[ CAS No. 106984-09-2 ] {[proInfo.proName]}

Name: 106984-09-2|tert-Butyl (2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)carbamate|97%
Brand: Ambeed
SKU: A185146
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Quality Control of [ 106984-09-2 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 106984-09-2 ]

SDS Specification

Alternatived Products of [ 106984-09-2 ]

Product Details of [ 106984-09-2 ]

CAS No. :	106984-09-2	MDL No. :	MFCD07779195
Formula :	C₁₃H₂₇NO₆	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XKKDQIAPTPFIGW-UHFFFAOYSA-N
M.W :	293.36	Pubchem ID :	10968359
Synonyms :	PROTAC Linker 12	Chemical Name :	tert-Butyl (2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)carbamate

Calculated chemistry of [ 106984-09-2 ]

Physicochemical Properties

Num. heavy atoms :	20
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.92
Num. rotatable bonds :	14
Num. H-bond acceptors :	6.0
Num. H-bond donors :	2.0
Molar Refractivity :	73.54
TPSA :	86.25 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) :	-8.23 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.6
Log Po/w (XLOGP3) :	-0.2
Log Po/w (WLOGP) :	0.55
Log Po/w (MLOGP) :	-0.34
Log Po/w (SILICOS-IT) :	1.28
Consensus Log Po/w :	0.98

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	1.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-0.61
Solubility :	72.2 mg/ml ; 0.246 mol/l
Class :	Very soluble
Log S (Ali) :	-1.15
Solubility :	20.5 mg/ml ; 0.07 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.71
Solubility :	0.573 mg/ml ; 0.00195 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.24

Safety of [ 106984-09-2 ]

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

Application In Synthesis of [ 106984-09-2 ]

* 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 [ 106984-09-2 ]
Downstream synthetic route of [ 106984-09-2 ]

[ 106984-09-2 ] Synthesis Path-Upstream 1~14

1
[ 106984-09-2 ]
[ 86770-74-3 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 2, p. 402 - 406

2
[ 24424-99-5 ]
[ 86770-74-3 ]
[ 106984-09-2 ]

Yield	Reaction Conditions	Operation in experiment
80%	at 20℃; for 2.16667 h;	EXAMPLE 5 Synthesis of 4-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)-2-(2,6-dioxopiperidin-3- yl)isoindoline- 1 ,3-dione Step 1: Synthesis of S9 To a round-bottom flask, 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethanol (2.9 g, 15 mmol) was diluted in 10 mL of ethanol. Di-tert-butyl dicarbonate (3.6 g, 16.5 mmol) was dissolved in 10 mL of ethanol and the solution was dropwised within a period of 10 min. The resulting reaction mixture was stirred at room temperature for 2 h. After evaporation of the solvent, the residue was purified by column chromatography with DCM/ MeOH to obtain S9 as colorless oil (3.69 g, 80percent yield). 1H NMR (400 MHz, CDCI₃) δ (ppm) 5.49 (s, 1H), 3.46-3.25 (m, 14H), 3.02 (s, 2H), 1.18 (s, 9H); ESI-MS calculated for Ci₃H₂₇NNa0₆ [M+Na]⁺ = 316.17, obtained: 316.18.
44%	With sodium hydroxide In tetrahydrofuran; water at 20℃; for 16 h;	Into a 100-mL round-bottom flask, was placed a solution of 2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethan-1-ol (3.0 g, 15.52 mmol, 1.00 equiv) in tetrahydrofuran/water (30/30 mL), di-tert-butyl dicarbonate (3.6 g, 16.49 mmol, 1.05 equiv), sodium hydroxide (2.5 g, 62.50 mmol, 4.00 equiv). The resulting solution was stirred for 16 h at room temperature. The resulting solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL3). The combined organic layers were washed with brine (20 mL1), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:1). This resulted in 2.0 g (44percent) of tert-butyl N-(2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl)carbamate as light yellow oil. LC-MS (ES⁺): m/z 294.05 [MH⁺], t_R=0.93 min, (1.9 minute run).
15%	at 20℃; for 18 h;	To a stirred solution of 87 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethanol (100μL, 0.55mmol) in 88 dioxane (1mL) was added Boc₂O (152μL, 0.66mmol). The mixture was stirred for 18hat rt and then evaporated under reduced pressure. The crude was taken up in DCM (6mL), washed with H₂O (2×6mL) and brine (1×5mL), dried over MgSO₄, filtered and evaporated under reduced pressure. The crude product was purified using flash silica column chromatography (99:1 DCM:MeOH) to yield the desired 89 tert-butyl N-(2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethyl)carbamate (24mg, 81.8μmol, 15percent), as a pale yellow oil (R_f 0.52, 9:1 DCM:MeOH). ¹H NMR (400MHz, CDCl₃) δ 3.75–3.67 (m, 4H, O-CH₂), 3.66–3.57 (m, 8H, O-CH₂CH₂-O), 3.52 (t, J=5.2Hz, 2H, O-CH₂), 3.29 (t, J=5.2Hz, 2H, NH-CH₂), 1.43 (s, 9H, CH₃ t Bu). ¹³C NMR (101MHz, CDCl₃) δ 156.31, 79.19, 72.77, 70.72, 70.67, 70.55, 70.36, 70.20, 61.76, 40.67, 28.56. HRMS-ESI calculated for C₁₃H₂₇NNaO₆ [M+Na]⁺ 316.1731, found m/z 316.1738. A solution of 91 bromine (7.3μL, 0.14mmol) in 67 DCM (0.2mL) at 0°C was added to a solution of 92 triphenylphosphine (37mg, 0.14mmol) and 93 Et₃N (20μL, 0.14mmol) in anhydrous DCM (0.2mL) at 0°C. Following stirring at 0°C for 30min, a solution of 89 tert-butyl N-(2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethyl)carbamate (42mg, 0.14mmol) in DCM (0.2mL) was added dropwise. After stirring at 0°C for 2h, the mixture was evaporated under reduced pressure. The crude product was purified using flash silica column chromatography (5:1 hexane:EA) to yield the desired 94 tert-butyl N-(2-{2-[2-(2-bromoethoxy)ethoxy]ethoxy}ethyl)carbamate (13mg, 36.5μmol, 26percent) as a colourless oil. ¹H NMR (400MHz, CDCl₃) δ 5.03 (br s, 1H, NH), 3.81 (t, J=6.3Hz, 2H, O-CH₂), 3.73–3.58 (m, 8H, O-CH₂CH₂-O), 3.54 (t, J=5.1Hz, 2H, O-CH₂), 3.47 (tJ=6.3, 1.2Hz, 2H, CH₂Br), 3.31 (q, J=5.6Hz, 2H, NH-CH₂), 1.44 (s, 9H, CH₃ t Bu). HRMS-ESI calculated for C₁₃H₂₆BrNNaO₅ [M+Na]⁺ 378.0887, found m/z 378.0894. To a solution of 9e (13mg, 35.1μmol) in anhydrous DMF (0.7mL) was added NaH (60percent by mass dispersion in mineral oil) (5.5mg, 0.14mmol). After stirring for 30min, a solution of tert-butyl N-(2-{2-[2-(2-bromoethoxy)ethoxy]ethoxy}ethyl)carbamate (12.5mg, 35.1μmol) in anhydrous DMF (0.6mL) was added. The reaction mixture was stirred for 18h, then quenched with H₂O (1.5mL), extracted with EA (4×2mL), washed with H₂O (2×7mL), dried over MgSO₄, filtered and evaporated under reduced pressure. The crude product was purified using flash silica column chromatography (99:1 DCM:MeOH) and semi-preparative RP-HPLC to yield the desired 17 (6.88mg, 10.7μmol, 31percent), as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ 7.97 (s, 1H, ArH indole), 7.81–7.75 (m, 3H, ArH indole and MeOPh), 7.58 (d, J=9.0Hz, 1H, ArH indole), 7.12–7.05 (m, 2H, ArH MeOPh), 6.95 (dd, J=8.9, 2.5Hz, 1H, ArH indole), 6.74 (br s, 1H, NH), 4.21–4.07 (m, 4H, N1-CH₂ & indole-O-CH₂), 3.86 (s, 3H, O-CH₃), 3.85–3.75 (m, 4H, O-CH₂ & O-CH₂ THP), 3.65–3.45 (m, 8H, O-CH₂CH₂-O), 3.37 (t, J=6.1Hz, 2H, O-CH₂), 3.19 (td, J=11.7, 2.0Hz, 2H, O-CH₂ THP), 3.05 (q, J=6.0Hz, 2H, NH-CH₂), 2.13–2.02 (m, 1H, CH THP), 1.41–1.21 (m, 13H, O-CH₂CH₂ THP, CH₃ t Bu). HRMS-ESI calculated for C₃₅H₄₈N₂NaO₉ [M+Na]⁺ 663.3252, found m/z 663.3247. Analytical RP-HPLC R_t=21.00min.

Reference： [1] Helvetica Chimica Acta, 1991, vol. 74, # 8, p. 1697 - 1706
[2] Angewandte Chemie - International Edition, 2013, vol. 52, # 40, p. 10593 - 10597[3] Angew. Chem., 2013, vol. 125, # 40, p. 10787 - 10791
[4] Inorganica Chimica Acta, 2011, vol. 365, # 1, p. 38 - 48
[5] Patent: WO2017/176958, 2017, A1, . Location in patent: Paragraph 0859-0860
[6] Angewandte Chemie - International Edition, 2015, vol. 54, # 35, p. 10327 - 10330[7] Angew. Chem., 2015, vol. 35, # 37, p. 10467 - 10471,5
[8] Patent: US2017/8904, 2017, A1, . Location in patent: Paragraph 0376; 0383
[9] European Journal of Medicinal Chemistry, 2018, vol. 145, p. 770 - 789
[10] Patent: US4705886, 1987, A,
[11] Journal of the American Chemical Society, 2011, vol. 133, # 24, p. 9242 - 9245
[12] Patent: WO2015/38938, 2015, A1, . Location in patent: Paragraph 0466; 0468
[13] Patent: WO2016/149501, 2016, A2, . Location in patent: Paragraph 0314

3
[ 302331-20-0 ]
[ 111-46-6 ]
[ 106984-09-2 ]

Yield	Reaction Conditions	Operation in experiment
72%	Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 1 h; Stage #2: at -5 - 50℃; for 24 h;	Weigh diethylene glycol(159g1.5mol) in a three-necked flask,500 ml of dry tetrahydrofuran was added,Cooled to below 0 °, a small amount of sodium hydride (24 g, 1 mol)After 1 hour of reaction, the mixture was cooled to -5 °,Boc-DEG-MS (141.5 g, 0.5 mol) was slowly added dropwise,After completion of the dropwise addition, the reaction was heated at 50 ° for 24 hours,TLC, the reaction was completed (developing solvent petroleum ether: ethyl acetate = 1: 1), 1 L of water was added, extracted twice with ethyl acetate,The ethyl acetate layers were combined, dried,Recovery was carried out under reduced pressure to give BOC-NH-PEG4105 g (yield 72percent)

Reference： [1] Patent: CN104774161, 2017, B, . Location in patent: Paragraph 0019; 0027; 0028

4
[ 24424-99-5 ]
[ 86770-67-4 ]
[ 106984-09-2 ]

Reference： [1] Journal of Organic Chemistry, 2002, vol. 67, # 7, p. 1993 - 2002
[2] Angewandte Chemie - International Edition, 2012, vol. 51, # 30, p. 7445 - 7448

5
[ 24424-99-5 ]
[ 106984-09-2 ]

Reference： [1] Patent: EP2824108, 2015, A1, . Location in patent: Paragraph 0119
[2] Patent: US2015/166595, 2015, A1, . Location in patent: Paragraph 0239

6
[ 34619-03-9 ]
[ 86770-74-3 ]
[ 106984-09-2 ]

Reference： [1] Tetrahedron Letters, 2011, vol. 52, # 22, p. 2906 - 2909

7
[ 112-60-7 ]
[ 106984-09-2 ]

Reference： [1] Helvetica Chimica Acta, 1991, vol. 74, # 8, p. 1697 - 1706
[2] Inorganica Chimica Acta, 2011, vol. 365, # 1, p. 38 - 48
[3] Journal of the American Chemical Society, 2011, vol. 133, # 24, p. 9242 - 9245
[4] Patent: US2015/166595, 2015, A1,
[5] Angewandte Chemie - International Edition, 2015, vol. 54, # 35, p. 10327 - 10330[6] Angew. Chem., 2015, vol. 35, # 37, p. 10467 - 10471,5

8
[ 86770-67-4 ]
[ 106984-09-2 ]

Reference： [1] Helvetica Chimica Acta, 1991, vol. 74, # 8, p. 1697 - 1706
[2] Inorganica Chimica Acta, 2011, vol. 365, # 1, p. 38 - 48
[3] Journal of the American Chemical Society, 2011, vol. 133, # 24, p. 9242 - 9245
[4] Angewandte Chemie - International Edition, 2015, vol. 54, # 35, p. 10327 - 10330[5] Angew. Chem., 2015, vol. 35, # 37, p. 10467 - 10471,5

9
[ 77544-60-6 ]
[ 106984-09-2 ]

Reference： [1] Inorganica Chimica Acta, 2011, vol. 365, # 1, p. 38 - 48
[2] Angewandte Chemie - International Edition, 2015, vol. 54, # 35, p. 10327 - 10330[3] Angew. Chem., 2015, vol. 35, # 37, p. 10467 - 10471,5

10
[ 65883-12-7 ]
[ 106984-09-2 ]

Reference： [1] Helvetica Chimica Acta, 1991, vol. 74, # 8, p. 1697 - 1706
[2] Journal of the American Chemical Society, 2011, vol. 133, # 24, p. 9242 - 9245

11
[ 147912-26-3 ]
[ 106984-09-2 ]

Reference： [1] Patent: EP2824108, 2015, A1,
[2] Patent: US2015/166595, 2015, A1,

12
[ 24424-99-5 ]
[ 106984-09-2 ]

Reference： [1] Patent: CN104774161, 2017, B,

13
[ 139115-91-6 ]
[ 106984-09-2 ]

Reference： [1] Patent: CN104774161, 2017, B,

14
[ 106984-09-2 ]
[ 437655-95-3 ]

Reference： [1] Inorganica Chimica Acta, 2011, vol. 365, # 1, p. 38 - 48

[ 106984-09-2 ] Synthesis Path-Downstream 1~88

1
[ 24529-88-2 ]
[ 106984-09-2 ]
(Z)-Octadec-9-enoic acid (R)-2-[(2-{2-[2-(2-tert-butoxycarbonylamino-ethoxy)-ethoxy]-ethoxy}-ethoxy)-hydroxy-phosphoryloxy]-1-((Z)-octadec-9-enoyloxymethyl)-ethyl ester [ No CAS ]

Reference： [1]Helvetica Chimica Acta,1991,vol. 74,p. 1697 - 1706

2
[ 24424-99-5 ]
[ 86770-74-3 ]
[ 106984-09-2 ]

Yield	Reaction Conditions	Operation in experiment
80%	In ethanol; at 20℃; for 2.16667h;	EXAMPLE 5 Synthesis of 4-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)-2-(2,6-dioxopiperidin-3- yl)isoindoline- 1 ,3-dione Step 1: Synthesis of S9 To a round-bottom flask, 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethanol (2.9 g, 15 mmol) was diluted in 10 mL of ethanol. Di-tert-butyl dicarbonate (3.6 g, 16.5 mmol) was dissolved in 10 mL of ethanol and the solution was dropwised within a period of 10 min. The resulting reaction mixture was stirred at room temperature for 2 h. After evaporation of the solvent, the residue was purified by column chromatography with DCM/ MeOH to obtain S9 as colorless oil (3.69 g, 80% yield). 1H NMR (400 MHz, CDCI3) delta (ppm) 5.49 (s, 1H), 3.46-3.25 (m, 14H), 3.02 (s, 2H), 1.18 (s, 9H); ESI-MS calculated for Ci3H27NNa06 [M+Na]+ = 316.17, obtained: 316.18.
79%	With potassium hydroxide; In 1,4-dioxane; at 10 - 20℃; for 16h;	To a stirred solution of 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethan-1-ol (1.0 g, 5.2 mmol, CAS86770-74-3) and KOH (0.32 g, 5.6 mmol) in 1,4 dioxane (4 mL) and water (8 mL) was added Boc-anhydride (1.24 g, 5.6 mmol) dropwise at 10 C. The resulting reaction mixture was allowed to warm to rt and stirred for 16 h. The reaction mixture was transferred into ice water and the resulting mixture was extracted using ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to afford crude product. The crude product was purified using silica gel column chromatography (8% MeOH-DCM) to give tert-butyl (2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)carbamate as a colorless oil (1.2 g, 79%). LC-MS (ESI+) m/z 293.13 (M+H)+.
44%	With sodium hydroxide; In tetrahydrofuran; water; at 20℃; for 16h;	Into a 100-mL round-bottom flask, was placed a solution of 2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethan-1-ol (3.0 g, 15.52 mmol, 1.00 equiv) in tetrahydrofuran/water (30/30 mL), di-tert-butyl dicarbonate (3.6 g, 16.49 mmol, 1.05 equiv), sodium hydroxide (2.5 g, 62.50 mmol, 4.00 equiv). The resulting solution was stirred for 16 h at room temperature. The resulting solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL3). The combined organic layers were washed with brine (20 mL1), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:1). This resulted in 2.0 g (44%) of tert-butyl N-(2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl)carbamate as light yellow oil. LC-MS (ES+): m/z 294.05 [MH+], tR=0.93 min, (1.9 minute run).

15%	In 1,4-dioxane; at 20℃; under 760.051 Torr; for 18h;	To a stirred solution of 87 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethanol (100muL, 0.55mmol) in 88 dioxane (1mL) was added Boc2O (152muL, 0.66mmol). The mixture was stirred for 18hat rt and then evaporated under reduced pressure. The crude was taken up in DCM (6mL), washed with H2O (2×6mL) and brine (1×5mL), dried over MgSO4, filtered and evaporated under reduced pressure. The crude product was purified using flash silica column chromatography (99:1 DCM:MeOH) to yield the desired 89 tert-butyl N-(2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethyl)carbamate (24mg, 81.8mumol, 15%), as a pale yellow oil (Rf 0.52, 9:1 DCM:MeOH). 1H NMR (400MHz, CDCl3) delta 3.75-3.67 (m, 4H, O-CH2), 3.66-3.57 (m, 8H, O-CH2CH2-O), 3.52 (t, J=5.2Hz, 2H, O-CH2), 3.29 (t, J=5.2Hz, 2H, NH-CH2), 1.43 (s, 9H, CH3 t Bu). 13C NMR (101MHz, CDCl3) delta 156.31, 79.19, 72.77, 70.72, 70.67, 70.55, 70.36, 70.20, 61.76, 40.67, 28.56. HRMS-ESI calculated for C13H27NNaO6 [M+Na]+ 316.1731, found m/z 316.1738. A solution of 91 bromine (7.3muL, 0.14mmol) in 67 DCM (0.2mL) at 0C was added to a solution of 92 triphenylphosphine (37mg, 0.14mmol) and 93 Et3N (20muL, 0.14mmol) in anhydrous DCM (0.2mL) at 0C. Following stirring at 0C for 30min, a solution of 89 tert-butyl N-(2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethyl)carbamate (42mg, 0.14mmol) in DCM (0.2mL) was added dropwise. After stirring at 0C for 2h, the mixture was evaporated under reduced pressure. The crude product was purified using flash silica column chromatography (5:1 hexane:EA) to yield the desired 94 tert-butyl N-(2-{2-[2-(2-bromoethoxy)ethoxy]ethoxy}ethyl)carbamate (13mg, 36.5mumol, 26%) as a colourless oil. 1H NMR (400MHz, CDCl3) delta 5.03 (br s, 1H, NH), 3.81 (t, J=6.3Hz, 2H, O-CH2), 3.73-3.58 (m, 8H, O-CH2CH2-O), 3.54 (t, J=5.1Hz, 2H, O-CH2), 3.47 (tJ=6.3, 1.2Hz, 2H, CH2Br), 3.31 (q, J=5.6Hz, 2H, NH-CH2), 1.44 (s, 9H, CH3 t Bu). HRMS-ESI calculated for C13H26BrNNaO5 [M+Na]+ 378.0887, found m/z 378.0894. To a solution of 9e (13mg, 35.1mumol) in anhydrous DMF (0.7mL) was added NaH (60% by mass dispersion in mineral oil) (5.5mg, 0.14mmol). After stirring for 30min, a solution of tert-butyl N-(2-{2-[2-(2-bromoethoxy)ethoxy]ethoxy}ethyl)carbamate (12.5mg, 35.1mumol) in anhydrous DMF (0.6mL) was added. The reaction mixture was stirred for 18h, then quenched with H2O (1.5mL), extracted with EA (4×2mL), washed with H2O (2×7mL), dried over MgSO4, filtered and evaporated under reduced pressure. The crude product was purified using flash silica column chromatography (99:1 DCM:MeOH) and semi-preparative RP-HPLC to yield the desired 17 (6.88mg, 10.7mumol, 31%), as a white solid. 1H NMR (400MHz, DMSO-d6) delta 7.97 (s, 1H, ArH indole), 7.81-7.75 (m, 3H, ArH indole and MeOPh), 7.58 (d, J=9.0Hz, 1H, ArH indole), 7.12-7.05 (m, 2H, ArH MeOPh), 6.95 (dd, J=8.9, 2.5Hz, 1H, ArH indole), 6.74 (br s, 1H, NH), 4.21-4.07 (m, 4H, N1-CH2 & indole-O-CH2), 3.86 (s, 3H, O-CH3), 3.85-3.75 (m, 4H, O-CH2 & O-CH2 THP), 3.65-3.45 (m, 8H, O-CH2CH2-O), 3.37 (t, J=6.1Hz, 2H, O-CH2), 3.19 (td, J=11.7, 2.0Hz, 2H, O-CH2 THP), 3.05 (q, J=6.0Hz, 2H, NH-CH2), 2.13-2.02 (m, 1H, CH THP), 1.41-1.21 (m, 13H, O-CH2CH2 THP, CH3 t Bu). HRMS-ESI calculated for C35H48N2NaO9 [M+Na]+ 663.3252, found m/z 663.3247. Analytical RP-HPLC Rt=21.00min.
	With triethylamine; In tetrahydrofuran; methanol; chloroform;	D. Synthesis of 11-tert-Butyloxycarbonylamino-3,6,9-trioxaundecanol (Compound XXVII) To a suspension of Compound XXVI (12 g; 62.1 mmole) in 100 ml of dry tetrahydrofuran was added di-tert-butyl dicarbonate (15 g; 68.7 mmole). Much gas was generated. Triethylamine (10 ml; 7.26 g; 71.3 mmole) was added and the mixture stirred at room temperature. When gas evolution ceased, the solution was diluted with methanol and 20 g of silica gel was added. The solvents were removed under reduced pressure and the residue was fractionated on a column of silica gel using 8:1 chloroform:methanol as eluant. Fractions containing the product were pooled and concentrated to a syrup. Correct elemental analyses were obtained for carbon, hydrogen and nitrogen.
	With sodium hydroxide; In water; acetonitrile; at 20℃; for 0.75h;	A solution of 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethanol (400 mg, 2.07 mmol, 0.33 mL) in 15 mL of acetonitrile/water (6:1) was treated with di-tert-butyl dicarbonate (603 mg, 2.77 mmol), followed by 2.8 mL of 1 N NaOH (aq). After stirring at RT for 45 mm, the organic solvent was removed in vacuo, the residue was dissolved in saturated NH4C1 (aq), and the desired carbamate was extracted with EtOAc. Removal of EtOAc provided the crude carbamate as a colorless oil.
	With sodium hydroxide; In water; acetonitrile; at 20℃; for 0.75h;	A solution of 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethanol (400 mg, 2.07 mmol, 0.33 mL) in 15 mL of acetonitrile/water (6:1) was treated with di-tert-butyl dicarbonate (603 mg, 2.77 mmol), followed by 2.8 mL of 1 N NaOH (aq). After stirring at RT for 45 mm, the organic solvent was removed in vacuo, the residue was dissolved in saturated NH4C1 (aq), and the desired carbamate was extracted with EtOAc. Removal of EtOAc provided the crude carbamate as a colorless oil.

Reference： [1]Chemical Communications,2019,vol. 55,p. 7187 - 7190
[2]Helvetica Chimica Acta,1991,vol. 74,p. 1697 - 1706
[3]Angewandte Chemie - International Edition,2013,vol. 52,p. 10593 - 10597
Angew. Chem.,2013,vol. 125,p. 10787 - 10791
[4]Inorganica Chimica Acta,2011,vol. 365,p. 38 - 48
[5]Patent: WO2017/176958,2017,A1 .Location in patent: Paragraph 0859-0860
[6]Patent: US2019/192668,2019,A1 .Location in patent: Paragraph 2580; 2581
[7]Angewandte Chemie - International Edition,2015,vol. 54,p. 10327 - 10330
Angew. Chem.,2015,vol. 35,p. 10467 - 10471,5
[8]Patent: US2017/8904,2017,A1 .Location in patent: Paragraph 0376; 0383
[9]European Journal of Medicinal Chemistry,2018,vol. 145,p. 770 - 789
[10]Patent: US4705886,1987,A
[11]Journal of the American Chemical Society,2011,vol. 133,p. 9242 - 9245
[12]Patent: WO2015/38938,2015,A1 .Location in patent: Paragraph 0466; 0468
[13]Patent: WO2016/149501,2016,A2 .Location in patent: Paragraph 0314
[14]MedChemComm,2019,vol. 10,p. 1037 - 1041

3
[ 331242-48-9 ]
[ 106984-09-2 ]
(2-{2-[2-(2-{5-[3-(3,5-dimethyl-biphenyl-4-yloxy)-propyl]-isoxazol-3-ylmethoxy}-ethoxy)-ethoxy]-ethoxy}-ethyl)-carbamic acid <i>tert</i>-butyl ester [ No CAS ]

Reference： [1]Australian Journal of Chemistry,2004,vol. 57,p. 553 - 564

4
[ 106984-09-2 ]
[ 331242-02-5 ]

Reference： [1]Australian Journal of Chemistry,2004,vol. 57,p. 553 - 564

5
[ 106984-09-2 ]
<i>N</i>-(2-{2-[2-(2-{5-[3-(3,5-dimethyl-biphenyl-4-yloxy)-propyl]-isoxazol-3-ylmethoxy}-ethoxy)-ethoxy]-ethoxy}-ethyl)-acetamide [ No CAS ]

Reference： [1]Australian Journal of Chemistry,2004,vol. 57,p. 553 - 564

6
[ 106984-09-2 ]
C₆₇H₈₆N₆O₁₄ [ No CAS ]

Reference： [1]Australian Journal of Chemistry,2004,vol. 57,p. 553 - 564

7
[ 106984-09-2 ]
[ 424829-28-7 ]

Reference： [1]Journal of Organic Chemistry,2002,vol. 67,p. 1993 - 2002

8
[ 106984-09-2 ]
4-[(S)-2-(Indan-5-ylcarbamoyl)-pyrrolidin-1-yl]-4-oxo-butyric acid 2-(2-{2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy}-ethoxycarbonyl)-3-{4-[(S)-2-(indan-5-ylcarbamoyl)-pyrrolidin-1-yl]-4-oxo-butyryloxy}-2-methyl-propyl ester [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2002,vol. 67,p. 1993 - 2002

9
[ 106984-09-2 ]
[ 424829-31-2 ]

Reference： [1]Journal of Organic Chemistry,2002,vol. 67,p. 1993 - 2002

10
[ 112-60-7 ]
[ 106984-09-2 ]

Reference： [1]Helvetica Chimica Acta,1991,vol. 74,p. 1697 - 1706
[2]Inorganica Chimica Acta,2011,vol. 365,p. 38 - 48
[3]Journal of the American Chemical Society,2011,vol. 133,p. 9242 - 9245
[4]Patent: US2015/166595,2015,A1
[5]Angewandte Chemie - International Edition,2015,vol. 54,p. 10327 - 10330
Angew. Chem.,2015,vol. 35,p. 10467 - 10471,5
[6]MedChemComm,2019,vol. 10,p. 1037 - 1041
[7]Patent: US2019/192668,2019,A1

11
[ 86770-67-4 ]
[ 106984-09-2 ]

Reference： [1]Helvetica Chimica Acta,1991,vol. 74,p. 1697 - 1706
[2]Inorganica Chimica Acta,2011,vol. 365,p. 38 - 48
[3]Journal of the American Chemical Society,2011,vol. 133,p. 9242 - 9245
[4]Angewandte Chemie - International Edition,2015,vol. 54,p. 10327 - 10330
Angew. Chem.,2015,vol. 35,p. 10467 - 10471,5
[5]MedChemComm,2019,vol. 10,p. 1037 - 1041

12
[ 65883-12-7 ]
[ 106984-09-2 ]

Reference： [1]Helvetica Chimica Acta,1991,vol. 74,p. 1697 - 1706
[2]Journal of the American Chemical Society,2011,vol. 133,p. 9242 - 9245
[3]MedChemComm,2019,vol. 10,p. 1037 - 1041

13
[ 106984-09-2 ]
[ 139115-96-1 ]

Reference： [1]Helvetica Chimica Acta,1991,vol. 74,p. 1697 - 1706

14
[ 106984-09-2 ]
[ 139116-02-2 ]

Reference： [1]Helvetica Chimica Acta,1991,vol. 74,p. 1697 - 1706

15
[ 106984-09-2 ]
[ 139116-05-5 ]

Reference： [1]Helvetica Chimica Acta,1991,vol. 74,p. 1697 - 1706

16
[ 106984-09-2 ]
[ 139116-11-3 ]

Reference： [1]Helvetica Chimica Acta,1991,vol. 74,p. 1697 - 1706

17
[ 106984-09-2 ]
[ 139115-99-4 ]

Reference： [1]Helvetica Chimica Acta,1991,vol. 74,p. 1697 - 1706

18
[ 1225383-33-4 ]
[ 106984-09-2 ]
C₄₄H₅₉N₃O₁₁ [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2010,vol. 132,p. 5820 - 5826

19
[ 305-53-3 ]
[ 106984-09-2 ]
(2-{2-[2-(2-tert-butoxycarbonylamino-ethoxy)-ethoxy]-ethoxy}-ethoxy)-acetic acid [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2009,vol. 48,p. 9658 - 9662

20
[ 106984-09-2 ]
C₂₀H₃₇NO₁₀ [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2009,vol. 48,p. 9658 - 9662

21
[ 106984-09-2 ]
[ 1207457-34-8 ]

Reference： [1]Angewandte Chemie - International Edition,2009,vol. 48,p. 9658 - 9662

22
[ 106984-09-2 ]
[ 1207457-35-9 ]

Reference： [1]Angewandte Chemie - International Edition,2009,vol. 48,p. 9658 - 9662

23
[ 106984-09-2 ]
rhodamine-CBT [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2009,vol. 48,p. 9658 - 9662

24
[ 77544-60-6 ]
[ 106984-09-2 ]

Reference： [1]Inorganica Chimica Acta,2011,vol. 365,p. 38 - 48
[2]Angewandte Chemie - International Edition,2015,vol. 54,p. 10327 - 10330
Angew. Chem.,2015,vol. 35,p. 10467 - 10471,5
[3]Angewandte Chemie - International Edition,2019,vol. 58,p. 13009 - 13013
Angew. Chem.,2019,vol. 131,p. 13143 - 13147,5
[4]Patent: US2019/192668,2019,A1

25
[ 79-08-3 ]
[ 106984-09-2 ]
(2-{2-[2-(2-tert-butoxycarbonylamino-ethoxy)-ethoxy]-ethoxy}-ethoxy)-acetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With sodium hydride; In tetrahydrofuran; at 20℃; for 4h;	Into a 50-mL round-bottom flask, was placed a solution of <strong>[106984-09-2]tert-butyl N-(2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl)carbamate</strong> (300.0 mg, 1.02 mmol, 1.00 equiv) in tetrahydrofuran (10 mL), sodium hydride (50.0 mg, 2.08 mmol, 1.20 equiv), 2-bromoacetic acid (141.0 mg, 1.01 mmol, 1.00 equiv). The resulting solution was stirred for 4 h at room temperature. The reaction was then quenched by the addition of water (20 mL). The resulting solution was extracted with ethyl acetate (20 mL3). The combined organic layers were washed with brine (20 mL1). The resulting mixture was concentrated under vacuum. This resulted in 310.0 mg (86%) of 14-[[(tert-butoxy)carbonyl]amino]-3,6,9,12-tetraoxatetradecanoic acid as light yellow oil.
53%	With sodium hydroxide; In tetrahydrofuran; toluene; at 45℃; for 16h;	To a stirred solution of <strong>[106984-09-2]tert-butyl (2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)carbamate</strong> (0.38 g, 1.29 mmol) and 2-bromoacetic acid (0.54 g, 3.8 mmol) in toluene:THF (1:1, 4 mL) was added NaOH (0.31 g, 7.7 mmol) at 45 C. The resulting reaction mixture stirred at 45 C. for 16 h. The reaction mixture was then evaporated, water (10 mL) was added and aqueous layer was acidified with 1 N HCl solution. The resulting mixture was extracted using DCM (3×50 mL) and the combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give 2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-oic acid as a colorless oil (0.24 g, 53%). LC-MS (ESI+) m/z 351.4 (M+H)+.

Reference： [1]Inorganica Chimica Acta,2011,vol. 365,p. 38 - 48
[2]Patent: US2017/8904,2017,A1 .Location in patent: Paragraph 0376; 0384
[3]Patent: US2019/192668,2019,A1 .Location in patent: Paragraph 2580; 2582

26
[ 106984-09-2 ]
[ 437655-95-3 ]

Reference： [1]Inorganica Chimica Acta,2011,vol. 365,p. 38 - 48

27
[ 106984-09-2 ]
(2-{2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy}-ethoxy)-acetic acid hydrochloride [ No CAS ]

Reference： [1]Inorganica Chimica Acta,2011,vol. 365,p. 38 - 48

28
[ 34619-03-9 ]
[ 86770-74-3 ]
[ 106984-09-2 ]

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 2906 - 2909

29
[ 106984-09-2 ]
[ 1310568-64-9 ]

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 2906 - 2909

30
[ 106984-09-2 ]
[ 1310568-65-0 ]

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 2906 - 2909

31
[ 106984-09-2 ]
[ 1310568-66-1 ]

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 2906 - 2909

32
[ 106984-09-2 ]
[ 1310568-67-2 ]

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 2906 - 2909

33
[ 106984-09-2 ]
[ 98-59-9 ]
[ 1246999-33-6 ]

Yield	Reaction Conditions	Operation in experiment
90%	With triethylamine; In dichloromethane; at 0 - 20℃; for 2.5h;	Step 2: Synthesis of S10 To a round-bottom flask, S9 (3.69 g, 12 mmol) was diluted in 100 mL of DCM. After cooling to 0 C, 4-toluenesulfonyl chloride (2.75 g, 14.4 mmol) and triethyl amine (2.51 mL, 18 mmol) were added sequentially. The resulting reaction mixture was stirred at 0 C for 30 min and then room temperature for 2 h. After workup with DCM and saturated NaHC03 solution, the combined organic layer was dried over anhydrous Na2S04. After filtration and evaporation, the residue was purified by column chromatography with hexane: ethyl acetate to give S 10 as colorless oil (4.98 g, 90 % yield). 1H NMR (400 MHz, CDC13) delta (ppm) 7.76 (d, = 8.4 Hz, 2H), 7.31 (d, = 8.4 Hz, 2H), 4.12 (m, 2H), 3.67-3.47 (m, 12H), 3.25-3.23 (m, 2H), 2.40 (s, 3H), 1.39 (s, 9H); ESI-MS calculated for C20H33NNaO8S [M+Na]+ = 470.18, obtained: 470.20.
73%	With triethylamine; In dichloromethane; at 20℃;	To a stirred solution of <strong>[106984-09-2]tert-butyl (2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)carbamate</strong> (8 g, 27.30 mmol, synthesized via Step 1 of Intermediate EN) in DCM (100 mL) was added TEA (5.52 g, 54.60 mmol) at rt. To the above reaction mixture was added dropwise TsCl (10.41 g, 54.60 mmol) in DCM (5 mL) at 0 C. After the addition, the reaction mixture was stirred at rt overnight. The mixture was concentrated in vacuo and the residue was purified via column chromatography (Petroleum ether/EtOAc=5%-80%) to give the title compound (10.9 g, 73%) as a yellow oil. LC-MS (ESI+): m/z 448.3 (M+H)+.
	With sodium hydroxide; In tetrahydrofuran; water; for 5.25h;Cooling with ice;	PREPARATION 21: T-BUTYL-2-(2-(2-(2-(P-METHYLPHENOXY)ETHOXY)ETHOXY)ETHOXY)ETHYL CARBAMATE To a reaction flask was added t-butyl-2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethylcarbamate (14.650 g). Tetrahydrofuran (75 mL) was added to dissolve t-butyl-2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethylcarbamate. To the reaction flask was added p-toluenesulfonyl chloride (11.439g). The mixture was cooled in an ice bath. To the reaction flask was dropwise added 20% sodium hydroxide aqueous solution (18.684 g) (over 15 min). The ice bath was removed when the addition was completed. The resultant mixture was stirred at the room temperature until the reaction was completed (for about 5 hr). To the reaction flask was again added 20% sodium hydroxide aqueous solution (8.715 g). The mixture was stirred for 2 hr in an oil bath at 40C. The resultant solution was directly used in the subsequent reaction.

330 mg	With pyridine; In dichloromethane; at 40℃; for 12h;	This oil was dissolved in DCM and treated with p-toluenesulfonyl chloride (1.18 g, 6.21 mmol) and pyridine (0.84 mL, 10.4 mmol). After stirring at 40 C for 12 h, the mixture was diluted with DCM and washed with iN HC1 (2 x 10 mL), H20 (10 mL), and brine (10 mL), then dried over Na2SO4 and concentrated. Purification via flash column chromatography on silica gel gave 330 mg (36% yield over 2 steps) of the tosylate as a colorless oil.
	With pyridine; In dichloromethane; at 40℃; for 12h;	This oil was dissolved in DCM and treated with p-toluenesulfonyl chloride (1.18 g,6.21 mmol) and pyridine (0.84 mL, 10.4 mmol). After stirring at 40 C for 12 h, the mixture was diluted with DCM and washed with iN HC1 (2 x 10 mL), H20 (10 mL), and brine (10 mL), then dried over Na2SO4 and concentrated. Purification via flash column chromatography on silica gel gave 330 mg (36% yield over 2 steps) of the tosylate as a colorless oil.

Reference： [1]Chemical Communications,2019,vol. 55,p. 7187 - 7190
[2]Tetrahedron Letters,2011,vol. 52,p. 2906 - 2909
[3]Patent: WO2017/176958,2017,A1 .Location in patent: Paragraph 0861-0862
[4]Angewandte Chemie - International Edition,2013,vol. 52,p. 10593 - 10597
Angew. Chem.,2013,vol. 125,p. 10787 - 10791
[5]Patent: US2019/192668,2019,A1 .Location in patent: Paragraph 3186; 3187
[6]Patent: EP2824108,2015,A1 .Location in patent: Paragraph 0120
[7]Patent: WO2015/38938,2015,A1 .Location in patent: Paragraph 0466; 0469
[8]Patent: WO2016/149501,2016,A2 .Location in patent: Paragraph 0315

34
[ 106984-09-2 ]
[ 1013921-36-2 ]

Reference： [1]Journal of the American Chemical Society,2011,vol. 133,p. 9242 - 9245
[2]Angewandte Chemie - International Edition,2013,vol. 52,p. 8957 - 8960
Angew. Chem.,2013,vol. 125,p. 9126 - 9129,4
[3]MedChemComm,2019,vol. 10,p. 1037 - 1041

35
[ 106984-09-2 ]
[ 1311203-07-2 ]

Reference： [1]Journal of the American Chemical Society,2011,vol. 133,p. 9242 - 9245

36
[ 106984-09-2 ]
[ 106-96-7 ]
[ 1219810-90-8 ]

Yield	Reaction Conditions	Operation in experiment
79.4%	With tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide; In water; at 0 - 20℃; for 5h;	tert-Butyl (2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)carbamate (9.0 g, 30.8 mmol) was dissolved in NaOH (40% aq.) (61.2 mL). Then TBAHS (522 mg, 1.54 mmol) was added into the mixture and followed with 3-bromoprop-l-yne (4.21 g, 35.4 mmol) at 0C, then warmed to r.t. for 5 hours. The reaction was monitored by TLC. When the starting material was consumed, the mixture was cooled to 0C. EtOAc (300 mL) and H20 (300 mL) were added, the organic phase was washed with H20 (200 mL x 2), evaporated the solvent, the crude was purified with column (DCM: EA = 3 : 1), 8.1 g of product was obtained as a light yellow oil. (79.4 % yield.) MR (400 MHz, CDCb) delta 4.20 (t, J= 4.6 Hz, 2H), 3.71 - 3.60 (m, 12H), 3.54 (t, J = 5.2 Hz, 2H), 3.31 (t, J= 5.1 Hz, 2H), 2.43 (t, J= 2.4 Hz, 1H), 1.45 (s, 9H).
55%		To a solution of <strong>[106984-09-2]tert-butyl (2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)carbamate</strong> (10.0 g, 34.1 mmol, Step 1 of Intermediate EN) in anhydrous THF (250 mL) was added sodium hydride (1.63 g, 40.94 mmol, 60% dispersion in mineral oil) in one portion under nitrogen atmosphere. The reaction mixture was stirred at rt for 0.5 h and thereafter it was cooled to 0 C. An 80% solution of 3-bromoprop-1-yne in toluene (5.7 mL, 51.2 mmol) was added dropwise to the reaction mixture at 0 C. over a period of 10 min. The resulting reaction mixture was stirred at 0 C. for 1 h and thereafter it was allowed to warm to rt. The resulting reaction mixture was stirred overnight at rt. Then the reaction mixture was quenched with a small aliquot of methanol (1.6 mL) and concentrated on a rotary evaporator. The obtained crude material was suspended in DCM (100 mL) and was washed with water (2×30 mL) and brine (50 mL). The resulting organic layer was dried over anhydrous sodium sulphate, filtered and concentrated on a rotary evaporator. The obtained crude product was purified by silica gel chromatography (gradient Ethyl acetate/Hexanes) to give the title compound (6.25 g, 55%) as a light yellow viscous liquid.
37%	With tetra-(n-butyl)ammonium iodide; potassium iodide; potassium hydroxide; In tetrahydrofuran; at 25℃; for 16h;	To a solution of <strong>[106984-09-2]tert-butyl N-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl]carbamate</strong> (2.00 g, 6.82 mmol, synthesized via Steps 1-3 of Intermediate AO) and 3-bromoprop-1-yne (973 mg, 8.18 mmol, 705 uL) in THF (30 mL) was added TBAI (151 mg, 409 umol), KI (169 mg, 1.02 mmol), KOH (382 mg, 6.82 mmol). The reaction mixture was stirred at 25 C. for 16 hours. On completion, the mixture was filtered, and the filterate was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography to give the title compound (0.85 g, 37% yield) as yellow oil. 1H NMR (400 MHz, CDCl3) delta 5.06 (s, 1H), 4.21 (d, J=2.4 Hz, 2H), 3.72-3.61 (m, 14H), 3.54 (t, J=5.2 Hz, 2H), 2.46-2.43 (m, 1H), 1.45 (s, 9H).

Reference： [1]Patent: WO2019/60693,2019,A1 .Location in patent: Paragraph 00418-00419
[2]Journal of the American Chemical Society,2011,vol. 133,p. 9242 - 9245
[3]Patent: US2019/192668,2019,A1 .Location in patent: Paragraph 2618; 2619
[4]Patent: US2019/192668,2019,A1 .Location in patent: Paragraph 2827; 2828
[5]Angewandte Chemie - International Edition,2013,vol. 52,p. 8957 - 8960
Angew. Chem.,2013,vol. 125,p. 9126 - 9129,4

37
C₁₄H₁₉NO₈ [ No CAS ]
[ 106984-09-2 ]
[ 1402209-74-8 ]

Reference： [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 7445 - 7448

38
C₁₄H₁₉NO₈ [ No CAS ]
[ 106984-09-2 ]
C₂₇H₄₆N₂O₁₄ [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 7445 - 7448

39
[ 106984-09-2 ]
[ 86770-74-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 402 - 406

40
[ 106984-09-2 ]
[ 1415920-66-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 402 - 406

41
[ 106984-09-2 ]
[ 1415920-60-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 402 - 406

42
[ 106984-09-2 ]
[ 1472653-59-0 ]

Reference： [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 8957 - 8960
Angew. Chem.,2013,vol. 125,p. 9126 - 9129,4

43
[ 106984-09-2 ]
[ 1474019-91-4 ]

Reference： [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 10593 - 10597
Angew. Chem.,2013,vol. 125,p. 10787 - 10791

44
[ 106984-09-2 ]
[ 1474019-94-7 ]

Reference： [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 10593 - 10597
Angew. Chem.,2013,vol. 125,p. 10787 - 10791

45
[ 106984-09-2 ]
[ 1474019-95-8 ]

Reference： [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 10593 - 10597
Angew. Chem.,2013,vol. 125,p. 10787 - 10791

46
[ 106984-09-2 ]
[ 1474019-97-0 ]

Reference： [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 10593 - 10597
Angew. Chem.,2013,vol. 125,p. 10787 - 10791

47
[ 106984-09-2 ]
[ 1474020-00-2 ]

Reference： [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 10593 - 10597
Angew. Chem.,2013,vol. 125,p. 10787 - 10791

48
[ 106984-09-2 ]
[ 1474020-03-5 ]

Reference： [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 10593 - 10597
Angew. Chem.,2013,vol. 125,p. 10787 - 10791

49
[ 106984-09-2 ]
C₂₄H₃₈N₄O₇S [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 10593 - 10597
Angew. Chem.,2013,vol. 125,p. 10787 - 10791

50
[ 106984-09-2 ]
[ 1246999-34-7 ]

Reference： [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 10593 - 10597
Angew. Chem.,2013,vol. 125,p. 10787 - 10791

51
[ 24424-99-5 ]
2-(2-(2-(-aminoethoxy)ethoxy)ethoxy)ethanol hydrochloride [ No CAS ]
[ 106984-09-2 ]

Yield	Reaction Conditions	Operation in experiment
		PREPARATION 20: T-BUTYL-2-(2-(2-(2-HYDROXYETHOXY)ETHOXY)ETHOXY)ETHYLCARBAMAT E To a reaction flask was added 2-(2-(2-(-aminoethoxy)ethoxy)ethoxy)ethanol hydrochloride (41.6 g). Distilled water (80 mL) was added to dissolve 2-(2-(2-(-aminoethoxy)ethoxy)ethoxy)ethanol hydrochloride. The solution was cooled in an ice bath. Anhydrous sodium carbonate (38.414 g) was dissolved in distilled water (200 mL) (over 1 hr). The mixture was dropwise added to the reaction flask. Di-t-butyl dicarbonate (51.370 g) was dissolved in tetrahydrofuran (120 mL). The mixture was dropwise added (over 160 min) to the reaction flask. The resultant mixture reacted overnight. After the reaction was completed, the reaction solution was concentrated and then extracted with ethyl acetate (150 mL) once, extracted with dichloromethane (150 mL) once. Two organic phases were combined, dried over anhydrous MgSO4 for 30 min, filtered and concentrated to give the target compound.
		To a reaction flask was added 2-(2-(2-(-aminoethoxy)ethoxy)ethoxy)ethanol hydrochloride (41.6 g). Distilled water (80 mL) was added to dissolve 2-(2-(2-(-aminoethoxy)ethoxy)ethoxy)ethanol hydrochloride. The solution was cooled in an ice bath. Anhydrous sodium carbonate (38.414 g) was dissolved in distilled water (200 mL) (over 1 hr). The mixture was dropwise added to the reaction flask. Di-t-butyl dicarbonate (51.370 g) was dissolved in tetrahydrofuran (120 mL). The mixture was dropwise added (over 160 min) to the reaction flask. The resultant mixture reacted overnight. After the reaction was completed, the reaction solution was concentrated and then extracted with ethyl acetate (150 mL) once, extracted with dichloromethane (150 mL) once. Two organic phases were combined, dried over anhydrous MgSO4 for 30 min, filtered and concentrated to give the target compound.

Reference： [1]Patent: EP2824108,2015,A1 .Location in patent: Paragraph 0119
[2]Patent: US2015/166595,2015,A1 .Location in patent: Paragraph 0239

52
2-(2-(2-(2-t-butoxyethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate [ No CAS ]
[ 106984-09-2 ]

Reference： [1]Patent: EP2824108,2015,A1
[2]Patent: US2015/166595,2015,A1

53
2-(2-(2-(2-(2-t-butoxyethoxy)ethoxy)ethoxy)ethyl)isoindol-1,3-dione [ No CAS ]
[ 106984-09-2 ]

Reference： [1]Patent: EP2824108,2015,A1
[2]Patent: US2015/166595,2015,A1

54
2-(2-(2-(2-t-butoxyethoxy)ethoxy)ethoxy)ethylamine [ No CAS ]
[ 106984-09-2 ]

Reference： [1]Patent: EP2824108,2015,A1
[2]Patent: US2015/166595,2015,A1

55
[ 147912-26-3 ]
[ 106984-09-2 ]

Reference： [1]Patent: EP2824108,2015,A1
[2]Patent: US2015/166595,2015,A1

56
[ 106984-09-2 ]
tert-butyl N-(2-(2-(2-(2-bromoethoxy)ethoxy)ethoxy)ethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With carbon tetrabromide; triphenylphosphine; In tetrahydrofuran; at 20℃; for 1h;	To a solution of 3 (200 mg, 0.68 mmol) and triphenylphosphine (358 mg, 1.36 mmol) in THF (4 mL) was added carbon tetrabromide (452 mg, 1.36 mmol) slowly at room temperature. The mixture was stirred at room temperaturefor 1 hr. Hexane (12 mL) was added to the mixture. Insoluble material was removed by filtration, then the filtrate was concentrated in vacuo. The residue was purified by column chromatography (eluted with 10%-50% EtOAc in hexane) to give 4 (216 mg, 0.606 mmol, 89 %) as colorless oil. 1H NMR (300 MHz, CDCl3) delta1.45 (9H, s), 3.28-3.37 (2H, m), 3.44-3.51 (2H, m), 3.52-3.57 (2H, m), 3.60-3.72 (8H, m), 3.82 (2H, t, J = 6.2 Hz), 5.02 (1H, brs).
26%		To a stirred solution of 87 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethanol (100muL, 0.55mmol) in 88 dioxane (1mL) was added Boc2O (152muL, 0.66mmol). The mixture was stirred for 18hat rt and then evaporated under reduced pressure. The crude was taken up in DCM (6mL), washed with H2O (2×6mL) and brine (1×5mL), dried over MgSO4, filtered and evaporated under reduced pressure. The crude product was purified using flash silica column chromatography (99:1 DCM:MeOH) to yield the desired 89 <strong>[106984-09-2]tert-butyl N-(2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethyl)carbamate</strong> (24mg, 81.8mumol, 15%), as a pale yellow oil (Rf 0.52, 9:1 DCM:MeOH). 1H NMR (400MHz, CDCl3) delta 3.75-3.67 (m, 4H, O-CH2), 3.66-3.57 (m, 8H, O-CH2CH2-O), 3.52 (t, J=5.2Hz, 2H, O-CH2), 3.29 (t, J=5.2Hz, 2H, NH-CH2), 1.43 (s, 9H, CH3 t Bu). 13C NMR (101MHz, CDCl3) delta 156.31, 79.19, 72.77, 70.72, 70.67, 70.55, 70.36, 70.20, 61.76, 40.67, 28.56. HRMS-ESI calculated for C13H27NNaO6 [M+Na]+ 316.1731, found m/z 316.1738. A solution of 91 bromine (7.3muL, 0.14mmol) in 67 DCM (0.2mL) at 0C was added to a solution of 92 triphenylphosphine (37mg, 0.14mmol) and 93 Et3N (20muL, 0.14mmol) in anhydrous DCM (0.2mL) at 0C. Following stirring at 0C for 30min, a solution of 89 <strong>[106984-09-2]tert-butyl N-(2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethyl)carbamate</strong> (42mg, 0.14mmol) in DCM (0.2mL) was added dropwise. After stirring at 0C for 2h, the mixture was evaporated under reduced pressure. The crude product was purified using flash silica column chromatography (5:1 hexane:EA) to yield the desired 94 tert-butyl N-(2-{2-[2-(2-bromoethoxy)ethoxy]ethoxy}ethyl)carbamate (13mg, 36.5mumol, 26%) as a colourless oil. 1H NMR (400MHz, CDCl3) delta 5.03 (br s, 1H, NH), 3.81 (t, J=6.3Hz, 2H, O-CH2), 3.73-3.58 (m, 8H, O-CH2CH2-O), 3.54 (t, J=5.1Hz, 2H, O-CH2), 3.47 (tJ=6.3, 1.2Hz, 2H, CH2Br), 3.31 (q, J=5.6Hz, 2H, NH-CH2), 1.44 (s, 9H, CH3 t Bu). HRMS-ESI calculated for C13H26BrNNaO5 [M+Na]+ 378.0887, found m/z 378.0894. To a solution of 9e (13mg, 35.1mumol) in anhydrous DMF (0.7mL) was added NaH (60% by mass dispersion in mineral oil) (5.5mg, 0.14mmol). After stirring for 30min, a solution of tert-butyl N-(2-{2-[2-(2-bromoethoxy)ethoxy]ethoxy}ethyl)carbamate (12.5mg, 35.1mumol) in anhydrous DMF (0.6mL) was added. The reaction mixture was stirred for 18h, then quenched with H2O (1.5mL), extracted with EA (4×2mL), washed with H2O (2×7mL), dried over MgSO4, filtered and evaporated under reduced pressure. The crude product was purified using flash silica column chromatography (99:1 DCM:MeOH) and semi-preparative RP-HPLC to yield the desired 17 (6.88mg, 10.7mumol, 31%), as a white solid. 1H NMR (400MHz, DMSO-d6) delta 7.97 (s, 1H, ArH indole), 7.81-7.75 (m, 3H, ArH indole and MeOPh), 7.58 (d, J=9.0Hz, 1H, ArH indole), 7.12-7.05 (m, 2H, ArH MeOPh), 6.95 (dd, J=8.9, 2.5Hz, 1H, ArH indole), 6.74 (br s, 1H, NH), 4.21-4.07 (m, 4H, N1-CH2 & indole-O-CH2), 3.86 (s, 3H, O-CH3), 3.85-3.75 (m, 4H, O-CH2 & O-CH2 THP), 3.65-3.45 (m, 8H, O-CH2CH2-O), 3.37 (t, J=6.1Hz, 2H, O-CH2), 3.19 (td, J=11.7, 2.0Hz, 2H, O-CH2 THP), 3.05 (q, J=6.0Hz, 2H, NH-CH2), 2.13-2.02 (m, 1H, CH THP), 1.41-1.21 (m, 13H, O-CH2CH2 THP, CH3 t Bu). HRMS-ESI calculated for C35H48N2NaO9 [M+Na]+ 663.3252, found m/z 663.3247. Analytical RP-HPLC Rt=21.00min.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29
[2]European Journal of Medicinal Chemistry,2018,vol. 145,p. 770 - 789
[3]Patent: WO2015/38938,2015,A1
[4]Patent: WO2016/149501,2016,A2

57
[ 106984-09-2 ]
C₄₂H₇₅NO₇ [ No CAS ]

Reference： [1]Patent: WO2015/38938,2015,A1

58
[ 106984-09-2 ]
2-bromo-N-(14-((3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-(6-methylheptan-2-yl)-2,3,4,7,8,9,10,1 1,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxy)-3,6,9,12-tetraoxatetradecyl)acetamide [ No CAS ]

Reference： [1]Patent: WO2015/38938,2015,A1

59
[ 106984-09-2 ]
[ 98-59-9 ]
tert-butyl 2-(2-(2-(2-(p-methylphenoxy)ethoxy)ethoxy)ethoxy)ethylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In tetrahydrofuran; water; at 20℃; for 5.25h;Cooling with ice;	To a reaction flask was added t-butyl-2-(2-(2-(2-hydroxyethoxyl)ethoxy)ethoxy)ethylcarbamate (14.650 g). Tetrahydrofuran (75 mL) was added to dissolve t-butyl-2-(2-(2-(2-hydroxyethoxyl)ethoxy)ethoxy)ethylcarbamate. To the reaction flask was added p-toluenesulfonyl chloride (11.439 g). The mixture was cooled in an ice bath. To the reaction flask was dropwise added 20% sodium hydroxide aqueous solution (18.684 g) (over 15 min). The ice bath was removed when the addition was completed. The resultant mixture was stirred at the room temperature until the reaction was completed (for about 5 hr). To the reaction flask was again added 20% sodium hydroxide aqueous solution (8.715 g). The mixture was stirred for 2 hr in an oil bath at 40 C. The resultant solution was directly used in the subsequent reaction.

Reference： [1]Patent: US2015/166595,2015,A1 .Location in patent: Paragraph 0240

60
[ 106984-09-2 ]
t-butyl-2-(2-(2-(2-(dimethylamino)ethoxy)ethoxy)ethoxy)ethylcarbamate [ No CAS ]

Reference： [1]Patent: US2015/166595,2015,A1

61
[ 106984-09-2 ]
2-(2-(2-(2-(dimethylamino)ethoxy)ethoxy)ethoxy)ethylamine hydrochloride [ No CAS ]

Reference： [1]Patent: US2015/166595,2015,A1

62
[ 106984-09-2 ]
diisopropylaethylamonium N,N,2,2-tetramethyl-4-oxo-N-(2-(phosphonooxy)ethyl)-3,8,11,14-tetraoxa-5-azahexadecan-16-aminium [ No CAS ]