Name: 81926-94-5|(4Z,7Z,10Z,13Z,16Z,19Z)-Ethyl docosa-4,7,10,13,16,19-hexaenoate|98%
Brand: Ambeed
SKU: A1154573
Rating: 94 (25 reviews)

1
[ 60-01-5 ]
[ 81926-94-5 ]
[ 105-54-4 ]
[ 124596-98-1 ]

Yield	Reaction Conditions	Operation in experiment
95 % Spectr.	at 65℃; for 72h; 10percent dosage immobilized nonregiospecific yeast lipase from Candida antarctica;

Reference： [1]Haraldsson, Gudmundur G.; Gudmundsson, Birgir Oe.; Almarsson, Oern [Tetrahedron Letters, 1993, vol. 34, # 36, p. 5791 - 5794]

2
[ 60-01-5 ]
[ 81926-94-5 ]
[ 124596-98-1 ]

Yield	Reaction Conditions	Operation in experiment
81%	With immobilized lipase from Candida Antarctica at 65℃; for 72h;

Reference： [1]Haraldsson, Gudmundur G.; Gudmundsson, Birgir Oe.; Almarsson, Oern [Tetrahedron, 1995, vol. 51, # 3, p. 941 - 952]

3
[ 81926-94-5 ]
[ 6217-54-5 ]

Yield	Reaction Conditions	Operation in experiment
91%		Cis-docosahexaenoic acid (DHA): To a solution of ethyl cis-docosahexaenoate (5 g, 14.0 mmol) in methanol (100 mL) was added an aqueous solution of NaOH (6 g, 150 mmol, in 20 mL of water) at rt and stirred for 1.5 h. The reaction mixture was poured into ice cooled water and acidified with dil. HCl. The solution was extracted with DCM (3 x 50 mL) and the combined layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and the solvent evaporated to give the acid (4.2 g, 91%) as an oil; LCMS (ESI, negative ion mode): m/z 327 (M-H)".
	With lithium hydroxide monohydrate; In ethanol; water; at 20℃; for 4h;Inert atmosphere;	A mixture of DHA ethyl ester (10.02 g, 28 mmol) and LiOH.H2O (5.8 g, 140 mmol) in EtOH-H2O (1:1) (60 mL) was left stirring until all the DHA ethyl ester was converted (TLC, CH2Cl2). Water (90 mL) were added, the reaction flask was covered with aluminium-foil and cooled to 0 C. Hydrogen iodide (57%; 20 mL) was added to the reaction mixture, followed successively by saturated KHCO3 (10 mL) and dropwise addition of a solution of I2 (21.32 g, 84 mmol) in EtOH (70 mL). The mixture was left stirring at 0-4 C in the dark for 18 h. The reaction was quenched by adding a saturated aq. solution of Na2S2O3 (100 mL). Solid NaCl was added to saturation and the product extracted with hexane (3 × 50 mL). The extract was washed with brine (2 × 50 mL), dried (Na2SO4) and evaporated under reduced pressure to give 8 (12.3 g; 97%) as pale yellow oil. Spectral data were in agreement with those previously reported [17].
	With lithium hydroxide;Inert atmosphere; Darkness;	Example 1 : Overview of l, l, l-trifluoro-3-(((2E,6Z,9Z, 12Z, 15Z,)-octadeca- 2,6,9.1 2, 1 -pcntaein- l -yl )tliio)propan-2-one synthesis The following information provides a general overview of the synthesis of the polyunsaturated ketone. Referring to Scheme 1, Step A and Step B are mentioned in more detail in Example 6, below. All steps toward making the C18 allylic alcohol (Scheme 1, below) were carried out essentially as described in J. Chem. Sec, Perkin Trans. 1, 2000, 2271 - 2276 ( Skattebol and Holmeide), with one modification: instead of sodium borohydride in the reduction of aldehyde to alcohol, d i i sobu ty I a I u m i n i u m hydride (DIBAH) was used to reduce over-reduction of the trans double bond. During the three last steps ( Scheme 1 , below), the following precautions modifications were introduced: All reactions were carried out under an argon atmosphere. The lights in the fume hoods were to be turned off. No other precautions regarding light protection were considered necessary. In addition, the 3 last steps (called A, B and C, respectively) are performed in the presence of alpha-tocopherol. The sequence of reagent addition in the Mitsonobu reaction was considered to be important in order to avoid isomerization. It is anticipated that it is of crucial importance that all of the thioacctic acid has reacted completely prior to introduction of C 18 allyl ic alcohol. Furthermore, both the crude and purified product of step (A) are flushed with argon capped with a septum and placed in the freezer when stored. Step (B) is carried out without purification, but again: the crude product is to be stored at -18C under argon atmosphere if storage is necessary. During the last step great care was taken to ensure that both the crude product and purified material was kept under argon. ethyl (4Z,7Z, 10Z, 13Z, 16Z, 19Z)-docosa-4,7, 10,13,16,19- (4Z,7Z, 10Z, 13 Z, 16Z, 19Z)-docosa- hexaenoate 4,7,10,13, 16,19-hexaenoic acid 1) KI, I2, KHC03 THF, H20, 3 days 2) MeOH, K2C03 (3Z,6Z,9Z,12Z,15-octadeca-3,6,9,12,15- 1} HCOOH ( 1 1}> A0 (150 ml) 2) LiOH, H20-MeOH, 0 oC methyl 3-(3-((2Z,5Z,8Z,l lZ,14Z)-heptadeca- 2,5,8,11.14-pentaen- 1 -yl)oxiran-2-yl)propanoate 3) NaI04 MeOH-H20 DBU Et,0 entaen- 1 -ol (2£,6Z,9Z,12Z,15Z)-octadeca-2,6,9, 12, 15-pentaenal C18 allylic iilc hol STEP A DIAD, PPh3 Mitsonobu CH3COSH (2EAZ,9Z, 12Z, 15Z)-octadeca-2,6,9, 12,15- pentaene-1 -thiol MeOH S-((2E,6Z,9Z, 12Z, 15Z)-octadeca-2,6,9, 12, 15-pentaen-l-yl) ethanethioate aHC03 1,1,1 -trifluoro-3 -(((2i?,6Z,9Z, 12Z, 15 Z)-octadeca- 2,6,9, 12 , 15-pentaen- 1 -yl)thio)propan-2-one Scheme 1 : Overview of synthesis of l, l, l-trifluoro-3-(((2E,6Z,9Z, 12Z, 15Z,)- octadeca-2,6,9, 12, 15-pentaein- l-yl)thio)propan-2-one

Reference： [1]Tetrahedron,1995,vol. 51,p. 941 - 952
[2]Journal of the American Oil Chemists' Society,2000,vol. 77,p. 1139 - 1145
[3]Patent: WO2010/4579,2010,A2 .Location in patent: Page/Page column 18
[4]Acta Chemica Scandinavica,1999,vol. 53,p. 436 - 445
[5]Angewandte Chemie - International Edition,2001,vol. 40,p. 1755 - 1757
[6]Tetrahedron,2010,vol. 66,p. 2728 - 2731
[7]Tetrahedron,2011,vol. 67,p. 1821 - 1836
[8]Molecules,2014,vol. 19,p. 3804 - 3812
[9]Patent: WO2015/11206,2015,A1 .Location in patent: Page/Page column 21; 22
[10]Patent: WO2019/219758,2019,A1 .Location in patent: Page/Page column 36-37

4
[ 81926-94-5 ]
[ 102783-20-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; Inert atmosphere;	11 DHA Alcohol, 11 An oven-dried 100 mL round bottomed flask was charged with lithium aluminum hydride (1.06 g, 28 mmol) in anhydrous THF (15 mL). The flask was cooled to 0° C. with an ice-water bath. To this suspension was added drop-wise a solution of DHA ethyl ester (5.00 g, 14 mmol) in THF (10 mL) via syringe under argon. When the addition was complete, the mixture was allowed to stir for 3 hr at 0° C. The reaction was monitored by TLC. After the reaction was complete, it was quenched at 0° C. by slow drop-wise addition of a saturated aqueous solution of sodium sulfate (5.5 mL). The mixture was then allowed to stir for 0.5 hr at RT and then filtered through a Büchner funnel. The residue was rinsed with THF. The filtrate and washings were combined and concentrated under reduced pressure to obtain 4.41 g of ALA alcohol as light yellow oil (100% yield) and is characterized by the following spectra: (0137) 1H NMR (300 MHz, CDCl3/TMS): δ5.50-5.25 (m, 12H), 3.66 (t, J=6.5 Hz, 2H), 2.95-2.72 (m, 10H), 2.22-2.05 (m, 4H), 1.70-1.55 (m, 2H), 0.98 (t, J=7.7 Hz, 3H). (0138) 13C NMR (75 MHz, CDCl3/TMS): δ 131.8, 129.2, 128.4, 128.3, 128.1, 128.0, 127.96, 127.89, 127.7, 126.8, 62.4, 32.4, 25.6, 25.5, 23.6, 20.5, 14.3.
91%	Stage #1: all-(Z)-ethyl 4,7,10,13,16,19-docosahexaenoate With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 0.833333h; Stage #2: With water In tetrahydrofuran	(all-ZV 4,7,10 ,13,16,19-docosahexaenol (63)A solution of ethyl (all-Z)-4,7,10,13,16,19-docosahexaenoate (10.72 g, 30.0 mmol) in THF, 30 niL, was added drop wise to a suspension OfLiAlH4 in THH, 140 niL, under N2-atmosphere at O0C. The resulting mixture was stirred at O0C for 50 minutes, before it was quenched with water, 50 mL, added IM HCl5 100 mL, and stirred at room temperature for 1 hr. The phases were separated and the water phase was extracted with diethyl ether, 100 mL x2. The organic phase was washed with IM HCl, 50 mL, dried (Na2SO4), filtered and evaporated in vacuo yielding 8.56 g (91%) of (all-Z)-4,7,10,13,16,19-docosahexaenol (63) as a colorless liquid.1H NMR (200 MHz, CDCl3) δ 1.00 (t, J=7.5 Hz, 3H), 1.63-1.73 (m, 2H), 1.83 (bs, IH), 2.04-2.24 (m, 4H), 2.88 (bs, 10H), 3.67 (t, J=6.4 Hz, 2H), 5.41 (bs, 12H)
	With lithium aluminium tetrahydride

Stage #1: all-(Z)-ethyl 4,7,10,13,16,19-docosahexaenoate With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 2h; Stage #2: With water In tetrahydrofuran

1 Example 1 Synthesis ProceduresPre aration of DHA alcohol: DHA ethyl esterOH Docosahexaen-1-olAn oven-dried 1 L round bottomed flask was charged with Lithium aluminum hydride (LAH) (4.17 g, 110 mmol) in anhydrous THF (60 mL). The flask was then cooled to 0 °C. To this was added drop wise, a solution of DHA ethyl ester (35.6 g, 100 mmol) in THF (40 mL) via addition funnel. After the addition was complete the reaction was allowed to stir for 2 h at 0 °C. The reaction was monitored by TLC. After the reaction was complete, it was quenched at 0 °C by slow drop wise addition of saturated aqueous solution of sodium sulfate. The mixture was then allowed to stir for 10-15 min and then filtered through Buchner funnel. The residue was washed with THF. The filtrate and washings were combined and concentrated under reduced pressure to obtain the product. The identity of the alcohol was confirmed by IR and GC-MS

Reference： [1]Current Patent Assignee: JIVA PHARMA - US2015/344402, 2015, A1 Location in patent: Paragraph 0135 - 0138
[2]Current Patent Assignee: BASF SE - WO2008/53331, 2008, A1 Location in patent: Page/Page column 63
[3]Baba, Naomichi; Alam, Md. Khorshed; Mori, Yoshihiro; Haider, Syed S.; Tanaka, Masatoshi; Nakajima, Shuhei; Shimizu, Sakayu [Journal of the Chemical Society. Perkin Transactions 1 (2001), 2001, # 3, p. 221 - 223]
[4]Current Patent Assignee: KONINKLIJKE DSM N.V. - WO2011/53892, 2011, A1 Location in patent: Page/Page column 44

5
[ 46118-02-9 ]
[ 81926-94-5 ]
3-(3,4-dihydroxyphenyl)propyl cis-4,7,10,13,16,19-docosahexaenoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With Novozym 435 at 37℃;

Reference： [1]Torres De Pinedo; Peñalver; Rondón; Morales [Tetrahedron, 2005, vol. 61, # 32, p. 7654 - 7660]

6
[ 3897-89-0 ]
[ 81926-94-5 ]
3,4-dihydroxybenzyl cis-4,7,10,13,16,19-docosahexaenoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With Novozym 435 at 37℃;

Reference： [1]Torres De Pinedo; Peñalver; Rondón; Morales [Tetrahedron, 2005, vol. 61, # 32, p. 7654 - 7660]

7
[ 3598-26-3 ]
[ 81926-94-5 ]
3,4-dihydroxycinnamyl cis-4,7,10,13,16,19-docosahexaenoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29%	With Novozym 435 at 37℃;

Reference： [1]Torres De Pinedo; Peñalver; Rondón; Morales [Tetrahedron, 2005, vol. 61, # 32, p. 7654 - 7660]

8
[ 10597-60-1 ]
[ 81926-94-5 ]
2-(3,4-dihydroxyphenyl)ethyl cis-4,7,10,13,16,19-docosahexaenoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With Novozym 435 at 37℃;

Reference： [1]Torres De Pinedo; Peñalver; Rondón; Morales [Tetrahedron, 2005, vol. 61, # 32, p. 7654 - 7660]

9
[ 81926-94-5 ]
[ 141-43-5 ]
[ 162758-94-3 ]

Yield	Reaction Conditions	Operation in experiment
78%	In neat (no solvent) at 80℃; for 24h;	4.2. General procedure for synthesis of the target compounds (4a-4o) General procedure: A mixture of 1a/2a/3a (3 mmol) and ethanolamine/3-amino-1-propanol/ 4-amino-1-butanol/5-amino-1-pentanol/6-amino-1-hexanol(9 mmol) were added in 20 mL round bottom flask. The reactionmixture was stirred for 24 h at 80 C, which was purified by silica gelcolumn chromatography (petroleum ether/ethyl acetate 1:1) to give thetarget compounds (4a-4o) as pale yellow oil in yield of 57-78% (Scheme1) 4.2.1. cis-Docosa-4,7,10,13,16,19-hexaenoic acid (2-hydroxy-ethyl)-amide (4a)Pale yellow oil, yield 78%, HPLC purity: 98.3% (tR = 7.06 min), 1HNMR (400 MHz, DMSO-d6, ppm): δ 7.76 (br, 1H, NH), 5.38-5.27 (m,12H, 6 -CH- -CH-), 4.61 (br, 1H, OH), 3.40-3.32 (m, 2H, CH2OH),3.11-3.08 (m, 2H, NHCH2), 2.83-2.77 (m, 10H, 5CH2), 2.26-2.23 (m,2H, CH2), 2.13-1.99 (m, 4H, 2CH2), 0.94-0.86 (m, 3H, CH3).13C NMR(100 MHz, DMSO-d6, ppm): δ 172.00 , 132.01, 129.42, 128.59, 128.56,128.48, 128.37, 128.35, 128.32, 128.21, 128.16, 127.41, 60.44, 41.91,35.63, 29.15, 25.68, 25.63, 25.58, 23.59, 20.50, 14.56. IR (KBr, cm 1): 3308 (N-H), 3028 (HC- -CH), 1638 (C- -O), 1548, 1406, 1268, 1069,916, 668. HRMS (TOF-MS, +): m/z [M+H]+ calculated for C24H38NO2+372.2897, found 372.2886
35 mg	With trifluoroacetic acid at 140℃;
186 mg	With novozyme 435 In <i>tert</i>-butyl alcohol at 45℃; Molecular sieve; Enzymatic reaction;	2.3. Lipase catalyzed synthesis of EPA-EA and DHA-EA General procedure: Substrate (200mg EPA-EE, 0.60mmol or 200mg DHA-EE 0.56, mmol) was dissolved in 6mL of tert-butyl methyl ether (TBME) and Novozyme 435 (100mg), ethanolamine (70μL, 1.15mmol) and molecular sieves (100mg) were added to the solution. The mixture was stirred at 45°C and 280rpm until TLC analysis (n-hexane/EtOAc 9:1) revealed the complete disappearance of the substrate, whereas the products were revealed after elution with n-hexane/EtOAc 1:1 containing 5% EtOH v/v. The mixture was then extracted with aqueous 2M HCl to remove the excess of amine and the organic phase was washed with water and dried on sodium sulphate. The organic solvent was removed under reduced pressure and the products EPA-EA or DHA-EA were recovered as yellow pale oils in 96% (190mg, 0.55mmol) and 94% (186mg, 0.50mmol) yield, respectively, and their NMR spectra (Figures SI1 and SI2) were found in accordance with those reported [27,28].

Reference： [1]Fang, Hua; Zhang, Jianyu; Ao, Mingtao; He, Fengming; Chen, Weizhu; Qian, Yuqing; Zhang, Yuxiang; Xu, Yang; Fang, Meijuan [Bioorganic Chemistry, 2020, vol. 105]
[2]Karaulov; Rybin; Kuklev; Akulin [Chemistry of Natural Compounds, 2004, vol. 40, # 3, p. 222 - 226]
[3]Sanfilippo, Claudia; Patti, Angela [Bioorganic Chemistry, 2021, vol. 113]

10
[ 81926-94-5 ]
(4Z,7Z,10Z,13Z,15E,19Z)-17-Hydroperoxy-docosa-4,7,10,13,15,19-hexaenoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: LiOH / 20 °C 2: lipoxygenase; O₂; borate buffer / 6 h / 0 - 4 °C / pH 9

Reference： [1]Onyango, Arnold N.; Inoue, Takafumi; Nakajima, Shuhei; Baba, Naomichi; Kaneko, Takao; Matsuo, Mitsuyoshi; Shimizu, Sakayu [Angewandte Chemie - International Edition, 2001, vol. 40, # 9, p. 1755 - 1757]

11
[ 81926-94-5 ]
(4Z,7Z,10Z,13Z,15E,19Z)-17-Hydroperoxy-docosa-4,7,10,13,15,19-hexaenoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: LiOH / 20 °C 2: lipoxygenase; O₂; borate buffer / 6 h / 0 - 4 °C / pH 9

Reference： [1]Onyango, Arnold N.; Inoue, Takafumi; Nakajima, Shuhei; Baba, Naomichi; Kaneko, Takao; Matsuo, Mitsuyoshi; Shimizu, Sakayu [Angewandte Chemie - International Edition, 2001, vol. 40, # 9, p. 1755 - 1757]

12
[ 81926-94-5 ]
(4Z,7Z,10Z,13Z,15E,19Z)-17-(1-Methoxy-1-methyl-ethylperoxy)-docosa-4,7,10,13,15,19-hexaenoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: LiOH / 20 °C 2: lipoxygenase; O₂; borate buffer / 6 h / 0 - 4 °C / pH 9 3: PPTS / tetrahydrofuran / 20 °C

Reference： [1]Onyango, Arnold N.; Inoue, Takafumi; Nakajima, Shuhei; Baba, Naomichi; Kaneko, Takao; Matsuo, Mitsuyoshi; Shimizu, Sakayu [Angewandte Chemie - International Edition, 2001, vol. 40, # 9, p. 1755 - 1757]

13
[ 81926-94-5 ]
(4Z,7Z,10Z,13Z,15E,19Z)-17-(1-Methoxy-1-methyl-ethylperoxy)-docosa-4,7,10,13,15,19-hexaenoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: LiOH / 20 °C 2: lipoxygenase; O₂; borate buffer / 6 h / 0 - 4 °C / pH 9 3: PPTS / tetrahydrofuran / 20 °C 4: lipase / 20 °C

Reference： [1]Onyango, Arnold N.; Inoue, Takafumi; Nakajima, Shuhei; Baba, Naomichi; Kaneko, Takao; Matsuo, Mitsuyoshi; Shimizu, Sakayu [Angewandte Chemie - International Edition, 2001, vol. 40, # 9, p. 1755 - 1757]

14
[ 81926-94-5 ]
C₄₈H₈₄NO₁₀P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: LiOH / 20 °C 2: lipoxygenase; O₂; borate buffer / 6 h / 0 - 4 °C / pH 9 3: PPTS / tetrahydrofuran / 20 °C 4: lipase / 20 °C 5: 30 percent / DCC; DMAP / CHCl₃ / 48 h / 20 °C 6: AcOH / tetrahydrofuran; H₂O / 24 h

Reference： [1]Onyango, Arnold N.; Inoue, Takafumi; Nakajima, Shuhei; Baba, Naomichi; Kaneko, Takao; Matsuo, Mitsuyoshi; Shimizu, Sakayu [Angewandte Chemie - International Edition, 2001, vol. 40, # 9, p. 1755 - 1757]

15
[ 81926-94-5 ]
[ 351525-54-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: LiOH / 20 °C 2: lipoxygenase; O₂; borate buffer / 6 h / 0 - 4 °C / pH 9 3: PPTS / tetrahydrofuran / 20 °C 4: lipase / 20 °C 5: 30 percent / DCC; DMAP / CHCl₃ / 48 h / 20 °C

Reference： [1]Onyango, Arnold N.; Inoue, Takafumi; Nakajima, Shuhei; Baba, Naomichi; Kaneko, Takao; Matsuo, Mitsuyoshi; Shimizu, Sakayu [Angewandte Chemie - International Edition, 2001, vol. 40, # 9, p. 1755 - 1757]

16
[ 81926-94-5 ]
[ 78144-19-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: lithium hydroxide / ethanol; H₂O / Ambient temperature 2: 95 percent / I₂, KI, KHCO₃ / tetrahydrofuran; H₂O / 48 h / Ambient temperature
	Multi-step reaction with 2 steps 1: lithium hydroxide monohydrate / water; ethanol / 4 h / 20 °C / Inert atmosphere 2: hydrogen iodide; potassium hydrogencarbonate; iodine / ethanol / 18 h / 0 - 4 °C / Inert atmosphere; Darkness
	Multi-step reaction with 2 steps 1: lithium hydroxide monohydrate; water / ethanol / 20 °C 2: iodine; potassium hydrogencarbonate; potassium iodide / tetrahydrofuran; water / 20 °C

Reference： [1]Flock; Lundquist; Skattebol [Acta Chemica Scandinavica, 1999, vol. 53, # 6, p. 436 - 445]
[2]Langseter, Anne Marie; Stenstroom, Yngve; Skattebool, Lars [Molecules, 2014, vol. 19, # 3, p. 3804 - 3812]
[3]Current Patent Assignee: COEGIN PHARMA AB - WO2019/219758, 2019, A1

17
[ 81926-94-5 ]
[ 137682-11-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: lithium hydroxide / ethanol; H₂O / Ambient temperature 2: 95 percent / I₂, KI, KHCO₃ / tetrahydrofuran; H₂O / 48 h / Ambient temperature 3: 93 percent / K₂CO₃ / 3 h / Ambient temperature 4: 46 percent / periodic acid / 6 h / Ambient temperature 5: 96 percent / aq. formic acid / dioxane / 1.5 h / Ambient temperature
	Multi-step reaction with 4 steps 1: lithium hydroxide / ethanol; H₂O / Ambient temperature 2: 95 percent / I₂, KI, KHCO₃ / tetrahydrofuran; H₂O / 48 h / Ambient temperature 3: 93 percent / K₂CO₃ / 3 h / Ambient temperature 4: periodic acid / diethyl ether / Ambient temperature
	Multi-step reaction with 3 steps 1.1: lithium hydroxide / Inert atmosphere; Darkness 2.1: potassium iodide; iodine; potassium hydrogencarbonate / tetrahydrofuran; water / 72 h / Inert atmosphere; Darkness 2.2: Inert atmosphere; Darkness 3.1: formic acid; acetic anhydride / Inert atmosphere; Darkness 3.2: 0 °C / Inert atmosphere; Darkness 3.3: Inert atmosphere; Darkness

Multi-step reaction with 4 steps 1: lithium hydroxide monohydrate; water / ethanol / 20 °C 2: iodine; potassium hydrogencarbonate; potassium iodide / tetrahydrofuran; water / 20 °C 3: potassium carbonate / 1 h / 20 °C 4: periodic acid / diethyl ether; tetrahydrofuran / 1 h / 20 °C

Reference： [1]Flock; Lundquist; Skattebol [Acta Chemica Scandinavica, 1999, vol. 53, # 6, p. 436 - 445]
[2]Flock; Lundquist; Skattebol [Acta Chemica Scandinavica, 1999, vol. 53, # 6, p. 436 - 445]
[3]Current Patent Assignee: COEGIN PHARMA AB - WO2015/11206, 2015, A1
[4]Current Patent Assignee: COEGIN PHARMA AB - WO2019/219758, 2019, A1

18
[ 81926-94-5 ]
[ 234087-71-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: lithium hydroxide / ethanol; H₂O / Ambient temperature 2: 95 percent / I₂, KI, KHCO₃ / tetrahydrofuran; H₂O / 48 h / Ambient temperature 3: 93 percent / K₂CO₃ / 3 h / Ambient temperature 4: 46 percent / periodic acid / 6 h / Ambient temperature 5: 96 percent / aq. formic acid / dioxane / 1.5 h / Ambient temperature 6: DBU / diethyl ether / 0.5 h / Ambient temperature
	Multi-step reaction with 5 steps 1: lithium hydroxide / ethanol; H₂O / Ambient temperature 2: 95 percent / I₂, KI, KHCO₃ / tetrahydrofuran; H₂O / 48 h / Ambient temperature 3: 93 percent / K₂CO₃ / 3 h / Ambient temperature 4: periodic acid / diethyl ether / Ambient temperature 5: DBU / diethyl ether / 0.5 h / Ambient temperature
	Multi-step reaction with 4 steps 1.1: lithium hydroxide monohydrate / water; ethanol / 4 h / 20 °C / Inert atmosphere 2.1: hydrogen iodide; potassium hydrogencarbonate; iodine / ethanol / 18 h / 0 - 4 °C / Inert atmosphere; Darkness 3.1: potassium carbonate / methanol / 0 - 20 °C / Inert atmosphere 3.2: 4 h / Inert atmosphere; Reflux 4.1: lithium hydroxide monohydrate / methanol; water / 0.5 h / Inert atmosphere; Cooling with ice 4.2: 1 h / 20 °C / pH 4 / Inert atmosphere 4.3: Inert atmosphere

	Multi-step reaction with 4 steps 1.1: lithium hydroxide / Inert atmosphere; Darkness 2.1: potassium iodide; iodine; potassium hydrogencarbonate / tetrahydrofuran; water / 72 h / Inert atmosphere; Darkness 2.2: Inert atmosphere; Darkness 3.1: formic acid; acetic anhydride / Inert atmosphere; Darkness 3.2: 0 °C / Inert atmosphere; Darkness 3.3: Inert atmosphere; Darkness 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / diethyl ether / Inert atmosphere; Darkness
	Multi-step reaction with 5 steps 1: lithium hydroxide monohydrate; water / ethanol / 20 °C 2: iodine; potassium hydrogencarbonate; potassium iodide / tetrahydrofuran; water / 20 °C 3: potassium carbonate / 1 h / 20 °C 4: periodic acid / diethyl ether; tetrahydrofuran / 1 h / 20 °C 5: 1,8-diazabicyclo[5.4.0]undec-7-ene / diethyl ether / 1 h / 20 °C

Reference： [1]Flock; Lundquist; Skattebol [Acta Chemica Scandinavica, 1999, vol. 53, # 6, p. 436 - 445]
[2]Flock; Lundquist; Skattebol [Acta Chemica Scandinavica, 1999, vol. 53, # 6, p. 436 - 445]
[3]Langseter, Anne Marie; Stenstroom, Yngve; Skattebool, Lars [Molecules, 2014, vol. 19, # 3, p. 3804 - 3812]
[4]Current Patent Assignee: COEGIN PHARMA AB - WO2015/11206, 2015, A1
[5]Current Patent Assignee: COEGIN PHARMA AB - WO2019/219758, 2019, A1

19
[ 81926-94-5 ]
[ 234087-73-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: lithium hydroxide / ethanol; H₂O / Ambient temperature 2: 95 percent / I₂, KI, KHCO₃ / tetrahydrofuran; H₂O / 48 h / Ambient temperature 3: 93 percent / K₂CO₃ / 3 h / Ambient temperature 4: 46 percent / periodic acid / 6 h / Ambient temperature 5: 96 percent / aq. formic acid / dioxane / 1.5 h / Ambient temperature 6: DBU / diethyl ether / 0.5 h / Ambient temperature 7: 85 percent / NaBH₄ / methanol / 0.5 h
	Multi-step reaction with 6 steps 1: lithium hydroxide / ethanol; H₂O / Ambient temperature 2: 95 percent / I₂, KI, KHCO₃ / tetrahydrofuran; H₂O / 48 h / Ambient temperature 3: 93 percent / K₂CO₃ / 3 h / Ambient temperature 4: periodic acid / diethyl ether / Ambient temperature 5: DBU / diethyl ether / 0.5 h / Ambient temperature 6: 85 percent / NaBH₄ / methanol / 0.5 h
	Multi-step reaction with 5 steps 1.1: lithium hydroxide monohydrate / water; ethanol / 4 h / 20 °C / Inert atmosphere 2.1: hydrogen iodide; potassium hydrogencarbonate; iodine / ethanol / 18 h / 0 - 4 °C / Inert atmosphere; Darkness 3.1: potassium carbonate / methanol / 0 - 20 °C / Inert atmosphere 3.2: 4 h / Inert atmosphere; Reflux 4.1: lithium hydroxide monohydrate / methanol; water / 0.5 h / Inert atmosphere; Cooling with ice 4.2: 1 h / 20 °C / pH 4 / Inert atmosphere 4.3: Inert atmosphere 5.1: sodium tetrahydroborate / Inert atmosphere

	Multi-step reaction with 5 steps 1.1: lithium hydroxide / Inert atmosphere; Darkness 2.1: potassium iodide; iodine; potassium hydrogencarbonate / tetrahydrofuran; water / 72 h / Inert atmosphere; Darkness 2.2: Inert atmosphere; Darkness 3.1: formic acid; acetic anhydride / Inert atmosphere; Darkness 3.2: 0 °C / Inert atmosphere; Darkness 3.3: Inert atmosphere; Darkness 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / diethyl ether / Inert atmosphere; Darkness 5.1: diisobutylaluminium hydride / toluene / Inert atmosphere; Darkness
	Multi-step reaction with 6 steps 1: lithium hydroxide monohydrate; water / ethanol / 20 °C 2: iodine; potassium hydrogencarbonate; potassium iodide / tetrahydrofuran; water / 20 °C 3: potassium carbonate / 1 h / 20 °C 4: periodic acid / diethyl ether; tetrahydrofuran / 1 h / 20 °C 5: 1,8-diazabicyclo[5.4.0]undec-7-ene / diethyl ether / 1 h / 20 °C 6: diisobutylaluminium hydride / toluene / 1.33 h / -78 °C

Reference： [1]Flock; Lundquist; Skattebol [Acta Chemica Scandinavica, 1999, vol. 53, # 6, p. 436 - 445]
[2]Flock; Lundquist; Skattebol [Acta Chemica Scandinavica, 1999, vol. 53, # 6, p. 436 - 445]
[3]Langseter, Anne Marie; Stenstroom, Yngve; Skattebool, Lars [Molecules, 2014, vol. 19, # 3, p. 3804 - 3812]
[4]Current Patent Assignee: COEGIN PHARMA AB - WO2015/11206, 2015, A1
[5]Current Patent Assignee: COEGIN PHARMA AB - WO2019/219758, 2019, A1

20
[ 2749-86-2 ]
[ 81926-94-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 11 steps 1: 94 percent / KOH / diethyl ether / 4 h 2: EtMgBr, CuBr*Me₂S / tetrahydrofuran / 1.) 50 deg C, 30 min; 0 deg C, 5 min, 2.) 0 deg C to r.t., 10 h 3: 1.) K₃Fe(CN)6, K₂CO₃, OsO₄, H₂O, 2.) Dowex 50 x 8 - 100 ion-exchange resin / 1.) t-BuOH, r.t., 48 h, 2.) MeOH, r.t., 13 h 4: conc. H₂SO₄, molecular sieves 4A, Na₂SO₄ / 13 h / Ambient temperature 5: 87 percent / H₂, ethylenediamine / P-2 Ni catalyst / ethanol / 5 h / 23 °C 6: 82 percent / pyridine / CH₂Cl₂ / 8 h / 0 °C 7: CaCO₃ / acetonitrile / 48 h / 90 °C 8: 73 percent / NaHMDS / tetrahydrofuran / 1.) 0 deg C, 10 min, 2.) -78 deg C to r.t., 3 h 9: 90 percent / 4 N aq. HCl, methylene blue / tetrahydrofuran / 0.5 h 10: 0.8 M aq. NaIO₄, 60-200 mesh SiO₂ / CH₂Cl₂ / 0.08 h / Ambient temperature 11: NaHMDS / 1.) THF, -75 deg C, 2.) CH₂Cl₂, -75 deg C to r.t., 4 h

Reference： [1]Taber, Douglass F.; You, Kamfia [Journal of Organic Chemistry, 1995, vol. 60, # 1, p. 139 - 142]

21
[ 53046-97-2 ]
[ 81926-94-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 81 percent / pyridine / CH₂Cl₂ / 13 h / Ambient temperature 2: acetonitrile / 13 h / Heating 3: NaHMDS / 1.) THF, -75 deg C, 2.) CH₂Cl₂, -75 deg C to r.t., 4 h

Reference： [1]Taber, Douglass F.; You, Kamfia [Journal of Organic Chemistry, 1995, vol. 60, # 1, p. 139 - 142]

22
[ 159145-93-4 ]
[ 81926-94-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1: conc. H₂SO₄, molecular sieves 4A, Na₂SO₄ / 13 h / Ambient temperature 2: 87 percent / H₂, ethylenediamine / P-2 Ni catalyst / ethanol / 5 h / 23 °C 3: 82 percent / pyridine / CH₂Cl₂ / 8 h / 0 °C 4: CaCO₃ / acetonitrile / 48 h / 90 °C 5: 73 percent / NaHMDS / tetrahydrofuran / 1.) 0 deg C, 10 min, 2.) -78 deg C to r.t., 3 h 6: 90 percent / 4 N aq. HCl, methylene blue / tetrahydrofuran / 0.5 h 7: 0.8 M aq. NaIO₄, 60-200 mesh SiO₂ / CH₂Cl₂ / 0.08 h / Ambient temperature 8: NaHMDS / 1.) THF, -75 deg C, 2.) CH₂Cl₂, -75 deg C to r.t., 4 h

Reference： [1]Taber, Douglass F.; You, Kamfia [Journal of Organic Chemistry, 1995, vol. 60, # 1, p. 139 - 142]

23
[ 159145-94-5 ]
[ 81926-94-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: 87 percent / H₂, ethylenediamine / P-2 Ni catalyst / ethanol / 5 h / 23 °C 2: 82 percent / pyridine / CH₂Cl₂ / 8 h / 0 °C 3: CaCO₃ / acetonitrile / 48 h / 90 °C 4: 73 percent / NaHMDS / tetrahydrofuran / 1.) 0 deg C, 10 min, 2.) -78 deg C to r.t., 3 h 5: 90 percent / 4 N aq. HCl, methylene blue / tetrahydrofuran / 0.5 h 6: 0.8 M aq. NaIO₄, 60-200 mesh SiO₂ / CH₂Cl₂ / 0.08 h / Ambient temperature 7: NaHMDS / 1.) THF, -75 deg C, 2.) CH₂Cl₂, -75 deg C to r.t., 4 h

Reference： [1]Taber, Douglass F.; You, Kamfia [Journal of Organic Chemistry, 1995, vol. 60, # 1, p. 139 - 142]

24
[ 159145-95-6 ]
[ 81926-94-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: 82 percent / pyridine / CH₂Cl₂ / 8 h / 0 °C 2: CaCO₃ / acetonitrile / 48 h / 90 °C 3: 73 percent / NaHMDS / tetrahydrofuran / 1.) 0 deg C, 10 min, 2.) -78 deg C to r.t., 3 h 4: 90 percent / 4 N aq. HCl, methylene blue / tetrahydrofuran / 0.5 h 5: 0.8 M aq. NaIO₄, 60-200 mesh SiO₂ / CH₂Cl₂ / 0.08 h / Ambient temperature 6: NaHMDS / 1.) THF, -75 deg C, 2.) CH₂Cl₂, -75 deg C to r.t., 4 h

Reference： [1]Taber, Douglass F.; You, Kamfia [Journal of Organic Chemistry, 1995, vol. 60, # 1, p. 139 - 142]

25
[ 159145-92-3 ]
[ 81926-94-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 1: 1.) K₃Fe(CN)6, K₂CO₃, OsO₄, H₂O, 2.) Dowex 50 x 8 - 100 ion-exchange resin / 1.) t-BuOH, r.t., 48 h, 2.) MeOH, r.t., 13 h 2: conc. H₂SO₄, molecular sieves 4A, Na₂SO₄ / 13 h / Ambient temperature 3: 87 percent / H₂, ethylenediamine / P-2 Ni catalyst / ethanol / 5 h / 23 °C 4: 82 percent / pyridine / CH₂Cl₂ / 8 h / 0 °C 5: CaCO₃ / acetonitrile / 48 h / 90 °C 6: 73 percent / NaHMDS / tetrahydrofuran / 1.) 0 deg C, 10 min, 2.) -78 deg C to r.t., 3 h 7: 90 percent / 4 N aq. HCl, methylene blue / tetrahydrofuran / 0.5 h 8: 0.8 M aq. NaIO₄, 60-200 mesh SiO₂ / CH₂Cl₂ / 0.08 h / Ambient temperature 9: NaHMDS / 1.) THF, -75 deg C, 2.) CH₂Cl₂, -75 deg C to r.t., 4 h

Reference： [1]Taber, Douglass F.; You, Kamfia [Journal of Organic Chemistry, 1995, vol. 60, # 1, p. 139 - 142]

26
[ 159146-00-6 ]
[ 81926-94-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 0.8 M aq. NaIO₄, 60-200 mesh SiO₂ / CH₂Cl₂ / 0.08 h / Ambient temperature 2: NaHMDS / 1.) THF, -75 deg C, 2.) CH₂Cl₂, -75 deg C to r.t., 4 h

Reference： [1]Taber, Douglass F.; You, Kamfia [Journal of Organic Chemistry, 1995, vol. 60, # 1, p. 139 - 142]

27
[ 159145-91-2 ]
[ 81926-94-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 10 steps 1: EtMgBr, CuBr*Me₂S / tetrahydrofuran / 1.) 50 deg C, 30 min; 0 deg C, 5 min, 2.) 0 deg C to r.t., 10 h 2: 1.) K₃Fe(CN)6, K₂CO₃, OsO₄, H₂O, 2.) Dowex 50 x 8 - 100 ion-exchange resin / 1.) t-BuOH, r.t., 48 h, 2.) MeOH, r.t., 13 h 3: conc. H₂SO₄, molecular sieves 4A, Na₂SO₄ / 13 h / Ambient temperature 4: 87 percent / H₂, ethylenediamine / P-2 Ni catalyst / ethanol / 5 h / 23 °C 5: 82 percent / pyridine / CH₂Cl₂ / 8 h / 0 °C 6: CaCO₃ / acetonitrile / 48 h / 90 °C 7: 73 percent / NaHMDS / tetrahydrofuran / 1.) 0 deg C, 10 min, 2.) -78 deg C to r.t., 3 h 8: 90 percent / 4 N aq. HCl, methylene blue / tetrahydrofuran / 0.5 h 9: 0.8 M aq. NaIO₄, 60-200 mesh SiO₂ / CH₂Cl₂ / 0.08 h / Ambient temperature 10: NaHMDS / 1.) THF, -75 deg C, 2.) CH₂Cl₂, -75 deg C to r.t., 4 h

Reference： [1]Taber, Douglass F.; You, Kamfia [Journal of Organic Chemistry, 1995, vol. 60, # 1, p. 139 - 142]

28
[ 159145-99-0 ]
[ 81926-94-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 90 percent / 4 N aq. HCl, methylene blue / tetrahydrofuran / 0.5 h 2: 0.8 M aq. NaIO₄, 60-200 mesh SiO₂ / CH₂Cl₂ / 0.08 h / Ambient temperature 3: NaHMDS / 1.) THF, -75 deg C, 2.) CH₂Cl₂, -75 deg C to r.t., 4 h

Reference： [1]Taber, Douglass F.; You, Kamfia [Journal of Organic Chemistry, 1995, vol. 60, # 1, p. 139 - 142]

29
[ 159145-96-7 ]
[ 81926-94-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: CaCO₃ / acetonitrile / 48 h / 90 °C 2: 73 percent / NaHMDS / tetrahydrofuran / 1.) 0 deg C, 10 min, 2.) -78 deg C to r.t., 3 h 3: 90 percent / 4 N aq. HCl, methylene blue / tetrahydrofuran / 0.5 h 4: 0.8 M aq. NaIO₄, 60-200 mesh SiO₂ / CH₂Cl₂ / 0.08 h / Ambient temperature 5: NaHMDS / 1.) THF, -75 deg C, 2.) CH₂Cl₂, -75 deg C to r.t., 4 h

Reference： [1]Taber, Douglass F.; You, Kamfia [Journal of Organic Chemistry, 1995, vol. 60, # 1, p. 139 - 142]

30
<(Z,Z)-8-(2,2-Dimethyl-1,3-dioxolan-4-yl)-3,6-octadienyl>triphenylphosphonium tosylate [ No CAS ]
[ 81926-94-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 73 percent / NaHMDS / tetrahydrofuran / 1.) 0 deg C, 10 min, 2.) -78 deg C to r.t., 3 h 2: 90 percent / 4 N aq. HCl, methylene blue / tetrahydrofuran / 0.5 h 3: 0.8 M aq. NaIO₄, 60-200 mesh SiO₂ / CH₂Cl₂ / 0.08 h / Ambient temperature 4: NaHMDS / 1.) THF, -75 deg C, 2.) CH₂Cl₂, -75 deg C to r.t., 4 h

Reference： [1]Taber, Douglass F.; You, Kamfia [Journal of Organic Chemistry, 1995, vol. 60, # 1, p. 139 - 142]

31
[ 161794-74-7 ]
[ 81926-94-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: acetonitrile / 13 h / Heating 2: NaHMDS / 1.) THF, -75 deg C, 2.) CH₂Cl₂, -75 deg C to r.t., 4 h

Reference： [1]Taber, Douglass F.; You, Kamfia [Journal of Organic Chemistry, 1995, vol. 60, # 1, p. 139 - 142]

32
[ 81926-94-5 ]
[ 124596-98-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 98 percent / EDTA, Na₂EDTA*2H₂O / ethanol; H₂O / 2 h / 60 - 65 °C 2: 80 percent / immobilized lipase from Candida antarctica / 72 h / 65 °C / 0.01 - 0.1 Torr

Reference： [1]Haraldsson, Gudmundur G.; Gudmundsson, Birgir Oe.; Almarsson, Oern [Tetrahedron, 1995, vol. 51, # 3, p. 941 - 952]

33
stigmasterol [ No CAS ]
[ 81926-94-5 ]
[ 86227-47-6 ]
[ 272107-20-7 ]
[ 272107-19-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate at 140 - 175℃; for 6 - 24h;	1A; 1B (A) A mixture of dry stigmasterol (3 g, 7.27 mmol) and a highly concentrated mixture of EPA and DHA omega-3 fatty acids in ethyl ester form (EPAX 5500, ProNova; 4.3 g, 12.6 mmol) were heated while being stirred magnetically at 140 to 145° C. for 2 hours under vacuum (5 mm). Subsequently the vacuum was disconnected and powdered sodium methoxide (40 mg, 0.75 mmol) was added quickly in one portion. The vacuum was connected immediately and the mixture was stirred at 140 to 145° C. for an additional 4 hours. Hexane (25 mL) was added to precipitate the residual stigmasterol and the mixture was centrifuged for 5 minutes at 15,000 g (0° C.), the supernatant was removed and the pellet was washed again with 5 mL of hexane. The remaining precipitate was centrifuged off and the supernatants combined. The organic phase was washed with water (5 mL), dried over sodium sulfate and the solvent removed under reduced pressure. TLC (hexane/diethylether/acetic acid (90:10:1), Rf 0.71. The yield was 5.9 g (85%). The ester product was a viscous oil.When the experiment was repeated using freshly made sodium ethoxide, almost the same level of conversion was obtained as with sodium methoxide. However, this was not seen with commercially available sodium ethoxide, which performed more poorly than sodium methoxide. (B) A highly concentrated mixture of EPA and DHA omega-3 fatty acids in ethyl ester form (EPAX5500 EE, BioNova; 221 g, 649 mmol) was heated while being stirred magnetically at 140 to 145° C. for 2 hours under vacuum (5 mm). A well dispersed mixture of dry stigmasterol (268 g, 649 mmol) and sodium methoxide (40 mg, 0.75 mmol) was added portionwise within 1 hour and the mixture was stirred at 170 to 175° C. for an additional 21 hours. The reaction mixture was liberated from unreacted material either by column chromatography (2% diethylether in hexane on silicagel) or by a sequential extraction using two immissible solvents. The unreacted stigmasterol was precipitated upon addition of hexane and the solution was then filtered. The filtrate was extracted with methanol to remove unreacted starting oil material. TLC (hexane/diethylether/acetic acid (90:10:1) gave an Rf equal to 0.71. The yield was 434 g (70%). The ester product was a viscous oil.When the experiment was repeated using freshly made sodium ethoxide, almost the same level of conversion was obtained as with sodium methoxide. However, this was not seen with commercially available sodium ethoxide, which performed more poorly than sodium methoxide.The procedure works also from a concentrated mixture of EPA and DHA omega-3 fatty acids in triglyceride form (EPAX5500 TG, BioNova) with a similar yield of final product

Reference： [1]Current Patent Assignee: KONINKLIJKE DSM N.V. - US6998501, 2006, B1 Location in patent: Page/Page column 7-8

34
[ 6928-85-4 ]
[ 81926-94-5 ]
[ 479411-48-8 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: N-amino-N'-methylpiperazine With trimethylaluminum In hexane; toluene at 7℃; for 0.616667h; Stage #2: all-(Z)-ethyl 4,7,10,13,16,19-docosahexaenoate In hexane; toluene at 25 - 70℃; for 2.1h; Stage #3: With hydrogenchloride In hexane; water; toluene at 39℃; for 0.166667h;	1 (Example 1) Synthesis of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(4-methylpiperazin-1-yl)docosahexaenoamide (Compound 1) (Example 1) Synthesis of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(4-methylpiperazin-1-yl)docosahexaenoamide (Compound 1) toluene (15 ml), dried using the molecular sieve MS 4A, was mixed with 10.3 ml of a n-hexane solution of 15% Me3Al. With the mixture being cooled in an ice-methanol bath, 1.69 ml (14.1 mmols) of 1-amino-4-methylpiperazine was added dropwise over about 2 minutes (inner temperature <7°C).. The 1-amino-4-methylpiperazine was finally washed using 2 ml of toluene.. After stirring for 35 minutes, the temperature was raised to room temperature, and 6 ml of a toluene solution of 5.0 g (14.0 mmols) of docosahexaenoic acid ethyl ester (hereinafter referred to as DHA ethyl ester) was added dropwise over 6 minutes (inner temperature 25∼26°C).. After stirring for 2 hours at 70°C, the mixture was cooled with ice, and 24 ml of 0.67N hydrochloric acid was added dropwise (inner temperature raised up to 39°C). The mixture was stirred for 10 minutes, and water and ethyl acetate were added.. Then, the mixture was filtered through Celite, the filtrate was separated into respective layers, and the organic layer was washed twice with 20 ml of a saturated aqueous solution of sodium chloride.. After this layer was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure on a 32°C water bath to obtain the captioned compound.. This compound was subjected to silica gel column chromatography (mobile phase: CHCl3AcOEtCHCl3:MeOH (4:1)), and then further subjected to silica gel column chromatography (mobile phase: CHCl3:MeOH (19:1)) for purification. NMR confirmed the purified compound to have the following structure (yield 5.4 g, purity 95%):

Reference： [1]Current Patent Assignee: MARUHA NICHIRO SEAFOODS - EP1408030, 2004, A1 Location in patent: Page 11

35
[ 81926-94-5 ]
[ 51387-90-7 ]
[ 479411-49-9 ]

Yield	Reaction Conditions	Operation in experiment
		(Example 2) Synthesis of (4Z,7Z,10Z,13Z,16Z,19Z)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]docosahexaenoamide (Compound 2) toluene (15 ml), dried using MS 4A, was mixed with 10.3 ml of a n-hexane solution of 15% Me3Al. With the mixture being cooled in an ice-methanol bath, 2.03 ml (14.1 mmols) of 2-(2-aminoethyl)-1-methylpyrrolidine was added dropwise over about 2 minutes (inner temperature -7+8C).. The 2-(2-aminoethyl)-1-methylpyrrolidine was finally washed using 2 ml of toluene.. After stirring for 20 minutes, the temperature was raised to room temperature, and 6 ml of a toluene solution of 5.0 g (14.0 mmols) of DHA ethyl ester was added dropwise over 2 minutes (inner temperature 28?29C).. After stirring for 2 hours at 70C, the mixture was cooled with ice, and 24 ml of 0.67N hydrochloric acid was added dropwise (inner temperature 12?27C).. The mixture was stirred for 10 minutes, and water and ethyl acetate were added.. Then, the mixture was filtered through Celite, the filtrate was separated into respective layers with the addition of a small amount of NaOH, and the organic layer was washed twice with 20 ml of a saturated aqueous solution of sodium chloride.. After this layer was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure on a 32C water bath to obtain the captioned compound (yield 4.7 g).. This compound was subjected to silica gel column chromatography (mobile phase: CHCl3:MeOH (19:19:1)) for purification. NMR confirmed the purified compound to have the following structure:

Reference： [1]Patent: EP1408030,2004,A1 .Location in patent: Page 11-12

36
[ 81926-94-5 ]
[ 140119-66-0 ]
[ 479411-56-8 ]

Yield	Reaction Conditions	Operation in experiment
39%	Stage #1: 1-methyl-2-(3-amino-1-propyl)pyrrolidine With trimethylaluminum In hexane; toluene at -15℃; for 0.35h; Stage #2: all-(Z)-ethyl 4,7,10,13,16,19-docosahexaenoate In hexane; toluene at 20 - 70℃; for 3h; Stage #3: With hydrogenchloride In hexane; water; toluene at 0℃;	11 (Example 11) Synthesis of (4Z,7Z,10Z,13Z,16Z,19Z)-N-[3-(1-methylpyrrolidin-2-yl)propyl]docosahexaenoamide (Compound 11) (Example 11) Synthesis of (4Z,7Z,10Z,13Z,16Z,19Z)-N-[3-(1-methylpyrrolidin-2-yl)propyl]docosahexaenoamide (Compound 11) toluene (1.34 ml), dried using MS 4A, was mixed with 0.86 ml of a n-hexane solution of 15% Me3Al. With the mixture being cooled in an ice-methanol bath, 0.167 g of 2-(3-aminopropyl)-1-methylpyrrolidine in 0.6 ml of toluene was added dropwise over about 1 minute (inner temperature - 15°C).. After stirring for 20 minutes, the temperature was raised to 20°C, and 0.6 ml of a toluene solution of 0.42 g (1.2 mmols) of DHA ethyl ester was added dropwise (inner temperature 20°C).. After stirring for 3 hours at 70°C, the mixture was cooled with ice, and 2.1 ml of 0.67N hydrochloric acid was added dropwise.. After 10 ml of an aqueous solution of 1N NaOH was added, the mixture was extracted with ethyl acetate, followed by washing the extract with water and a saturated aqueous solution of sodium chloride.. The washed product was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure.. The residue was purified by silica gel column chromatography (mobile phase: CHCl3:MeOH (50:19:14:1)), thereby obtaining 0.21 g of the captioned compound (amount yielded: 0.46 mmol, yield: 39%, purity: 97.9%). NMR confirmed the purified compound to have the following structure:

Reference： [1]Current Patent Assignee: MARUHA NICHIRO SEAFOODS - EP1408030, 2004, A1 Location in patent: Page 19-20

37
[ 26171-06-2 ]
[ 81926-94-5 ]
(4Z,7Z,10Z,13Z,16Z,19Z)-N-[(1-methylpyrrolidin-2-yl)methyl]docosahexaenoamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: 1-methyl-2-aminomethyl-pyrrolidine With trimethylaluminum In hexane; toluene at -10 - 0℃; for 0.366667h; Stage #2: all-(Z)-ethyl 4,7,10,13,16,19-docosahexaenoate In hexane; toluene at 10 - 70℃; for 2.53333h; Stage #3: With hydrogenchloride In hexane; water; toluene at 0℃;	9 (Example 9) Synthesis of (4Z,7Z,10Z,13Z,16Z,19Z)-N-[(1-methylpyrrolidin-2-yl)methyl]docosahexaenoamide (Compound 9) (Example 9) Synthesis of (4Z,7Z,10Z,13Z,16Z,19Z)-N-[(1-methylpyrrolidin-2-yl)methyl]docosahexaenoamide (Compound 9) toluene (5 ml), dried using MS 4A, was mixed with 3.2 ml of an n-hexane solution of 15% Me3Al. With the mixture being cooled in an ice-methanol bath, a toluene solution (2 ml) of 0.6 g of 2-aminomethyl-1-methylpyrrolidine was added dropwise over about 2 minutes (inner temperature -10+0°C).. After stirring for 20 minutes, the temperature was raised to 12°C, and 2 ml of a toluene solution of 1.56 g (4.38 mmols) of DHA ethyl ester was added dropwise over 2 minutes (inner temperature 10∼13°C).. After stirring for 2.5 hours at 70°C, the mixture was cooled with ice, and 7.5 ml of 0.67N hydrochloric acid was added dropwise.. After 35 ml of 1N NaOH was added, the mixture was extracted twice with ethyl acetate, followed by washing the extract twice with 20 ml of water and 20 ml of a saturated aqueous solution of sodium chloride.. The washed product was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure on a 40°C water bath to obtain the captioned compound.. This compound was subjected to silica gel column chromatography (mobile phase: CHCl3:MeOH (50:19:1)) for purification (1.4 g, 3.3 mmols, yield 75%). NMR confirmed the purified compound to have the following structure:

Reference： [1]Current Patent Assignee: MARUHA NICHIRO SEAFOODS - EP1408030, 2004, A1 Location in patent: Page 18-19

38
[ 81926-94-5 ]
[ 75-03-6 ]
[ 914294-15-8 ]

Yield	Reaction Conditions	Operation in experiment
20%	Stage #1: all-(Z)-ethyl 4,7,10,13,16,19-docosahexaenoate With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78 - 0℃; for 5.25h; Stage #2: ethyl iodide In tetrahydrofuran; hexane at -78 - -15℃; for 3h;	Butyllithium (440 ml, 0.67 mol, 1.6 M in hexane) was added dropwise to a stirred solution of diisopropylamine (111 ml, 0.78 mol) in dry THF (750 ml) under N2 at 0 C. The resulting solution was stirred at -78 C for 45 min. before dropwise addition of DHA EE (200 g, 0.56 mol) in dry THF (1.61). The addition of the ester was complete in 4 hours, The dark-green solution was stirred at -78 °C for 30 min. before EtI (65 ml, 0.81 mol) Was added. The solution was allowed to reach -40 C before an additional amount of EtI (5 ml, 0.06 mol) was added, and finally reach -15 °C (during 3 hours from -78 C) before the mixture was poured into water and extracted with hexane (2x). The combined organic phases were washed with 1 M HCl, water, dried (Na2SO4), filtered and evaporated in vacuo. The product was purified by flash chromatography on silica gel eluting with heptane/EtOAc (99:1 followed by 50:1) to give 42.2 g (20%) of the titled compound as a yellow oil;[0128] 1H-NMR (200 MHz; CDCl3) δ 0.8-1.0 (m, 6H), 1.2-1.4 (m, 411), 1.5-1.7 (m, 2H), 2.12 (m, 2H), 2.3-2.5 (m, 2H), 2.8-3.0 (m, 10H), 4.18 (t, J7.1 Hz, 211), 5.3-5.6 (m, 12H);[0129] MS (electrospray); 407 [M+Na].
20%	Stage #1: all-(Z)-ethyl 4,7,10,13,16,19-docosahexaenoate With n-butyllithium; diisopropylamine In tetrahydrofuran at -78 - 0℃; for 4.5h; Inert atmosphere; Stage #2: ethyl iodide In tetrahydrofuran at -78 - -15℃; Inert atmosphere;	Synthesis of α-Ethyl DHA EE (PRB-2) Butyl lithium (440 ml, 0.76 mol, 1.6M in nucleic acid) was added dropwise to a stirred solution of diisopropylamine (111 ml. 0.78 mol) in dry THF (750 ml) under a nitrogen atmosphere at 0 ° C. The resulting solution was stirred at -78 ° C for 45 minutes and then added dropwise to DHA EE (200 g, 0.56 mol) in dry THF (1.61 ml). Ester was added over 4 hours. After stirring the dark green solution at -78 C for 30 minutes, EtI (65 ml. 0.81 mol) was added thereto. When the temperature of the solution became -40 C, EtI (5 ml, 0.06 mol) was additionally added. After the solution was finally heated to -15 C (over -3 hours at -78 ° C), the mixture was poured into water and extracted with hexane (2x). The combined organic layer was washed with 1M hydrochloric acid and water, dried under Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The result was eluted with heptane / EtOAc (99: 1 to 50: 1) by flash chromatography on silica gel to obtain 42.2 g (20%) of a yellow oil compound
330 mg	Stage #1: all-(Z)-ethyl 4,7,10,13,16,19-docosahexaenoate With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.166667h; Inert atmosphere; Stage #2: ethyl iodide In tetrahydrofuran; hexane at -78 - 20℃; for 1h;	9 Butyl lithium (0.96 ml, 1.54 mmol in 1.6 M in hexane) was added dropwise to a stirred solution of diisopropylamine (0.23 ml, 1.6 mmol) in dry THF (5 ml) under a nitrogen atmosphere at 0°C. The resulting solution was stirred at 0°C for 20 minutes, cooled to -78°C and stirred an additional 10 minutes before dropwise addition of ethyl ethyl(4Z,7Z, 1 OZ, 1 3Z, 1 6Z, 1 9Z)-docosa-4, 11,10,13,16,1 9-hexaenoate (499 mg, 1.4 mmol) in dry THF (5 ml). The mixture was stirred at -78°C for 10 minutes before addition of ethyl iodide (0.16 ml, 2.09 mmol). The mixture was allowed to warm to room temperature over 1 hour. The mixture was then poured into water, and extracted with heptane. The combined organic phase was washed with 1M HC1 and then dried (Na2SO4). Filtration and evaporation under reduced pressure followed by filtration through a silica plug (hexane:EtOAC 98:2) gave the ethyl ester (330 mg):

Reference： [1]Current Patent Assignee: BASF SE - WO2009/56983, 2009, A1 Location in patent: Page/Page column 23
[2]Current Patent Assignee: CNS PHARM CO LTD - KR2020/16613, 2020, A Location in patent: Paragraph 0136-0139
[3]Current Patent Assignee: BIOZEP - WO2017/93732, 2017, A1 Location in patent: Page/Page column 62

39
[ 100-55-0 ]
[ 81926-94-5 ]
pyridin-3-ylmethyl all-Z-4,7,10,13,16,19-docosahexaeneoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With potassium carbonate In tetrahydrofuran for 14h; Reflux; Inert atmosphere;	1 Synthesis of pyridin-3-ylmethyl docosahexaeneoate using K2CO3 EXAMPLE 1 Synthesis of pyridin-3-ylmethyl docosahexaeneoate using K2CO3 1 g (2.8 mmol) of ethyl docosahexaeneoate (purity higher than 95%; supplied by Interchim) is placed in 5 ml of THF degassed by nitrogen bubbling in the presence of 1.53 g (11 mmol) of ground K2CO3 and 1.06 ml (10.9 mmol) of nicotinyl alcohol (purity higher than 98%; provided by Acros). The reaction mixture is heated under reflux for 7 h and then 0.76 g (5.5 mmol) of K2CO3 is added and heating is continued for 7 h. After cooling, the reaction mixture is taken up in water and then extracted with ethyl acetate. The organic phases are dried on MgSO4, filtered and then concentrated to dryness. The residue obtained is purified by silica flash chromatography (CH2Cl2→90/10 CH2Cl2/ethyl acetate gradient for 15 min). A clear oil is isolated (0.84 g, yield 71%). Silica gel TLC 60 F 254 Merck, 90/10 CH2Cl2/AcOEt, Rf=0.35.

Reference： [1]Current Patent Assignee: PIERRE FABRE PARCIPATIONS - US2009/312354, 2009, A1 Location in patent: Page/Page column 4

40
[ 81926-94-5 ]
[ 86227-47-6 ]
[ 10417-94-4 ]
[ 6217-54-5 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: all-(Z)-ethyl 4,7,10,13,16,19-docosahexaenoate; eicosapentaenoic acid ethyl ester With water; sodium hydroxide In methanol at 20℃; for 1.5h; Stage #2: With hydrogenchloride In water Cooling with ice;	Mixture of cis-eicosapentaenoic acid and cis-docosahexaenoic acid: To a solution of a mixture of ethyl cis-eicosapentaenoate and ethyl cis-docosahexaenoate (5 g) in methanol (100 mL) was added an aqueous solution of NaOH (6 g, in 20 mL of water) at rt and stirred for 1.5 h. The reaction mixture was poured into ice cooled water and acidified with dil. HCl. The solution was extracted with DCM (3 x 50 mL) and the combined layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent to give the mixture of acids (4.3 g) as an oil; LCMS (ESI, negative ion mode): m/z 301, 327 (M-H)".

Reference： [1]Current Patent Assignee: LAILA GROUP PVT LTD - WO2010/4579, 2010, A2 Location in patent: Page/Page column 20

41
[ 81926-94-5 ]
[ 1278408-69-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: water 2: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 15 h / 20 °C / Inert atmosphere