61.8 9.7 20.6 7.8 Found 30.6 6.8 Not det'd Not det'd

Reference： [1]Current Patent Assignee: BIOLINK LIFE SCIENCES INC - US2007/83063, 2007, A1 Location in patent: Page/Page column 7-8
[2]Current Patent Assignee: BIOLINK LIFE SCIENCES INC - US2007/83063, 2007, A1 Location in patent: Page/Page column 6; 7

34
[ 1892-29-1 ]
[ 99-66-1 ]
[ 877864-16-9 ]

Yield	Reaction Conditions	Operation in experiment
35%	With dmap; triethylamine; dicyclohexyl-carbodiimide In tetrahydrofuran for 16h;	To a solution of 11 (10.00 g, 64.83 mmol) and valproicacid (11.22 g, 77.80 mmol) in THF (100 mL) were added DCC (16.03 g, 77.80mmol), DMAP (9.50 g, 77.80 mmol) and Et3N (13.60 mL, 97.25 mmol) andstirred for 16 h. The reaction mixture was filtered, concentrated and purifiedby silica gel column chromatography using EtOAc in petroleum ether to afford 18c (7.56 g, 35% yield)as a colourlessoil. 1H NMR (300 MHz, CDCl3) d0.89 (t, J = 7.2 Hz, 6H), 1.22 - 1.65(m, 8H), 2.34 - 2.40 (m, 1H), 2.86 - 2.94 (m, 4H), 3.89 (m, 2H), 4.35 (t, J = 6.6 Hz, 2H).
22%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 18h;	14 To a solution of SL-1 (7 g, 45.45 mmol) and valproic acid (7.85 g, 54.5 mmol) in DCM (80 mL) was added DCC (11.26 g, 54.5 mmol), followed by DMAP (6.65 g, 54.5 mmol), and the resulting suspension was stirred at RT for 18 h. After usual aqueous work-up and chromatographic purification, 2.82 g (22%) of I-C1-PD11 were obtained as a colorless oil. 1H NMR (CDCL3, 300 MHz): δ 0.86-0.93 (m, 6H), 1.22-1.29 (m, 8H), 1.32-1.59 (m, 4H), 2.37 (m, 1H), 3.89 (t, 2H, J=5.7 Hz), 4.35 (t, 2H, J=6.5 Hz).

Reference： [1]Jain, Arun K.; Gund, Machhindra G.; Desai, Dattatraya C.; Borhade, Namdev; Senthilkumar, Subrayan P.; Dhiman, Mini; Mangu, Naveen K.; Mali, Sunil V.; Dubash, Nauzer P.; Halder, Somnath; Satyam, Apparao [Bioorganic Chemistry, 2013, vol. 49, p. 40 - 48]
[2]Current Patent Assignee: PIRAMAL ENTERPRISES LIMITED - US2006/46967, 2006, A1 Location in patent: Page/Page column 132

35
[ 877865-34-4 ]
[ 99-66-1 ]
C₁₂H₂₃NO₅S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With triethylamine; dicyclohexyl-carbodiimide In tetrahydrofuran	81 This prodrug was synthesized as shown in Scheme 11, Method B using as reagents valproic acid (725 mg, 5.03 mmol), LI-2b (1 g, 5.03 mmol), TEA (611 mg, 6.04 mmol), DCC (1.25 g, 6.04 mmol) and DMAP (100 mg). Yield: 832 mg (51%). 1H-NMR (300 MHz, CDCl3): δ 0.89 (t, 6H, J=7.09 Hz), 1.22-1.77 (m, 8H), 2.36-2.40 (m, 1H), 2.93-3.00 (m, 4H), 4.34 (t, 2H, J=6.8 Hz), 4.70 (t, 2H, J=6.35 Hz). MS (CI)+ m/z: 326 [M+H]+

Reference： [1]Current Patent Assignee: PIRAMAL ENTERPRISES LIMITED - US2006/46967, 2006, A1 Location in patent: Page/Page column 114; 143

36
C₁₇H₃₁N₃O₆S₂ [ No CAS ]
[ 99-66-1 ]
C₃₃H₅₉N₃O₈S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; triethylamine; dicyclohexyl-carbodiimide In tetrahydrofuran at 0 - 20℃;	61.2 To a solution of the above boc-hydrazide (4.0 & 7.44 mmol) in DCM (20 mL) was added 50% TFA/DCM (10 mL) and stirred at RT for 1 h. DCM was removed under vacuum, the resulting residue triturated with diethyl ether (2*20 mL) and dried to give a colorless oil, which was dissolved in THF (20 mL). To the above solution at 0-5° C. was added TEA (2.1 mL, 14.88 mmol), valproic acid (1.18 g, 8.184 mmol), DCC (2.3 g, 11.16 mmol) and DMAP (0.909 g, 7.44 mmol) and the mixture was stirred overnight at RT. The mixture was filtered, concentrated and purified by column chromatography to afford 2.59 g (51%) of I-AA-MPD27 as a colorless gummy material. 1H NMR (CDCl3, 300 MHz): δ 0.85 (t, 6H, J=7.2 Hz), 1.3 (t, 6H, J=7.11 Hz), 1.21-1.80 (m, 26H), 2.2-2.3 (m, 1H), 2.35 (s, 2H), 2.81-2.94 (m, 4H), 3.21 (d, 2H, J=6.6 Hz), 3.65-3.68 (m, 1H), 4.19 (q, 2H, J=7.11 Hz), 4.36 (t, 2H, J=6.51 Hz), 4.39 (t, 2H, J=6.51 Hz), 5.51 (t, 1H), 8.17 (s, 1H). MS: m/z 712 [M+Na]+, 728 [M+K]+, 688 [M-H]-.

Reference： [1]Current Patent Assignee: PIRAMAL ENTERPRISES LIMITED - US2006/46967, 2006, A1 Location in patent: Page/Page column 140

37
[ 99-66-1 ]
1-[5-(4-bromophenyl)-4-(2,4-dichlorophenyl)pyrimidin-2-yl]methanamine hydrochloride [ No CAS ]
[ 919005-58-6 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine In dichloromethane at 20℃;	1 N-[[5-(4-Bromophenyl)-4-(2,4-dichlorophenyl)pyrimidin-2-yl]methyl]-2-propyl pentanamide N-[[5-(4-Bromophenyl)-4-(2,4-dichlorophenyl)pyrimidin-2-yl]methyl]-2-propyl pentanamide A mixture of 0.5 g of the compound from Preparation 4.1, 0.17 g of 2-propylpentanoic acid, 0.55 ml of triethylamine and 0.7 g of PyBOP in 10 ml of DCM is stirred overnight at RT. It is concentrated under vacuum, extracted with AcOEt, the organic phase is washed with 1N HCl solution, with water, then with saturated NaHCO3 solution, dried over MgSO4, and the solvent is evaporated under vacuum. The residue is taken up in EtOH 95, the crystalline product that forms is dried and then washed with pentane. 0.285 g of the expected compound is obtained.

Reference： [1]Current Patent Assignee: SANOFI - US2008/176867, 2008, A1 Location in patent: Page/Page column 11

38
[ 99-66-1 ]
[ 21209-51-8 ]
[ 852055-98-2 ]

Yield	Reaction Conditions	Operation in experiment
92%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 20h;	A mixture of 2-propylpentanoic acid (valproic acid, 6. 48 g, 44. 93 mmole), N- carbobenzyloxy-L-serine benzyl ester (Z-Ser-OBzl, 14.80 g, 44.93 mmole), EDC (8.61 g, 44. 91mmole), and DMAP (549 mg, 4.49 mmole) in anhydrous dichloromethane (50 mL) was stirred under an argon atmosphere at room temperature for 20 hours. After 20 hours, the dichloromethane was washed with water (3 x50 mL), dried over magnesium sulfate (5 g), filtered and concentrated under reduced pressure. The remaining colorless oil (20.87 g) was purified by column chromatography on silica gel (150 g, 0.035-0. 070 mm, 6 nm pore diameter), eluting with hexanes/ethyl acetate (3: 1). After concentration of, the product containing fractions under reduced pressure and drying under high vacuum until the weight was constant, the experiment produced the protected L-serine- valproate ester SPIC00101 (18.9 g, 92% yield) as a colorless oil. IH NMR (300 MHz, DMSO): 5 = 7.96 (1H, d, J= 8. 1 Hz), 7.35 (1OH, m), 5.14 (2H, s), 5.05 (2H, s), 4.51 (1H, m), 4.29 (2H, m), 2.29 (1H, m), 1.50-1. 25 (4H, m), 1. 25-1. 10 (4H, m), 0.80 (6H, t, J= 6.6 Hz). 13C NMR (75 MHz, DMSO): b = 174. 88,169. 15,155. 85,136. 58,135. 45,128. 26, 128. 18, 127.47, 127.71, 127.57, 66.32, 65.66, 62.47, 53.09, 44.20, 33.86, 33.79, 19.95, 13.85

Reference： [1]Patent: WO2005/46575,2005,A2 .Location in patent: Page/Page column 159-161

39
[ 99-66-1 ]
[ 13500-53-3 ]
[ 852056-02-1 ]

Yield	Reaction Conditions	Operation in experiment
82.4%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 20h;	A mixture of 2-propylpentanoic acid (valproic acid, 4.32 g, 30 mmole), N- carbobenzyloxy-L-hydroxyproline benzyl ester (Z-Hyp-OBzl, 10.66 g, 30 mmole) l, EDC (5.74 g, 30 mmole), and DMAP (366 mg, 3 mmole) in anhydrous dichloromethane (30 mL) was stirred under an argon atmosphere at room temperature for 20 hours. After 20 hours, the dichloromethane was washed with water (3x30 mL), dried over magnesium sulfate (5 g), filtered and concentrated under reduced pressure. The remaining colorless oil SPIC00201 (11.95 g, 24.7 mmole, 82.4% yield) was used without purification. 'H NMR (300 MHz, CDCl3) : 5 = 7.29 (1OH, m), 5.28-5. 00 (5H, m), 4.55 (1/2H, t, J= 8 Hz), 4.46 (1/2H, t, J= 8 Hz), 3. 80-3. 60 (2H, m), 2.43-2. 16 (3H, m), 1.60-1. 45 (2H, m), 1.40-1. 32 (2H, m), 1.28-1. 20 (4H, m), 0. 86 (6H, m). 3C NMR (75 MHz, DMSO) : 8 = 174. 74,171. 40,171. 05,153. 79,153. 31,136. 34, 136.20, 135.57, 135.38, 128.24, 128.13, 127. 95,127. 87,127. 67,127. 52, 127. 28, 127.10, 72.29, 71.53, 66.34, 66.10, 57.66, 57.19, 52.27, 51.89, 44.13, 40.33, 35.78, 34.79, 34.04, 33. 92, 33. 35, 20.00, 19. 91,13. 79, 13. 73.

Reference： [1]Patent: WO2005/46575,2005,A2 .Location in patent: Page/Page column 159; 162-163

40
[ 99-66-1 ]
[ 84500-41-4 ]
[ 852056-03-2 ]

Yield	Reaction Conditions	Operation in experiment
89.8%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 20h;	A mixture of 2-propylpentanoic acid (valproic acid, 4.32 g, 30 mmole), N- carbobenzyloxy-L-threonine benzyl ester (Z-Thr-OBzl, 10.30 g, 30 mmole), EDC (5.74 g, 30 mmole), and DMAP (366 mg, 3.0 mmole) in anhydrous dichloromethane (30 mL) was stirred under an argon atmosphere at room temperature for 20 hours. After 20 hours, the dichloromethane was washed with water (3x30 mL), dried over magnesium sulfate (5 g), filtered and concentrated under reduced pressure. The remaining colorless oil (13.44 g) was purified by column chromatography on silica gel (100 g, 0.035-0. 070 mm, 6 nm pore diameter), eluting with hexanes/ethyl acetate (4: 1). After concentration of the product containing fractions under reduced pressure and drying under high vacuum until the weight was constant, the experiment produced the protected L-threonine-valproate ester SPIC00301 (12.65 g, 89.8% yield) as a colorless oil. 'H NMR (300 MHz, CDCl3) : 8 = 7.40-7. 05 (11H, m), 5.45 (1H, m), 5.17-5. 02 (4H, m), 4.53 (1H, d, J= 9.6 Hz), 2.24 (1H, m), 1.58-1. 40 (2H, m), 1.40-1. 15 (9H, m), 0.86 (6H, m). 13C NMR (75 MHz, DMSO): 8 = 174. 24,169. 29,156. 48, 136.61, 135.34, 128.26, 128.20, 127.74, 127.67, 127.58, 69.04, 66.33, 65.78, 57.62, 44.50, 33.89, 33.80, 20.03, 19. 91, 16.40, 13.87.

Reference： [1]Patent: WO2005/46575,2005,A2 .Location in patent: Page/Page column 159; 164-165

41
[ 99-66-1 ]
(S)-allylglycine methyl ester hydrochloride [ No CAS ]
[ 1048107-04-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 18h;	A.1 DIEA (2.52 mL, 14.5 mmol) was added to a mixture of (S)-methyl 2-aminopent-4-enoate hydrochloride (500 mg, 3.03 mmol) [Del Valle, J. R.; Goodman, M. J. of Org. Chem. 2004, 69, 8946-8948], 2-propylpentanoic acid (417 mg, 2.89 mmol), EDC (581 mg, 3.03 mmol), and HOBt (409 mg, 3.03 mmol) in DMF (15 mL) at rt. The mixture was stirred for 18 h and subsequently poured into 200 mL 1M HCl. The aqueous layer was extracted with EtOAc/hexanes (95:5) (2×200 mL). The combined organic extracts were washed with brine, dried with MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to give (S)-methyl 2-(2-propylpentanamido)pent-4-enoate 852 mg (quantitative yield) as a white solid. LC-MS (M+H)+=256.16. 1H NMR (500 MHz, CDCl3) δ 5.90 (s, 1H) 5.64-5.85 (m, 1H) 4.95-5.14 (m, 2H) 4.04 (dd, J=5.04, 2.29 Hz, 2H) 3.75 (s, 3H) 2.28-2.46 (m, 1H) 2.07-2.29 (m, 2H) 1.62-1.64 (m, 1H) 1.46-1.47 (m, 1H) 1.18-1.36 (m, 4H) 0.87 (t, J=6.87 Hz, 3H).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2008/194535, 2008, A1 Location in patent: Page/Page column 14

42
[ 99-66-1 ]
[ 591-19-5 ]
[ 923556-89-2 ]

Yield	Reaction Conditions	Operation in experiment
47%	Stage #1: valproic acid With triethylamine; HATU In N,N-dimethyl-formamide at 0℃; for 0.25h; Stage #2: m-Bromoaniline In N,N-dimethyl-formamide at 0℃; for 2h;	71.1 Step 1: Et3N (3.24 mL, 23.25 mmol ) was added to a solution of 2-propylpentanoic acid in (2 g, 11.62 mmol) in DMF. The reaction mixture was cooled to 0 0C. HATU (6.63g, 17.4 mmol) was added to the reaction mixture which was stirred for 15 min and then 3-bromoaniline (2.5 g, 17.43 mmol) was added. The reaction mixture was stirred for 2h at 0 0C. The reaction mixture was diluted with H2O, extracted with EtOAc, and organic layer was concentrated under reduced pressure. The residue was washed with pentane to give λf-(3-bromophenyl)-2-propylpentanamide as a white solid. Yield (1.6 g, 47 %); 1H NMR (400 MHz, CDCl3) δ 7.82 (s, IH), 7.44 (d, J= 8.0 Hz, IH), 7.23 (d, J= 7.6 Hz, IH), 7.17 (t, J= 8.0 Hz, IH), 7.12 (bs, IH), 2.21-2.14 (m, IH), 1.73-1.63 (m, 2H), 1.51- 1.45 (m, 2H), 1.43-1.25 (m, 4H), 0.92 (t, J= 7.2 Hz, 6H).

Reference： [1]Current Patent Assignee: KUBOTA PHARMACEUTICAL HOLDINGS CO LTD - WO2010/48332, 2010, A2 Location in patent: Page/Page column 199

43
[ 99-66-1 ]
[ 41863-52-9 ]
[ 1085446-56-5 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: valproic acid With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 2h; Stage #2: N-tert-butoxycarbonyl-L-alanine hydrazide	6.2 Step 2: tert-Butyl{(1S)-1-methyl-2-oxo -242-(2-propylpentanoyl)hydrazine]ethyl}carbamate; To a solution of valproic acid in DCM (0.17 M) cooled to 0° C., was added WSCDI (1.5 eq.), DMAP (0.1 eq.) and tert-butyl[(1S)-2-hydrazino-1-methyl-2-oxoethyl]carbamate (1.0 eq.). The mixture was stirred at RT for 2 h then solvent was removed and EtOAc was added. The organic phase was treated with HCl 1N, NaHCO3 (sat.), brine and dried over Na2SO4. Solvent was removed in vacuo affording a colorless oil. MS (ES+) m/z 330 (M+H)+.

Reference： [1]Current Patent Assignee: ISTITUTO DI RICERCHE DI BIOLOGIA MOLECOLARE P. ANGELETTI S.R.L. - US2010/152128, 2010, A1 Location in patent: Page/Page column 19

44
[ 99-66-1 ]
[ 1235891-78-7 ]
[ 1186293-01-5 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: valproic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-N-methylmethanamine In N,N-dimethyl-formamide at 20℃; for 16h;	5 A solution of 2-propylpentanoic acid (1.2 eq), TBTU (1.2 eq) and DIPEA (1.2 eq) in DMF (0.18 M) was stirred at RT for 30 min, then D2 (Example 4) (1 eq) was added and stirring was continued at RT for 16 h. The reaction mixture was purified by preparative RP-ΗPLC, usingH2O (0.1% TFA) and MeCN (0.1% TFA) as eluents and the pooled product fractions were lyophilized to give the title compound El as colorless oil.MS (ES) C23H28FN3O requires: 381, found: 382 (M+H)+. 1H-NMR (300 MHz, OMSO-d6, 300K) δ: 8.36 (s, 0.3H); 8.33 (s, 0.7H); 7.86-7.74 (m, 4H);7.47-7.30 (m, 3H); 4.74 (s, 0.6H); 4.64 (s, 1.4H); 2.95 (s, 0.9H); 2.86 (s, 2.1H); 2.83-2.73 (m,IH); 1.60-1.40 (m, 2H); 1.40-1.10 (m, 6H); 0.84 (t, J= 7.1 Hz, 4.1H); 0.75 (t, J= 7.2 Hz, 1.9H).

Reference： [1]Current Patent Assignee: ISTITUTO DI RICERCHE DI BIOLOGIA MOLECOLARE P. ANGELETTI S.R.L. - WO2010/82044, 2010, A1 Location in patent: Page/Page column 37

45
[ 99-66-1 ]
[ 27079-92-1 ]
[ 1342894-09-0 ]

Yield	Reaction Conditions	Operation in experiment
	With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 3h;	1.A Step A. 1 eq. of valproic acid and 1 eq. p-hydroxybenzylbromide are dissolved in dichloromethane (DCM), with the addition of 1 eq. N, N'-dic clohexylcarbodiimide (DCC), 4-(dimethyIamino)pyridine (DMAP) as the catalyst. The mixture is stirred for 3 h at room temperature. Acetone is added to precipitate DCC. After the solvent is removed by vacuum, the product is purified by flash column chromatography to give compound 1.

Reference： [1]Current Patent Assignee: STATE UNIVERSITY OF NEW YORK - WO2011/133385, 2011, A2 Location in patent: Page/Page column 35

46
[ 3416-18-0 ]
[ 99-66-1 ]
[ 1361333-64-3 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: valproic acid With thionyl chloride In toluene for 2h; Reflux; Stage #2: 5-hydroxyoxindole In dichloromethane at 70℃; for 0.25h; Microwave irradiation;	4 Preparation 4: 2-oxoindolin-5-yl 2-propylpentanoateTo 2,2-di-n-propylacetic acid (290 mg, 2.01 mmol, 1.5 equiv.) in dry toluene (3 ml) was added thionyl chloride (0.20 ml, 2.0 equiv.), and the reaction mixture was refluxed for 2 hours. The volatiles were removed in vacuo, the residue was redissolved in dry OCM (3 ml) and added to 5-hydroxyindolin-2-one (200 mg, 1.34 mmol, 1 equiv., possibly impure) in MW vial. The reaction mixture was heated in microwave (70°C, 15 min). Purification by ISCO Combiflash (100% OCM - 5% MeOH/DCM) gave a brown gummy semi-solid. As indicated by the data below, the final product was the title compound P4. H NMR (CDCI3): 7.75 (1H, br s), 6.94 (1H, s), 6.90-6.78 (2H, m), 3.53 (2H, s), 2.62-2.52 (1H, m), 1.80-1.35 (8H, m), 0.94 (6H, t).13C NMR (CDCI3): 176.7, 175.5, 146.1, 139.7, 126.2, 120.9, 118.8, 109.7, 45.3, 36.3, 34.7 (2), 20.7 (2), 14.0 (2).MS: (MH+39) 317.1

Reference： [1]Current Patent Assignee: UNIVERSITY OF GREENWICH - WO2012/25726, 2012, A1 Location in patent: Page/Page column 20

47
[ 99-66-1 ]
copper dichloride [ No CAS ]
[ 108558-25-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: valproic acid With sodium hydroxide In water at 20℃; Stage #2: copper dichloride In water	1.1.3.1 1.1.3 bis-(2-propylpentanoato)(1,10-phenanthroline)copper(II) [Cu(Valp)4-phen] (4); The synthesis is illustrated in FIG. 1A 1.1.3.1. Tetrakis-μ-2-propylpentanoato dicopper(II) [Cu2(Valp)4] (3)A solution of CuCl2 (13.44 g, 0.1 mol) in water (200 mL) was filtered and added with continuous stirring to sodium valproate, prepared by neutralizing valproic acid (14.42 g, 0.1 mol) in water (100 mL) with 1 M NaOH (100 mL) at 20° C. A blue green powder was immediately obtained, recovered by vacuum filtration and dried over silica-gel in a dessicator for 24 h.Yield: 90% (28.597 g).Anal. Calc. for C32H60Cu2O8 (3): C, 53.54; H, 8.70%. Found: C, 53.38; H, 8.55%; M.p.=293-294 (with decomposition); IR (neat, cm-1): ν(C-H) 2957, νas(COO-) 1578, νsy(COO-) 1417.

Reference： [1]Current Patent Assignee: CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE; UNIVERSITY OF PARIS SUD - US2012/142658, 2012, A1 Location in patent: Page/Page column 3-4

48
[ 22632-59-3 ]
[ 99-66-1 ]

Yield	Reaction Conditions	Operation in experiment
92%	With 2C₃₃H₃₇N*H₂O₇S₂; water at 80℃; for 48h;	3 General procedure: [0063] As shown in the following Table 3, by using carboxylic acid esters, each of which produced a water-solublealcohol, a hydrolysis reaction of a carboxylic acid ester was performed. That is, 1 mmol of the carboxylic acid ester and4 mL of water were added to the ammonium pyrosulfate catalyst (5 mol%) obtained in Example 1(1), and the mixturewas heated at 60°C to 80°C for 24 to 48 hours while stirring was performed. The reaction mixture thus obtained waspartly sampled and was analyzed by 1H NMR (CDCl3), and by comparison between the following signals, the yield of acarboxylic acid was calculated. The chemical shifts (ppm) are shown below. In addition, the results are shown in Table 3.
80 %Spectr.	With 2C₃₃H₃₇N*H₂O₇S₂; water at 60℃;

Reference： [1]Current Patent Assignee: TOKAI NATIONAL HIGHER EDUCATION AND RESEARCH SYSTEM - EP2799422, 2014, A1 Location in patent: Paragraph 0063; 0064; 0065
[2]Koshikari, Yoshiki; Sakakura, Akira; Ishihara, Kazuaki [Organic Letters, 2012, vol. 14, # 12, p. 3194 - 3197]

49
[ 99-66-1 ]
(3aRS,4RS,6aSR)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine [ No CAS ]
2-propyl-N-{(3aRS,4RS,6aSR)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}pentanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 20h; Inert atmosphere;	5.3.1. N-[(3aS^∗,4S^∗,6aR^∗)-2-Benzyloctahydrocyclopenta[c]pyrrol-4-yl]-2,2-dicyclohexylacetamide (38) General procedure: (3aS∗,6aR∗)-2-Benzyloctahydrocyclopenta[c]pyrrol-4-amine (500 mg, 2.311 mmol), 2,2-dicyclohexylacetic acid (570 mg, 2.54 mmol), and 1-hydroxybenzotriazole (389 mg, 2.54 mmol) were combined in dichloromethane (20 mL). The reaction was stirred at room temperature for 10 min, then N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (0.449 mL, 2.54 mmol) was added dropwise. The reaction was stirred at room temperature for 20 h, and then the reaction was quenched with 10 mL of water. The reaction was extracted with 2 × 20 mL of dichloromethane, the solvent was removed in vacuo, and the crude material was chromatographed over a 40 g silica gel cartridge eluting with 30-50% ethyl acetate/hexanes to give N-[(3aS∗,4S∗,6aR∗)-2-benzyloctahydrocyclopenta[c]pyrrol-4-yl]-2,2-dicyclohexylacetamide (299 mg, 0.707 mmol, 30% yield)

Reference： [1]Location in patent: experimental part Beebe, Xenia; Darczak, Daria; Henry, Rodger F.; Vortherms, Timothy; Janis, Richard; Namovic, Marian; Donnelly-Roberts, Diana; Kage, Karen L.; Surowy, Carol; Milicic, Ivan; Niforatos, Wende; Swensen, Andrew; Marsh, Kennan C.; Wetter, Jill M.; Franklin, Pamela; Baker, Scott; Zhong, Chengmin; Simler, Gricelda; Gomez, Erica; Boyce-Rustay, Janel M.; Zhu, Chang Z.; Stewart, Andrew O.; Jarvis, Michael F.; Scott, Victoria E. [Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 13, p. 4128 - 4139]

50
[ 99-66-1 ]
[ 112-27-6 ]
[ 1398285-82-9 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; dicyclohexyl-carbodiimide In dichloromethane; acetonitrile at 20℃; for 24h; Molecular sieve; Inert atmosphere;	9 EXAMPLE 9; Protocol for the synthesis of VPA-linker-Dextran conjugate: Two conjugates of valproic acid were synthesized according to the following protocol. Two different linkers were used for the two conjugates. These are- triethylene glycol (TEG) and pentaethylene glycol (PEG). We used dextrans with molecular weights about 1 KDa.Synthesis of VPA-linker conjugate1) Add 6.1962 ml (46.43 mmol) of triethylene glycol to 20 ml dried acetonitrile in a conical flask and dissolve it with the help of magnetic stirrer, (sol- A)2) Take 20 ml dried dicholoromethane (DCM) (dried over molecular sieves) in a 125 ml conical flask and add sol-A slowly to DCM in this flask while shaking. (sol-B)3) Now, add 1848 μ^ of valproic acid (1664 mg, or, 11.6 mmol), 432.2 mg of DMAP, dimethyl aminopyridine (3.49mmol) and purge with argon gas.Dissolve 2631.4 mg of DCC, dicyclohexyl carbodiimide (12.76 mmol) in 10 ml of dried DCM and add this solution dropwise for 5 minutes. Purge with argon gas. After that continue the reaction at room temperature for 24 hours

Reference： [1]Current Patent Assignee: STATE UNIVERSITY SYSTEM OF FLORIDA - WO2012/121862, 2012, A2 Location in patent: Page/Page column 37

51
[ 99-66-1 ]
[ 76-87-9 ]
[ 1443219-79-1 ]

Yield	Reaction Conditions	Operation in experiment
85%	In methanol Reflux;	Synthesis General procedure: vp1, vp2 and vp3 complexes were obtained by the same method: asolution of VPA (0.1442 g, 1 mmol) in MeOH (50 mL), was added withthe stoichiometric amount for the corresponding organotin oxide or hydroxide(Me3SnOH: 0.1808 g, 1 mmol; (Bu3Sn)2O: 0.2981 g, 0.5 mmol;Ph3SnOH: 0.3670 g, 1 mmol respectively for compounds vp1, vp2and vp3). The solution was kept refluxing overnight. White solids were recovered on cooling after concentration in a rotary evaporator.After filtration and vacuum drying, the solids were recrystallized from chloroform and analyzed. Yields: vp1, 78%; vp2, 80%; vp3, 85%.

Reference： [1]Pellerito, Ornella; Prinzivalli, Cristina; Foresti, Elisabetta; Sabatino, Piera; Abbate, Michele; Casella, Girolamo; Fiore, Tiziana; Scopelliti, Michelangelo; Pellerito, Claudia; Giuliano, Michela; Grasso, Giulia; Pellerito, Lorenzo [Journal of Inorganic Biochemistry, 2013, vol. 125, p. 16 - 25]

52
[ 877864-29-4 ]
[ 99-66-1 ]
2-((2-((((1-(2-ethoxy-2-oxoethyl)cyclohexyl)methyl)carbamoyl)oxy)ethyl)disulfanyl)ethyl 2-propylpentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With dmap; triethylamine; dicyclohexyl-carbodiimide In dichloromethane for 24h;	General Procedure for the synthesis of compounds 3a, 3c and 3e General procedure: A solution of the appropriateintermediate 15a or 15d (1.00 mmol), the appropriateDrug-2, (1.20 mmol), DCC (1.20 mmol), DMAP (0.10 mmol) and Et3N(1.50 mmol) in CH2Cl2 (10 mL) was stirred for 24 h. Thereaction mixture was filtered; the filtrate was concentrated and purified bysilica gel column chromatography to afford the title compounds.

Reference： [1]Jain, Arun K.; Gund, Machhindra G.; Desai, Dattatraya C.; Borhade, Namdev; Senthilkumar, Subrayan P.; Dhiman, Mini; Mangu, Naveen K.; Mali, Sunil V.; Dubash, Nauzer P.; Halder, Somnath; Satyam, Apparao [Bioorganic Chemistry, 2013, vol. 49, p. 40 - 48]

53
[ 99-66-1 ]
[ 1211468-41-5 ]
[ 1548597-71-2 ]

Yield	Reaction Conditions	Operation in experiment
78%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃; for 24h;	1 Synthesis of 2-amino-6-substituted-5,6,7,8-tetrahydropyridopyrimidines (1a-4d) General procedure: 0.2 mmol of substituted acids (1 equiv.) and 2-amino-6-substituted-5,6,7,8-tetrahydropyridopyrimidin-4-ols (1.0 equiv.) were taken in DCM (5 mL) followed by addition of triethylamine (1.1 equiv.), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDC) (1.1 equiv.) and 1-hydroxybenzotriazole (HOBT) (1.1 equiv.) at 0 °C. The reaction mixture was stirred at room temperature overnight. Following completion, the reaction mixture was washed with saturated aqueous sodium bicarbonate and brine. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to give the product in 78-85% yield.

Reference： [1]Sharma, Monika; Deekshith, Vanamala; Semwal, Arvind; Sriram, Dharmarajan; Yogeeswari, Perumal [Bioorganic Chemistry, 2014, vol. 52, p. 69 - 76]

54
[ 99-66-1 ]
[ 1548597-55-2 ]
[ 1548597-89-2 ]

Yield	Reaction Conditions	Operation in experiment
63%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃; for 24h;	5 Synthesis of 2-amino-6-substituted-5,6,7,8-tetrahydropyridopyrimidines (1a-4d) General procedure: 0.2 mmol of substituted acids (1 equiv.) and 2-amino-6-substituted-5,6,7,8-tetrahydropyridopyrimidin-4-ols (1.0 equiv.) were taken in DCM (5 mL) followed by addition of triethylamine (1.1 equiv.), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDC) (1.1 equiv.) and 1-hydroxybenzotriazole (HOBT) (1.1 equiv.) at 0 °C. The reaction mixture was stirred at room temperature overnight. Following completion, the reaction mixture was washed with saturated aqueous sodium bicarbonate and brine. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to give the product in 78-85% yield.

Reference： [1]Sharma, Monika; Deekshith, Vanamala; Semwal, Arvind; Sriram, Dharmarajan; Yogeeswari, Perumal [Bioorganic Chemistry, 2014, vol. 52, p. 69 - 76]

55
[ 99-66-1 ]
[ 1548597-60-9 ]
[ 1548598-00-0 ]

Yield	Reaction Conditions	Operation in experiment
78%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃; for 24h;	9 Synthesis of 2-amino-6-substituted-5,6,7,8-tetrahydropyridopyrimidines (1a-4d) General procedure: 0.2 mmol of substituted acids (1 equiv.) and 2-amino-6-substituted-5,6,7,8-tetrahydropyridopyrimidin-4-ols (1.0 equiv.) were taken in DCM (5 mL) followed by addition of triethylamine (1.1 equiv.), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDC) (1.1 equiv.) and 1-hydroxybenzotriazole (HOBT) (1.1 equiv.) at 0 °C. The reaction mixture was stirred at room temperature overnight. Following completion, the reaction mixture was washed with saturated aqueous sodium bicarbonate and brine. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to give the product in 78-85% yield.

Reference： [1]Sharma, Monika; Deekshith, Vanamala; Semwal, Arvind; Sriram, Dharmarajan; Yogeeswari, Perumal [Bioorganic Chemistry, 2014, vol. 52, p. 69 - 76]

56
[ 99-66-1 ]
[ 1548597-65-4 ]
[ 1548598-12-4 ]

Yield	Reaction Conditions	Operation in experiment
61%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃; for 24h;	13 Synthesis of 2-amino-6-substituted-5,6,7,8-tetrahydropyridopyrimidines (1a-4d) General procedure: 0.2 mmol of substituted acids (1 equiv.) and 2-amino-6-substituted-5,6,7,8-tetrahydropyridopyrimidin-4-ols (1.0 equiv.) were taken in DCM (5 mL) followed by addition of triethylamine (1.1 equiv.), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDC) (1.1 equiv.) and 1-hydroxybenzotriazole (HOBT) (1.1 equiv.) at 0 °C. The reaction mixture was stirred at room temperature overnight. Following completion, the reaction mixture was washed with saturated aqueous sodium bicarbonate and brine. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to give the product in 78-85% yield.

Reference： [1]Sharma, Monika; Deekshith, Vanamala; Semwal, Arvind; Sriram, Dharmarajan; Yogeeswari, Perumal [Bioorganic Chemistry, 2014, vol. 52, p. 69 - 76]

57
[ 1069-66-5 ]
[ 99-66-1 ]

Reference： [1]Canadian Journal of Chemistry,2014,vol. 92,p. 9 - 15
[2]Applied Organometallic Chemistry,2019,vol. 33

58
[ 99-66-1 ]
[ 1069-66-5 ]
trisodium hydrogentetravalproate [ No CAS ]

Reference： [1]Canadian Journal of Chemistry,2014,vol. 92,p. 9 - 15

59
[ 99-66-1 ]
[ 1602491-06-4 ]
[ 71989-31-6 ]
[ 84624-17-9 ]
Fmoc-D-Ile-OH [ No CAS ]
[ 1602491-13-3 ]

Yield	Reaction Conditions	Operation in experiment
2 mg		To 10 (0.037 mmol) in CH2Cl2/DMF (1:1) were added 2-propylpentanoic acid (14 muL, 0.088 mmol), HOBt·H2O (13 mg, 0.085 mmol), DIPCDI (14 muL, 0.088 mmol), and DIEA (15 muL, 0.088 mmol). The mixture was agitated for 2 h, and the product was isolated and purified as above to yield 17 (2.0 mg, 7% from Fmoc-NH-SAL-resin) as a white powder. 1H NMR (300 MHz, CD3OD): delta 0.85-0.98 (m, 24H), 1.19-1.50 (m, 10H), 1.55-1.62 (m, 4H), 1.69-1.73 (m, 1H), 1.76-1.88 (m, 1H), 1.93-2.16 (m, 10H), 2.20-2.35 (m, 2H), 2.38-2.45 (m, 1H), 2.60-2.68 (m, 1H), 3.48-3.61 (m, 3H), 3.63-3.72 (m, 2H), 3.67 (d, J = 8.7 Hz, 1H), 3.79-3.87 (m,1H), 3.91-3.98 (m, 1H), 4.16-4.27 (m, 1H), 4.38-4.47 (m, 3H), 4.65 (dd, J = 8.1, 4.8 Hz, 1H), 7.99-8.10 (m, 2H). LRMALDIMS, m/z 783.47 for [M+Na]+ (calcd for C41H72N6NaO7 783.54).

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 2482 - 2488

60
[ 99-66-1 ]
[ 1313484-36-4 ]
C₂₂H₄₀O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 19h; Inert atmosphere;	4-Oxocyclohexylcarboxylate 43 General procedure: To a stirred solution of alcohol 40 (293 mg, 0.96 mmol) in CH2Cl2 (10 ml) were added EDC·HCl (238 mg, 1.24 mmol), DMAP (29 mg, 0.24 mmol) and 4-oxocyclohexanecarboxylic acid (163 mg, 1.15 mmol). The reaction mixture was stirred for 19 h at room temperature. The organic layer was washed with 1 M HCl (1 × 10 ml), aqueous saturated NaHCO3-solution (10 ml) and water (2 × 10 ml), dried (MgSO4) and evaporated under reduced pressure. Purification by flash chromatography on silica (petroleum ether/EtOAc 1:1) gave ester 43 (360 mg, 87%) as a colourless oil.

Reference： [1]Bruss, Hanna; Schuster, Hannah; Martinez, Remi; Kaiser, Markus; Antonchick, Andrey P.; Waldmann, Herbert [Beilstein Journal of Organic Chemistry, 2014, vol. 10, p. 194 - 208]

61
[ 99-66-1 ]
[ 62-53-3 ]
N-(2-propylpentyl)aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With platinum⁽⁰⁾-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex; phenylsilane; 1,2-bis-(diphenylphosphino)ethane In dibutyl ether at 60℃; for 18h; Schlenk technique; Inert atmosphere;
76%	With tris(2,4-pentanedionato)ruthenium(III); hydrogen; bis(trifluoromethanesulfonyl)amide; [2-((diphenylphospino)methyl)-2-methyl-1,3-propanediyl]bis[diphenylphosphine] In dibutyl ether at 160℃; for 18h; Autoclave;

Reference： [1]Sorribes, Iván; Junge, Kathrin; Beller, Matthias [Journal of the American Chemical Society, 2014, vol. 136, # 40, p. 14314 - 14319]
[2]Sorribes, Iván; Cabrero-Antonino, Jose R.; Vicent, Cristian; Junge, Kathrin; Beller, Matthias [Journal of the American Chemical Society, 2015, vol. 137, # 42, p. 13580 - 13587]

62
[ 99-66-1 ]
[ 3182-93-2 ]
N-valproyl-L-phenylalanine ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With dmap; triethylamine; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 2h;	2.2.1. synthesis of N-valproyl- L-phenylalanine ethyl ester(3) Compound 3 was obtained using a method already described [20]. briefly, L-phenylalanine ethyl ester hydrochloride (1), valproic acid (2) triethylammine (TEA), N,N'-dicyclohexylcarbodiimide (DCC) (0.005 mol of each compound) and 4-dimethylaminopyridine (DMAP) (0.0005 mol)were dissolved in dry CH2Cl2 solution. The mixture was setat room temperature with constant stirring and monitored byTLC using a mixture of petroleum ether/chloroform/ethylacetate (10:65:25) as eluent. After 2 h, water (0.5 mL) was added to the mixture to inactivate coupling agents unreacted and the mixture was then filtered. The separate solution was dried with anhydrous Na2SO4, filtered and evaporated under reduced pressure. The resulting mass was solubilized in CH2Cl2 (20 mL) and shaken with acidic aqueous solution (pH 4) (2 x 10 mL) and then with (2 x 10 mL) pH 7 solution in a separator funnel. The organic phase was separated, dried as above and evaporated under reduced pressure. The resulting crude mass was purified by crystallization from ethylacetate/cyclohexane (1:4) followed by crystallization from methyl alcohol/water (2:8). Colourless crystals from methyl alcohol/water were obtained. M.p. 115-122 °C. Yield: 1.29 g (72%). IR, MS, 1H and 13C-NMR spectral data were in agreement with those previously reported [23].

Reference： [1]De Caro, Viviana; Scaturro, Anna Lisa; Sutera, Flavia Maria; Avellone, Giuseppe; Schiera, Gabriella; Ferrantelli, Evelina; Carafa, Maria; Rizzo, Valerio; Carletti, Fabio; Sardo, Pierangelo; Giannola, Libero Italo [Medicinal Chemistry, 2015, vol. 11, # 1, p. 30 - 40]

63
[ 342373-13-1 ]
[ 99-66-1 ]
2-(4-(4-phenylbutyl)phenyl)-N-(2-propylpentanoyloxyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59.4%	Stage #1: valproic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 3h; Stage #2: N-hydroxy-2-(4-(4-phenylbutyl)phenyl)acetamide In tetrahydrofuran	29 Example 29 2-(4-(4-Phenylbutyl)phenyl)-N-(2-propylpentanoyloxyl)acetamide (50) Example 29 2-(4-(4-Phenylbutyl)phenyl)-N-(2-propylpentanoyloxyl)acetamide (50) Title compound was prepared by following the protocol described in Synth. Commun., 2010, 40, pp. 927-935. To a solution of valproic acid (0.136 g, 0.946 mmol) in dry THF (10 mL) was added CDI (0.230 g, 1.419 mmol). The reaction mixture was stirred for 3 hours at RT. The hydroxamate 1 (0.268 g, 0.946 mmol) was then added and the combined mixture was stirred overnight. The solvent was partially evaporated; the remaining solution was diluted with EtOAc and washed twice with a 5% KHSO4 aqueous solution, then brine. The organic phase was finally dried over anhydrous MgSO4, filtered and evaporated. The residue was purified 3 times by flash chromatography, eluting with 20% AcOEt in hexanes, then eluting with DCM (second purification), and finally with MeOH (2.5%) in DCM (third purification), to afford title compound 50 (0.230 g, 59.4%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 11.86 (s, 1H), 7.28-7.24 (m, 2H), 7.18-7.10 (m, 7H), 3.40 (s, 2H), 2.61-2.55 (m, 4H), 2.49-2.46 (m, 1H, partially overlaps with the residual signal of DMSO), 1.58-1.25 (m, 12H), 0.85 (t, J=7.2 Hz, 6H). LRMS (ESI): (calc.) 409.7 (found) 410.3 (MH)+.
59.4%	Stage #1: valproic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 3h; Stage #2: N-hydroxy-2-(4-(4-phenylbutyl)phenyl)acetamide In tetrahydrofuran	29 EXAMPLE 29 2-(4-(4-Phenylbutyl)phenyl)-N-(2-propylpentanoy-loxy)acetamide (50) To a solution of valproic acid (0.136 g, 0.946 mmol) in dry THF (10 mL) was added CDI (0.230 g, 1.419 mmol). The reaction mixture was stirred for 3 hours at RT. The hydroxamate 1 (0.268 g, 0.946 mmol) was then added and the combined mixture was stirred overnight. The solvent was partially evaporated; the remaining solution was diluted with EtOAc and washed twice with a 5% KHSO4 aqueous solution, then brine. The organic phase was finally dried over anhydrous MgSO4, filtered and evaporated. The residue was purified 3 times by flash chromatography, eluting with 20% AcOEt in hexanes, then eluting with DCM (second purification), and finally with MeOH (2.5%) in DCM (third purification), to afford title compound 50 (0.230 g, 59.4%)as a white solid. ‘H NMR (DMSO-d6) ö(ppm): 11.86 (s,1H), 7.28-7.24 (m, 2H), 7.18-7.10 (m, 7H), 3.40 (s, 2H),2.61-2.55 (m, 4H), 2.49-2.46 (m, 1H, partially overlaps with the residual signal of DMSO), 1.58-1.25 (m, 12H), 0.85 (t, J=7.2 Hz, 6H). LRMS (ESI): (calc.) 409.7 (found) 410.3(MH).

Reference： [1]Current Patent Assignee: MIRATI THERAPEUTICS, INC. - US2015/203517, 2015, A1 Location in patent: Paragraph 0387; 0388
[2]Current Patent Assignee: MIRATI THERAPEUTICS, INC. - US9636298, 2017, B2 Location in patent: Page/Page column 85; 86

64
[ 99-66-1 ]
methyl (S)-4-(2-amino-3-(1H-indol-3-yl)propanamido)benzoate hydrochloride [ No CAS ]
methyl (S)-4-(3-(1H-indol-3-yl)-2-(2-propylpentanamido)propanamido)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	Stage #1: valproic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In dichloromethane for 0.5h; Stage #2: methyl (S)-4-(2-amino-3-(1H-indol-3-yl)propanamido)benzoate hydrochloride With triethylamine In dichloromethane	8 4.1.5. Methyl (S)-4-(2-acetamido-3-(1H-indol-3-yl)propanamido)benzoate (7b) General procedure: To a solution of acetic acid (0.12 g, 2 mmol) in anhydrous CH2Cl2, was added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU, 0.71 g, 2.2 mmol), followed by Et3N (0.3 g, 3 mmol). 30 min later, compound 6 (0.82 g, 2.2 mmol) was added followed by Et3N (0.3 g, 3 mmol). After the reaction finished, the solution was washed with 1 N HCl (2 * 30 mL), saturated NaHCO3 (2 * 30 mL) and brine (2 * 30 mL), dried over Na2SO4 overnight, and the solvent was evaporated under vacuum. The crude product was recrystallized by EtOAc and petroleum ether to achieve a white pure solid (0.38 g, 50%). 4.1.8 Methyl (S)-4-(3-(1H-indol-3-yl)-2-(2-propylpentanamido)propanamido)benzoate (7e) Using the synthetic method for 7b, compound 6 and 2-propylpentanoic acid gave 7e as a white pure solid (54% yield). Mp: 191-194 °C 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 10.43 (s, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 8.7 Hz, 2H), 7.74 (d, J = 8.7 Hz, 2H), 7.66 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 1.9 Hz, 1H), 7.04 (t, J = 7.3 Hz, 1H), 6.96 (t, J = 7.3 Hz, 1H), 4.79-4.74 (m, 1H), 3.82 (s, 3H), 3.21-2.96 (m, 2H), 2.30-2.13 (m, 1H), 1.46-1.12 (m, 8H), 0.79 (t, J = 7.0 Hz, 3H), 0.69 (t, J = 7.3 Hz, 3H). ESI-MS m/z: 464.6 [M+H]+.

Reference： [1]Li, Xiaoyang; Wu, Jingde; Li, Xiaoguang; Mu, Weiwei; Liu, Xueliang; Jin, Yiming; Xu, Wenfang; Zhang, Yingjie [Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 19, p. 6258 - 6270]

65
[ 99-66-1 ]
[ 214557-38-7 ]
2-propyl-N-(4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl)pentanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In chloroform at 120℃; Glovebox; Inert atmosphere;	2-Propyl-N-(4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl)pentanamide (ADT-NVal) In aglovebox, ADT-NH2 (200 mg, 0.888 mmol), 2-propylpentanoic acid (192 μL, 1.20 mmol),EDC·HCl (230 mg, 1.20 mmol), and 4-dimethylaminopyridine (15 mg, 0.12 mmol) were addedto an oven-dried pressure vessel and dissolved in dry CHCl3 (8 mL) under N2, and the reactionstirred at 120 °C for 2.5 days. The reaction mixture was diluted with DCM and washed with 0.1M HCl, 0.5 M K2CO3, and brine. The organic layer was dried with Na2SO4 and purified viacolumn chromatography (20-50% Hex:EtOAc gradient). Pure product was obtained as anorange-red solid (170 mg, 54% yield).

Reference： [1]Hammers, Matthew D.; Singh, Loveprit; Montoya, Leticia A.; Moghaddam, Alan D.; Pluth, Michael D. [Synlett, 2016, vol. 27, # 9, p. 1349 - 1353]

66
[ 18274-81-2 ]
[ 99-66-1 ]
2-propylpentanoic acid 4-(5-thioxo-5H-1,2-dithiol-3-yl)phenyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 24h; Inert atmosphere;	4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl 2-propylpentanoate (ADT-OVal) Valproic acid (32mg, 0.22 mmol), ADT-OH (52 mg, 0.22 mmol), EDC·HCl (44 mg, 0.22 mmol), and 4-dimethylaminopyridine (2 mg, 0.02 mmol) were dissolved in dry THF (4 mL) and stirred atroom temperature under N2 for 24 hours. After stirring, the solvent was removed under vacuum.The crude residue was dissolved in EtOAc and washed with water, brine, and dried with Na2SO4.The crude product was purified via preparative TLC (3:2 Hex:EtOAc) to afford the pure productas a dark red solid (52 mg, 67% yield).

Reference： [1]Hammers, Matthew D.; Singh, Loveprit; Montoya, Leticia A.; Moghaddam, Alan D.; Pluth, Michael D. [Synlett, 2016, vol. 27, # 9, p. 1349 - 1353]

67
hydrotris(3,5-methylphenylpyrazolyl)boratozinc(II) hydroxide [ No CAS ]
[ 99-66-1 ]
C₃₈H₄₃BN₆O₂Zn [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73.4%	In methanol; dichloromethane at 20℃; Inert atmosphere;	2.5 Synthesis of (Tp^Ph,Me)Zn(valproate) (3) (TpPh,Me)ZnOH (18.6mg, 0.03mmol) was dissolved in 10mL of CH2Cl2. To this solution, valproic acid (3.8mg, 0.03mmol) dissolved in 5mL of MeOH was added. The reaction was allowed to stir at room temperature overnight under a nitrogen atmosphere. The solution was then evaporated to dryness on a rotary evaporator. The solid was dissolved in heptane and recrystallized by slow evaporation. Clear crystals were produced (16.7mg, 73.4% yield). X-ray quality crystals were obtained by slow evaporation from acetonitrile. 1H NMR (CDCl3, 300MHz): δ=7.58-7.65 (m, 6H, ArH), 7.27-7.37 (m, 9H, ArH), 6.20 (s, 3H, pyrazole C-H), 2.53 (s, 9H, CH3), 1.64 (p, 1H, JH-H=5.9Hz, O2CCH), 0.93-1.16m, 8H, CH2), 0.77 (t, 6H, JH-H=6.8Hz, CH3).). IR (solid ATR): 2548, 1545cm-1. Anal. Calc. for C38H43O2N6BZn: C, 65.95; H, 6.26; N, 12.15. Found: C, 66.86; H, 6.73; N, 11.47%.

Reference： [1]Sun Cao, Phoebus; Sommer, Roger D.; Grice, Kyle A. [Polyhedron, 2016, vol. 114, p. 344 - 350]

68
[ 99-66-1 ]
[ 2430-27-5 ]

Reference： [1]Chemistry - A European Journal,2016,vol. 22,p. 14042 - 14047

69
[ 50893-53-3 ]
[ 99-66-1 ]
C₁₁H₁₉ClO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: valproic acid With N-ethyl-N,N-diisopropylamine In dichloromethane at -10℃; for 0.5h; Stage #2: carbonochloridic acid 1-chloro-ethyl ester In dichloromethane at -10 - 0℃; for 1h;	1.2 Synthesis of Compound 5 To a solution of compound 3 ( 1 .0 mmol) in dry DCM (1 .8 ml) was added N,N-diisopropylethylamine (2.0 mmol) at -10°C and stirred at same temperature for 30 min, followed by drop wise addition of 1-chloroethylchloroformate 4 (1.1 mmol) at the same temperature and the reaction mixture was allowed to stir for 1 h at 0°C. On completion of the reaction (monitored by TLC), the reaction mixture the solvent was evaporated and the crude was purified through column to get compound 5.

Reference： [1]Current Patent Assignee: CELLIXBIO PRIVATE LTD - JP2015/533114, 2015, A Location in patent: Paragraph 0200; 0201; 0202

70
[ 99-66-1 ]
[ 373-88-6 ]
2-propyl-N-(2,2,2-trifluoroethyl)pentanamide [ No CAS ]