[ CAS No. 127828-22-2 ] {[proInfo.proName]}

Name: 127828-22-2|tert-Butyl (2-(2-aminoethoxy)ethyl)carbamate|97%
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Quality Control of [ 127828-22-2 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 127828-22-2 ]

SDS Specification

Alternatived Products of [ 127828-22-2 ]

Product Details of [ 127828-22-2 ]

CAS No. :	127828-22-2	MDL No. :	MFCD12031501
Formula :	C₉H₂₀N₂O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	VULKFBHOEKTQSF-UHFFFAOYSA-N
M.W :	204.27	Pubchem ID :	12106198
Synonyms :		Chemical Name :	tert-Butyl (2-(2-aminoethoxy)ethyl)carbamate

Calculated chemistry of [ 127828-22-2 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.89
Num. rotatable bonds :	8
Num. H-bond acceptors :	4.0
Num. H-bond donors :	2.0
Molar Refractivity :	53.68
TPSA :	73.58 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.66 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.44
Log Po/w (XLOGP3) :	-0.16
Log Po/w (WLOGP) :	0.49
Log Po/w (MLOGP) :	0.12
Log Po/w (SILICOS-IT) :	0.17
Consensus Log Po/w :	0.61

Druglikeness

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

Water Solubility

Log S (ESOL) :	-0.48
Solubility :	68.0 mg/ml ; 0.333 mol/l
Class :	Very soluble
Log S (Ali) :	-0.93
Solubility :	24.0 mg/ml ; 0.117 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.84
Solubility :	2.97 mg/ml ; 0.0145 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	2.59

Safety of [ 127828-22-2 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 127828-22-2 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 127828-22-2 ]
Downstream synthetic route of [ 127828-22-2 ]

[ 127828-22-2 ] Synthesis Path-Upstream 1~8

1
[ 176220-30-7 ]
[ 127828-22-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With palladium 10% on activated carbon; hydrogen In methanol at 25℃; for 8 h;	Compound 16 (1.7 g, 7.7 mmol) was dissolved in MeOH (25 mL) and the solution was degassed several times with Ar before adding a catalytic amount of Pd/C 10percent. The atmosphere was filled with H₂ and the reaction was stirred 8 h at 25 °C. The mixture was filtered and the solvent was removed under reduced pressure. No further purification was needed (quantitative yield). ¹H NMR (300 MHz, CDCl₃) δ 5.08 (br s, 1H), 3.66-3.47 (m, 4H), 3.37-3.22 (m, 2H), 3.22-3.10 (m, 2H), 3.02-2.84 (m, 2H), 1.43 (s, 9H); ESI-MS m/z 205 [M+H]⁺, 227 [M+Na]⁺.
79%	Stage #1: With triphenylphosphine In tetrahydrofuran at 20℃; for 2 h; Stage #2: With water In tetrahydrofuran at 20℃;	A solution of 0.82 g (3.1 mmol) of triphenylphosphine in 10 ml of tetrahydrofurane was added to a solution of 0.6 g (2.6 mmol) of 2c in 20 ml of tetrahydrofurane. The resulting solution was stirred for 2 h at room temperature. Subsequently, 200 ml of water was added, and the mixture was stirred overnight at room temperature. Then the mixture was evaporated to 75 ml and filtered. The filtrate was washed with 25 ml of dichloromethane and evaporated to get the product. Yield: 0.5 g (79percent). ¹H NMR (CDCl₃): δ 3.50 (m, 4H, H₂+ H₃), 3.33 (m, 2H, H₄), 2.86 (t, 2H, H₁). ESI-MS: m/z 205.2 (M+H).
3 g	With palladium 10% on activated carbon; hydrogen In methanol at 20℃; Inert atmosphere	Step 4: Synthesis of tert-butyl (2-(2-aminoethoxy)ethyl)carbamate (58) A solution of tert-butyl (2-(2-azidoethoxy)ethyl)carbamate 57 (5.0 g, 0.0217 mol) in methanol (100 mL) was added 10percent Pd/C (2.5 g) under Ar. The mixture was stirred under H₂ (50 psi) at room temperature overnight. After filtration through a pad of celite, the organic layer was concentrated under reduced pressure to provide tert-butyl (2-(2-aminoethoxy)ethyl)carbamate 58 (3.0 g). The product was used in the next step without further purification. ¹H NMR (400 MHz, MeOD) δ 3.48-3.45 (m, 4H), 3.23-3.20 (t, 2H), 2.77-2.75 (m, 2H), 1.43 (s, 9H).

Reference： [1] European Journal of Medicinal Chemistry, 2016, vol. 117, p. 301 - 320
[2] Patent: EP1745802, 2007, A1, . Location in patent: Page/Page column 17
[3] Patent: US6664265, 2003, B2, . Location in patent: Page column 23
[4] Patent: US2003/130518, 2003, A1,
[5] Patent: US2003/139441, 2003, A1,
[6] Patent: US2003/187016, 2003, A1,
[7] Patent: US6677347, 2004, B2,
[8] Patent: US6660735, 2003, B2, . Location in patent: Page column 21
[9] Patent: US2004/10007, 2004, A1, . Location in patent: Page 75; 98
[10] Patent: US2011/269965, 2011, A1, . Location in patent: Page/Page column 34
[11] Patent: US2013/116263, 2013, A1, . Location in patent: Paragraph 0697
[12] Patent: WO2009/113828, 2009, A2, . Location in patent: Page/Page column 46-47

2
[ 24424-99-5 ]
[ 60792-79-2 ]
[ 127828-22-2 ]

Yield	Reaction Conditions	Operation in experiment
74%	Stage #1: With sodium hydroxide In methanol at 20℃; for 0.5 h; Stage #2: at 20℃; for 18.25 h;	In a typical run, sodium hydroxide (400 mg, 10 mmol) was dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 min. A solution containing Boc₂O (740 mg, 3.40 mmol) in THF (15 mL) was then added dropwise, at room temperature, over a period of 15 min. The resulting reaction mixture was stirred at room temperature for 18 h. It was then concentrated under reduced pressure. The resulting residue was taken up in CH₂Cl₂(200 mL) and stirred vigorously at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 2-(2-aminoethoxy)ethylcarbamate (850 mg, 74percent).tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (420, 2.06 mmol) was then taken up in CH₃CN (20 mL) along with nicotinic acid (253 mg, 2.06 mmol) and EDCI (434 mg, 2.3 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then diluted with EtOAc (20 mL), washed with saturated aqueous NaHCO₃, brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (9:1 CH₂Cl₂/MeOH) to afford tert-butyl 2-(2-(nicotinamido)ethoxy)ethylcarbamate (280 mg, 44percent). MS calculated for C₁₅H₂₃N₃O₄: 309.17; found: [M+H]⁺310.tert-Butyl 2-(2-(nicotinamido)ethoxy)ethylcarbamate (140 mg, 0.453 mmol) was taken up in 25percent TFA in CH₂Cl₂(10 mL). The reaction mixture was allowed to stand at room temperature for 2 h and then concentrated under reduced pressure to afford the TFA salt of N-(2-(2-aminoethoxy)ethyl)nicotinamide. This material was then taken up in CH₃CN (10 mL) along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (148 mg, 0.453 mmol), HATU (190 mg, 0.498 mmol) and DIEA (0.24 mL). The resulting reaction mixture was stirred at room temperature for 2 h. It was then diluted with EtOAc and washed successively with saturated aqueous NaHCO₃and brine. The organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (9:1 CH₂Cl₂/MeOH) afforded N-(2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethoxy)ethyl)nicotinamide (75 mg, 31percent). MS calculated for C₃₁H₄₆N₂O₅: 526.34; found: [M+H]⁺527.
74%	Stage #1: With sodium hydroxide In methanol at 20℃; for 0.5 h; Stage #2: at 20℃; for 18.25 h;	Example 6 Preparation of N-(2-(2-(5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenamidoethoxy)ethyl)-5-methyl-4-oxo-5-phenyl-4,5-dihydrofuran-2-carboxamide (I-3) In a typical run, sodium hydroxide (400 mg, 10 mmol) was dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 min A solution containing Boc₂O (740 mg, 3.40 mmol) in THF (15 mL) was then added dropwise, at room temperature, over a period of 15 min. The resulting reaction mixture was stirred at room temperature for 18 h. It was then concentrated under reduced pressure. The resulting residue was taken up in CH₂Cl₂ (200 mL) and stirred vigorously at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 2-(2-aminoethoxy)ethylcarbamate (850 mg, 74percent).
74%	Stage #1: With sodium hydroxide In methanol at 20℃; for 0.5 h; Stage #2: at 20℃; for 18.25 h;	Example 6 Preparation of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanamido)ethoxy)ethyl)docosa-4,7,10,13,16,19-hexaenamide In a typical run, sodium hydroxide (400 mg, 10 mmol) was dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added. The resulting reaction mixture is stirred at room temperature for 30 min. A solution containing Boc₂O (740 mg, 3.40 mmol) in THF (15 mL) was then added dropwise, at room temperature, over a period of 15 min. The resulting reaction mixture was stirred at room temperature for 18 h. It was then concentrated under reduced pressure. The resulting residue was taken up in CH₂Cl₂ (200 mL) and stirred vigorously at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 2-(2-aminoethoxy)ethylcarbamate (850 mg, 74percent).

74%	Stage #1: With sodium hydroxide In methanol at 20℃; for 0.5 h; Stage #2: at 20℃; for 18.25 h;	Example 3 Preparation of 2-hydroxy-N-(2-(2-(2-((2Z,5Z,8Z,11Z,14Z,17Z)-eicosa-2,5,8,11,14,17-hexaenylthio)acetamido)ethoxy)ethyl)benzamide (1-1) In a typical run, sodium hydroxide (400 mg, 10 mmol) is dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) is added. The resulting reaction mixture is stirred at room temperature for 30 min. A solution containing Boc₂O (740 mg, 3.40 mmol) in THF (15 mL) is then added dropwise, at room temperature, over a period of 15 min. The resulting reaction mixture is stirred at room temperature for 18 h and then concentrated under reduced pressure. The resulting residue is taken up in CH₂Cl₂ (200 mL) and stirred vigorously at room temperature for 4 h. The mixture is filtered and the filtrate is concentrated under reduced pressure to afford tert-butyl 2-(2-aminoethoxy)ethylcarbamate (850 mg, 74percent).
74%	Stage #1: With sodium hydroxide In methanol at 20℃; for 0.5 h; Stage #2: at 20℃; for 18.25 h;	Example 7 Preparation of 5-((2-(2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)ethoxy)ethyl)carbamoyl)-2-methylpyrazine 1-oxide (I-4) In a typical run, sodium hydroxide (400 mg, 10 mmol) was dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 min A solution containing Boc₂O (740 mg, 3.40 mmol) in THF (15 mL) was then added dropwise, at room temperature, over a period of 15 min. The resulting reaction mixture was stirred at room temperature for 18 h. It was then concentrated under reduced pressure. The resulting residue was taken up in CH₂Cl₂ (200 mL) and stirred vigorously at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 2-(2-aminoethoxy)ethylcarbamate (850 mg, 74percent).
74%	Stage #1: With sodium hydroxide In methanol at 20℃; for 0.5 h; Stage #2: at 20℃; for 18.25 h;	Example 13 Preparation of (E)-methyl 4-(2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethoxy)ethylamino)-4-oxobut-2-enoate (Compound I-3) Sodium hydroxide (400 mg, 10 mmol) was dissolved in 70 mL of MeOH and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 min A solution containing Boc₂O (740 mg, 3.40 mmol) in 15 mL of THF was then added dropwise, at room temperature, over a period of 15 min. The resulting reaction mixture was stirred at room temperature for 18 h, then concentrated under reduced pressure. The resulting residue was taken up in 200 mL of CH₂Cl₂ and stirred vigorously at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford 850 mg of tert-butyl 2-(2-aminoethoxy)ethylcarbamate (74percent yield).
74%	Stage #1: With sodium hydroxide In methanol at 20℃; for 0.5 h; Stage #2: at 20℃; for 18.25 h;	Example 6 Preparation of (S)-N-(2-(2-(5-(1,2-dithiolan-3-yl)pentanamido)ethoxy)ethyl)-2-hydroxybenzamide (I-3) In a typical run, sodium hydroxide (400 mg, 10 mmol) was dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)-ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 minutes. A solution containing Boc₂O (740 mg, 3.40 mmol) in THF (15 mL) was then added dropwise, at room temperature, over a period of 15 minutes. The resulting reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The resulting residue was taken up in CH₂Cl₂ (200 mL) and stirred vigorously at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 2-(2-aminoethoxy)ethylcarbamate (850 mg, 74percent).
74%	With sodium hydroxide In methanol at 20℃; for 18 h;	Example 6; Preparation of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-((E)-6-(4-hydroxy-6-methoxy-7- methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4- enamido)ethoxy)ethyl)docosa-4,7,10,13,16,19-hexaenamide (I-2); In a typical run, sodium hydroxide (400 mg, 10 mmol) was dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 min A solution containing Boc₂O (740 mg, 3.40 mmol) in THF (15 mL) was then added dropwise, at room temperature, over a period of 15 min The resulting reaction mixture was stirred at room temperature for 18 h, and then concentrated under reduced pressure. The resulting residue was taken up in CH₂Cl₂(200 mL) and stirred vigorously at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 2-(2-aminoethoxy)ethylcarbamate (850 mg, 74percent).tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (1.47 mmol) was then taken up in CH₃CN (10 mL) along with mycophenolic acid (470 mg, 1.47 mmol) and EDCI (310 mg, 1.62 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It is then diluted with EtOAc (50 mL), washed with saturated aqueous NaHCO₃, brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (9:1 CH₂Cl₂/MeOH) to afford 620 mg of (E)-tert-butyl 2-(2-(6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4- enamido)ethoxy)ethylcarbamate (83percent yield).(E)-tert-Butyl 2-(2-(6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3- dihydroisobenzofuran-5-yl)-4-methylhex-4-enamido)ethoxy)ethylcarbamate (620 mg, 1.22 mmol) was taken up in 10 mL of 4 M HC1 in dioxane and allowed to stir at room temperature for 2 h. The resulting reaction mixture was concentrated under reduced pressure to afford the HCl salt of (E)-N-(2-(2-aminoethoxy)ethyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3- dihydroisobenzofuran-5-yl)-4-methylhex-4-enamide This material was taken up in CH₃CN (10 mL) along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (400 mg, 1.22 mmol), HATU (510 mg, 1.34 mmol) and DIEA (640 μL, 3.66 mmol). The resulting reaction mixture was stirred at room temperature for 2 h. It was then diluted with EtOAc and washed successively with saturated aqueous NaHCO₃and brine. The organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (5percent MeOH in CH₂Cl₂) afforded 600 mg of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2- (2-((E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4- methylhex-4-enamido)ethoxy)ethyl)docosa-4,7,10,13,16,19-hexaenamide (68percent yield). MS (EI) calcd for C₄₃H₆₀N₂O₇: 716.44; found 717 (M+1).
74%	Stage #1: With sodium hydroxide In methanol at 20℃; for 0.5 h; Stage #2: at 20℃; for 18.25 h;	The same procedure outlined in example 8 was used, substituting tert-butyl (2-(2-aminoethoxy)ethyl)carbamate for tert-butyl 2-aminoethylcarbamate. tert-Butyl (2-(2-aminoethoxy)ethyl)carbamate, in turn, could be prepared as follows: Sodium hydroxide (400 mg, 10 mmol) was dissolved in 70 mL of MeOH and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 min. A solution containing Boc₂O (740 mg, 3.40 mmol) in 15 mL of THF was then added dropwise, at room temperature, over a period of 15 min. The resulting reaction mixture was stirred at room temperature for 18 h, then concentrated under reduced pressure. The resulting residue was taken up in 200 mL of CH₂Cl₂and stirred vigorously at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford 850 mg of tert-butyl 2-(2-aminoethoxy)ethylcarbamate (74percent yield). Compound I-32: MS (EI) calcd for C₃₀H₄₉N₅O₃527.38; found 528 [M+H]⁺.
74%	Stage #1: With sodium hydroxide In methanol at 20℃; for 0.5 h; Stage #2: at 20℃; for 18.25 h;	Preparation of 1-((3R,5R)-7-(2-(2-(4Z,7Z,1OZ,13Z,16Z,19Z)-docosa-4,7,1O,13,16,19- hexaenamidoethoxy)ethylamino)-3 ,5-dihydroxy-7-oxoheptyl)-5-(4-fluorophenyl)-2- isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide (1-32):1) EDCIH2N°NH2 H2N°NHBoc2) HCIOH OH 0H / N NH2\/[0239j In a typical run, sodium hydroxide (400 mg, 10 mmol) is dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) is added. The resulting reaction mixture is stirred at room temperature for 30 mm. A solution containing Boc2O (740 mg, 3.40 mmol) in THF (15 mL) is then added dropwise, at room temperature, over a period of 15 mm. The resulting reaction mixture is stirred at room temperature for 18 h and then concentrated under reduced pressure. The resulting residue is taken up in CH2C12 (200 mL) and stirred vigorously at room temperature for 4 h. The mixture is filtered and the filtrate is concentrated under reduced pressure to afford 850 mg of tert-butyl 2-(2- aminoethoxy)ethylcarbamate (74percent yield).
74%	Stage #1: With sodium hydroxide In methanol at 20℃; for 0.5 h; Stage #2: at 20℃; for 18 h;	[0241j In a typical run, sodium hydroxide (400 mg, 10 mmol) was dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 mm. A solution containing Boc2O (740 mg, 3.40 mmol) in THF (15 mL) was then added dropwise, at room temperature, over a period of 15 mm. The resulting reaction mixture was stirred at room temperature for 18 h. It was then concentrated under reduced pressure. The resulting residue was taken up in CH2C12 (200 mL) and stirred vigorously at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford tertbutyl 2-(2-aminoethoxy)ethylcarbamate (850 mg, 74percent).
74%	Stage #1: With sodium hydroxide In methanol at 20℃; for 0.5 h; Stage #2: at 20℃; for 18.25 h;	[0329] In a typical run, sodium hydroxide (400 mg, 10 mmol) was dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 min. A solution containing Boc₂0 (740 mg, 3.40 mmol) in THF (15 mL) was then added dropwise, at room temperature, over a period of 15 min. The resulting reaction mixture was stirred at room temperature for 18 h. It was then concentrated under reduced pressure. The resulting residue was taken up in CH₂C1₂ (200 mL) and stirred vigorously at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 2-(2- aminoethoxy)ethylcarbamate (850 mg, 74percent).
74%	Stage #1: With sodium hydroxide In methanol at 20℃; for 0.5 h; Stage #2: at 20℃; for 18 h;	Example 6 Preparation of (4Z,7Z,10Z,13Z,16Z,19Z)—N-(2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethoxy)ethyl)docosa-4,7,10,13,16,19-hexaenamide (I-13) (0371) (0372) In a typical run, sodium hydroxide (400 mg, 10 mmol) is dissolved in MeOH (70 L) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) is added. The resulting reaction mixture is stirred at room temperature for 30 min. A solution containing Boc₂O (740 mg, 3.40 mmol) in THF (15 mL) is then added dropwise, at room temperature, over a period of 15 min. The resulting reaction mixture is stirred at room temperature for 18 h and then concentrated under reduced pressure. The resulting residue is taken up in CH₂Cl₂(200 mL) and stirred vigorously at room temperature for 4 h. The mixture is filtered and the filtrate is concentrated under reduced pressure to afford 850 mg of tert-butyl 2-(2-aminoethoxy)ethylcarbamate (74percent yield). (0373) tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (150 mg, 0.735 mmol) was then taken up in CH₃CN (10 mL) along with indomethacin (263 mg, 0.735 mmol) and EDCI (155 mg, 0.81 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then diluted with EtOAc (20 mL), washed with saturated aqueous NaHCO₃, brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (9:1 CH₂Cl₂/MeOH) to afford 310 mg of tert-butyl 2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethoxy)ethylcarbamate (78percent). (0374) tert-Butyl 2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethoxy)ethylcarbamate was taken up in 10 mL of 4 M HCl in dioxane and allowed to stand at room temperature for 2 h. The resulting reaction mixture was concentrated under reduced pressure to afford the HCl salt of N-(2-(2-aminoethoxy)ethyl)-2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamide. This material was taken up in CH₃CN (10 mL) along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (187 mg, 0.57 mmol), HATU (238 mg, 0.63 mmol) and DIEA (300 μL, 1.71 mmol). The resulting reaction mixture was stirred at room temperature for 2 h, diluted with EtOAc and washed successively with saturated aqueous NaHCO₃and brine. The organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (5percent MeOH—CH₂Cl₂) afforded (4Z,7Z,10Z,13Z,16Z,19Z)—N-(2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethoxy)ethyl)docosa-4,7,10,13,16,19-hexaenamide. MS (EI) calcd for C₄₅H₅₆ClN₃O₅: 753.39; found 754 (M+1).

Reference： [1] Journal of Organic Chemistry, 2007, vol. 72, # 7, p. 2289 - 2296
[2] Patent: US2011/53990, 2011, A1, . Location in patent: Page/Page column 19
[3] Patent: US2011/82202, 2011, A1, . Location in patent: Page/Page column 21-22
[4] Patent: US2011/82210, 2011, A1, . Location in patent: Page/Page column 34-35
[5] Patent: US2011/82120, 2011, A1, . Location in patent: Page/Page column 18
[6] Patent: US2011/82156, 2011, A1, . Location in patent: Page/Page column 19
[7] Patent: US2011/172240, 2011, A1, . Location in patent: Page/Page column 36
[8] Patent: US2011/82192, 2011, A1, . Location in patent: Page/Page column 29
[9] Patent: US2011/213028, 2011, A1, . Location in patent: Page/Page column 29
[10] Patent: US2012/277305, 2012, A1, . Location in patent: Page/Page column 36-37
[11] Patent: WO2013/166176, 2013, A1, . Location in patent: Paragraph 0239
[12] Patent: WO2013/177536, 2013, A2, . Location in patent: Paragraph 0241
[13] Patent: WO2014/107730, 2014, A2, . Location in patent: Paragraph 0329
[14] Patent: US9216224, 2015, B2, . Location in patent: Page/Page column 53-54
[15] Patent: US2012/252810, 2012, A1, . Location in patent: Page/Page column 31-32
[16] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 21, p. 5260 - 5262
[17] Patent: WO2018/5794, 2018, A2, . Location in patent: Page/Page column 213

3
[ 2752-17-2 ]
[ 24424-99-5 ]
[ 127828-22-2 ]

Yield	Reaction Conditions	Operation in experiment
71.5%	at 0 - 20℃;	This compound was synthesized according to the procedure described previously with slight modifications.²⁵ To a cooled (0 °C) solution of 2,2'-oxybis(ethylamine) (10.0 mL, 94.1 mmol) in methanol (1000 mL) was added dropwise a solution of di-tert-butyl dicarbonate ((Boc)₂O; 10.3 g, 47.0 mmol) in THF (300 mL), and the mixture was stirred for 1 h at the same temperature and additional 24 h at room temperature. After removing the solvent in vacuo, the residue was dissolved in 1 N NaOH (200 mL), and extracted with chloroform (300 mL .x. 3). The organic phases were combined, dried over anhydrous MgSO₄. The solvent was removed in vacuo to provide 1 as a colorless oil (6.88 g, 71.5percent). ¹H NMR (CDCl₃): δ 1.39 (9H, s, Boc), 2.79-2.82 (2H, t, CH₂), 3.24-3.28 (2H, dd, CH₂), 3.41-3.43 (2H, t, CH₂), 3.44-3.47 (2H, t, CH₂), 5.00 (1H, d, NH). ESI-MS (M+H)⁺: m/z 205, found: 205

Reference： [1] Tetrahedron Letters, 2006, vol. 47, # 17, p. 2915 - 2919
[2] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 2, p. 978 - 984
[3] Journal of the American Chemical Society, 2010, vol. 132, # 21, p. 7291 - 7293
[4] Chemical Communications, 2017, vol. 53, # 62, p. 8751 - 8754
[5] Chemistry - An Asian Journal, 2012, vol. 7, # 2, p. 272 - 276

4
[ 1046804-80-1 ]
[ 127828-22-2 ]

Reference： [1] Patent: EP2123283, 2009, A1, . Location in patent: Page/Page column 15
[2] Patent: US2009/325894, 2009, A1, . Location in patent: Page/Page column 10
[3] Chemistry - A European Journal, 2010, vol. 16, # 3, p. 878 - 889

5
[ 24424-99-5 ]
[ 60792-79-2 ]
[ 127828-22-2 ]

Reference： [1] European Journal of Organic Chemistry, 2002, # 17, p. 3004 - 3014

6
[ 24424-99-5 ]
[ 127828-22-2 ]

Reference： [1] Patent: US2011/269965, 2011, A1,
[2] Patent: US2013/116263, 2013, A1,
[3] European Journal of Medicinal Chemistry, 2016, vol. 117, p. 301 - 320

7
[ 302331-20-0 ]
[ 127828-22-2 ]

Reference： [1] Patent: US2011/269965, 2011, A1,
[2] Patent: US2013/116263, 2013, A1,
[3] Patent: WO2009/113828, 2009, A2,

8
[ 139115-91-6 ]
[ 127828-22-2 ]

Reference： [1] Patent: US2011/269965, 2011, A1,
[2] Patent: US2013/116263, 2013, A1,

[ 127828-22-2 ] Synthesis Path-Downstream 1~88

1
[ 127828-22-2 ]
[ 197777-76-7 ]
(2-{2-[4-(2-Hydroxy-4-phenyl-cyclohexyl)-benzoylamino]-ethoxy}-ethyl)-carbamic acid tert-butyl ester [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1994,vol. 116,p. 2211 - 2212

2
[ 127828-22-2 ]
4-((1S,2R,4R)-2-Hydroxy-4-phenyl-cyclohexyl)-benzoic acid [ No CAS ]
(2-{2-[4-((1S,2R,4R)-2-Hydroxy-4-phenyl-cyclohexyl)-benzoylamino]-ethoxy}-ethyl)-carbamic acid tert-butyl ester [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1998,vol. 120,p. 1945 - 1958

3
[ 463-71-8 ]
[ 127828-22-2 ]
[ 497962-47-7 ]

Reference： [1]European Journal of Organic Chemistry,2002,p. 3004 - 3014
[2]Journal of Organic Chemistry,2007,vol. 72,p. 2289 - 2296

4
[ 463-71-8 ]
[ 127828-22-2 ]
[ 497962-48-8 ]

Reference： [1]European Journal of Organic Chemistry,2002,p. 3004 - 3014

5
[ 24424-99-5 ]
[ 60792-79-2 ]
[ 127828-22-2 ]
di-tert-butyl 3-oxapentane-1,5-diyldicarbamate [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2002,p. 3004 - 3014

6
[ 6382-93-0 ]
[ 127828-22-2 ]
[ 632323-84-3 ]

Reference： [1]Tetrahedron Letters,2003,vol. 44,p. 2953 - 2956
[2]Organic and biomolecular chemistry,2003,vol. 1,p. 3186 - 3192

7
[ 2752-17-2 ]
[ 24424-99-5 ]
[ 127828-22-2 ]

Yield	Reaction Conditions	Operation in experiment
71.5%	In tetrahydrofuran; at 0 - 20℃;	This compound was synthesized according to the procedure described previously with slight modifications.25 To a cooled (0 C) solution of 2,2'-oxybis(ethylamine) (10.0 mL, 94.1 mmol) in methanol (1000 mL) was added dropwise a solution of di-tert-butyl dicarbonate ((Boc)2O; 10.3 g, 47.0 mmol) in THF (300 mL), and the mixture was stirred for 1 h at the same temperature and additional 24 h at room temperature. After removing the solvent in vacuo, the residue was dissolved in 1 N NaOH (200 mL), and extracted with chloroform (300 mL × 3). The organic phases were combined, dried over anhydrous MgSO4. The solvent was removed in vacuo to provide 1 as a colorless oil (6.88 g, 71.5%). 1H NMR (CDCl3): delta 1.39 (9H, s, Boc), 2.79-2.82 (2H, t, CH2), 3.24-3.28 (2H, dd, CH2), 3.41-3.43 (2H, t, CH2), 3.44-3.47 (2H, t, CH2), 5.00 (1H, d, NH). ESI-MS (M+H)+: m/z 205, found: 205

Reference： [1]Tetrahedron Letters,2006,vol. 47,p. 2915 - 2919
[2]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 978 - 984
[3]Chemical Communications,2019,vol. 55,p. 10128 - 10131
[4]Journal of the American Chemical Society,2010,vol. 132,p. 7291 - 7293
[5]Chemical Communications,2017,vol. 53,p. 8751 - 8754
[6]Chemistry - An Asian Journal,2012,vol. 7,p. 272 - 276
[7]European Journal of Medicinal Chemistry,2019,vol. 175,p. 20 - 33

8
[ 653-37-2 ]
[ 127828-22-2 ]
[2-(2-[1-Pentafluorophenyl-meth-(E)-ylidene]-amino}-ethoxy)-ethyl]-carbamic acid tert-butyl ester [ No CAS ]

Reference： [1]Tetrahedron Letters,2006,vol. 47,p. 2915 - 2919

9
[ 874301-24-3 ]
[ 127828-22-2 ]
[2-(2-[2'-(4-hydroxy-phenyl)-6-(4-methyl-piperazin-1-yl)-1H,3'H-[2,5']bibenzoimidazolyl-4-carbonyl]-amino}-ethoxy)-ethyl]-carbamic acid tert-butyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 68 - 72

10
[ 127828-22-2 ]
[ 497962-47-7 ]
[ 497962-48-8 ]

Reference： [1]Journal of Organic Chemistry,2007,vol. 72,p. 2289 - 2296

11
[ 24424-99-5 ]
[ 60792-79-2 ]
[ 127828-22-2 ]

Yield	Reaction Conditions	Operation in experiment
74%		In a typical run, sodium hydroxide (400 mg, 10 mmol) was dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 min. A solution containing Boc2O (740 mg, 3.40 mmol) in THF (15 mL) was then added dropwise, at room temperature, over a period of 15 min. The resulting reaction mixture was stirred at room temperature for 18 h. It was then concentrated under reduced pressure. The resulting residue was taken up in CH2Cl2 (200 mL) and stirred vigorously at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 2-(2-aminoethoxy)ethylcarbamate (850 mg, 74%).tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (420, 2.06 mmol) was then taken up in CH3CN (20 mL) along with nicotinic acid (253 mg, 2.06 mmol) and EDCI (434 mg, 2.3 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then diluted with EtOAc (20 mL), washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (9:1 CH2Cl2/MeOH) to afford tert-butyl 2-(2-(nicotinamido)ethoxy)ethylcarbamate (280 mg, 44%). MS calculated for C15H23N3O4: 309.17; found: [M+H]+310.tert-Butyl 2-(2-(nicotinamido)ethoxy)ethylcarbamate (140 mg, 0.453 mmol) was taken up in 25% TFA in CH2Cl2 (10 mL). The reaction mixture was allowed to stand at room temperature for 2 h and then concentrated under reduced pressure to afford the TFA salt of N-(2-(2-aminoethoxy)ethyl)nicotinamide. This material was then taken up in CH3CN (10 mL) along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (148 mg, 0.453 mmol), HATU (190 mg, 0.498 mmol) and DIEA (0.24 mL). The resulting reaction mixture was stirred at room temperature for 2 h. It was then diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (9:1 CH2Cl2/MeOH) afforded N-(2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethoxy)ethyl)nicotinamide (75 mg, 31%). MS calculated for C31H46N2O5: 526.34; found: [M+H]+527.
74%		Example 6 Preparation of N-(2-(2-(5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenamidoethoxy)ethyl)-5-methyl-4-oxo-5-phenyl-4,5-dihydrofuran-2-carboxamide (I-3) In a typical run, sodium hydroxide (400 mg, 10 mmol) was dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 min A solution containing Boc2O (740 mg, 3.40 mmol) in THF (15 mL) was then added dropwise, at room temperature, over a period of 15 min. The resulting reaction mixture was stirred at room temperature for 18 h. It was then concentrated under reduced pressure. The resulting residue was taken up in CH2Cl2 (200 mL) and stirred vigorously at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 2-(2-aminoethoxy)ethylcarbamate (850 mg, 74%).
74%		Example 6 Preparation of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanamido)ethoxy)ethyl)docosa-4,7,10,13,16,19-hexaenamide In a typical run, sodium hydroxide (400 mg, 10 mmol) was dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added. The resulting reaction mixture is stirred at room temperature for 30 min. A solution containing Boc2O (740 mg, 3.40 mmol) in THF (15 mL) was then added dropwise, at room temperature, over a period of 15 min. The resulting reaction mixture was stirred at room temperature for 18 h. It was then concentrated under reduced pressure. The resulting residue was taken up in CH2Cl2 (200 mL) and stirred vigorously at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 2-(2-aminoethoxy)ethylcarbamate (850 mg, 74%).

74%		Example 3 Preparation of 2-hydroxy-N-(2-(2-(2-((2Z,5Z,8Z,11Z,14Z,17Z)-eicosa-2,5,8,11,14,17-hexaenylthio)acetamido)ethoxy)ethyl)benzamide (1-1) In a typical run, sodium hydroxide (400 mg, 10 mmol) is dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) is added. The resulting reaction mixture is stirred at room temperature for 30 min. A solution containing Boc2O (740 mg, 3.40 mmol) in THF (15 mL) is then added dropwise, at room temperature, over a period of 15 min. The resulting reaction mixture is stirred at room temperature for 18 h and then concentrated under reduced pressure. The resulting residue is taken up in CH2Cl2 (200 mL) and stirred vigorously at room temperature for 4 h. The mixture is filtered and the filtrate is concentrated under reduced pressure to afford tert-butyl 2-(2-aminoethoxy)ethylcarbamate (850 mg, 74%).
74%		Example 7 Preparation of 5-((2-(2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)ethoxy)ethyl)carbamoyl)-2-methylpyrazine 1-oxide (I-4) In a typical run, sodium hydroxide (400 mg, 10 mmol) was dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 min A solution containing Boc2O (740 mg, 3.40 mmol) in THF (15 mL) was then added dropwise, at room temperature, over a period of 15 min. The resulting reaction mixture was stirred at room temperature for 18 h. It was then concentrated under reduced pressure. The resulting residue was taken up in CH2Cl2 (200 mL) and stirred vigorously at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 2-(2-aminoethoxy)ethylcarbamate (850 mg, 74%).
74%		Example 13 Preparation of (E)-methyl 4-(2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethoxy)ethylamino)-4-oxobut-2-enoate (Compound I-3) Sodium hydroxide (400 mg, 10 mmol) was dissolved in 70 mL of MeOH and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 min A solution containing Boc2O (740 mg, 3.40 mmol) in 15 mL of THF was then added dropwise, at room temperature, over a period of 15 min. The resulting reaction mixture was stirred at room temperature for 18 h, then concentrated under reduced pressure. The resulting residue was taken up in 200 mL of CH2Cl2 and stirred vigorously at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford 850 mg of tert-butyl 2-(2-aminoethoxy)ethylcarbamate (74% yield).
74%		Example 6 Preparation of (S)-N-(2-(2-(5-(1,2-dithiolan-3-yl)pentanamido)ethoxy)ethyl)-2-hydroxybenzamide (I-3) In a typical run, sodium hydroxide (400 mg, 10 mmol) was dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)-ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 minutes. A solution containing Boc2O (740 mg, 3.40 mmol) in THF (15 mL) was then added dropwise, at room temperature, over a period of 15 minutes. The resulting reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The resulting residue was taken up in CH2Cl2 (200 mL) and stirred vigorously at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 2-(2-aminoethoxy)ethylcarbamate (850 mg, 74%).
74%	With sodium hydroxide; In methanol; at 20℃; for 18h;	Example 6; Preparation of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-((E)-6-(4-hydroxy-6-methoxy-7- methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4- enamido)ethoxy)ethyl)docosa-4,7,10,13,16,19-hexaenamide (I-2); In a typical run, sodium hydroxide (400 mg, 10 mmol) was dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 min A solution containing Boc2O (740 mg, 3.40 mmol) in THF (15 mL) was then added dropwise, at room temperature, over a period of 15 min The resulting reaction mixture was stirred at room temperature for 18 h, and then concentrated under reduced pressure. The resulting residue was taken up in CH2Cl2 (200 mL) and stirred vigorously at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 2-(2-aminoethoxy)ethylcarbamate (850 mg, 74%).tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (1.47 mmol) was then taken up in CH3CN (10 mL) along with mycophenolic acid (470 mg, 1.47 mmol) and EDCI (310 mg, 1.62 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It is then diluted with EtOAc (50 mL), washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (9:1 CH2Cl2/MeOH) to afford 620 mg of (E)-tert-butyl 2-(2-(6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4- enamido)ethoxy)ethylcarbamate (83% yield).(E)-tert-Butyl 2-(2-(6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3- dihydroisobenzofuran-5-yl)-4-methylhex-4-enamido)ethoxy)ethylcarbamate (620 mg, 1.22 mmol) was taken up in 10 mL of 4 M HC1 in dioxane and allowed to stir at room temperature for 2 h. The resulting reaction mixture was concentrated under reduced pressure to afford the HCl salt of (E)-N-(2-(2-aminoethoxy)ethyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3- dihydroisobenzofuran-5-yl)-4-methylhex-4-enamide This material was taken up in CH3CN (10 mL) along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (400 mg, 1.22 mmol), HATU (510 mg, 1.34 mmol) and DIEA (640 muL, 3.66 mmol). The resulting reaction mixture was stirred at room temperature for 2 h. It was then diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (5% MeOH in CH2Cl2) afforded 600 mg of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2- (2-((E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4- methylhex-4-enamido)ethoxy)ethyl)docosa-4,7,10,13,16,19-hexaenamide (68% yield). MS (EI) calcd for C43H60N2O7: 716.44; found 717 (M+1).
74%		The same procedure outlined in example 8 was used, substituting tert-butyl (2-(2-aminoethoxy)ethyl)carbamate for tert-butyl 2-aminoethylcarbamate. tert-Butyl (2-(2-aminoethoxy)ethyl)carbamate, in turn, could be prepared as follows: Sodium hydroxide (400 mg, 10 mmol) was dissolved in 70 mL of MeOH and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 min. A solution containing Boc2O (740 mg, 3.40 mmol) in 15 mL of THF was then added dropwise, at room temperature, over a period of 15 min. The resulting reaction mixture was stirred at room temperature for 18 h, then concentrated under reduced pressure. The resulting residue was taken up in 200 mL of CH2Cl2 and stirred vigorously at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford 850 mg of tert-butyl 2-(2-aminoethoxy)ethylcarbamate (74% yield). Compound I-32: MS (EI) calcd for C30H49N5O3 527.38; found 528 [M+H]+.
74%		Preparation of 1-((3R,5R)-7-(2-(2-(4Z,7Z,1OZ,13Z,16Z,19Z)-docosa-4,7,1O,13,16,19- hexaenamidoethoxy)ethylamino)-3 ,5-dihydroxy-7-oxoheptyl)-5-(4-fluorophenyl)-2- isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide (1-32):1) EDCIH2NNH2 H2NNHBoc2) HCIOH OH 0H / N NH2/[0239j In a typical run, sodium hydroxide (400 mg, 10 mmol) is dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) is added. The resulting reaction mixture is stirred at room temperature for 30 mm. A solution containing Boc2O (740 mg, 3.40 mmol) in THF (15 mL) is then added dropwise, at room temperature, over a period of 15 mm. The resulting reaction mixture is stirred at room temperature for 18 h and then concentrated under reduced pressure. The resulting residue is taken up in CH2C12 (200 mL) and stirred vigorously at room temperature for 4 h. The mixture is filtered and the filtrate is concentrated under reduced pressure to afford 850 mg of tert-butyl 2-(2- aminoethoxy)ethylcarbamate (74% yield).
74%		[0241j In a typical run, sodium hydroxide (400 mg, 10 mmol) was dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 mm. A solution containing Boc2O (740 mg, 3.40 mmol) in THF (15 mL) was then added dropwise, at room temperature, over a period of 15 mm. The resulting reaction mixture was stirred at room temperature for 18 h. It was then concentrated under reduced pressure. The resulting residue was taken up in CH2C12 (200 mL) and stirred vigorously at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford tertbutyl 2-(2-aminoethoxy)ethylcarbamate (850 mg, 74%).
74%		[0329] In a typical run, sodium hydroxide (400 mg, 10 mmol) was dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 min. A solution containing Boc20 (740 mg, 3.40 mmol) in THF (15 mL) was then added dropwise, at room temperature, over a period of 15 min. The resulting reaction mixture was stirred at room temperature for 18 h. It was then concentrated under reduced pressure. The resulting residue was taken up in CH2C12 (200 mL) and stirred vigorously at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 2-(2- aminoethoxy)ethylcarbamate (850 mg, 74%).
74%		Example 6 Preparation of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethoxy)ethyl)docosa-4,7,10,13,16,19-hexaenamide (I-13) (0371) (0372) In a typical run, sodium hydroxide (400 mg, 10 mmol) is dissolved in MeOH (70 L) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) is added. The resulting reaction mixture is stirred at room temperature for 30 min. A solution containing Boc2O (740 mg, 3.40 mmol) in THF (15 mL) is then added dropwise, at room temperature, over a period of 15 min. The resulting reaction mixture is stirred at room temperature for 18 h and then concentrated under reduced pressure. The resulting residue is taken up in CH2Cl2 (200 mL) and stirred vigorously at room temperature for 4 h. The mixture is filtered and the filtrate is concentrated under reduced pressure to afford 850 mg of tert-butyl 2-(2-aminoethoxy)ethylcarbamate (74% yield). (0373) tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (150 mg, 0.735 mmol) was then taken up in CH3CN (10 mL) along with indomethacin (263 mg, 0.735 mmol) and EDCI (155 mg, 0.81 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then diluted with EtOAc (20 mL), washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (9:1 CH2Cl2/MeOH) to afford 310 mg of tert-butyl 2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethoxy)ethylcarbamate (78%). (0374) tert-Butyl 2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethoxy)ethylcarbamate was taken up in 10 mL of 4 M HCl in dioxane and allowed to stand at room temperature for 2 h. The resulting reaction mixture was concentrated under reduced pressure to afford the HCl salt of N-(2-(2-aminoethoxy)ethyl)-2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamide. This material was taken up in CH3CN (10 mL) along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (187 mg, 0.57 mmol), HATU (238 mg, 0.63 mmol) and DIEA (300 muL, 1.71 mmol). The resulting reaction mixture was stirred at room temperature for 2 h, diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (5% MeOH-CH2Cl2) afforded (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethoxy)ethyl)docosa-4,7,10,13,16,19-hexaenamide. MS (EI) calcd for C45H56ClN3O5: 753.39; found 754 (M+1).
		In a typical run, sodium hydroxide (400 mg, 10 mmol) is dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) is added. The resulting reaction mixture is stirred at room temperature for 30 min. A solution containing Boc2O (740 mg, 3.40 mmol) in THF (15 mL) is then added dropwise, at room temperature, over a period of 15 min. The resulting reaction mixture is stirred at room temperature for 18 h. It is then concentrated under reduced pressure. The resulting residue is taken up in CH2Cl2 (200 mL) and stirred vigorously at room temperature for 4 h. The mixture is filtered and the filtrate is concentrated under reduced pressure to afford tert-butyl 2-(2-aminoethoxy)ethylcarbamate.
		A mixture of NaOH (763 mg, 19.1 mmol) in MeOH(127 mL) was heated to reflux until the NaOH dissolved. The solution was cooledto rt and2,2'-oxydiethanamine bis HCl salt (1.907 g, 10.77 mmol) was added. After 30min, the mixture was a clear solution and a solution of Boc2O (1.42g, 6.51 mmol) in anhydrous THF (65 mL) was added dropwise under argon. After 18h, the reaction mixture was concentrated invacuo and the resulting solid was triturated with CH2Cl2(5 x 50 mL). The combined organic layers were dried (MgSO4),filtered, and concentrated to give crude S5mixed with both the starting bis-amine and the bis-Boc protected material. Thismixture was deemed (via NMR) to be ~64% product by mass and was used as is in asubsequent step.
		To a solution of NaOH (400 mg, 10 mmol) in anhydrous MeOH (70 mL) was added 2,2'-oxydiethanamine dihydrochloride (1.0 g, 5.7 mmol). The reaction mixture was stirred for 30 minutes at room temperature, and di-fer/-butyl dicarbonate (740 mg, 3.40 mmol) in anhydrous THF (15 mL) was added drop wise at room temperature over 15 minutes. The reaction was stirred overnight. The mixture was concentrated in vacuo. The residue was taken up in CH2CI2 (200 mL) and was stirred vigorously at room temperature for four hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was used directly in the next reaction. The crude mixture can also be purified by silica gel chromatography to afford Compound 52A. LCMS (Method A): m/z 205.3 (M+H)+

Reference： [1]Journal of Organic Chemistry,2007,vol. 72,p. 2289 - 2296
[2]Patent: US2011/53990,2011,A1 .Location in patent: Page/Page column 19
[3]Patent: US2011/82202,2011,A1 .Location in patent: Page/Page column 21-22
[4]Patent: US2011/82210,2011,A1 .Location in patent: Page/Page column 34-35
[5]Patent: US2011/82120,2011,A1 .Location in patent: Page/Page column 18
[6]Patent: US2011/82156,2011,A1 .Location in patent: Page/Page column 19
[7]Patent: US2011/172240,2011,A1 .Location in patent: Page/Page column 36
[8]Patent: US2011/82192,2011,A1 .Location in patent: Page/Page column 29
[9]Patent: US2011/213028,2011,A1 .Location in patent: Page/Page column 29
[10]Patent: US2012/277305,2012,A1 .Location in patent: Page/Page column 36-37
[11]Patent: WO2013/166176,2013,A1 .Location in patent: Paragraph 0239
[12]Patent: WO2013/177536,2013,A2 .Location in patent: Paragraph 0241
[13]Patent: WO2014/107730,2014,A2 .Location in patent: Paragraph 0329
[14]Patent: US9216224,2015,B2 .Location in patent: Page/Page column 53-54
[15]Patent: US2012/252810,2012,A1 .Location in patent: Page/Page column 31-32
[16]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 5260 - 5262
[17]Patent: WO2018/5794,2018,A2 .Location in patent: Page/Page column 213

12
[ 79410-20-1 ]
[ 127828-22-2 ]
[ 943249-85-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 4220 - 4228
[2]Journal of Organic Chemistry,2007,vol. 72,p. 6776 - 6785

13
[ 16526-68-4 ]
[ 127828-22-2 ]
[ 950830-76-9 ]

Reference： [1]Journal of Organic Chemistry,2007,vol. 72,p. 6776 - 6785

14
[ 554-95-0 ]
[ 127828-22-2 ]
[ 950830-78-1 ]

Reference： [1]Journal of Organic Chemistry,2007,vol. 72,p. 6776 - 6785

15
[ 127828-22-2 ]
[ 497962-48-8 ]

Reference： [1]Journal of Organic Chemistry,2007,vol. 72,p. 2289 - 2296

16
[ 127828-22-2 ]
[ 887150-21-2 ]

Reference： [1]Tetrahedron Letters,2006,vol. 47,p. 2915 - 2919

17
[ 127828-22-2 ]
[ 632323-85-4 ]

Reference： [1]Organic and biomolecular chemistry,2003,vol. 1,p. 3186 - 3192
[2]Tetrahedron Letters,2003,vol. 44,p. 2953 - 2956

18
[ 127828-22-2 ]
[ 632323-91-2 ]

Reference： [1]Organic and biomolecular chemistry,2003,vol. 1,p. 3186 - 3192
[2]Tetrahedron Letters,2003,vol. 44,p. 2953 - 2956

19
[ 127828-22-2 ]
[2-(2-{(R)-5-Guanidino-2-[(E)-3-(4-hydroxy-phenyl)-acryloylamino]-pentanoylamino}-ethoxy)-ethyl]-carbamic acid tert-butyl ester [ No CAS ]

Reference： [1]Tetrahedron Letters,2003,vol. 44,p. 2953 - 2956

20
[ 39061-97-7 ]
[ 127828-22-2 ]
[ 436856-76-7 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane;	Part E A stirred solution of 4-chloro-3-nitroquinoline (31.4 g, 0.151 mol) in 500 mL of anhydrous CH2Cl2, under N2, was treated with triethylamine (43 mL, 0.308 mol) and <strong>[127828-22-2]tert-butyl 2-(2-aminoethoxy)ethylcarbamate</strong> (0.151 mol). After stirring overnight, the reaction mixture was washed with H2O (2*300 mL) and brine (300 mL). The organic portion was dried over Na2SO4 and concentrated to give a bright yellow solid. Recrystallization from ethyl acetate/hexanes gave 43.6 g of tert-butyl 2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethylcarbamate as bright yellow crystals.
	With triethylamine; In dichloromethane;	A stirred solution of 4-chloro-3-nitroquinoline (31.4 g, 0.151 mol) in 500 mL of anhydrous CH2Cl2, under N2, was treated with triethylamine (43 mL, 0.308 mol) and <strong>[127828-22-2]tert-butyl 2-(2-aminoethoxy)ethylcarbamate</strong> (0.151 mol). After stirring overnight, the reaction mixture was washed with H2O (2×300 mL) and brine (300 mL). The organic portion was dried over Na2SO4 and concentrated to give a bright yellow solid. Recrystallization from ethyl acetate/hexanes gave 43.6 g of tert-butyl 2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethylcarbamate as bright yellow crystals.

Reference： [1]Patent: US2003/130518,2003,A1
[2]Patent: US6660735,2003,B2 .Location in patent: Page column 21

21
[ 176220-30-7 ]
[ 127828-22-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With palladium 10% on activated carbon; hydrogen; In methanol; at 25℃; for 8h;	Compound 16 (1.7 g, 7.7 mmol) was dissolved in MeOH (25 mL) and the solution was degassed several times with Ar before adding a catalytic amount of Pd/C 10%. The atmosphere was filled with H2 and the reaction was stirred 8 h at 25 C. The mixture was filtered and the solvent was removed under reduced pressure. No further purification was needed (quantitative yield). 1H NMR (300 MHz, CDCl3) delta 5.08 (br s, 1H), 3.66-3.47 (m, 4H), 3.37-3.22 (m, 2H), 3.22-3.10 (m, 2H), 3.02-2.84 (m, 2H), 1.43 (s, 9H); ESI-MS m/z 205 [M+H]+, 227 [M+Na]+.
79%		A solution of 0.82 g (3.1 mmol) of triphenylphosphine in 10 ml of tetrahydrofurane was added to a solution of 0.6 g (2.6 mmol) of 2c in 20 ml of tetrahydrofurane. The resulting solution was stirred for 2 h at room temperature. Subsequently, 200 ml of water was added, and the mixture was stirred overnight at room temperature. Then the mixture was evaporated to 75 ml and filtered. The filtrate was washed with 25 ml of dichloromethane and evaporated to get the product. Yield: 0.5 g (79%). 1H NMR (CDCl3): delta 3.50 (m, 4H, H2+ H3), 3.33 (m, 2H, H4), 2.86 (t, 2H, H1). ESI-MS: m/z 205.2 (M+H).
	With hydrogen;palladium 10% on activated carbon; In methanol; under 2206.72 Torr; for 24h;	A solution of tert-butyl 2-(2-azidoethoxy)ethylcarbamate (47.0 g, 0.204 mol) in MeOH was treated with 4 g of 10% Pd on carbon and shaken under H2 (3 Kg/cm2) for 24 h. The solution was then filtered through a Celite pad and concentrated to give 35.3 g of crude tert-butyl 2-(2-aminoethoxy)ethylcarbamate as a colorless liquid that was used without further purification.

	Pd on carbon; In methanol;	Part D A solution of tert-butyl 2-(2-azidoethoxy)ethylcarbamate (47.0 g, 0.204 mol) in MeOH was treated with 4 g of 10% Pd on carbon and shaken under H2 (3 Kg/cm2) for 24 h. The solution was then filtered through a Celite pad and concentrated to give 35.3 g of crude tert-butyl 2-(2-aminoethoxy)ethylcarbamate as a colorless liquid that was used without further purification.
	Pd on carbon; In methanol;	Part D A solution of tert-butyl 2-(2-azidoethoxy)ethylcarbamate (47.0 g, 0.204 mol) in MeOH was treated with 4 g of 10% Pd on carbon and shaken under H2 (3 Kg/cm2) for 24 h. The solution was then filtered through a Celite pad and concentrated to give 35.3 g of crude tert-butyl 2-(2-aminoethoxy)ethylcarbamate as a colorless liquid that was used without further purification.
	With hydrogen;palladium on activated charcoal; In methanol; under 2206.72 Torr; for 24h;	A solution of tert-butyl 2-(2-azidoethoxy)ethylcarbamate (47.0 g, 0.204 mol) in MeOH was treated with 4 g of 10% Pd on carbon and shaken under H2 (3 Kg/cm2) for 24 h. The solution was then filtered through a Celite pad and concentrated to give 35.3 g of crude tert-butyl 2-(2-aminoethoxy)ethylcarbamate as a colorless liquid that was used without further purification.
	With hydrogen;palladium 10% on activated carbon; In toluene; under 1551.49 Torr; for 22.5h;	A solution of tert-butyl 2-(2-azidoethoxy)ethylcarbamate (52 g, 226 mmol) in methanol (500 mL) was added to a Parr vessel containing 10% palladium on carbon (4 g) which had been wetted with toluene (30 mL). The mixture was placed under hydrogen pressure (30 psi; 2.0×105 Pa). After 18.5 hours analysis by thin layer chromatography indicated that the reaction was not complete. Catalyst (0.5 g) was added and the hydrogenation was continued for an additional 4 hours. The reaction mixture was filtered through a layer of Celite filter aid and a glass wool filter pad. The filter cake was rinsed with a mixture of isopropanol and methanol. The filtrate was concentrated under reduced pressure to provide tert-butyl 2-(2-aminoethoxy)ethylcarbamate.; A solution of tert-butyl 2-(2-azidoethoxy)ethylcarbamate (52 g, 226 mmol) in methanol (500 mL) was added to a Parr vessel containing 10% palladium on carbon (4 g) which had been wetted with toluene (30 mL). The mixture was placed under hydrogen pressure (30 psi; 2.0×105 Pa). After 18.5 hours analysis by thin layer chromatography indicated that the reaction was not complete. Catalyst (0.5 g) was added and the hydrogenation was continued for an additional 4 hours. The reaction mixture was filtered through a layer of Celite filter aid and a glass wool filter pad. The filter cake was rinsed with a mixture of isopropanol and methanol. The filtrate was concentrated under reduced pressure to provide tert-butyl 2-(2-aminoethoxy)ethylcarbamate.
	With hydrogen;palladium 10% on activated carbon; In methanol; under 1500.15 Torr; for 18.5h;	Part DA solution of tert-butyl 2-(2-azidoethoxy)ethylcarbamate (52 g, 226 mmol) in methanol (500 mL) was added to a Parr vessel containing 10% palladium on carbon (4 g) which had been wetted with toluene (30 mL). The mixture was placed under hydrogen pressure (30 psi; 2.0×105 Pa). After 18.5 hours analysis by thin layer chromatography indicated that the reaction was not complete. Catalyst (0.5 g) was added and the hydrogenation was continued for an additional 4 hours. The reaction mixture was filtered through a layer of CELITE filter aid and a glass wool filter pad. The filter cake was rinsed with a mixture of isopropanol and methanol. The filtrate was concentrated under reduced pressure to provide tert-butyl 2-(2-aminoethoxy)ethylcarbamate.
3 g	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; under 2585.81 Torr;Inert atmosphere;	Step 4: Synthesis of tert-butyl (2-(2-aminoethoxy)ethyl)carbamate (58) A solution of tert-butyl (2-(2-azidoethoxy)ethyl)carbamate 57 (5.0 g, 0.0217 mol) in methanol (100 mL) was added 10% Pd/C (2.5 g) under Ar. The mixture was stirred under H2 (50 psi) at room temperature overnight. After filtration through a pad of celite, the organic layer was concentrated under reduced pressure to provide tert-butyl (2-(2-aminoethoxy)ethyl)carbamate 58 (3.0 g). The product was used in the next step without further purification. 1H NMR (400 MHz, MeOD) delta 3.48-3.45 (m, 4H), 3.23-3.20 (t, 2H), 2.77-2.75 (m, 2H), 1.43 (s, 9H).
		To 146g of [2-{2-(t-butoxycarbonylamino)ethoxy}ethyl]methane sulfonate was dissolved in 500ml DMF, was added 134g of sodium azide. The reaction mixture was stirred at 7O0C for 2Oh1 and then concentrated under reduced pressure. The resulting residue was dissolved in 1,200ml water and extracted with EA. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was dissolved in 2,000ml THF, to which was added 162g of triphenylphosphine. The reaction mixture was stirred at RT for 2h, after which was added 200ml water. The reaction mixture was stirred at RT for 18h and concentrated to 500ml under reduced pressure. Then the resulting precipitate was filtered off. The filtrate was further concentrated under reduced pressure to remove THF, and washed with MC. The aq layer was concentrated to obtain 86.2g of compd 42 as a liquid. 1H NMR (400MHz; CDCI3) delta 4.96 (br s, IH), 3.54- 3.48 (m, 4H), 3.34 (q, 2H), 2.88 (t, 2H), 1.48-1.46 (m, HH).

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 117,p. 301 - 320
[2]MedChemComm,2019,vol. 10,p. 1037 - 1041
[3]Patent: EP1745802,2007,A1 .Location in patent: Page/Page column 17
[4]Patent: US6664265,2003,B2 .Location in patent: Page column 23
[5]Patent: US2003/130518,2003,A1
[6]Patent: US2003/139441,2003,A1
[7]Patent: US6660735,2003,B2 .Location in patent: Page column 21
[8]Patent: US2004/10007,2004,A1 .Location in patent: Page 75; 98
[9]Patent: US2011/269965,2011,A1 .Location in patent: Page/Page column 34
[10]Patent: US2013/116263,2013,A1 .Location in patent: Paragraph 0697
[11]Patent: WO2009/113828,2009,A2 .Location in patent: Page/Page column 46-47

22
[ 437384-55-9 ]
[ 127828-22-2 ]
[ 634925-61-4 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 1h;	Under a nitrogen atmosphere, a solution of <strong>[127828-22-2]tert-butyl 2-(2-aminoethoxy)ethylcarbamate</strong> (23.1 g, 113 mmol) in N,N-dimethylformamide (100 mL) was added over a 1 hour period to a solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (25.02 g, 113 mmol) in N,N-dimethylformamide (400 mL) containing triethylamine (24 mL, 175 mmol). The reaction mixture was allowed to stir at ambient temperature overnight. The N,N-dimethylformamide was removed under reduced pressure. The residue was dissolved in ethyl acetate (500 mL), washed with water (3×100 ml), dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography (450 g of silica gel eluting sequentially with 3/1 hexanes/ethyl acetate (1.2 L), 2/1 hexanes/ethyl acetate (1.2 L), and 1/1 hexanes/ethyl acetate (1 L)) to provide 20.67 g of tert-butyl 2-{2-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]ethoxy}ethylcarbamate.

Reference： [1]Patent: US2004/10007,2004,A1 .Location in patent: Page 75

Yield	Reaction Conditions	Operation in experiment
76%		b) Preparation of 5-(tert-butyloxycarbonylamino)-3-oxa-pentyl amine. A solution of the above nitrile (3.9 g, 19.5 mmoles) in acetic acid (60 mL) was treated with Pd/C (0.8 g of 5%) and hydrogenated on a Parr apparatus at 45 psig for 1 hour, during which time the shaker bottle was repressurized as necessary. The catalyst was removed by filtration through celite and the majority of the acetic acid was removed under reduced pressure. The residue was taken up in water and the acidic solution was extracted twice with CH2 Cl2, and the extracts were discarded. The aqueous solution was brought to pH 12 with 50% NaOH and extracted with CH2 Cl2. The combined extracts were dried (Na2 SO4) and removal of the solvent gave the amine as an oil (3.0 g, 76%). NMR (CDCl3) delta 1.56 (s, 9H), 2.92 (t, 2H), 3.39 (t, 2H), 3.58 (m, 4H), 5.12 (s, 1H).
		B 2-[2-(tert-Butoxycarbonylamino)ethoxy]ethylamine A mixture of 7.4 g of the compound obtained in the previous step, 1.5 g of Raney nickel, 1.5 ml of hydrazine monohydrate and 60 ml of EtOH is stirred for 4 hours at RT. A further 1.5 ml of hydrazine monohydrate are added and the mixture is stirred for 2 hours at RT. The catalyst is filtered off and washed with EtOH and the filtrate is concentrated under vacuum to give 6.22 g of the expected product, which is used as such in the next step.

24
[ 18523-48-3 ]
[ 127828-22-2 ]
[ 1013663-35-8 ]

Reference： [1]Chemistry Letters,2008,vol. 37,p. 52 - 53

25
[ 89581-70-4 ]
[ 358-23-6 ]
[ 127828-22-2 ]
[ 634927-83-6 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of 6-chloro-4-hydroxy-5-methyl-3-nitropyridin-2(iH)-one (10.9 g, 53.4 mmol) in dichloromethane (380 mL) was cooled to 0 C. Triethylamine (22.3 mL, 160 mmol) was added, and the solution was stirred for ten minutes. Trifluoromethanesulfonic anhydride (18.0 mL, 107 mmol) was then added dropwise over a period of five minutes, and the solution was stirred for 1.5 hours at 0 C. A solution of <strong>[127828-22-2]tert-butyl 2-(2-aminoethoxy)ethylcarbamate</strong> (12.0 g, 58.8 mmol), prepared as described in Parts A through D of Example 102, in a small amount of dichloromethane was then added over a period of five minutes, and the reaction was allowed to warm to room temperature slowly and stirred overnight. The solution was then washed with water (2×150 mL) and brine (150 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting sequentially with 80:20 hexanes:ethyl acetate and 50:50 hexanes:ethyl acetate) to provide a yellow oil, which was dissolved in diethyl ether and concentrated under reduced pressure to provide 16.5 g of trifluoromethanesulfonic acid 4-[(2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl)amino]-6-chloro-5-methyl-3-nitropyridin-2-yl ester as a solid.

Reference： [1]Patent: US2004/10007,2004,A1 .Location in patent: Page 107-108

26
[ 87781-93-9 ]
[ 127828-22-2 ]
[ 1187357-70-5 ]

Yield	Reaction Conditions	Operation in experiment
	In anhydrous methoxyethanol; water; for 16h;Reflux;	6.3g of compd 42 and 2.Og of 2-bromohypoxanthine were dispersed in 55ml monomethoxyethanol and 17.5ml water. The reaction mixture was stirred at reflux for 16h, and the solvent was removed under reduced pressure. Then the concentrate was stirred in 20ml MC and 10ml water for 30 min, and the resulting precipitate was collected by filtration to obtain 2.1g of compd 43 as a pale yellow solid. 1H NMR (500MHz; DMSOd6) delta 12.43 (br s, IH), 10.45 (br s, IH), 7.89 (s, 0.2H), 7.61 (s, 0.8H), 6.77 (m, IH), <n="49"/>6.34 (s, 0.8H), 6.12 (s, 0.2H), 3.52 (t, 2H), 3.41 (m, 4H), 3.09 (q, 2H), 1.36 (s, 9H).

Reference： [1]Patent: WO2009/113828,2009,A2 .Location in patent: Page/Page column 47-48

27
[ 1187358-05-9 ]
[ 127828-22-2 ]
C₁₅H₂₈N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In water; acetonitrile; at 0 - 20℃;	To a stirred solution of 5g of 2-{(3-butynyl)-l-oxy}ethyl methanesulfonate and 5.32g of 2-[2-{2-(t-butoxycarbonyl)amino}ethyl-l- oxy]ethylamine in 60ml acetonitrile, was added drop-wise 3.6g of potassium carbonate dissolved in water at O0C. The reaction solution was allowed to slowly warm to RT and stirred for another 24h, and then concentrated under reduced pressure. The resulting residue was dissolved in MC and washed with water. The organic layer was concentrated and dissolved in 80ml THF and 80ml water, to which was added 8.4g of BoC2O dissolved in 50ml THF. The reaction mixture was stirred at RT for 16h, which was followed by removal of THF in vacuo and extraction with EA. The organic layer was washed in series with 0.5M aq citric acid, water, and brine. The organic <n="34"/>layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (hexane -> 1:4 EA/hexane) to obtain 2.45g of compd 9 as a pale yellow oil. 1H NMR (400MHz; CDCI3) delta 5.08 (br s, 0.5H), 4.93 (br s, 0.5H), 3.61-3.46 (m, 12H), 3.31 (m, 2H), 2.48 (m, 2H), 1.99 (t, IH), 1.48 (s, 9H), 1.46 (s, 9H).

Reference： [1]Patent: WO2009/113828,2009,A2 .Location in patent: Page/Page column 32-33

28
[ 108-30-5 ]
[ 127828-22-2 ]
[ 843674-01-1 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; at 0℃;Cooling with ice;	Example 5 4-(2-(2-(tert-butoxycarbonylamino)ethoxy)ethylamino)-4-oxobutanoic acid In a one-necked flask (250 mL), 20.155 g (98.7 mmol) of the compound 4 and 50 mL of THF (dried over molecular sieves) were dissolved and the reaction mixture was cooled on an ice-water bath. To the flask, a mixture prepared by dissolving 12.844 g (128.4 mmol) of succinic anhydride in 50 mL of THF was added slowly, and then 42 mL of triethylamine was also added slowly with stirring on an ice-water bath. After reaction completion, the solution was dried to remove the solvent, and the resultant concentrate was dissolved in chloroform, washed with 5% citric acid twice, saturated brine once, dried over anhydrous MgSO4, filtered, and dried to yield the title compound 5.
	With triethylamine; In tetrahydrofuran;Cooling with ice;	Example 5 4-(2-(2-(tert-butoxycarbonylamino)ethoxy)ethylamino)-4-oxobutanoic acid In a one-necked flask (250 mL), 20.155 g (98.7 mmol) of the compound 4 and 50 mL of THF (dried over molecular sieves) were dissolved and the reaction mixture was cooled on an ice-water bath. To the flask, a mixture prepared by dissolving 12.844 g (128.4 mmol) of succinic anhydride in 50 mL of THF was added slowly, and then 42 mL of triethylamine was also added slowly with stirring on an ice-water bath. After reaction completion, the solution was dried to remove the solvent, and the resultant concentrate was dissolved in chloroform, washed with 5% citric acid twice, saturated brine once, dried over anhydrous MgSO4, filtered, and dried to yield the title compound 5.

Reference： [1]Patent: EP2123283,2009,A1 .Location in patent: Page/Page column 15
[2]Patent: US2009/325894,2009,A1 .Location in patent: Page/Page column 10

29
[ 1046804-80-1 ]
[ 127828-22-2 ]

Yield	Reaction Conditions	Operation in experiment
	With methylamine; In water; at 20℃;	Example 4 Tert-butyl 2-(2-aminoethoxy)ethylcarbamate To a one-necked flask (250 mL), 14.912 g (44.65 mmol) of the compound 3 and 52 mL of methylamine aqueous solution were added and the reaction mixture was stirred overnight at room temperature. After reaction completion, 150 mL of water were added. The solution was extracted with 100 mL of chloroform three times. The resultant organic phases were combined, washed with water twice, and saturated brine once, dried over anhydrous MgSO4, filtered, and dried to give a crude product. The crude product was dissolved in chloroform and extracted with 5% citric acid aqueous solution. The organic phase was removed; the pH value of the citric acid layer was adjusted to 14, and the layer was extracted with chloroform three times. The resultant organic Phases were combined, washed with saturated brine once, dried over anhydrous MgSO4, filtered, and dried to give 7.362 g of the title compound 4.
	With methylamine; In water; at 20℃;	Example 4 Tert-butyl 2-(2-aminoethoxy)ethylcarbamate To a one-necked flask (250 mL), 14.912 g (44.65 mmol) of the compound 3 and 52 mL of methylamine aqueous solution were added and the reaction mixture was stirred overnight at room temperature. After reaction completion, 150 mL of water were added. The solution was extracted with 100 mL of chloroform three times. The resultant organic phases were combined, washed with water twice, and saturated brine once, dried over anhydrous MgSO4, filtered, and dried to give a crude product. The crude product was dissolved in chloroform and extracted with 5% citric acid aqueous solution. The organic phase was removed; the pH value of the citric acid layer was adjusted to 14, and the layer was extracted with chloroform three times. The resultant organic Phases were combined, washed with saturated brine once, dried over anhydrous MgSO4, filtered, and dried to give 7.362 g of the title compound 4.

Reference： [1]Patent: EP2123283,2009,A1 .Location in patent: Page/Page column 15
[2]Patent: US2009/325894,2009,A1 .Location in patent: Page/Page column 10
[3]Chemistry - A European Journal,2010,vol. 16,p. 878 - 889

30
[ 1161-13-3 ]
[ 127828-22-2 ]
C₂₆H₃₅N₃O₆ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 1062 - 1075

31
[ 501-53-1 ]
[ 127828-22-2 ]
[ 1228371-44-5 ]

Reference： [1]Journal of the American Chemical Society,2010,vol. 132,p. 7291 - 7293

32
[ 7044-91-9 ]
[ 127828-22-2 ]
C₃₄H₄₆N₄O₆ [ No CAS ]

Reference： [1]Chemistry - A European Journal,2010,vol. 16,p. 878 - 889

33
[ 5060-65-1 ]
[ 127828-22-2 ]
[ 1072434-50-4 ]

Reference： [1]Chemistry - A European Journal,2010,vol. 16,p. 878 - 889

34
[ 19800-49-8 ]
[ 127828-22-2 ]
C₃₀H₄₄N₄O₆ [ No CAS ]

Reference： [1]Chemistry - A European Journal,2010,vol. 16,p. 878 - 889

35
[ 14096-51-6 ]
silver nitrate [ No CAS ]
[ 68-12-2 ]
[ 127828-22-2 ]
[Pt(ethylenediamine)Cl(NONBoc)](NO₃) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A solution of 38.6 mg (0.23 mmol) of AgNO3 in 1 ml of dimethylformamide (DMF) was added portionwise over 1.5 h to a stirred solution of 78.2 mg (0.24 mmol) of 1 in 1.6 ml of DMF at room temperature in the dark. The mixture was stirred for 5 h in the dark, and the AgCl precipitate was then filtered off. The resulting pale-yellow DMF solution of [PtenCl(dmf)](NO3) was used as a starting material for the preparation of 1b and 1c as described below.A solution of 1a obtained as above was added to 40 mg (0.2 mmol) of NONBoc (2d) in the dark. The resulting solution was stirred overnight in the dark at room temperature. Then DMF was removed in vacuo. Excess of water was added to the residue, and a yellow precipitate of PtenCl2 was filtered off. The remaining filtrate of 1c was lyophilized. Yield: 87 mg. 195Pt NMR (H2O): delta -2645.

Reference： [1]Patent: EP1745802,2007,A1 .Location in patent: Page/Page column 17; 27

36
[ 59-67-6 ]
[ 127828-22-2 ]
tert-butyl 2-(2-(nicotinamido)ethoxy)ethylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 20℃; for 18h;	In a typical run, sodium hydroxide (400 mg, 10 mmol) was dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 min. A solution containing Boc2O (740 mg, 3.40 mmol) in THF (15 mL) was then added dropwise, at room temperature, over a period of 15 min. The resulting reaction mixture was stirred at room temperature for 18 h. It was then concentrated under reduced pressure. The resulting residue was taken up in CH2Cl2 (200 mL) and stirred vigorously at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford <strong>[127828-22-2]tert-butyl 2-(2-aminoethoxy)ethylcarbamate</strong> (850 mg, 74%).tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (420, 2.06 mmol) was then taken up in CH3CN (20 mL) along with nicotinic acid (253 mg, 2.06 mmol) and EDCI (434 mg, 2.3 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then diluted with EtOAc (20 mL), washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (9:1 CH2Cl2/MeOH) to afford tert-butyl 2-(2-(nicotinamido)ethoxy)ethylcarbamate (280 mg, 44%). MS calculated for C15H23N3O4: 309.17; found: [M+H]+310.tert-Butyl 2-(2-(nicotinamido)ethoxy)ethylcarbamate (140 mg, 0.453 mmol) was taken up in 25% TFA in CH2Cl2 (10 mL). The reaction mixture was allowed to stand at room temperature for 2 h and then concentrated under reduced pressure to afford the TFA salt of N-(2-(2-aminoethoxy)ethyl)nicotinamide. This material was then taken up in CH3CN (10 mL) along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (148 mg, 0.453 mmol), HATU (190 mg, 0.498 mmol) and DIEA (0.24 mL). The resulting reaction mixture was stirred at room temperature for 2 h. It was then diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (9:1 CH2Cl2/MeOH) afforded N-(2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethoxy)ethyl)nicotinamide (75 mg, 31%). MS calculated for C31H46N2O5: 526.34; found: [M+H]+527.

Reference： [1]Patent: US2011/53990,2011,A1 .Location in patent: Page/Page column 19

37
[ 127828-22-2 ]
[ 69-72-7 ]
[ 1235236-32-4 ]

Yield	Reaction Conditions	Operation in experiment
33%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 18h;	tert-Butyl 2-(2-aminoethoxy)ethylcarbamate was then taken up in CH2Cl2 (20 mL) along with salicylic acid (576 mg, 4.17 mmol) and EDCI (905 mg. 4.72 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then diluted with CH2Cl2 (20 mL), washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by chromatography (9:1 CH2Cl2/MeOH) to afford tert-butyl 2-(2-(2-hydroxybenzamido)ethoxy)ethylcarbamate (450 mg, 33%). Mass calculated for C16H24N2O5: 324.17; found: [M+H]+=325.
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 20℃; for 18h;	tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (1.2 mmol) is then taken up in CH3CN (10 mL) along with salicylic acid (1.2 mmol) and EDCI (1.5 mmol). The resulting reaction mixture is stirred at room temperature for 18 h. It is then diluted with EtOAc (20 mL), washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue is purified by silica gel chromatography (9:1 CH2Cl2/MeOH) to afford tert-butyl 2-(2-(2-hydroxybenzamido)ethoxy)ethylcarbamate.

Reference： [1]Patent: US2011/82192,2011,A1 .Location in patent: Page/Page column 29
[2]Patent: US2011/82120,2011,A1 .Location in patent: Page/Page column 18

38
[ 127828-22-2 ]
[ 51037-30-0 ]
[ 1286228-17-8 ]

Yield	Reaction Conditions	Operation in experiment
85%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 18h;	tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (570 mg, 2.8 mmol) was taken up in CH3CN (8 mL) and DMF (8 mL) along with Acipimox (435 mg, 2.8 mmol) HATU (1.17 g, 3.1 mmol) and DIEA (730 muL, 4.2 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then diluted with EtOAc (50 mL), washed with water (3*10 mL), brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (9:1 CH2Cl2/MeOH) to afford 5-((2-(2-((tert-butoxycarbonyl)amino)ethoxy) ethyl)carbamoyl)-2-methylpyrazine 1-oxide (810 mg, 85%).

Reference： [1]Patent: US2011/82156,2011,A1 .Location in patent: Page/Page column 19

39
[ 77103-91-4 ]
[ 127828-22-2 ]
[ 1281971-05-8 ]

Yield	Reaction Conditions	Operation in experiment
36%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 20℃; for 18h;	Acifran (370 mg, 1.7 mmol) was taken up in CH3CN (15 mL) along tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (350 mg, 1.71 mmol) and EDC (970 mg, 5.05 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then diluted with EtOAc (60 mL) and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (CH2Cl2) to afford tert-butyl 2-(2-(2-methyl-3-oxo-2-phenyl-2,3-dihydrofuran-5-carboxamido)ethoxy)ethylcarbamate (250 mg, 36%).

Reference： [1]Patent: US2011/82202,2011,A1 .Location in patent: Page/Page column 22

40
[ 42017-89-0 ]
[ 127828-22-2 ]
[ 1286173-97-4 ]

Yield	Reaction Conditions	Operation in experiment
35%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 18h;	tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (300 mg, 1.47 mmol) was taken up in CH2Cl2 (15 mL) along with <strong>[42017-89-0]2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoic acid</strong> (<strong>[42017-89-0]fenofibric acid</strong>, 467 mg, 1.47 mmol) and EDCI (310 mg, 1.47 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (9:1 CH2Cl2/MeOH) to afford tert-butyl 2-(2-(2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanamido)ethoxy)ethylcarbamate (260 mg, 35%).

Reference： [1]Patent: US2011/82210,2011,A1 .Location in patent: Page/Page column 27; 34-35

41
[ 24424-99-5 ]
[ 1187358-05-9 ]
[ 127828-22-2 ]
[ 1187357-17-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In tetrahydrofuran; aq citric acid, water, and brine; water; acetonitrile;	EXAMPLE 9 Preparation of N-[2-{2-(t-butoxycarbonyl)aminoethoxy}ethyl]-N-[2-{(3-butynyl)-1-oxy}ethyl]-N-(t-butoxycarbonyl)amine (9) To a stirred solution of 5 g of 2-{(3-butynyl)-1-oxy}ethyl methanesulfonate and 5.32 g of 2-[2-{2-(t-butoxycarbonyl)amino}ethyl-1-oxy]ethylamine in 60 ml acetonitrile, was added drop-wise 3.6 g of potassium carbonate dissolved in water at 0 C. The reaction solution was allowed to slowly warm to RT and stirred for another 24 h, and then concentrated under reduced pressure. The resulting residue was dissolved in MC and washed with water. The organic layer was concentrated and dissolved in 80 ml THF and 80 ml water, to which was added 8.4 g of Boc2O dissolved in 50 ml THF. The reaction mixture was stirred at RT for 16 h, which was followed by removal of THF in vacuo and extraction with EA. The organic layer was washed in series with 0.5M aq citric acid, water, and brine. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (hexane 1:4 EA/hexane) to obtain 2.45 g of compd 9 as a pale yellow oil. 1H NMR (400 MHz; CDCl3) delta 5.08 (br s, 0.5H), 4.93 (br s, 0.5H), 3.61-3.46 (m, 12H), 3.31 (m, 2H), 2.48 (m, 2H), 1.99 (t, 1H), 1.48 (s, 9H), 1.46 (s, 9H).

Reference： [1]Patent: US2011/178031,2011,A1

42
[2-{2-(t-butoxycarbonylamino)ethoxy}ethyl]methane sulfonate [ No CAS ]
[ 127828-22-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium azide; triphenylphosphine; In tetrahydrofuran; water; N,N-dimethyl-formamide;	EXAMPLE 42 Preparation of 2-{2-(t-butoxycarbonylamino)ethoxy}ethylamine (42) To 146 g of [2-{2-(t-butoxycarbonylamino)ethoxy}ethyl]methane sulfonate was dissolved in 500 ml DMF, was added 134 g of sodium azide. The reaction mixture was stirred at 70 C. for 20 h, and then concentrated under reduced pressure. The resulting residue was dissolved in 1,200 ml water and extracted with EA. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was dissolved in 2,000 ml THF, to which was added 162 g of triphenylphosphine. The reaction mixture was stirred at RT for 2 h, after which was added 200 ml water. The reaction mixture was stirred at RT for 18 h and concentrated to 500 ml under reduced pressure. Then the resulting precipitate was filtered off. The filtrate was further concentrated under reduced pressure to remove THF, and washed with MC. The aq layer was concentrated to obtain 86.2 g of compd 42 as a liquid. 1H NMR (400 MHz; CDCl3) delta 4.96 (br s, 1H), 3.54-3.48 (m, 4H), 3.34 (q, 2H), 2.88 (t, 2H), 1.48-1.46 (m, 11H).

Reference： [1]Patent: US2011/178031,2011,A1

43
[ 2756-87-8 ]
[ 127828-22-2 ]
[ 1314800-97-9 ]

Yield	Reaction Conditions	Operation in experiment
64%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 20℃; for 18h;	tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (1.0 g, 4.90 mmol) was then taken up in 20 mL of CH3CN along with mono methyl fumarate (637 mg, 4.90 mmol) and EDCI (1.7 g. 5.39 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then diluted with EtOAc (20 mL), washed with saturated aqueous NaHCO3, brine, dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (9:1 CH2Cl2/MeOH) to afford 1.0 g of (E)-methyl 4-(2-(2-(tert-butoxycarbonyl)ethoxy)ethylamino)-4-oxobut-2-enoate (64% yield). MS (EI) calcd for C14H24N2O6: 316.16. found: 317 (M+1).

Reference： [1]Patent: US2011/172240,2011,A1 .Location in patent: Page/Page column 36

44
[ 24280-93-1 ]
[ 127828-22-2 ]
[ 1333040-60-0 ]

Yield	Reaction Conditions	Operation in experiment
83%	With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In acetonitrile; at 20℃; for 18h;	Example 6; Preparation of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-((E)-6-(4-hydroxy-6-methoxy-7- methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4- enamido)ethoxy)ethyl)docosa-4,7,10,13,16,19-hexaenamide (I-2); In a typical run, sodium hydroxide (400 mg, 10 mmol) was dissolved in MeOH (70 mL) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 min A solution containing Boc2O (740 mg, 3.40 mmol) in THF (15 mL) was then added dropwise, at room temperature, over a period of 15 min The resulting reaction mixture was stirred at room temperature for 18 h, and then concentrated under reduced pressure. The resulting residue was taken up in CH2Cl2 (200 mL) and stirred vigorously at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford <strong>[127828-22-2]tert-butyl 2-(2-aminoethoxy)ethylcarbamate</strong> (850 mg, 74%).tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (1.47 mmol) was then taken up in CH3CN (10 mL) along with mycophenolic acid (470 mg, 1.47 mmol) and EDCI (310 mg, 1.62 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It is then diluted with EtOAc (50 mL), washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (9:1 CH2Cl2/MeOH) to afford 620 mg of (E)-tert-butyl 2-(2-(6- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4- enamido)ethoxy)ethylcarbamate (83% yield).(E)-tert-Butyl 2-(2-(6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3- dihydroisobenzofuran-5-yl)-4-methylhex-4-enamido)ethoxy)ethylcarbamate (620 mg, 1.22 mmol) was taken up in 10 mL of 4 M HC1 in dioxane and allowed to stir at room temperature for 2 h. The resulting reaction mixture was concentrated under reduced pressure to afford the HCl salt of (E)-N-(2-(2-aminoethoxy)ethyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3- dihydroisobenzofuran-5-yl)-4-methylhex-4-enamide This material was taken up in CH3CN (10 mL) along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (400 mg, 1.22 mmol), HATU (510 mg, 1.34 mmol) and DIEA (640 muL, 3.66 mmol). The resulting reaction mixture was stirred at room temperature for 2 h. It was then diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (5% MeOH in CH2Cl2) afforded 600 mg of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2- (2-((E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4- methylhex-4-enamido)ethoxy)ethyl)docosa-4,7,10,13,16,19-hexaenamide (68% yield). MS (EI) calcd for C43H60N2O7: 716.44; found 717 (M+1).

Reference： [1]Patent: US2011/213028,2011,A1 .Location in patent: Page/Page column 29

45
[ 532-55-8 ]
[ 127828-22-2 ]
C₁₇H₂₅N₃O₄S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 5436 - 5441

46
[ 127828-22-2 ]
[ 1334539-26-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 5436 - 5441

47
[ 127828-22-2 ]
[ 1334539-37-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 5436 - 5441

48
[ 1233921-11-3 ]
[ 127828-22-2 ]
[ 1334241-14-3 ]

Reference： [1]Angewandte Chemie - International Edition,2011,vol. 50,p. 8428 - 8431

49
[ 43083-12-1 ]
[ 5098-14-6 ]
[ 127828-22-2 ]
[ 960253-94-5 ]

Yield	Reaction Conditions	Operation in experiment
77%		Part EUnder a nitrogen atmosphere, aminomalononitrile p-toluenesulfonate (55.0 g, 0.217 mol) and anhydrous THF (1.1 L) were combined, and triethylamine (23.1 g, 0.228 mol) was added with stirring to the resulting suspension. After the suspension was stirred for 25 minutes; the reaction became homogeneous, and trimethyl orthobutyrate (36.5 mL, 0.228 mol) was added. The solution was heated at reflux for 75 minutes. An analysis by TLC indicated the presence of starting material, and additional trimethyl orthobutyrate (3.5 mL) was added. The solution was heated at reflux for another 15 minutes and allowed to cool to 25 C. Triethylamine (32 mL, 0.29 mol) and <strong>[127828-22-2]tert-butyl 2-(2-aminoethoxy)ethylcarbamate</strong> (48.8 g, 0.239 mol) were added, and the reaction was stirred for 18 hours at room temperature. The volatiles were removed under reduced pressure, and the residue was partitioned between dichloromethane (1 L) and saturated aqueous sodium bicarbonate (250 mL). The organic layer was separated and washed sequentially with saturated aqueous sodium carbonate (250 mL) and brine (250 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was combined with material from another run and purified by column chromatography on silica gel (eluting with 20% ethyl acetate in hexane) to provide 67 g (77%) of tert-butyl 2-[2-(5-amino-4-cyano-2-propyl-1H-imidazol-1-yl)ethoxy]ethylcarbamate as an orange semi-solid.

Reference： [1]Patent: US2011/269965,2011,A1 .Location in patent: Page/Page column 34

50
[ 24424-99-5 ]
[ 127828-22-2 ]

Reference： [1]Patent: US2011/269965,2011,A1
[2]Patent: US2013/116263,2013,A1
[3]European Journal of Medicinal Chemistry,2016,vol. 117,p. 301 - 320
[4]MedChemComm,2019,vol. 10,p. 1037 - 1041

51
[ 127828-22-2 ]
[ 960253-96-7 ]

Reference： [1]Patent: US2011/269965,2011,A1

52
[ 139115-91-6 ]
[ 127828-22-2 ]

Reference： [1]Patent: US2011/269965,2011,A1
[2]Patent: US2013/116263,2013,A1
[3]MedChemComm,2019,vol. 10,p. 1037 - 1041

53
[ 302331-20-0 ]
[ 127828-22-2 ]

Reference： [1]Patent: US2011/269965,2011,A1
[2]Patent: US2013/116263,2013,A1
[3]Patent: WO2009/113828,2009,A2
[4]MedChemComm,2019,vol. 10,p. 1037 - 1041

54
N-trifluoroacetyl-4-nitrophenylalanine [ No CAS ]
[ 127828-22-2 ]
1-(tert-butyloxycarbonyl)-10-trifluoroacetyl-9-(4-nitrobenzyl)-8-oxo-1,7,10-triaza-4-oxadecane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80.6%		To a chilled solution (-15 C) of 2 (1.41 g, 4.61 mmol) in THF (20 mL) was added N-methylmorpholine (NMM; 0.51 mL, 4.61 mmol) and subsequently isobutylchloroformate (IBCF; 0.61 mL, 4.61 mmol) under N2 atmosphere. After 5 min, a solution of 1 (0.857 g, 4.19 mmol) in THF (10 mL) was added dropwise at the same temperature, and the mixture was stirred for 30 min at the same temperature and then at room temperature for 1 h. After removing the solvent in vacuo, the residue was dissolved in ethyl acetate (50 mL). The organic phase was washed with 5% NaHCO3 (30 mL × 2), 5% citric acid (30 mL × 3), saturated NaCl solution (30 mL × 1), successively and dried over anhydrous MgSO4. After removal of the solvent in vacuo, the residue was subjected to flash chromatography on silica gel using a mixture of chloroform/methanol (100:1) as an eluent to provide 3 as a pale yellow solid (1.67 g, 80.6%) melting at 128-129 C. 1H NMR (CDCl3): delta 1.44 (9H, s, Boc), 3.17-3.51 (10H, overlapped, CH2), 4.76-4.78 (1H, dd, CH), 6.89 (1H, d, NH), 7.35-7.37 (2H, d, aromatic), 8.14-8.16 (2H, d, aromatic). ESI-MS (M+Na)+: m/z 515, found: 515. Anal. Calcd for C20H27N4O7F3: C, 48.78; H, 5.53; N, 11.38. Found: C, 48.46; H, 5.30; N, 11.21.

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 978 - 984

55
[ 70-34-8 ]
[ 127828-22-2 ]
[ 1359745-84-8 ]

Reference： [1]Chemistry - An Asian Journal,2012,vol. 7,p. 272 - 276

56
(E)-4-(pyridin-3-yl)but-3-enoic acid [ No CAS ]
[ 127828-22-2 ]
[ 1401711-71-4 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 20℃; for 18h;	tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (2.0 mmol) is taken up in CH3CN (20 mL) along with (E)-4-(pyridin-3-yl)but-3-enoic acid (2.0 mmol) and EDCI (2.2 mmol). The resulting reaction mixture is stirred at room temperature for 18 h. It is then diluted with EtOAc (20 mL), washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue is purified by silica gel chromatography (9:1 CH2Cl2/MeOH) to afford (E)-tert-butyl 2-(2-(4-(pyridin-3-yl)but-3-enamido)ethoxy)ethylcarbamate.

Reference： [1]Patent: US2012/252810,2012,A1 .Location in patent: Page/Page column 32

57
[ 6635-24-1 ]
[ 127828-22-2 ]
[ 1411773-62-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 4h;	tert-Butyl (2-(2-aminoethoxy)ethyl)carbamate was prepared according to the procedure outlined in WO 201 108521 1. The same experimental procedure outlined in example 5 was used to prepare 3,4,5-triacetoxybenzoic acid. This material, 3,4,5- triacetoxybenzoic acid (500 mg, 1.69 mmol) was taken up in 5 mL CH2CI2 along with tert- butyl (2-(2-aminoethoxy)ethyl)carbamate (380 mg, 1.1 equivalents), HATU (835 mg, 1.3 equivalents) and DIE A (571 ul, 2.0 equivalents). The resulting reaction mixture was stirred at room temperature for 4 h. The organic layer was then washed with saturated NH4CI, brine, dried (Na2S04) and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (0-60% gradient EtOAc in pentanes) to afford 5-((2-(2-((tert- butoxycarbonyl)amino)ethoxy)ethyl)carbamoyl)benzene-l ,2,3-triyl triacetate.

Reference： [1]Patent: WO2012/154564,2012,A1 .Location in patent: Page/Page column 92

58
[ 641611-84-9 ]
[ 127828-22-2 ]
[ 1429628-73-8 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 3228 - 3234

59
[ 1432910-07-0 ]
[ 127828-22-2 ]
[ 1432910-03-6 ]

Yield	Reaction Conditions	Operation in experiment
2 g	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 18h;	Step 5: Synthesis of tert-butyl (2-(2-((6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-8-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)ethoxy)ethyl)carbamate (60) A mixture of 58 (1.0 g, 0.0023 mol) and <strong>[127828-22-2]tert-butyl (2-(2-aminoethoxy)ethyl)carbamate</strong> 59 (1.4 g, 0.0069 mol) and DIPEA (1.18 g, 0.0092 mol) in THF (15 mL) was stirred at rt for 18 h. The mixture was evaporated to afford 60 (2.0 g), which was used for next step without further purification. LCMS m/z 580.08 (M+H)+

Reference： [1]Patent: US2013/116263,2013,A1 .Location in patent: Paragraph 0698

60
[ 134523-01-6 ]
[ 127828-22-2 ]
tert-butyl 2-(2-((3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanamido)ethoxy)ethylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 20℃; for 18h;	[0240j tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (150mg, 0.735 mmol) is then taken up in CH3CN (10 mL) along with the sodium salt of atorvastatin (0.735 mmol) and EDCI (155 mg, 0.81 mmol). The resulting reaction mixture is stirred at room temperature for 18 h. It is then diluted with EtOAc (20 mL), washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue is purified by silica gel chromatography (9:1 CH2C12/MeOH) to afford tert-butyl 2-(2-((3R,5R)-7-(2-(4-fluorophenyl)-5 - isopropyl-3-phenyl-4-(phenylcarbamoyl)- 1 H-pyrrol- 1 -yl)-3,5-dihydroxyheptanamido)ethoxy)ethylcarbamate.

Reference： [1]Patent: WO2013/166176,2013,A1 .Location in patent: Paragraph 0240

61
[ 59-67-6 ]
[ 127828-22-2 ]
tert-butyl 2-(2-(nicotinamido)ethoxy)ethylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 20℃; for 18h;	[0242j tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (420, 2.06 mmol) was then taken up in CH3CN (20 mL) along with nicotinic acid (253 mg, 2.06 mmol) and EDCI (434 mg, 2.3 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then diluted with EtOAc (20 mL), washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (9:1 CH2C12/MeOH) to afford tert-butyl 2-(2- (nicotinamido)ethoxy)ethylcarbamate (280 mg, 44%). MS calculated for C15H23N304:309.17; found: [M+H] 310.
44%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 20℃; for 18h;	[0330] tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (420, 2.06 mmol) was then taken up in CH3CN (20 mL) along with nicotinic acid (253 mg, 2.06 mmol) and EDCI (434 mg, 2.3 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then diluted with EtOAc (20 mL), washed with saturated aqueous NaHC03, brine, dried over Na2S04, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (9: 1 CH2Cl2/MeOH) to afford tert-butyl 2-(2- (nicotinamido)ethoxy)ethylcarbamate (280 mg, 44%). MS calculated for C15H23N3O4: 309.17; found: [M+H]+ 310.

Reference： [1]Patent: WO2013/177536,2013,A2 .Location in patent: Paragraph 0242
[2]Patent: WO2014/107730,2014,A2 .Location in patent: Paragraph 0330

62
N-((2,2-dimethylchroman-6-yl)sulfonyl)-N-(4-phenoxybenzyl)glycine [ No CAS ]
[ 127828-22-2 ]
tert-butyl (2-(2-(2-((2,2-dimethyl-N-(4-phenoxybenzyl)chromane)-6-sulfonamido)acetamido)ethoxy)ethyl)carbamate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 6610 - 6622

63
Black Hole Quencher-2 dye [ No CAS ]
[ 127828-22-2 ]
C₃₄H₄₄N₈O₈ [ No CAS ]

Reference： [1]Bioconjugate Chemistry,2015,vol. 26,p. 1461 - 1465

64
[ 5651-60-5 ]
[ 127828-22-2 ]
C₂₅H₂₆N₂O₅ [ No CAS ]

Reference： [1]Tetrahedron Letters,2016,vol. 57,p. 466 - 471

65
[ 53-86-1 ]
[ 127828-22-2 ]
tert-butyl 2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethoxy)ethylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 20℃; for 18h;	Example 6 Preparation of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethoxy)ethyl)docosa-4,7,10,13,16,19-hexaenamide (I-13) (0371) (0372) In a typical run, sodium hydroxide (400 mg, 10 mmol) is dissolved in MeOH (70 L) and 2-(2-aminoethoxy)ethanamine dihydrochloride (1.0 g, 5.65 mmol) is added. The resulting reaction mixture is stirred at room temperature for 30 min. A solution containing Boc2O (740 mg, 3.40 mmol) in THF (15 mL) is then added dropwise, at room temperature, over a period of 15 min. The resulting reaction mixture is stirred at room temperature for 18 h and then concentrated under reduced pressure. The resulting residue is taken up in CH2Cl2 (200 mL) and stirred vigorously at room temperature for 4 h. The mixture is filtered and the filtrate is concentrated under reduced pressure to afford 850 mg of <strong>[127828-22-2]tert-butyl 2-(2-aminoethoxy)ethylcarbamate</strong> (74% yield). (0373) tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (150 mg, 0.735 mmol) was then taken up in CH3CN (10 mL) along with indomethacin (263 mg, 0.735 mmol) and EDCI (155 mg, 0.81 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then diluted with EtOAc (20 mL), washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (9:1 CH2Cl2/MeOH) to afford 310 mg of tert-butyl 2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethoxy)ethylcarbamate (78%). (0374) tert-Butyl 2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethoxy)ethylcarbamate was taken up in 10 mL of 4 M HCl in dioxane and allowed to stand at room temperature for 2 h. The resulting reaction mixture was concentrated under reduced pressure to afford the HCl salt of N-(2-(2-aminoethoxy)ethyl)-2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamide. This material was taken up in CH3CN (10 mL) along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (187 mg, 0.57 mmol), HATU (238 mg, 0.63 mmol) and DIEA (300 muL, 1.71 mmol). The resulting reaction mixture was stirred at room temperature for 2 h, diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (5% MeOH-CH2Cl2) afforded (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethoxy)ethyl)docosa-4,7,10,13,16,19-hexaenamide. MS (EI) calcd for C45H56ClN3O5: 753.39; found 754 (M+1).

Reference： [1]Patent: US9216224,2015,B2 .Location in patent: Page/Page column 53-54

66
[ 55750-48-6 ]
[ 127828-22-2 ]
[ 131274-15-2 ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium carbonate; at 0℃; for 2h;	(1) 20 g of tert-butyl terminal amino-terminated diethylene glycol carbamate was added to 100 ml of saturated sodium bicarbonate, 13.8 g of N-methoxycarbonyl maleimide was weighed and added slowly at 0C. The above solution was stirred for 2 h. TLC showed the reaction was complete and ethyl acetate was extracted 3 times. The ethyl acetate phase was dried over anhydrous sodium sulfate, spin-dried, and purified by column to obtain 22 g of a product. Yield: 90%
	With sodium hydrogencarbonate; In water; at 0℃; for 1.5h;	Step 1t-Butyl (2-(2-aminoethoxy)ethyl)carbamate (204 mg, 1 mmol) was dissolved in saturated aq. NaHCO3 (1 0 mL). The solution was cooled to 0 C. Methyl-2,5-dioxo-2,5- dihydro-1 H-pyrrole-1 -carboxylate (155 mg, 1.0 mmol) was then added. The reaction was stirred for 1 .5 h at 0 C. The pH was adjusted to 1 -2 with 2M HCl, and the mixture was extracted with EtOAc (3 X 20 mL). The combined organic phases was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by ISCO using a 0-4% gradient of MeOH in DCM to obtain tert-butyl (2-(2-(2,5-dioxo-2,5-dihydro-1 H-pyrrol- 1 -yl)ethoxy)ethyl)carbamate. 1H NMR (400 MHz, CD3OD): 6.82 (s, 2H), 3.68 (t, J = 5.4 Hz, 2H), 3.59 (t, J = 5.4 Hz, 2H), 3.46 (t, J = 5.6 Hz, 2H), 3.1 8-3.14 (m, 2H), 1.43 (s, 9H). MS m/z 1 85.1 (M+1 -Boc). Retention time 0.918 min.

Reference： [1]Patent: CN107501378,2017,A .Location in patent: Paragraph 0038; 0042; 0046; 0050
[2]Patent: WO2015/189791,2015,A1 .Location in patent: Page/Page column 77

67
[ 127828-22-2 ]
(2-(2-(tert-butoxycarbonyl)aminoethoxy)ethylaminocarbonyl)-L-isoleucine [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 117,p. 301 - 320

68
[ 127828-22-2 ]
(2-(2-(tert-butoxycarbonyl)aminoethoxy)ethylaminocarbonyl)-L-isoleucine-L-valine-(3,4-dehydro-L-proline)-(O-benzyl)-L-tyrosine-L-phenylalanine methyl ester [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 117,p. 301 - 320

69
[ 127828-22-2 ]
(2-(2-(tert-butoxycarbonyl)aminoethoxy)ethylaminocarbonyl)-L-isoleucine-L-valine-(3,4-dehydro)-L-proline-(O-benzyl)-L-tyrosine-L-phenylalanine [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 117,p. 301 - 320

70
(2S,3S)-benzyl-2-isocyanato-3-methylpentanoate [ No CAS ]
[ 127828-22-2 ]
(2-(2-(tert-butoxycarbonyl)aminoethoxy)ethylaminocarbonyl)-L-isoleucine benzyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With triethylamine; In tetrahydrofuran; at 25℃; for 12h;Inert atmosphere;	To a stirred solution of the previously synthesized isocyanate (225mg, 0.93mmol) and 17 (190mg, 0.93mmol) in dry THF (10mL), TEA (150muL, 1.02mmol) was added and the mixture was stirred at 25C under Ar atmosphere for 12h. Solvent was removed under reduced pressure. The crude was purified by means of flash chromatography on silica gel (ethylacetate/petroleum ether 1:1) to afford title compound (62% yield) as an off-white solid. 1H NMR (300MHz, CDCl3) delta 5.35 (br s, 1H), 5.16 (qd, J=12.3, 2.2Hz, 2H), 5.05 (br s, 1H), 4.55 (ddd, J=38.2, 9.0, 4.4Hz, 1H), 3.66-3.42 (m, 4H), 3.42-3.17 (m, 4H), 2.00-1.78 (m, 1H), 1.45 (s, 9H), 1.23-1.04 (m, 1H), 0.98-0.72 (m, 6H); ESI-MS m/z 452 [M+H]+.

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 117,p. 301 - 320

71
[ 127828-22-2 ]
C₁₄H₃₀N₄O₃ [ No CAS ]