[ CAS No. 159858-22-7 ] {[proInfo.proName]}

Name: 159858-22-7|Fmoc-Val-Cit-PAB-OH|98%
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SKU: A192152
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Quality Control of [ 159858-22-7 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 159858-22-7 ]

SDS Specification

Alternatived Products of [ 159858-22-7 ]

Product Details of [ 159858-22-7 ]

CAS No. :	159858-22-7	MDL No. :	MFCD22417106
Formula :	C₃₃H₃₉N₅O₆	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DALMAZHDNFCDRP-VMPREFPWSA-N
M.W :	601.69	Pubchem ID :	59165375
Synonyms :	Fmoc-Val-Cit-PAB

Calculated chemistry of [ 159858-22-7 ]

Physicochemical Properties

Num. heavy atoms :	44
Num. arom. heavy atoms :	18
Fraction Csp3 :	0.33
Num. rotatable bonds :	18
Num. H-bond acceptors :	6.0
Num. H-bond donors :	6.0
Molar Refractivity :	166.11
TPSA :	171.88 Å²

Pharmacokinetics

GI absorption :	Low
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.64 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.24
Log Po/w (XLOGP3) :	3.28
Log Po/w (WLOGP) :	3.27
Log Po/w (MLOGP) :	1.82
Log Po/w (SILICOS-IT) :	3.5
Consensus Log Po/w :	3.02

Druglikeness

Lipinski :	3.0
Ghose :	None
Veber :	2.0
Egan :	1.0
Muegge :	4.0
Bioavailability Score :	0.17

Water Solubility

Log S (ESOL) :	-4.75
Solubility :	0.0107 mg/ml ; 0.0000177 mol/l
Class :	Moderately soluble
Log S (Ali) :	-6.56
Solubility :	0.000164 mg/ml ; 0.000000273 mol/l
Class :	Poorly soluble
Log S (SILICOS-IT) :	-8.92
Solubility :	0.000000722 mg/ml ; 0.0000000012 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	5.09

Safety of [ 159858-22-7 ]

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

Application In Synthesis of [ 159858-22-7 ]

* 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 [ 159858-22-7 ]
Downstream synthetic route of [ 159858-22-7 ]

[ 159858-22-7 ] Synthesis Path-Upstream 1~12

1
[ 159858-21-6 ]
[ 623-04-1 ]
[ 159858-22-7 ]

Yield	Reaction Conditions	Operation in experiment
88%	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 48 h; Darkness	DCM/MeOH=2/1 mixed solvent 60 ml was added to the reaction flask, followed by addition of Fmoc-vc2g (4.2 mmol) and1.04 g (2 eq) of PABOH was added. After stirring the dissolved portion, 2.0 g (2 eq) of EEDQ was added. The reaction system is protected from light at room temperatureStir the reaction for 2.0 days. After completion of the reaction, the mixture was concentrated under reduced pressure at 40°C to give a white solid. Collect white solids and add methyl tert-butylEthyl ether (100 ml) was stirred and filtered, and the filter cake was washed with methyl tert-butyl ether. The resulting white solid was dried at 40 °C under reduced pressure to give 2.2 g.About 88percent
85%	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 36 h; Darkness; Inert atmosphere	Fmoc-Val-Cit-PABOH 2. To a solution of Fmoc-protected dipeptide 1 (0.30 g, 0.60 mmol) in CH₂Cl₂/MeOH (2: 1 , 9 mL) was added P-aminobenzyl alcohol (0.12 g, 0.98 mmol ) and EEDQ (0.24 g, 0.98 mmol), and the reaction mixture was stirred in the dark for 1.5 d. The solvents were evaporated, and the resultant was triturated with Et₂0 (25 mL). The resulting suspension was sonicated for 20 min and left to stand for 30 min. The crude product was collected by filtration and then purified by flash chromatography using a pre-packed 50 g silica column [solvent A: MeOH; solvent B: CH₂C1₂; gradient: 0percentA / 100percentB (1 CV), 0percentA / 100percentB -→ 20percentA / 80percentB (10 CV), 20percentA / 80percentB (2 CV); flow rate: 40 mL/min; monitored at 254 and 280 nm] to afford Fmoc-protected compound 2 (0.31 g, 0.51 mmol, 85percent yield) as a brown solid. [000188] NMR (500 MHz, DMSO-d6) 6 10.00 (1 H, s), 8.13 (1 H, d, J = 7.7 Hz), 7.92 (2H, d, J = 7.5 Hz), 7.81 - 7.71 (2H, m), 7.57 (2H, d, J= 8.4 Hz), 7.49 - 7.40 (3H, m), 7.35 (2H, t, J= 7.4 Hz), 7.26 (2H, d, J = 8.3 Hz), 5.99 (1 H, t, J = 6.5 Hz), 5.43 (2H, s), 5.12 (1 H, t, J= 5.6 Hz), 4.45 (2H, d, J= 5.4 Hz), 4.32 (1H, d,J= 10.1 Hz), 4.29 - 4.19 (3H, m), 4.00 - 3.88 (1H, m), 3.12 - 2.91 (2H, m), 2.09 - 1.94 (1H, m), 1.80-1.31 (4H, m), 0.90 (3H, d, .7=6.6 Hz), 0.88 (3H, d,J=6.7 Hz). [000189] ^I3C NMR (125 MHz, DMSO-d6) δ 171.7, 170.9, 159.3, 156.6, 144.4, 144.2, 141.2, 138.0, 137.9, 128.1, 127.6, 127.4, 125.8, 120.6, 119.3, 66.2, 63.1, 60.6, 47.2,30.9,30.0, 27.3, 19.7, 18.8, 15.0.
82%	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol at 20℃; for 36 h;	Fmoc-val-cit (1 eq),Add 2 eq of p-aminobenzyl alcohol (2 eq) to DMC / MeOH (2: 1), add EEDQ (2 eq) and shake for 1.5 days at room temperature.After completion of the reaction, the solvent is dried and precipitated with ether. Repeat after filtering with Ether. Yield: yellow solid 82percent.

77%	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 40℃;	Step 3 Synthesis of (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (92) To the suspension of compound 90 (70 g, 0.141 mol) in DCM/MeOH (1 L/500 mL) was added compound 91 (34.7 g, 0.282 mol) followed by EEDQ (69.7 g, 0.282 mol). The mixture was stirred at 40° C. overnight. The reaction mixture was filtered and the wet cake was suspended in EtOAc/TBME (500 mL/200 mL) and stirred for 30 min, then filtered. The solid was washed with EtOAc/TBME to provide compound 92 as off-white solid 65 g (77percent). ¹H NMR (400 MHz, DMSO-d6) δ=9.98 (s, 1H), 8.11 (d, 1H), 7.87 (d, 2H), 7.77 (m, 2H), 7.52 (d, 2H), 7.39 (m, 3H), 7.30 (m, 2H), 7.21 (d, 2H), 5.97 (m, 1H), 5.41 (s, 2H), 5.10 (m, 1H), 4.42 (m, 3H), 4.22 (m, 3H), 3.90 (m, 1H), 2.93 (m, 2H), 1.98 (m, 1H), 1.50 (m, 2H), 1.30 (m, 2H), 0.84 (m, 6H).
76%	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃;	A solution of compound 28 (1 g, 2.01 mmol, leq) andp-aminobenzyl alcohol (273 mg, 2.21 mmol, 1.1 eq) in a mixture of DCM/MeOH (20 mL/10 mL) was treated with EEDQ (996 mg, 4.03 mmol, 2 eq). The mixture was stirred in the dark at room temperature overnight. The solvents were removed under vacuum and the resulting solid residue was triturated with 10 mL of ethyl ether. The solid was collected by filtration and washed with ethyl ether to yield the product (925 mg, 76percent yield): ¹H NMR (DMSO-5 d, J -8.5 Hz), 7.74 (2H, t, J = 6.7 Hz), 7.89 (2H, d, J = 7.6 Hz)₅ 8.12 (IH, d, J = 7.3 Hz); ¹³ C NMR (DMSO-c^) δ 18.34, 19.28, 26.84, 29.56, 30.47, 46.67, 53.05, 60.05, 62.55, 65.65, 118.71, 119.98, 125.23, 126.79, 126.94, 127.51, 137.27, 137.36, 140.55, 143.60, 143.73, 155.93, 158.69, 170.17, 171.06.
65%	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In methanol; dichloromethane at 20℃; for 16 h; Darkness	EEDQ (840 mg, 3.4 mmol) is added to a solution containing compound [12] (870 mg, 1 .7 mmol) and p-aminobenzyl alcohol (227 mg, 1 .8 mmol) in dichloro- methane/methanol 2:1 (15 mL). The reaction is left in the dark at room temperature for 16 hours. The solvents are removed, and the resulting solid residue filtrated using diethyl ether to give product [14] as a white solid, 660 mg (65percent yield). MS: m/z 624 [M+Na]⁺.¹H NMR (400 MHz, DMSO) δ 10.00 (bs, 1 H), 8.13 (m, 4H), 7.92 (d, J = 7.3 Hz, 2H), 7.76 (d, J = 7.6 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.51 - 7.10 (m, 2H), 6.02 (s, 1 H), 5.43 (m, 4H), 5.13 (s, 1 H), 4.47 (s, 3H), 4.31 (m 4H), 3.13 - 2.74 (m, 2H), 2.03 (s, 1 H), 1 .83 - 1 .55 (m, 2H), 1 .43 (s, 2H), 0.90 (d, J = 6.7 Hz, 6H).¹³C NMR (101 MHz, DMSO) δ 171 .2, 170.4, 158.93, 156.15, 144.6, 143.8, 140.7, 137.5, 127.6, 127.2 (2C) 125.3, 120.1 (2C), 1 18.9, 65.7, 62.6, 60.1 , 53.0, 46.7, 31 .0, 30.5, 26.7, 19.6, 18.7.

Reference： [1] International Journal of Molecular Sciences, 2017, vol. 18, # 9,
[2] Patent: CN107789630, 2018, A, . Location in patent: Paragraph 0073; 0074; 0075
[3] Patent: WO2017/66668, 2017, A1, . Location in patent: Paragraph 000187-000189
[4] Journal of Controlled Release, 2012, vol. 160, # 3, p. 618 - 629
[5] Patent: KR2017/41562, 2017, A, . Location in patent: Paragraph 0431-0432
[6] Patent: US2016/271270, 2016, A1, . Location in patent: Paragraph 0379; 0382
[7] Patent: WO2008/34124, 2008, A2, . Location in patent: Page/Page column 79
[8] Patent: WO2018/178060, 2018, A1, . Location in patent: Page/Page column 64; 65; 67
[9] Patent: WO2014/80251, 2014, A1, . Location in patent: Sheet 16/23
[10] Bioconjugate Chemistry, 2015, vol. 26, # 11, p. 2261 - 2278
[11] Nature Communications, 2017, vol. 8, # 1,

2
[ 1037794-22-1 ]
[ 130878-68-1 ]
[ 159858-22-7 ]

Reference： [1] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 989 - 1000
[2] Patent: WO2015/95227, 2015, A2, . Location in patent: Page/Page column 144
[3] Patent: WO2017/66668, 2017, A1, . Location in patent: Paragraph 000160

3
[ 68858-20-8 ]
[ 159858-22-7 ]

Reference： [1] Journal of Controlled Release, 2012, vol. 160, # 3, p. 618 - 629
[2] Patent: WO2014/80251, 2014, A1,
[3] Bioconjugate Chemistry, 2015, vol. 26, # 11, p. 2261 - 2278
[4] Patent: US2016/271270, 2016, A1,
[5] International Journal of Molecular Sciences, 2017, vol. 18, # 9,
[6] Patent: CN107789630, 2018, A,
[7] Patent: WO2018/178060, 2018, A1,

4
[ 130878-68-1 ]
[ 159858-22-7 ]

Reference： [1] Journal of Controlled Release, 2012, vol. 160, # 3, p. 618 - 629
[2] Patent: WO2014/80251, 2014, A1,
[3] Patent: WO2017/66668, 2017, A1,
[4] Patent: KR2017/41562, 2017, A,
[5] Patent: CN107789630, 2018, A,

5
[ 372-75-8 ]
[ 159858-22-7 ]

Reference： [1] Patent: WO2015/95227, 2015, A2,
[2] Patent: WO2017/66668, 2017, A1,
[3] Patent: WO2017/66668, 2017, A1,
[4] Patent: KR2017/41562, 2017, A,
[5] International Journal of Molecular Sciences, 2017, vol. 18, # 9,

6
[ 870487-04-0 ]
[ 159858-22-7 ]

Reference： [1] Patent: WO2015/95227, 2015, A2,
[2] Patent: WO2017/66668, 2017, A1,
[3] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 989 - 1000

7
[ 1037793-80-8 ]
[ 159858-22-7 ]

Reference： [1] Patent: WO2015/95227, 2015, A2,

8
[ 623-04-1 ]
[ 159858-22-7 ]

Reference： [1] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 989 - 1000

9
[ 159858-22-7 ]
[ 159857-81-5 ]

Reference： [1] Patent: EP2486933, 2015, B1,
[2] Patent: WO2017/66668, 2017, A1,
[3] Patent: WO2017/66668, 2017, A1,
[4] International Journal of Molecular Sciences, 2017, vol. 18, # 9,
[5] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 989 - 1000
[6] Patent: CN107789630, 2018, A,
[7] Patent: CN108743968, 2018, A,

10
[ 159858-22-7 ]
[ 159857-79-1 ]

Yield	Reaction Conditions	Operation in experiment
96%	With diethylamine In N,N-dimethyl-formamide for 2 h;	[0438] Fmoc-val-cit-PAB-OH (14.61 g, 24.3 mmol, 1.0 eq.; see, e.g., U.S. Patent No. 6,214,345 to Firestone et al.) was diluted with DMF (120 mL, 0.2 M) and to this solution was added a diethylamine (60 mL). The reaction was monitored by HPLC and found to be complete in 2 h. The reaction mixture was concentrated and the resulting residue was precipitated using ethyl acetate (ca. 100 mL) under sonication over for 10 min. Ether (200 mL) was added and the precipitate was further sonicated for 5 min. The solution was allowed to stand for 30 min. without stirring and was then filtered and dried under high vacuum to provide Val-cit-P AB-OH, which was used in the next step without further purification. Yield: 8.84 g (96percent). Val-cit-PAB-OH (8.0 g, 21 mmol) was diluted with DMF (110 mL) and the resulting solution was treated with MC-OSu (Willner et at, 1993, Bioconjugate Chem. 4:521; 6.5 g, 21 mmol, 1.0 eq.). The reaction was complete according to HPLC after 2 h. The reaction mixture was concentrated and the resulting oil was precipitated using ethyl acetate (50 mL). After sonicating for 15 min, ether (400 mL) was added and the mixture was sonicated further until all large particles were broken up. The solution was then filtered and the solid dried to provide an off-white solid intermediate. Yield: 11.63 g (96percent); ES-MS m/z 757.9 [M-H]
96%	With diethylamine In N,N-dimethyl-formamide for 2 h;	[0454] Fmoc-val-cit-P AB-OH (14.61 g, 24.3 mmol, 1.0 eq., see, e.g., U.S. Patent No. 6,214,345 to Firestone et al.) was diluted with DMF (120 mL, 0.2 M) and to this solution was added a diethylamine (60 mL). The reaction was monitored by HPLC and found to be complete in 2 h. The reaction mixture was concentrated and the resulting residue was precipitated using ethyl acetate (ca. 100 mL) under sonication for 10 min. Ether (200 mL) was added and the precipitate was further sonicated for 5 min. The solution was allowed to stand for 30 min. without stirring and was then filtered and dried under high vacuum to provide Val-cit-P AB-OH, which was used in the next step without further purification. Yield: 8.84 g (96percent). Val-cit-P AB-OH (8.0 g, 21 mmol) was diluted with DMF (110 mL) and the resulting solution was treated with MC-OSu (Willner et al, 1993, EPO <DP n="138"/>Bioconjugate Chem. 4:521; 6.5 g, 21 mmol, 1.0 eq.). The reaction was complete according to HPLC after 2 h. The reaction mixture was concentrated and the resulting oil was precipitated using ethyl acetate (50 mL). After sonicating for 15 min, ether (400 niL) was added and the mixture was sonicated further until all large particles were broken up. The solution was then filtered and the solid dried to provide an off-white solid intermediate. Yield: 11.63 g (96percent); ES-MS m/z 757.9 [M-H]
96%	With diethylamine In N,N-dimethyl-formamide for 2 h;	Example 1 - Preparation of compound AB Fmoc-val-cit-PAB-OH (14.61 g, 24.3 mmol), 1.0 eq., ) was diluted with DMF (120 mL, 0.2 M) and to this solution was added a diethylamine (60 mL). The reaction was monitored by HPLC and found to be complete in 2 h. The reaction mixture was concentrated and the resulting residue was precipitated using ethyl acetate (ca. 100 mL) under sonication over for 10 min. Ether (200 mL) was added and the precipitate was further sonicated for 5 min. The solution was allowed to stand for 30 min. without stirring and was then filtered and dried under high vacuum to provide Val-cit-PAB-OH, which was used in the next step without further purification. Yield: 8.84 g (96percent). Val-cit-PAB-OH (8.0 g, 21 mmol) was diluted with DMF (110 mL) and the resulting solution was treated with MC-OSu (Willner et al., (1993) Bioconjugate Chem. 4:521; 6.5 g, 21 mmol, 1.0 eq.).

93%	With diethylamine In 1-methyl-pyrrolidin-2-one at 20℃; for 16 h; Inert atmosphere	Val-Cit-PABOH 3. To a solution of Fmoc-protected compound 2 (0.31 g, 0.51 mmol) in NMP (5 mL) was added diethylamine (1 mL), and the reaction mixture was stirred for 16 h at ambient temperature. The solvent was then evaporated under reduced pressure, and the resulting oil was triturated with CH₂C1₂, and the mixture was sonicated for 30 min. The solid was collected by filtration and washed with CH₂C1₂ (3 x 10 mL) to afford desired compound 3 (0.19 g, 0.49 mmol, 93percent yield) as a brown solid. [000191] NMR (500 MHz, DMSO-d6) δ 10.03 (1H, s), 8.18 (1H, d, J= 6.2 Hz), 7.52 (2H, d, J= 8.4 Hz), 7.22 (2H, d,J = 8.4 Hz), 5.97 (1H, t, J = 5.8 Hz), 5.39 (2H, s), 5.08 (1H, s), 4.51 - 4.43 (3H, m), 3.13 - 2.95 (2H, m), 2.92 (1H, dd, J= 13.2, 6.3 Hz), 1.93 (2H, dd, J= 11.9, 6.5 Hz), 1.74 - 1.61 (1H, m), 1.61 - 1.49 (1H, m), 1.47-1.29 (2H,m),0.87 (3H, d, ,7=6.8 Hz), 0.78 (3H, d, .7=6.8 Hz). [000192] ⁿC NMR (125 MHz, DMSO-d6) δ 170.9, 159.3, 137.9, 137.9, 127.4, 119.4, 63.0, 59.8, 53.0, 31.6,30.5,27.1, 19.8, 17.5.
90%	at 20℃; for 24 h;	490 mg (0.815 mmol) of Fmoc-vc-PABOH was added to 10 ml of NMP, dissolved under stirring, and then diethylamine was added.2ml. The reaction was stirred at room temperature for 24 h. After completion of the reaction, the mixture was concentrated under reduced pressure at 40° C., and 20 ml of DCM was added to the resulting oil and stirred.The crystals were crystallized and filtered. The filter cake was washed with DCM and the resulting solid was dried under reduced pressure to give 277 mg in 90percent yield.
90%	With diethylamine In 1-methyl-pyrrolidin-2-one at 20℃; for 24 h;	Fmoc-vc-PABOH 490 mg (0.815 mmol) was added to 10 ml of NMP and stirred to dissolve, and then 2 ml of diethylamine was added.The reaction was stirred at room temperature for 24 h. After completion of the reaction, the mixture was concentrated under reduced pressure at 40 ° C.Crystallization, filtration, filter cake washed with DCM,The obtained solid was dried under reduced pressure to give 277 mg.The yield was 90percent.
72%	With piperidine In N,N-dimethyl-formamide at 20℃;	To a solution of compound 29 (622 mg, 1.03 mmol) in 10 mL of anhydrous DMF was added piperidine (2 mL). The mixture was stirred at room temperature overnight and then the solvents were evaporated under vacuum. The residue was triturated with DCM and the resulting solid was filtered and washed with DCM to give the product (283 mg, 72percent yield): ¹H NMR (DMSO-^) δ 0.79 (3H, d, J = 6.7 Hz), 0.89 (3H, d, J = 6.7 Hz), 1.38-1.42 (2H, m), 1.52-1.68 (2H, m), 1.94 (IH, sext, J = 6.3 Hz), 2.89-3.01 (2H, m), 3.05 (IH, d, J = 4.7 Hz), 4.46 (2H, s), 5.09 (IH, brs), 5.40 (2H, s), 5.98 (IH, t, J = 5.3 Hz), 7.23 (2H, d, J - 8.2 Hz), 7.54 (2H, d, J = 8.5 Hz), 8.14 (IH, brs), 10.03 (IH, s); ¹³ C NMR (DMSO-
60%	With piperidine In N,N-dimethyl-formamide at 20℃; for 3 h;	Piperidine (2.2 mL) is added to a solution of compound [14] (660 mg, 1 .09 mmol) in anhydrous dimethylformamide (5 mL) and the reaction left at room temperature for 3 h. The solvent is removed under vacuum and the residue treated with di- chloromethane in order to obtain a solid that is filtered to give product [15], 240 mg (60percent mg). MS: m/z 380 [M+H]⁺.¹H NMR (400 MHz, DMSO) δ 10.1 1 (s, 1 H), 8.25 (s, 1 H), 7.58 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 6.10 (s, 1 H), 5.46 (s, 2H), 4.48 (m, 3H), 3.23 - 3.09 (m, 2H), 3.1 1 - 2.88 (m, 2H), 1 .99 (dd, J = 12.2, 6.4 Hz, 2H), 1 .99 (dd, J = 12.2, 6.4 Hz, 1 H), 1 .81 - 1 .55 (m, 2H), 1 .55 - 1 .28 (m, 2H), 1 .04 - 0.68 (m, 6H).¹³C NMR (101 MHz, DMSO) δ 173.3, 170.4, 158.9, 137.5, 126.9 (2C), 125.3, 1 19.9 (2C), 62.6, 59.3, 52.6, 31 .1 , 29.9, 26.6, 19.3, 17.0 (2C).
597 mg	With piperidine In N,N-dimethyl-formamide at 20℃; for 1 h;	Step 2. To a solution of compound 44-3 (2.14 mmol) in DMF (10 mL) was added compound 44-4 (0.6 mL, 4.5 mmol) and stirred at r.t. for 1 h. The mixture was concentrated and washed with MTBE (30 mL x 3), filtered and the filtrate was concentrated to give 44-5 (597 mg, Yield: 70 percent).

Reference： [1] Patent: WO2007/8603, 2007, A1, . Location in patent: Page/Page column 137; 165; 166
[2] Patent: WO2007/8848, 2007, A2, . Location in patent: Page/Page column 108; 136; 137
[3] Patent: EP2486933, 2015, B1, . Location in patent: Paragraph 0495
[4] Patent: WO2017/66668, 2017, A1, . Location in patent: Paragraph 000190-000192
[5] Patent: CN107789630, 2018, A, . Location in patent: Paragraph 0076; 0077; 0078
[6] Patent: CN108743968, 2018, A, . Location in patent: Paragraph 0019; 0020; 0021
[7] International Journal of Molecular Sciences, 2017, vol. 18, # 9,
[8] Patent: WO2008/34124, 2008, A2, . Location in patent: Page/Page column 79
[9] Patent: WO2018/178060, 2018, A1, . Location in patent: Page/Page column 64; 65; 67; 68
[10] Patent: WO2014/80251, 2014, A1, . Location in patent: Sheet 16/23
[11] Patent: WO2015/95227, 2015, A2, . Location in patent: Page/Page column 144; 145
[12] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 989 - 1000
[13] Chemical Science, 2018, vol. 9, # 31, p. 6490 - 6496

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[ 5070-13-3 ]
[ 159858-22-7 ]
[ 863971-53-3 ]

Yield	Reaction Conditions	Operation in experiment
89%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1 h; Inert atmosphere	N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valyl-N⁵-carbamoyl-N-[4-(hydroxymethyl)phenyl]-L-ornithinamide (1.3 g, 2.16 mmol) (prepared as reported in EP0624377A2) and bis(4-nitrophenyl) carbonate (1.32 g, 4.34 mmol) were dissolved in 6 mL of dry DMF under nitrogen atmosphere, DIPEA (0.75 mL, 4.35 mmol) was added and the resulting solution was stirred an hour at room temperature. Diethylether (120 mL) was added, the resulting precipitate is filtered off, washed with diethylether and dried under vacuum affording N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valyl-N⁵- carbamoyl-N-[4-([(4-nitrophenoxy)carbonyl]oxy}methyl)phenyl]-L-ornithinamide (1.47 g, 89percent yield).ESI MS: m/z 767 (MH+)¹H NMR (400 MHz, DMSO-de) δ 0.86 (d, J = 6.7 Hz, 3 H), 0.88 (d, J = 6.7 Hz, 3 H), 1.30 - 1.52 (m, 2 H), 1.60 (m, 1 H), 1.69 (m, 1 H), 1.99 (m, 1 H), 2.90 - 3.10 (m, 2 H), 3.93 (dd, J = 8.9, 7.0 Hz, 1 H), 4.14 - 4.34 (m, 3 H), 4.42 (m, 1 H), 5.24 (s, 2 H), 5.39 (s, 2 H), 5.97 (t, J = 5.5 Hz, 1 H), 7.32 (m, 2 H), 7.42 (m, 5 H), 7.55 (m, 2 H), 7.65 (d, J = 8.4 Hz, 2 H), 7.74 (t, J = 7.9 Hz, 2 H), 7.88 (d, J = 7.6 Hz, 2 H), 8.12 (d, J = 7.4 Hz, 1 H), 8.31 (m, 2 H), 10.12 (s, 1 H)
89%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1 h; Inert atmosphere	N-[(9H-fl uoren-9-ylmethoxy)carbonyl]-L-valyl-N5-carbamoyl-N-[4-(hydroxymethyl)phenyl]-L-ornithinamide (1.3 g, 2.16 mmcl) (prepared as reported in EP0624377A2) and bis(4-nitrophenyl) carbonate (1.32 g, 4.34 mmol) were dissolved in 6 ml of dry DMF under nitrogen atmosphere, DIPEA (0.75 ml, 4.35 mmol) was added and the resulting solution was stirred an hour at room temperature. Diethylether (120 ml) was added, the resulting precipitate is filtered off,washed with diethylether and dried under vacuum affording N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valyl-N5- carbamoyl-N-[4-([(4-nitrophenoxy)carbonyl]oxy}methyl)phenyl]-L-ornithinamide (68) (1.47 g, 89percent yield). MS (ESI): 767 [M+H].1H NMR (400 MHz, DMSO-d6) 0.86 (d, J = 6.7 Hz, 3 H), 0.88 (d, J = 6.7 Hz, 3 H), 1.30- 1.52 (m, 2 H), 1.60 (m, 1H), 1.69 (m, 1 H), 1.99 (m, 1 H), 2.90-3.10 (m, 2 H), 3.93 (dd, J = 8.9, 7.0 Hz, 1 H), 4.14-4.34 (m, 3 H), 4.42 (m, 1H), 5.24 (s, 2 H), 5.39 (s, 2 H), 5.97 (t, J = 5.5 Hz, 1 H), 7.32 (m, 2 H), 7.42 (m, 5 H), 755 (m, 2 H), 7.65 (d, J 8.4Hz, 2 H), 7.74 (t, J = 7.9 Hz, 2 H), 7.88 (d, J = 7.6 Hz, 2 H), 8.12 (d, J = 7.4 Hz, 1 H), 8.31 (m, 2 H), 10.12 (s, I H)
84%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1.5 h;	(0321) (9H-fluoren-9-yl)methyl((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate 84 (0.5 g, 0.831 mmol) was dissolved in DMF (5 mL) and compound 53a (0.506 g, 1.662 mmol) was added, followed by DIEA (0.23 mL, 1.320 mmol) at RT. The reaction mixture was stirred for 1.5 h at RT. LC/MS showed no starting material was left. The reaction mixture was then treated with 30 mL of Et₂O and stirred at RT for 30 min. The precipitate that formed was filtered and washed with additional Et₂O. The solid was dried under high vacuum to afford (9H-fluoren-9-yl)methyl((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)-phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-1-oxobutan-2-yl)carbamate 85 (0.533 gm, 84percent) as an off yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.12 (s, 1H), 8.37-8.22 (m, 2H), 8.12 (d, J=7.5 Hz, 1H), 7.88 (d, J=7.5 Hz, 2H), 7.76-7.50 (m, 5H), 7.44-7.15 (m, 7H), 5.96 (t, J=5.5 Hz, 1H), 5.39 (s, 2H), 5.24 (s, 2H), 4.49-4.39 (m, 1H), 4.34-4.10 (m, 3H), 3.93 (dd, J=8.8, 7.3 Hz, 1H), 3.13-2.82 (m, 2H), 2.05-1.88 (m, 1H), 1.75-1.53 (m, 2H), 1.50-1.28 (m, 2H), 0.87 (dd, J=11.1, 6.7 Hz, 6H); MS (ESI⁺) m/z 767.3 (M+H)⁺.

81%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16 h;	To a solution of compound 16-8 (5.0 g, 8.3 mmol) and bis(p-nitrophenol) carbonate (7.6 g, 25 mmol) in 100 mL of DMF was added 2.92 mL(16.6 mmol) of diisopropylethylamine. The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo. The residue was treated with ether, filtered, washed with ether, 5percent citic acid, water, ether and dried in vacuo to give 5.0 g (81percent) of compound 16-9.
81%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16 h;	Compound 16-9: To a solution of compound 16-8 (5.0 g, 8.3 mmol) and bis(pnitrophenol)carbonate (7.6 g, 25 mmol) in 100 mL ofDMF was added 2.92 m1(16.6 mmol)of diisopropylethylamine. The reaction mixture was stirred at room temperature for 16 hours.The solvent was removed in vacuo. The residue was treated with ether, filtered, washed with20 ether, 5percent citic acid, water, ether and dried in vacuo to give 5.0 g (81 percent) of compound 16-9.].4-7.
81%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16 h;	To a solution of compound 16-8 (5.0 g, 8.3 mmol) and bis(pnitrophenol)carbonate (7.6 g, 25 mmol) in 100 mL of DMF was added 2.92 mL(16.6 mmol) of15 diisopropylethylamine. The reaction mixture was stirred at room temperature for 16 hours. Thesolvent was removed in vacuo. The residue was treated with ether, filtered, washed with ether, 5percentcitic acid, water, ether and dried in vacuo to give 5.0 g (81 percent) of compound 16-9.
64%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 18 h; Inert atmosphere	To a solution of alcohol 59 (Dubowchik, Firestone et al. 2002) (270 mg, 0.45 mmol) in DMF (4 mL) under Ar is added bis(4-nitrophenyl) carbonate (220 mg, 0.72 mmol), followed by i- Pr₂NEt (90 pL, 0.51 mmol) and the reaction is stirred at rt. After 18 h, the mixture is diluted with MeOH (10 mL) then concentrated under reduced pressure and the residue is azeotroped with toluene (4 x 10 mL). The crude product is purified by column chromatography on silica gel (MeOH/CHCI₃= 0:1 to 1 :4), to afford the title compound 60 as a yellow solid (219 mg, 64percent). H NMR (500 MHz, 3:1 CDCI₃/CD₃OD) δ 0.95 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H), 1.50-1.60 (m, 2H), 1.68-1.75 (m, 1 H), 1.89-1.96 (m, 1H), 2.06- 2.13 (m, 1 H), 3.08-3.13, (m, 1 H), 3.21-3.26, (m, 1 H), 4.00 (d, J = 6.5 Hz, 1 H), 4.22 (dd, J = 6.5, 6.5 Hz, 1 H), 4.35-4.38 (m, 1 H), 4.45-4.49 (m, 1 H), 4.56-4.58 (m, 1 H), 5.25 (s, 2H), 7.31 (dd, J = 7.5, 7.5 Hz, 2H), 7.38-7.41 (m, 6H), 7.61-7.64 (m, 4H), 7.77 (d, J = 7.7 Hz, 2H);³C NMR (126 MHz, 3:1 CDCI₃/CD₃OD) δ 18.1 , 19.3, 26.6, 29.5, 31.2, 39.2, 53.5, 61.0, 67.3, 70.9, 120.2, 120.4, 122.1 , 125.2, 125.3, 125.5, 127.3, 128.0, 129.8, 139.0, 141.6, 144.0, 144.1 , 145.7, 152.8, 155.9, 157.4, 160.8, 170.9, 172.9; HRMS-ESI: m/z calcd for C oH42N₆Oio a [M+Na]⁺789.2860, found 789.2853.
57%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃;	Step 4 Synthesis of (9H-fluoren-9-yl)methyl ((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-1-oxobutan-2-yl)carbamate (94) To a solution of (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (3.74 g, 8.31 mmol, 92) in anhydrous DMF (120 mL) was added bis(4-nitrophenyl) carbonate (3.78 g, 12.4 mmol, 93) in portions, followed by DIPEA (1.21 g, 9.32 mmol) at 0° C. dropwise. The reaction mixture was stirred at room temperature overnight. TLC (MeOH: CH₂Cl₂=1:10) showed that the reaction was completed. The reaction mixture was added dropwise to MTBE (2.5 L) with stirring. The crude product was collected by filtration. The filtrate cake was washed with MTBE and dried under high vacuum to afford compound 94 as brown solid 2.7 g (57percent).

Reference： [1] Patent: WO2015/44003, 2015, A1, . Location in patent: Page/Page column 39
[2] Patent: WO2016/71418, 2016, A1, . Location in patent: Page/Page column 66; 67
[3] Patent: US2016/130299, 2016, A1, . Location in patent: Paragraph 0321
[4] Patent: WO2012/166560, 2012, A1, . Location in patent: Page/Page column 172
[5] Patent: WO2013/192360, 2013, A1, . Location in patent: Paragraph 00495
[6] Patent: WO2013/185117, 2013, A1, . Location in patent: Paragraph 00481
[7] Patent: WO2014/88432, 2014, A1, . Location in patent: Page/Page column 88; 89
[8] Patent: US2016/271270, 2016, A1, . Location in patent: Paragraph 0379; 0384
[9] Patent: US10086085, 2018, B2, . Location in patent: Page/Page column 209-213

12
[ 7693-46-1 ]
[ 159858-22-7 ]
[ 863971-53-3 ]

Yield	Reaction Conditions	Operation in experiment
49%	With pyridine In tetrahydrofuran; N,N-dimethyl-formamide at 0℃;	Dissolve Fmoc-val-cit-pab-OH (1 eq) in THF: DMF (5: 1) and slowly add pyridine (4eq) at 0 ° C.4-nitrophenyl carbonochloridate (3 eq) is added and stirred at 0 ° C.The reaction is confirmed by HPLC. After completion of the reaction, the solvent is dried and then columed. Yield: yellow solid 49percent.

Reference： [1] Journal of Controlled Release, 2012, vol. 160, # 3, p. 618 - 629
[2] Patent: KR2017/41562, 2017, A, . Location in patent: Paragraph 0434-0435
[3] Nature Communications, 2017, vol. 8, # 1,

[ 159858-22-7 ] Synthesis Path-Downstream 1~87

1
[ 159858-21-6 ]
[ 623-04-1 ]
[ 159858-22-7 ]

Yield	Reaction Conditions	Operation in experiment
Ca. 88%	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 20℃; for 48h;Darkness;	DCM/MeOH=2/1 mixed solvent 60 ml was added to the reaction flask, followed by addition of Fmoc-vc2g (4.2 mmol) and1.04 g (2 eq) of PABOH was added. After stirring the dissolved portion, 2.0 g (2 eq) of EEDQ was added. The reaction system is protected from light at room temperatureStir the reaction for 2.0 days. After completion of the reaction, the mixture was concentrated under reduced pressure at 40C to give a white solid. Collect white solids and add methyl tert-butylEthyl ether (100 ml) was stirred and filtered, and the filter cake was washed with methyl tert-butyl ether. The resulting white solid was dried at 40 C under reduced pressure to give 2.2 g.About 88%
88%	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 20℃; for 48h;Darkness;	Add 60 ml of DCM/MeOH=2/1 mixed solvent to the reaction flask.Add Fmoc-vc 2g (4.2mmol) andPABOH 1.04g (2eq),After stirring the dissolved fraction, EEDQ 2.0 g (2 eq) was added.The reaction system was stirred at room temperature for 2.0 d in the dark.After completion of the reaction, concentration under reduced pressure at 40 C gave a white solid.The white solid was collected and stirred with 100 ml of methyl tert-butyl ether.Filtered, the filter cake was washed with methyl tert-butyl ether.The obtained white solid was dried under reduced pressure at 40 C to give 2.2 g.The yield is about 88%.
87%	With 1-bromo-2,3,4-tri-O-acetyl-alpha-D-glucuronic acid methyl ester; In methanol; dichloromethane; at 20℃; for 48h;Darkness;	The Fmoc-Val-Cit 4 (1.0 g, 2.01 mmol) and p-aminobenzyl alcohol (492 mg, 4.0 mmol) were dissolved in a 1 : 1 solution of dichloromethane / methanol (30 mL). To this mixture was added N-Ethoxycarbonyl-2-ethoxy- 1 ,2-dihy droquinoline (992 mg, 4.0 mol). The reaction flask was wrapped in foil and the hood lights were turned off, while the reaction wns stirred at room temperature for 48 hours. (1046) [0558] The reaction mixture was evaporated to dryness and the resulting solid was titurated with ether. The suspension was stirred overnight in ether, then filtered to give a yellow solid. The solids were again washed with ether to give 990 mg for a 87% yield. MS (ESI): mie 572.66 (Mi l) , 573, (M + Na)+, 595.

85%	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 20℃; for 36h;Darkness; Inert atmosphere;	Fmoc-Val-Cit-PABOH 2. To a solution of Fmoc-protected dipeptide 1 (0.30 g, 0.60 mmol) in CH2Cl2/MeOH (2: 1 , 9 mL) was added P-aminobenzyl alcohol (0.12 g, 0.98 mmol ) and EEDQ (0.24 g, 0.98 mmol), and the reaction mixture was stirred in the dark for 1.5 d. The solvents were evaporated, and the resultant was triturated with Et20 (25 mL). The resulting suspension was sonicated for 20 min and left to stand for 30 min. The crude product was collected by filtration and then purified by flash chromatography using a pre-packed 50 g silica column [solvent A: MeOH; solvent B: CH2C12; gradient: 0%A / 100%B (1 CV), 0%A / 100%B -? 20%A / 80%B (10 CV), 20%A / 80%B (2 CV); flow rate: 40 mL/min; monitored at 254 and 280 nm] to afford Fmoc-protected compound 2 (0.31 g, 0.51 mmol, 85% yield) as a brown solid. [000188] NMR (500 MHz, DMSO-d6) 6 10.00 (1 H, s), 8.13 (1 H, d, J = 7.7 Hz), 7.92 (2H, d, J = 7.5 Hz), 7.81 - 7.71 (2H, m), 7.57 (2H, d, J= 8.4 Hz), 7.49 - 7.40 (3H, m), 7.35 (2H, t, J= 7.4 Hz), 7.26 (2H, d, J = 8.3 Hz), 5.99 (1 H, t, J = 6.5 Hz), 5.43 (2H, s), 5.12 (1 H, t, J= 5.6 Hz), 4.45 (2H, d, J= 5.4 Hz), 4.32 (1H, d,J= 10.1 Hz), 4.29 - 4.19 (3H, m), 4.00 - 3.88 (1H, m), 3.12 - 2.91 (2H, m), 2.09 - 1.94 (1H, m), 1.80-1.31 (4H, m), 0.90 (3H, d, .7=6.6 Hz), 0.88 (3H, d,J=6.7 Hz). [000189] I3C NMR (125 MHz, DMSO-d6) delta 171.7, 170.9, 159.3, 156.6, 144.4, 144.2, 141.2, 138.0, 137.9, 128.1, 127.6, 127.4, 125.8, 120.6, 119.3, 66.2, 63.1, 60.6, 47.2,30.9,30.0, 27.3, 19.7, 18.8, 15.0.
82%	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; at 20℃; for 36h;	Fmoc-val-cit (1 eq),Add 2 eq of p-aminobenzyl alcohol (2 eq) to DMC / MeOH (2: 1), add EEDQ (2 eq) and shake for 1.5 days at room temperature.After completion of the reaction, the solvent is dried and precipitated with ether. Repeat after filtering with Ether. Yield: yellow solid 82%.
80%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In water; ethyl acetate; N,N-dimethyl-formamide; at 0 - 5℃;	Fmoc-Val-Cit (1 eq.), HATH (1.4 eq.) were solubilized in a mixture of anhydrous N,N-Dimethylformamide (9.5 vol.) and Ethyl acetate (5 vol.) at 20C. The reaction mixture was then cooled to 0-5C. Separately, a solution of 4-Aminobenzyl alcohol (1.5 eq.) in Ethyl acetate (2 vol.) and anhydrous N,N-Dimethylformamide (0.5 vol.) was prepared. A solution of N,N-Diisopropylethylamine (1.4 eq.) in Ethyl acetate (2 vol.) was also prepared. Water (1 vol.) was added to the cooled Fmoc-Val-Cit/HATU solution before adding the 4- Aminobenzyl alcohol solution quickly. Immediately thereafter, the DIPEA solution was added over 25-35 minutes. The reaction mixture was stirred at 0-5C for 1-2 hours until reaction was complete. Pre-chilled Methyl tert-butyl ether (20 vol.) was then added over 10 minutes and the resulting mixture was stirred for 1-3 hours. Solids were filtered, washed and dried under vacuum. Solids were re-slurried in Acetonitrile (20 vol.), filtered, washed and dried under vacuum (80% yield). MS: m/e 602 (MH)+, 624 (M+Na)+.
77%	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 40℃;	Step 3 Synthesis of (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (92) To the suspension of compound 90 (70 g, 0.141 mol) in DCM/MeOH (1 L/500 mL) was added compound 91 (34.7 g, 0.282 mol) followed by EEDQ (69.7 g, 0.282 mol). The mixture was stirred at 40 C. overnight. The reaction mixture was filtered and the wet cake was suspended in EtOAc/TBME (500 mL/200 mL) and stirred for 30 min, then filtered. The solid was washed with EtOAc/TBME to provide compound 92 as off-white solid 65 g (77%). 1H NMR (400 MHz, DMSO-d6) delta=9.98 (s, 1H), 8.11 (d, 1H), 7.87 (d, 2H), 7.77 (m, 2H), 7.52 (d, 2H), 7.39 (m, 3H), 7.30 (m, 2H), 7.21 (d, 2H), 5.97 (m, 1H), 5.41 (s, 2H), 5.10 (m, 1H), 4.42 (m, 3H), 4.22 (m, 3H), 3.90 (m, 1H), 2.93 (m, 2H), 1.98 (m, 1H), 1.50 (m, 2H), 1.30 (m, 2H), 0.84 (m, 6H).
76%	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 20℃;	A solution of compound 28 (1 g, 2.01 mmol, leq) andp-aminobenzyl alcohol (273 mg, 2.21 mmol, 1.1 eq) in a mixture of DCM/MeOH (20 mL/10 mL) was treated with EEDQ (996 mg, 4.03 mmol, 2 eq). The mixture was stirred in the dark at room temperature overnight. The solvents were removed under vacuum and the resulting solid residue was triturated with 10 mL of ethyl ether. The solid was collected by filtration and washed with ethyl ether to yield the product (925 mg, 76% yield): 1H NMR (DMSO-<fc) delta 0.87 (6H, d, t = 7.5 Hz), 1.36-1.47 (2H, m), 1.51-1.75 (2H, m), 1.99 (IH, sext, J = 6.7 Hz), 2.90-3.04 (3H, m), 3.93 (IH, dd, J = 7.3, 8.8 Hz), 4.23-4.38 (4 H, m), 4.43 (2H, d, J = 5.3 Hz), 5.13 (IH, t, J = 5.6 Hz), 5.43 (2H, brs), 5.99 (IH, t, J = 5.6 Hz), 7.23 (2H, d, J = 8.5 Hz), 7.32 (2H, t, J = 7.3 Hz), 7.39-7.48 (3H, m), 7.54 (2H5 d, J -8.5 Hz), 7.74 (2H, t, J = 6.7 Hz), 7.89 (2H, d, J = 7.6 Hz)5 8.12 (IH, d, J = 7.3 Hz); 13 C NMR (DMSO-c^) delta 18.34, 19.28, 26.84, 29.56, 30.47, 46.67, 53.05, 60.05, 62.55, 65.65, 118.71, 119.98, 125.23, 126.79, 126.94, 127.51, 137.27, 137.36, 140.55, 143.60, 143.73, 155.93, 158.69, 170.17, 171.06.
65%	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 20℃; for 16h;Darkness;	EEDQ (840 mg, 3.4 mmol) is added to a solution containing compound [12] (870 mg, 1 .7 mmol) and p-aminobenzyl alcohol (227 mg, 1 .8 mmol) in dichloro- methane/methanol 2:1 (15 mL). The reaction is left in the dark at room temperature for 16 hours. The solvents are removed, and the resulting solid residue filtrated using diethyl ether to give product [14] as a white solid, 660 mg (65% yield). MS: m/z 624 [M+Na]+.1H NMR (400 MHz, DMSO) delta 10.00 (bs, 1 H), 8.13 (m, 4H), 7.92 (d, J = 7.3 Hz, 2H), 7.76 (d, J = 7.6 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.51 - 7.10 (m, 2H), 6.02 (s, 1 H), 5.43 (m, 4H), 5.13 (s, 1 H), 4.47 (s, 3H), 4.31 (m 4H), 3.13 - 2.74 (m, 2H), 2.03 (s, 1 H), 1 .83 - 1 .55 (m, 2H), 1 .43 (s, 2H), 0.90 (d, J = 6.7 Hz, 6H).13C NMR (101 MHz, DMSO) delta 171 .2, 170.4, 158.93, 156.15, 144.6, 143.8, 140.7, 137.5, 127.6, 127.2 (2C) 125.3, 120.1 (2C), 1 18.9, 65.7, 62.6, 60.1 , 53.0, 46.7, 31 .0, 30.5, 26.7, 19.6, 18.7.
59%	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 20℃; for 15h;	b) Fmoc-Val-Cit-PABA (32) A solution of Fmoc-Val-Cit-OH 31 (600 mg, 1.21 mmol), 4-aminobenzyl alcohol (298 mg, 2.42 mmol) and 2-Ethoxy-1-ethoxycarbonyl-1 ,2-dihydroquinoline (598 mg, 2.42 mmol) in CH2CI2/MeOH (12.6 ml_, 2:1 ) was stirred at rt for 15 h. Upon completion, the mixture was diluted with Et20 (30 ml_), sonicaated briefly, filtered and washed with Et20 to yield Fmoc- Val-Cit-PABC (428 mg, 0.710 mmol, 59%) as an off-white solid
	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In methanol; dichloromethane; at 20℃;Darkness;	The reaction product of reaction step b (7.6 g, 15.3 mmol) and PABOH (3.76 g, 30.6 mmol) were dissolved in a mixture of 140 mL of CH2Cl2 and 70 mL of CH3OH.EEDQ (7.5 g, 30.6 mmol) was added in the dark.Stirring at room temperatureReaction, after the reaction is completed, spin the reaction solution,Wash with ether,Filter by suction.

Reference： [1]International Journal of Molecular Sciences,2017,vol. 18
[2]Patent: CN107789630,2018,A .Location in patent: Paragraph 0073; 0074; 0075
[3]Patent: CN108743968,2018,A .Location in patent: Paragraph 0016; 0017; 0018
[4]Patent: WO2020/14541,2020,A2 .Location in patent: Paragraph 0546; 0551; 0557-0558
[5]Patent: WO2017/66668,2017,A1 .Location in patent: Paragraph 000187-000189
[6]Journal of Controlled Release,2012,vol. 160,p. 618 - 629
[7]Patent: KR2017/41562,2017,A .Location in patent: Paragraph 0431-0432
[8]Patent: WO2019/108797,2019,A1 .Location in patent: Paragraph 0114; 0119
[9]Patent: US2016/271270,2016,A1 .Location in patent: Paragraph 0379; 0382
[10]Patent: WO2008/34124,2008,A2 .Location in patent: Page/Page column 79
[11]Patent: WO2018/178060,2018,A1 .Location in patent: Page/Page column 64; 65; 67
[12]Patent: WO2020/25108,2020,A1 .Location in patent: Page/Page column 48-49
[13]Patent: WO2014/80251,2014,A1 .Location in patent: Sheet 16/23
[14]Bioconjugate Chemistry,2015,vol. 26,p. 2261 - 2278
[15]Nature Communications,2017,vol. 8
[16]Patent: CN109200291,2019,A .Location in patent: Paragraph 0051; 0063; 0067

2
[ 159858-22-7 ]
[ 159857-79-1 ]

Yield	Reaction Conditions	Operation in experiment
96%	With diethylamine; In N,N-dimethyl-formamide; for 2h;	[0438] Fmoc-val-cit-PAB-OH (14.61 g, 24.3 mmol, 1.0 eq.; see, e.g., U.S. Patent No. 6,214,345 to Firestone et al.) was diluted with DMF (120 mL, 0.2 M) and to this solution was added a diethylamine (60 mL). The reaction was monitored by HPLC and found to be complete in 2 h. The reaction mixture was concentrated and the resulting residue was precipitated using ethyl acetate (ca. 100 mL) under sonication over for 10 min. Ether (200 mL) was added and the precipitate was further sonicated for 5 min. The solution was allowed to stand for 30 min. without stirring and was then filtered and dried under high vacuum to provide Val-cit-P AB-OH, which was used in the next step without further purification. Yield: 8.84 g (96%). Val-cit-PAB-OH (8.0 g, 21 mmol) was diluted with DMF (110 mL) and the resulting solution was treated with MC-OSu (Willner et at, 1993, Bioconjugate Chem. 4:521; 6.5 g, 21 mmol, 1.0 eq.). The reaction was complete according to HPLC after 2 h. The reaction mixture was concentrated and the resulting oil was precipitated using ethyl acetate (50 mL). After sonicating for 15 min, ether (400 mL) was added and the mixture was sonicated further until all large particles were broken up. The solution was then filtered and the solid dried to provide an off-white solid intermediate. Yield: 11.63 g (96%); ES-MS m/z 757.9 [M-H]
96%	With diethylamine; In N,N-dimethyl-formamide; for 2h;	[0454] Fmoc-val-cit-P AB-OH (14.61 g, 24.3 mmol, 1.0 eq., see, e.g., U.S. Patent No. 6,214,345 to Firestone et al.) was diluted with DMF (120 mL, 0.2 M) and to this solution was added a diethylamine (60 mL). The reaction was monitored by HPLC and found to be complete in 2 h. The reaction mixture was concentrated and the resulting residue was precipitated using ethyl acetate (ca. 100 mL) under sonication for 10 min. Ether (200 mL) was added and the precipitate was further sonicated for 5 min. The solution was allowed to stand for 30 min. without stirring and was then filtered and dried under high vacuum to provide Val-cit-P AB-OH, which was used in the next step without further purification. Yield: 8.84 g (96%). Val-cit-P AB-OH (8.0 g, 21 mmol) was diluted with DMF (110 mL) and the resulting solution was treated with MC-OSu (Willner et al, 1993, EPO <DP n="138"/>Bioconjugate Chem. 4:521; 6.5 g, 21 mmol, 1.0 eq.). The reaction was complete according to HPLC after 2 h. The reaction mixture was concentrated and the resulting oil was precipitated using ethyl acetate (50 mL). After sonicating for 15 min, ether (400 niL) was added and the mixture was sonicated further until all large particles were broken up. The solution was then filtered and the solid dried to provide an off-white solid intermediate. Yield: 11.63 g (96%); ES-MS m/z 757.9 [M-H]
96%	With diethylamine; In N,N-dimethyl-formamide; for 2h;	Example 1 - Preparation of compound AB Fmoc-val-cit-PAB-OH (14.61 g, 24.3 mmol), 1.0 eq., ) was diluted with DMF (120 mL, 0.2 M) and to this solution was added a diethylamine (60 mL). The reaction was monitored by HPLC and found to be complete in 2 h. The reaction mixture was concentrated and the resulting residue was precipitated using ethyl acetate (ca. 100 mL) under sonication over for 10 min. Ether (200 mL) was added and the precipitate was further sonicated for 5 min. The solution was allowed to stand for 30 min. without stirring and was then filtered and dried under high vacuum to provide Val-cit-PAB-OH, which was used in the next step without further purification. Yield: 8.84 g (96%). Val-cit-PAB-OH (8.0 g, 21 mmol) was diluted with DMF (110 mL) and the resulting solution was treated with MC-OSu (Willner et al., (1993) Bioconjugate Chem. 4:521; 6.5 g, 21 mmol, 1.0 eq.).

93%	With diethylamine; In 1-methyl-pyrrolidin-2-one; at 20℃; for 16h;Inert atmosphere;	Val-Cit-PABOH 3. To a solution of Fmoc-protected compound 2 (0.31 g, 0.51 mmol) in NMP (5 mL) was added diethylamine (1 mL), and the reaction mixture was stirred for 16 h at ambient temperature. The solvent was then evaporated under reduced pressure, and the resulting oil was triturated with CH2C12, and the mixture was sonicated for 30 min. The solid was collected by filtration and washed with CH2C12 (3 x 10 mL) to afford desired compound 3 (0.19 g, 0.49 mmol, 93% yield) as a brown solid. [000191] NMR (500 MHz, DMSO-d6) delta 10.03 (1H, s), 8.18 (1H, d, J= 6.2 Hz), 7.52 (2H, d, J= 8.4 Hz), 7.22 (2H, d,J = 8.4 Hz), 5.97 (1H, t, J = 5.8 Hz), 5.39 (2H, s), 5.08 (1H, s), 4.51 - 4.43 (3H, m), 3.13 - 2.95 (2H, m), 2.92 (1H, dd, J= 13.2, 6.3 Hz), 1.93 (2H, dd, J= 11.9, 6.5 Hz), 1.74 - 1.61 (1H, m), 1.61 - 1.49 (1H, m), 1.47-1.29 (2H,m),0.87 (3H, d, ,7=6.8 Hz), 0.78 (3H, d, .7=6.8 Hz). [000192] nC NMR (125 MHz, DMSO-d6) delta 170.9, 159.3, 137.9, 137.9, 127.4, 119.4, 63.0, 59.8, 53.0, 31.6,30.5,27.1, 19.8, 17.5.
90%	With diethylamine; at 20℃; for 24h;	490 mg (0.815 mmol) of Fmoc-vc-PABOH was added to 10 ml of NMP, dissolved under stirring, and then diethylamine was added.2ml. The reaction was stirred at room temperature for 24 h. After completion of the reaction, the mixture was concentrated under reduced pressure at 40 C., and 20 ml of DCM was added to the resulting oil and stirred.The crystals were crystallized and filtered. The filter cake was washed with DCM and the resulting solid was dried under reduced pressure to give 277 mg in 90% yield.
90%	With diethylamine; In 1-methyl-pyrrolidin-2-one; at 20℃; for 24h;	Fmoc-vc-PABOH 490 mg (0.815 mmol) was added to 10 ml of NMP and stirred to dissolve, and then 2 ml of diethylamine was added.The reaction was stirred at room temperature for 24 h. After completion of the reaction, the mixture was concentrated under reduced pressure at 40 C.Crystallization, filtration, filter cake washed with DCM,The obtained solid was dried under reduced pressure to give 277 mg.The yield was 90%.
90%	With diethylamine; In N,N-dimethyl-formamide; at 20℃;	Fmoc-Val-Cit-PABOH (1 eq.) was suspended in anhydrous N,N- Dimethylformamide (5 vol.) and the resulting suspension was stirred at 20C until a homogeneous suspension formed. Diethylamine (2 eq.) was then added at 20C and the reaction mixture was stirred at 20C for 2-3 hours until reaction was complete. Acetonitrile (2 vol.) was then added and distilled off three times to remove the base. The reaction mixture was heated to 35C and Ethyl acetate (5 vol.) was added over 60 minutes at 35C. Methyl tert-butyl ether (10 vol.) was then added over 60 minutes at 35C. The resulting mixture was stirred at 40C for 2-4 hours until a homogeneous suspension was obtained and then cooled to 20C over 90 minutes. The suspension was then stirred at 20C for 1 hour before being cooled to 0-5C over 90 minutes. The product suspension was stirred at 0-5C for 2-3 hours before being filtered, washed and dried under vacuum. Solids were re-suspended in Methyl tert-butyl ether (15 vol.) and the resulting mixture was heated to 40C and stirred at that temperature for 1-2 hours until a homogeneous suspension was obtained. The resulting mixture was cooled to 20C and stirred at that temperature for 2-4 hours before being filtered, washed and dried under vacuum (90% yield). MS: m/e 380 (MH)+, 402 (M+Na)+.
72%	With piperidine; In N,N-dimethyl-formamide; at 20℃;	To a solution of compound 29 (622 mg, 1.03 mmol) in 10 mL of anhydrous DMF was added piperidine (2 mL). The mixture was stirred at room temperature overnight and then the solvents were evaporated under vacuum. The residue was triturated with DCM and the resulting solid was filtered and washed with DCM to give the product (283 mg, 72% yield): 1H NMR (DMSO-^) delta 0.79 (3H, d, J = 6.7 Hz), 0.89 (3H, d, J = 6.7 Hz), 1.38-1.42 (2H, m), 1.52-1.68 (2H, m), 1.94 (IH, sext, J = 6.3 Hz), 2.89-3.01 (2H, m), 3.05 (IH, d, J = 4.7 Hz), 4.46 (2H, s), 5.09 (IH, brs), 5.40 (2H, s), 5.98 (IH, t, J = 5.3 Hz), 7.23 (2H, d, J - 8.2 Hz), 7.54 (2H, d, J = 8.5 Hz), 8.14 (IH, brs), 10.03 (IH, s); 13 C NMR (DMSO-
60%	With piperidine; In N,N-dimethyl-formamide; at 20℃; for 3h;	Piperidine (2.2 mL) is added to a solution of compound [14] (660 mg, 1 .09 mmol) in anhydrous dimethylformamide (5 mL) and the reaction left at room temperature for 3 h. The solvent is removed under vacuum and the residue treated with di- chloromethane in order to obtain a solid that is filtered to give product [15], 240 mg (60% mg). MS: m/z 380 [M+H]+.1H NMR (400 MHz, DMSO) delta 10.1 1 (s, 1 H), 8.25 (s, 1 H), 7.58 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 6.10 (s, 1 H), 5.46 (s, 2H), 4.48 (m, 3H), 3.23 - 3.09 (m, 2H), 3.1 1 - 2.88 (m, 2H), 1 .99 (dd, J = 12.2, 6.4 Hz, 2H), 1 .99 (dd, J = 12.2, 6.4 Hz, 1 H), 1 .81 - 1 .55 (m, 2H), 1 .55 - 1 .28 (m, 2H), 1 .04 - 0.68 (m, 6H).13C NMR (101 MHz, DMSO) delta 173.3, 170.4, 158.9, 137.5, 126.9 (2C), 125.3, 1 19.9 (2C), 62.6, 59.3, 52.6, 31 .1 , 29.9, 26.6, 19.3, 17.0 (2C).
597 mg	With piperidine; In N,N-dimethyl-formamide; at 20℃; for 1h;	Step 2. To a solution of compound 44-3 (2.14 mmol) in DMF (10 mL) was added compound 44-4 (0.6 mL, 4.5 mmol) and stirred at r.t. for 1 h. The mixture was concentrated and washed with MTBE (30 mL x 3), filtered and the filtrate was concentrated to give 44-5 (597 mg, Yield: 70 %).
2.3 g	With diethylamine; In N,N-dimethyl-formamide; at 20℃;	The reaction product of the previous step (8.4 g, 19 mmol) was dissolved in 150 mL of DMF.25 mL of Et 2 NH was added, and the reaction was stirred at room temperature overnight.After the reaction is completed, the solvent is dried.After washing the ether three times,A yellowish solid of 2.3 g was obtained
	With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 24h;	: Procedure A: A solution of compound 8 (0.270 g, 0.450 mmol, 1.0 equiv) in DMF (0.2 M) was treated with triethylamine (1.25 mL, 8.90 mmol, 19.8 equiv) followed by stirring at room temperature for 24 hours. DMF and excess triethylamine were removed under reduced pressure. The resulting residue was dissolved in DMF (0.1 M) and to the solution Mc-OSu (0.150 g, 0.500 mmol, 1.1 equiv) was added. The reaction mixture was stirred at room temperature for 20 hours. DMF was removed under reduced pressure and the resulting residue was purified by flash column chromatography using 3-12% MeOH-CH2Cl2 as solvent. The product was obtained as white solid. Yield: 86%.

Reference： [1]Patent: WO2007/8603,2007,A1 .Location in patent: Page/Page column 137; 165; 166
[2]Patent: WO2007/8848,2007,A2 .Location in patent: Page/Page column 108; 136; 137
[3]Patent: EP2486933,2015,B1 .Location in patent: Paragraph 0495
[4]Patent: WO2017/66668,2017,A1 .Location in patent: Paragraph 000190-000192
[5]Patent: CN107789630,2018,A .Location in patent: Paragraph 0076; 0077; 0078
[6]Patent: CN108743968,2018,A .Location in patent: Paragraph 0019; 0020; 0021
[7]Patent: WO2019/108797,2019,A1 .Location in patent: Paragraph 0115
[8]International Journal of Molecular Sciences,2017,vol. 18
[9]Patent: WO2008/34124,2008,A2 .Location in patent: Page/Page column 79
[10]Patent: WO2018/178060,2018,A1 .Location in patent: Page/Page column 64; 65; 67; 68
[11]Patent: WO2014/80251,2014,A1 .Location in patent: Sheet 16/23
[12]Patent: WO2015/95227,2015,A2 .Location in patent: Page/Page column 144; 145
[13]Journal of Medicinal Chemistry,2018,vol. 61,p. 989 - 1000
[14]Chemical Science,2018,vol. 9,p. 6490 - 6496
[15]Patent: CN109200291,2019,A .Location in patent: Paragraph 0051; 0063; 0068
[16]Tetrahedron Letters,2018,vol. 59,p. 3594 - 3599

3
[ 68858-20-8 ]
[ 159858-22-7 ]

Reference： [1]Journal of Controlled Release,2012,vol. 160,p. 618 - 629
[2]Patent: WO2014/80251,2014,A1
[3]Bioconjugate Chemistry,2015,vol. 26,p. 2261 - 2278
[4]Patent: US2016/271270,2016,A1
[5]International Journal of Molecular Sciences,2017,vol. 18
[6]Patent: CN107789630,2018,A
[7]Patent: WO2018/178060,2018,A1
[8]Patent: CN108743968,2018,A
[9]Patent: CN109200291,2019,A
[10]Patent: WO2019/108797,2019,A1
[11]Patent: WO2020/14541,2020,A2

4
[ 7693-46-1 ]
[ 159858-22-7 ]
[ 863971-53-3 ]

Yield	Reaction Conditions	Operation in experiment
49%	With pyridine; In tetrahydrofuran; N,N-dimethyl-formamide; at 0℃;	Dissolve Fmoc-val-cit-pab-OH (1 eq) in THF: DMF (5: 1) and slowly add pyridine (4eq) at 0 C.4-nitrophenyl carbonochloridate (3 eq) is added and stirred at 0 C.The reaction is confirmed by HPLC. After completion of the reaction, the solvent is dried and then columed. Yield: yellow solid 49%.

Reference： [1]Journal of Controlled Release,2012,vol. 160,p. 618 - 629
[2]Patent: KR2017/41562,2017,A .Location in patent: Paragraph 0434-0435
[3]Nature Communications,2017,vol. 8

5
[ 130878-68-1 ]
[ 159858-22-7 ]

Reference： [1]Journal of Controlled Release,2012,vol. 160,p. 618 - 629
[2]Patent: WO2014/80251,2014,A1
[3]Patent: WO2017/66668,2017,A1
[4]Patent: KR2017/41562,2017,A
[5]Patent: CN107789630,2018,A
[6]Patent: CN108743968,2018,A
[7]Patent: CN109200291,2019,A
[8]Tetrahedron Letters,2018,vol. 59,p. 3594 - 3599
[9]Patent: WO2019/108797,2019,A1
[10]Patent: WO2020/25108,2020,A1
[11]Patent: WO2020/14541,2020,A2

6
[ 5070-13-3 ]
[ 159858-22-7 ]
[ 863971-53-3 ]

Yield	Reaction Conditions	Operation in experiment
89%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;Inert atmosphere;	N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valyl-N5-carbamoyl-N-[4-(hydroxymethyl)phenyl]-L-ornithinamide (1.3 g, 2.16 mmol) (prepared as reported in EP0624377A2) and bis(4-nitrophenyl) carbonate (1.32 g, 4.34 mmol) were dissolved in 6 mL of dry DMF under nitrogen atmosphere, DIPEA (0.75 mL, 4.35 mmol) was added and the resulting solution was stirred an hour at room temperature. Diethylether (120 mL) was added, the resulting precipitate is filtered off, washed with diethylether and dried under vacuum affording N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valyl-N5- carbamoyl-N-[4-([(4-nitrophenoxy)carbonyl]oxy}methyl)phenyl]-L-ornithinamide (1.47 g, 89% yield).ESI MS: m/z 767 (MH+)1H NMR (400 MHz, DMSO-de) delta 0.86 (d, J = 6.7 Hz, 3 H), 0.88 (d, J = 6.7 Hz, 3 H), 1.30 - 1.52 (m, 2 H), 1.60 (m, 1 H), 1.69 (m, 1 H), 1.99 (m, 1 H), 2.90 - 3.10 (m, 2 H), 3.93 (dd, J = 8.9, 7.0 Hz, 1 H), 4.14 - 4.34 (m, 3 H), 4.42 (m, 1 H), 5.24 (s, 2 H), 5.39 (s, 2 H), 5.97 (t, J = 5.5 Hz, 1 H), 7.32 (m, 2 H), 7.42 (m, 5 H), 7.55 (m, 2 H), 7.65 (d, J = 8.4 Hz, 2 H), 7.74 (t, J = 7.9 Hz, 2 H), 7.88 (d, J = 7.6 Hz, 2 H), 8.12 (d, J = 7.4 Hz, 1 H), 8.31 (m, 2 H), 10.12 (s, 1 H)
89%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;Inert atmosphere;	N-[(9H-fl uoren-9-ylmethoxy)carbonyl]-L-valyl-N5-carbamoyl-N-[4-(hydroxymethyl)phenyl]-L-ornithinamide (1.3 g, 2.16 mmcl) (prepared as reported in EP0624377A2) and bis(4-nitrophenyl) carbonate (1.32 g, 4.34 mmol) were dissolved in 6 ml of dry DMF under nitrogen atmosphere, DIPEA (0.75 ml, 4.35 mmol) was added and the resulting solution was stirred an hour at room temperature. Diethylether (120 ml) was added, the resulting precipitate is filtered off,washed with diethylether and dried under vacuum affording N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valyl-N5- carbamoyl-N-[4-([(4-nitrophenoxy)carbonyl]oxy}methyl)phenyl]-L-ornithinamide (68) (1.47 g, 89% yield). MS (ESI): 767 [M+H].1H NMR (400 MHz, DMSO-d6) 0.86 (d, J = 6.7 Hz, 3 H), 0.88 (d, J = 6.7 Hz, 3 H), 1.30- 1.52 (m, 2 H), 1.60 (m, 1H), 1.69 (m, 1 H), 1.99 (m, 1 H), 2.90-3.10 (m, 2 H), 3.93 (dd, J = 8.9, 7.0 Hz, 1 H), 4.14-4.34 (m, 3 H), 4.42 (m, 1H), 5.24 (s, 2 H), 5.39 (s, 2 H), 5.97 (t, J = 5.5 Hz, 1 H), 7.32 (m, 2 H), 7.42 (m, 5 H), 755 (m, 2 H), 7.65 (d, J 8.4Hz, 2 H), 7.74 (t, J = 7.9 Hz, 2 H), 7.88 (d, J = 7.6 Hz, 2 H), 8.12 (d, J = 7.4 Hz, 1 H), 8.31 (m, 2 H), 10.12 (s, I H)
84%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1.5h;	(0321) (9H-fluoren-9-yl)methyl((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate 84 (0.5 g, 0.831 mmol) was dissolved in DMF (5 mL) and compound 53a (0.506 g, 1.662 mmol) was added, followed by DIEA (0.23 mL, 1.320 mmol) at RT. The reaction mixture was stirred for 1.5 h at RT. LC/MS showed no starting material was left. The reaction mixture was then treated with 30 mL of Et2O and stirred at RT for 30 min. The precipitate that formed was filtered and washed with additional Et2O. The solid was dried under high vacuum to afford (9H-fluoren-9-yl)methyl((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)-phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-1-oxobutan-2-yl)carbamate 85 (0.533 gm, 84%) as an off yellow solid. 1H NMR (400 MHz, DMSO-d6) delta 10.12 (s, 1H), 8.37-8.22 (m, 2H), 8.12 (d, J=7.5 Hz, 1H), 7.88 (d, J=7.5 Hz, 2H), 7.76-7.50 (m, 5H), 7.44-7.15 (m, 7H), 5.96 (t, J=5.5 Hz, 1H), 5.39 (s, 2H), 5.24 (s, 2H), 4.49-4.39 (m, 1H), 4.34-4.10 (m, 3H), 3.93 (dd, J=8.8, 7.3 Hz, 1H), 3.13-2.82 (m, 2H), 2.05-1.88 (m, 1H), 1.75-1.53 (m, 2H), 1.50-1.28 (m, 2H), 0.87 (dd, J=11.1, 6.7 Hz, 6H); MS (ESI+) m/z 767.3 (M+H)+.

83%	With N-ethyl-N,N-diisopropylamine; at 20℃; for 3h;	c) Fmoc-Val-Cit-PAB-PNP (33) A solution of Fmoc-Val-Cit-PABA 32 (200 mg, 0.332 mmol), bis(4-nitrophenyl) carbonate (202 mg, 0.665 mmol) and DIPEA (86.8 pL, 0.498 mmol) was stirred at rt for 3 h. Upon completion, the mixture was concentrated under a stream of N2. The crude residue was precipitated with EtOAc (3 ml.) and Et20 (30 ml_), allowed to stand for 30 min and then filtered to yield Fmoc-Val-Cit-PAB-PNP (210 mg, 0.274 mmol, 83%) as a light brown solid.
81%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;	To a solution of compound 16-8 (5.0 g, 8.3 mmol) and bis(p-nitrophenol) carbonate (7.6 g, 25 mmol) in 100 mL of DMF was added 2.92 mL(16.6 mmol) of diisopropylethylamine. The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo. The residue was treated with ether, filtered, washed with ether, 5% citic acid, water, ether and dried in vacuo to give 5.0 g (81%) of compound 16-9.
81%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;	Compound 16-9: To a solution of compound 16-8 (5.0 g, 8.3 mmol) and bis(pnitrophenol)carbonate (7.6 g, 25 mmol) in 100 mL ofDMF was added 2.92 m1(16.6 mmol)of diisopropylethylamine. The reaction mixture was stirred at room temperature for 16 hours.The solvent was removed in vacuo. The residue was treated with ether, filtered, washed with20 ether, 5% citic acid, water, ether and dried in vacuo to give 5.0 g (81 %) of compound 16-9.].4-7.
81%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;	To a solution of compound 16-8 (5.0 g, 8.3 mmol) and bis(pnitrophenol)carbonate (7.6 g, 25 mmol) in 100 mL of DMF was added 2.92 mL(16.6 mmol) of15 diisopropylethylamine. The reaction mixture was stirred at room temperature for 16 hours. Thesolvent was removed in vacuo. The residue was treated with ether, filtered, washed with ether, 5%citic acid, water, ether and dried in vacuo to give 5.0 g (81 %) of compound 16-9.
81.6%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1.5h;	In the 500 ml round bottom flask, add 30 g of compound 16 (49.92 mmol, 1.0 eq), then adding 240 ml of stirring to dissolve in DMF, after 22.76 g b (P) carbon ester (74.87 mmol, 1.5 eq), and drop into the 9.68 g of DIPEA (74.87 mmol, 1.5 eq), stirring at the room temperature reaction 1.5 h, TLC detection and complete raw material reaction, stopping the reaction. After treatment: under intense stirring to the reaction flask by adding isopropyl ether 1.5 L, stirring 2 h leans the upper liquid, residue is added in 800 ml isopropyl ether continue to stir vigorously 1 h, filtered, the filter cake is placed in 600 ml of isopropyl ether stirring overnight, filtered, shall be coloured powdery solid 31.2 g, yield is 81.6%.
64%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h;Inert atmosphere;	To a solution of alcohol 59 (Dubowchik, Firestone et al. 2002) (270 mg, 0.45 mmol) in DMF (4 mL) under Ar is added bis(4-nitrophenyl) carbonate (220 mg, 0.72 mmol), followed by i- Pr2NEt (90 pL, 0.51 mmol) and the reaction is stirred at rt. After 18 h, the mixture is diluted with MeOH (10 mL) then concentrated under reduced pressure and the residue is azeotroped with toluene (4 x 10 mL). The crude product is purified by column chromatography on silica gel (MeOH/CHCI3= 0:1 to 1 :4), to afford the title compound 60 as a yellow solid (219 mg, 64%). H NMR (500 MHz, 3:1 CDCI3/CD3OD) delta 0.95 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H), 1.50-1.60 (m, 2H), 1.68-1.75 (m, 1 H), 1.89-1.96 (m, 1H), 2.06- 2.13 (m, 1 H), 3.08-3.13, (m, 1 H), 3.21-3.26, (m, 1 H), 4.00 (d, J = 6.5 Hz, 1 H), 4.22 (dd, J = 6.5, 6.5 Hz, 1 H), 4.35-4.38 (m, 1 H), 4.45-4.49 (m, 1 H), 4.56-4.58 (m, 1 H), 5.25 (s, 2H), 7.31 (dd, J = 7.5, 7.5 Hz, 2H), 7.38-7.41 (m, 6H), 7.61-7.64 (m, 4H), 7.77 (d, J = 7.7 Hz, 2H);3C NMR (126 MHz, 3:1 CDCI3/CD3OD) delta 18.1 , 19.3, 26.6, 29.5, 31.2, 39.2, 53.5, 61.0, 67.3, 70.9, 120.2, 120.4, 122.1 , 125.2, 125.3, 125.5, 127.3, 128.0, 129.8, 139.0, 141.6, 144.0, 144.1 , 145.7, 152.8, 155.9, 157.4, 160.8, 170.9, 172.9; HRMS-ESI: m/z calcd for C oH42N6Oio a [M+Na]+789.2860, found 789.2853.
57%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃;	Step 4 Synthesis of (9H-fluoren-9-yl)methyl ((S)-3-methyl-1-(((S)-1-((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-1-oxobutan-2-yl)carbamate (94) To a solution of (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (3.74 g, 8.31 mmol, 92) in anhydrous DMF (120 mL) was added bis(4-nitrophenyl) carbonate (3.78 g, 12.4 mmol, 93) in portions, followed by DIPEA (1.21 g, 9.32 mmol) at 0 C. dropwise. The reaction mixture was stirred at room temperature overnight. TLC (MeOH: CH2Cl2=1:10) showed that the reaction was completed. The reaction mixture was added dropwise to MTBE (2.5 L) with stirring. The crude product was collected by filtration. The filtrate cake was washed with MTBE and dried under high vacuum to afford compound 94 as brown solid 2.7 g (57%).
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 5h;	N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valyl-N 5 -carbamoyl-N-[4-(hydroxymethyl)phenyl]-L-ornithinamide 251 (725 mg, 1.2 mmol) was dissolved in 6 mL of DMF followed by sonication for 10 minutes. A stir bar was then added and this solution was allowed to stir at room temperature. Bis(4-nitrophenyl)carbonate (403 mg, 1.33 mmol) was then added followed by Hunig's base (0.44 mL, 2.5 mmol). The reaction was allowed to stir at room temperature for 5 hours. 213 (227 mg, 1.2 mmol) dissolved in 1 mL of DMF was added. The reaction was allowed to stir at room temperature for 1 minute. Crude reaction was injected onto a 24 g C18 pre-column (which was previously equilibrated with acetonitrile and then water, with 0.02% TFA in each phase). Material was purified by medium pressure reverse phase C18 chromatography (Gradient: 5% to 60% acetonitrile in water with 0.02% TFA in each phase) with the appropriate test tubes concentrated using a genevac producing N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valyl-N 5 -carbamoyl-N-[4-(4,7,10,10-tetramethyl-3,8-dioxo-2,9-dioxa-4,7-diazaundec-1-yl)phenyl]-L-ornithinamide 252 (395 mg, 40%, 2 steps) as a brown solid. LC-MS (Protocol B): m/z 816.7 [M+H]+, retention time=1.88 minutes.

Reference： [1]Patent: WO2015/44003,2015,A1 .Location in patent: Page/Page column 39
[2]Patent: WO2016/71418,2016,A1 .Location in patent: Page/Page column 66; 67
[3]Patent: US2016/130299,2016,A1 .Location in patent: Paragraph 0321
[4]Patent: WO2020/25108,2020,A1 .Location in patent: Page/Page column 48-49
[5]Patent: WO2012/166560,2012,A1 .Location in patent: Page/Page column 172
[6]Patent: WO2013/192360,2013,A1 .Location in patent: Paragraph 00495
[7]Patent: WO2013/185117,2013,A1 .Location in patent: Paragraph 00481
[8]Patent: CN109464654,2019,A .Location in patent: Paragraph 0071; 0090; 0091-0092
[9]Patent: WO2014/88432,2014,A1 .Location in patent: Page/Page column 88; 89
[10]Patent: US2016/271270,2016,A1 .Location in patent: Paragraph 0379; 0384
[11]Patent: US10086085,2018,B2 .Location in patent: Page/Page column 209-213

7
[ 159858-22-7 ]
[ 1611498-13-5 ]

Reference： [1]Patent: WO2014/80251,2014,A1

8
[ 159858-22-7 ]
[ 1611498-14-6 ]

Reference： [1]Patent: WO2014/80251,2014,A1

9
[ 159858-22-7 ]
N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N⁵-carbamoyl-N-{4-[({methyl[2-(methylamino)ethyl]carbamoyl}oxy)methyl]phenyl}-L-ornithinamide hydrochloride [ No CAS ]

Reference： [1]Patent: WO2015/44003,2015,A1

10
[ 159858-22-7 ]
N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N⁵-carbamoyl-N-[4-([{2-[([(8S)-8-(chloromethyl)-2-methyl-6-({5-[2-(pyrrolidin-1-yl)ethoxy]-1H-indol-2-yl}carbonyl)-7,8-dihydro-6H-thieno[2,3-e]indol-4-yl]oxy}carbonyl)(methyl)amino]ethyl}(methyl)carbamoyl]oxy}methyl)phenyl]-L-ornithinamide [ No CAS ]

Reference： [1]Patent: WO2015/44003,2015,A1

11
[ 159858-22-7 ]
N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valyl-N-{4-[10-(biphenyl-4-yl)-4,7,10-trimethyl-3,8-dioxo-2,9-dioxa-4,7-diazaundec-1-yl]phenyl}-N⁵-carbamoyl-L-ornithinamide [ No CAS ]

Reference： [1]Patent: WO2015/44003,2015,A1
[2]Patent: WO2016/71418,2016,A1

12
[ 159858-22-7 ]
N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]L-valyl-N-{4-[11-(biphenyl-4-yl)-4,6,6,8,11-pentamethyl-3,9-dioxo-2,10-dioxa-4,8-diazadodec-1-yl]phenyl}-N⁵-carbamoyl-L-ornithinamide [ No CAS ]

Reference： [1]Patent: WO2015/44003,2015,A1
[2]Patent: WO2016/71418,2016,A1

13
[ 159858-22-7 ]
N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N-{4-[10-(biphenyl-4-yl)-4,7,10-trimethyl-3,8-dioxo-2,9-dioxa-4,7-diazaundec-1-yl]phenyl}-N⁵-carbamoyl-L-ornithinamide [ No CAS ]

Reference： [1]Patent: WO2015/44003,2015,A1
[2]Patent: WO2016/71418,2016,A1

14
[ 159858-22-7 ]
C₆₃H₈₁ClN₁₂O₁₄S₂ [ No CAS ]

Reference： [1]Patent: WO2015/44003,2015,A1

15
2-[(1R,2R)-4-[(1E)-2-[(1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-2,3,10,16-tetraoxo-17-(prop-2-en-1-yl)-11,28-dioxa-4-azatricyclo[22.3.1.0^4,9]octacos-18-en-12-yl]prop-1-en-1-yl]-2-methoxycyclohexyl]oxy}acetic acid [ No CAS ]
[ 159858-22-7 ]
[4-[(2S)-2-[(2S)-2-amino-3-methylbutanamido]-5-(carbamoylamino)pentanamido]phenyl]methyl N-([(1R,2R)-4-[(1E)-2-[(1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-2,3,10,16-tetraoxo-17-(prop-2-en-1-yl)-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-en-12-yl]prop-1-en-1-yl]-2-methoxycyclohexyl]oxy}methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%		[0475] Synthesis [4-[(2S)-2-[(2S)-2-amino-3-methylbutanamido]-5(carbamoylamino) pentanamido]phenyl]methyl N-([[(JR, 2R)-4-[(JE)-2-[(JR, 9S,12S, 13R, 14S,1 7R, 1 8E, 21S,23S, 24R, 25S,2 7R)-1, 14-dihydroxy-23, 25-dimethoxy-] 3,19,21,2 7-tetramethyl-2, 3,10, 16-tetraoxo-1 7-(prop-2 -en-i -yl)-]], 28-dioxa-4 -azatricyclo[22. 3.1.0 9]octacos-18-en-12-yl]prop-1 -en-i - yl]-2-methoxycyclohexyl] oxy]methyl) carbamate (6.3): [0476] To a 4 dram vial containing 50 mg (58 tmol) of 6.1 was added 300 .iL of DMF followed by 23 .il (87 tmol) of diphenylphosphoryl azide and 14 .iL (1.2 mmol) of Hunig? s base. The reaction mixture was then stirred at RT for 1 h. Afterwards, 52 mg (87 imol) of 6.2, and 2 .iL (3 imol) of dibutyltin dilaurate was added at 60 C. The reaction was then stirred for an additional 2 h at 60 C at which time LC/MS indicated the reaction was complete. After quenching with a 100 tL of diethyl amine, the reaction mixture was directly purified by preparatory HPLC (gradient 5-95 acetonitrile/water 0.05 % TFA) to yield 15 mg, 21 % yield, of 6.3. Analytical UPLC-MS: tr = 1.82 mm. MS (m/z) [M + H1 cald for C74H114N10022, 1238.71, found 1238.70.

Reference： [1]Patent: WO2015/95755,2015,A1 .Location in patent: Paragraph 0475; 0476

16
[ 1037794-22-1 ]
[ 130878-68-1 ]
[ 159858-22-7 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide; at 20℃; for 3h;	Step 1. Compound 44-1 (600 mg, 2.14 mmol) and compound 44-2 (936 mg, 2.14 mmol) were dissolved in DMF (5 mL) and stirred at r.t. for 3 h to give 44-3 as a mixture.
	In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere;	Synthesis of Fmoc-Val-Cit-PABOH: A solution of Fmoc-Cit-PABOH (1.0 equiv) in DMF (0.2 M) was treated with piperidine (5.0 equiv) and allowed to stir at room temperature for 4 h. Solvent DMF and excess piperidine were removed under reduced pressure. Resulted residue was sonicated in ether and ether discarded. Then the solid was washed with CH2C12. Solid was dried under vacuum and then dissolved in DMF (0.2 M). To the solution Fmoc-Val-OSu (1.1 equiv) was added and allowed to stir at room temperature for 16 h. The solvent DMF was removed under reduced pressure and crude was dissolved in methanol. Compound slurry was prepared in celite for solid loading in column. Product was purified by silica gel flash column chromatography using 1 -12% MeOH-CH2Cl2. Compound Fmoc-Val- Cit-PABOH was obtained as white solid. Yield: 85% (2 steps).
	With piperidine; In N,N-dimethyl-formamide; at 20℃; for 20h;	Procedure A: A solution of compound 17 (2.600 g, 5.170 mmol, 1.0 equiv) in DMF (0.2 M) was treated with triethylamine (14.5 mL, 104 mmol, 20.0 equiv) followed by stirring at room temperature for 24 hours. DMF and excess triethylamine were removed under reduced pressure. The resulting residue was dissolved in DMF (0.1 M) and to the solution Fmoc-Val- OSu (2.480 g, 5.680 mmol, 1.1 equiv) was added. The reaction mixture was stirred at room temperature for 20 hours. DMF was removed under reduced pressure and the resulting residue was purified by flash column chromatography using 3-12% MeOH-CH2Cl2 as solvent. The product was obtained as white solid. Yield: 78%. Procedure B: A solution of compound 17 (1.000 g, 1.990 mmol, 1.0 equiv) in DMF (0.2 M) was treated with piperidine (1.00 mL, 10.1 mmol, 5.0 equiv) and stirred at room temperature for 5 hours. DMF and excess piperidine were removed under reduced pressure. Trace piperidine was removed by repeated co-evaporation with DMF. The resulting residue was dissolved in DMF (0.1 M) and to the solution Fmoc-Val-OSu (1.040 g, 2.390 mmol, 1.2 equiv) was added. The reaction mixture was stirred at room temperature for 20 hours. DMF was removed under reduced pressure and the resulting residue was purified by flash column chromatography using 3-12% MeOH-CH2Cl2 as solvent. The product was obtained as white solid. Yield: 85%.

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 989 - 1000
[2]Patent: WO2015/95227,2015,A2 .Location in patent: Page/Page column 144
[3]Patent: WO2017/66668,2017,A1 .Location in patent: Paragraph 000160
[4]Tetrahedron Letters,2018,vol. 59,p. 3594 - 3599

17
[ 1037793-80-8 ]
[ 159858-22-7 ]

Reference： [1]Patent: WO2015/95227,2015,A2

18
[ 372-75-8 ]
[ 159858-22-7 ]

Reference： [1]Patent: WO2015/95227,2015,A2
[2]Patent: WO2017/66668,2017,A1
[3]Patent: WO2017/66668,2017,A1
[4]Patent: KR2017/41562,2017,A
[5]International Journal of Molecular Sciences,2017,vol. 18
[6]Tetrahedron Letters,2018,vol. 59,p. 3594 - 3599
[7]Tetrahedron Letters,2018,vol. 59,p. 3594 - 3599
[8]Patent: WO2020/25108,2020,A1

19
[ 159858-22-7 ]
7-(4-((4-((S)-2-((S)-2-(2-(6-(2,5-dioxopyrrolidin-1-yl)hexanamido)acetamido)-3-methylbutanamido)-5-ureidopentanamido)benzyloxy)carbonyl)piperazin-1-yl)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2015/95227,2015,A2

20
[ 159858-22-7 ]
N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N-5-carbamoyl-N-{4-[([(4-nitrobenzyl)oxy]carbonyl}oxy)methyl]phenyl}-L-ornithinamide [ No CAS ]

Reference： [1]Patent: WO2015/95227,2015,A2

21
(S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-5-ureidopentanoic acid [ No CAS ]
[ 159858-22-7 ]

Reference： [1]Patent: WO2015/95227,2015,A2
[2]Patent: WO2017/66668,2017,A1
[3]Journal of Medicinal Chemistry,2018,vol. 61,p. 989 - 1000
[4]Tetrahedron Letters,2018,vol. 59,p. 3594 - 3599

22
[ 870487-04-0 ]
[ 159858-22-7 ]

Reference： [1]Patent: WO2015/95227,2015,A2
[2]Patent: WO2017/66668,2017,A1
[3]Journal of Medicinal Chemistry,2018,vol. 61,p. 989 - 1000
[4]Tetrahedron Letters,2018,vol. 59,p. 3594 - 3599

23
C₃₆H₅₀ClN₃O₉S [ No CAS ]
[ 159858-22-7 ]
C₆₉H₈₇ClN₈O₁₄S [ No CAS ]

Reference： [1]Bioconjugate Chemistry,2015,vol. 26,p. 2261 - 2278

24
[ 159858-22-7 ]
[ 159857-80-4 ]

Reference： [1]Patent: EP2486933,2015,B1
[2]Patent: WO2017/66668,2017,A1
[3]International Journal of Molecular Sciences,2017,vol. 18
[4]Journal of Medicinal Chemistry,2018,vol. 61,p. 989 - 1000
[5]Patent: CN107789630,2018,A
[6]Patent: CN108743968,2018,A
[7]Patent: CN109200291,2019,A
[8]Tetrahedron Letters,2018,vol. 59,p. 3594 - 3599
[9]Patent: WO2019/108797,2019,A1
[10]Patent: WO2020/14541,2020,A2

25
[ 159858-22-7 ]
[ 159857-81-5 ]

Reference： [1]Patent: EP2486933,2015,B1
[2]Patent: WO2017/66668,2017,A1
[3]Patent: WO2017/66668,2017,A1
[4]International Journal of Molecular Sciences,2017,vol. 18
[5]Journal of Medicinal Chemistry,2018,vol. 61,p. 989 - 1000
[6]Patent: CN107789630,2018,A
[7]Patent: CN108743968,2018,A
[8]Patent: CN109200291,2019,A
[9]Patent: WO2019/108797,2019,A1
[10]Patent: WO2020/14541,2020,A2

26
2-((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-6a,8a-dimethyl-4-oxo-10-propyl-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]-indeno[1,2-d][1,3]dioxol-8b-yl)-2-oxoethyl dihydrogen phosphate [ No CAS ]
[ 159858-22-7 ]
4-((S)-2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanamido)benzyl (2-((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-6a,8a-dimethyl-4-oxo-10-propyl-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-8b-yl)-2-oxoethyl) dihydrogenpyrophosphate [ No CAS ]

Reference： [1]Patent: WO2015/153401,2015,A1

27
2-((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-6a,8a-dimethyl-4-oxo-10-propyl-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]-indeno[1,2-d][1,3]dioxol-8b-yl)-2-oxoethyl dihydrogen phosphate [ No CAS ]
[ 102691-36-1 ]
[ 159858-22-7 ]
C₆₁H₇₆N₆O₁₇P₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred solution of (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1- ((4(hydroxymethyl)phenyl)amino)- 1 -oxo-5-ureidopentan-2-yl)amino)-3-methyl- 1 -oxobutan-2- yl)carbamate (0.05 g, 0.083 mmol) in DMF (1.2 ml) was added 3- ((bis(diisopropylamino)phosphino)oxy)propanenitrile (29uL, 0.09 mmol). To this mixture was added 0.45M tetrazole in acetonitrile (0.20 mL, 0.09 mmol) dropwise and the resulting mixture was stirred for 20 minutes at room temperature. To this was added 9-1 (0.042 g, 0.083 mmol) and 5-(ethylthio)-lH-tetrazole (0.02 g, 0.16 mmol) and allowed to stir to 30 minutes at room temperature. To this was added 6 M tertbutyl hydroperoxide in decane (0.03 mL, 0.18 mmol) and allowed to stir at room temperature for 30 minutes. To this was added DBU (0.12 mL, 0.83 mmol) and the resulting solution was stirred overnight at room temperature. The crude reaction was purified by direct injection using reverse phase preparative chromatography (Phenomenex Gemini -NX CI 8 OBD 5 uM 30 x 100mm; 5-40% MeCN/water w/ 0.1% NH4OH modifier over 20 min) to give 17-1 as a solid (18.5 mg, 23%). LRMS (ES) (M+H)+ : observed = 952.6, calculated = 951.9.

Reference： [1]Patent: WO2015/153401,2015,A1 .Location in patent: Page/Page column 82

28
[ 102691-36-1 ]
[ 51372-29-3 ]
[ 159858-22-7 ]
(9H-fluoren-9-yl)methyl ((2S)-1-(((2S)-1-((4-((((2-cyanoethoxy)(2-((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-6a,8a-dimethyl-4-oxo-10-propyl-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-8b-yl)-2-oxoethoxy)phosphoryl)oxy)methyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%		To a stirred solution of (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1- ((4(hydroxymethyl)phenyl)amino)- 1 -oxo-5-ureidopentan-2-yl)amino)-3-methyl- 1 -oxobutan-2- yl)carbamate (0.20 g, 0.33 mmol) in DMF (4.7 mL) was added 3- ((bis(diisopropylamino)phosphino)oxy)propanenitrile (0.11 g, 0.37 mmol). To this mixture was added 0.45M tetrazole in acetonitrile (0.81 mL, 0.37 mmol) dropwise and the resulting mixture was stirred for 20 minutes at room temperature. To this was added Budesonide (0.22 g, 0.50 mmol) and 5-(ethylthio)-lH-tetrazole (0.09 g, 0.67 mmol) and allowed to stir to 30 minutes at room temperature. To this was added 6 M tertbutyl hydroperoxide in decane (0.12 mL, 0.73 mmol) and allowed to stir at room temperature for 1 hour. The crude reaction was loaded directly onto silica gel and flash column separation using a 0- 100% ethyl acetate/ hexane gradient followed by a 0-50% isopropanol DCM gradient gave 12-1 as a solid. (0.10 g, 27%) LRMS (ES) (M+H)+ : observed = 1 147.7, calculated = 1147.2.

Reference： [1]Patent: WO2015/153401,2015,A1 .Location in patent: Page/Page column 71; 72

29
[ 51372-29-3 ]
[ 159858-22-7 ]
4-((S)-2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanamido)benzyl (2-((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-6a,8a-dimethyl-4-oxo-10-propyl-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-8b-yl)-2-oxoethyl) hydrogenphosphate [ No CAS ]

Reference： [1]Patent: WO2015/153401,2015,A1

30
[ 159858-22-7 ]
(R)-benzyl 2-((((4-((S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamido)-5-ureidopentanamido)-benzyl)oxy)carbonyl)(methyl)amino)-3-methylbutanoate [ No CAS ]

Reference： [1]Patent: US2016/130299,2016,A1

31
[ 159858-22-7 ]
(R)-2-((((4-((S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamido)-5-ureidopentanamido)-benzyl)oxy)carbonyl)(methyl)amino)-3-methylbutanoic acid [ No CAS ]

Reference： [1]Patent: US2016/130299,2016,A1

32
[ 159858-22-7 ]
4-((S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamido)-5-ureidopentanamido)benzyl methyl(2-(methylamino)ethyl)carbamate [ No CAS ]

Reference： [1]Patent: US2016/271270,2016,A1

33
[ 159858-22-7 ]
N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valyl-N⁵-carbamoyl-N-[4-(4,7,10,10-tetramethyl-3,8-dioxo-2,9-dioxa-4,7-diazaundec-1-yl)phenyl]-L-ornithinamide [ No CAS ]

Reference： [1]Patent: US2016/271270,2016,A1
[2]Patent: US10086085,2018,B2

34
[ 75-44-5 ]
ethyl (S,E)-4-((S)-2-((S)-3-(3-aminophenyl)-3-methyl-2-(methylamino)butanamido)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoate [ No CAS ]
[ 159858-22-7 ]
ethyl (S,E)-4-((S)-2-((S)-3-(3-((((4-((S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamido)-5-ureidopentanamido)benzyl)oxy)carbonyl)amino)phenyl)-3-methyl-2-(methylamino)butanamido)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%		ethyl (S,E)-4-((S)-2-((R)-3-(3-((((4-((S)-2-((S)-2- ((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamido)-5- ureidopentanamido)benzyl)oxy)carbonyl)amino)phenyl)-3-methyl-2- (methylamino)butanamido)-N,3,3-trimethylbutanamido)-2,5-dimethylhex-2-enoate.To an oven-dried 50 mL pressure vessel equipped with a teflon-coated magnetic stir bar is charged with compound A19 (167 mg, 0.323 mmol, 1 eq) (**Note: compound A19 was dried under lyophilizer pump for 15 h prior to use) and 4 mL of anhydrous CH2Cl2 to this was added 15 % w/v phosgene in toluene (5 mL) at rt. The reaction mixture was flushed with Argon and it was stirred in a sealed vessel for 17h at rt, then concentrated under reduced pressure to remove volatiles, and dried under high vacuum for at least 2 hours. To this residue was added Fmoc valine-citruline-p-aminobenzyl alcohol (253 mg, 0.42 mmol, 1.3 eq). This mixture was dissolved in 3 mL of anhydrous N,N-Dimethylformamide. The reaction mixture was stirred at 45 oC for 2 h, then at ambient temperature for 12 h. After removal of all volatiles in vacuo the residue was purified by flash column chromatography on a Teledyne ISCO (24g silica flash column, gradient: CH2Cl2 to 12% MeOH/CH2Cl2) to give compound A18 (247 mg, 0.215 mmol, 67%) as an off-white solid. LC-MS (ESI): 1144.7 (M+1).

Reference： [1]Patent: WO2016/123582,2016,A1 .Location in patent: Paragraph 00375; 00377-00378

35
[ 75-44-5 ]
C₃₄H₅₆N₄O₆ [ No CAS ]
[ 159858-22-7 ]
C₆₈H₉₃N₉O₁₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10 mg		To an argon-flushed solution of A9 (27 mg, 0.04 mmol) in 1 mL CH2Cl2 was added 15 % w/v phosgene in toluene (0.6 mL, 0.06 mmol). The reaction mixture was heated to 50 oC in a sealed tube for 4h, cooled to ambient temperature, and the volatiles removed in vacuo. To the residue was added a vacuum-dried solution of Fmoc-valine-citruline-p- aminobenzyl alcohol (26 mg, 0.04 mmol) in 1 mL DMF. The reaction mixture was stirred at 45 oC under argon for 6 h, then at ambient temperature for 24 hr. After removal of all volatiles in vacuo the residue was purified on silica gel (90:10 CH2Cl2:MeOH eluent) to give 10 mg (0.008 mmol) A10 as a white solid.

Reference： [1]Patent: WO2016/123582,2016,A1 .Location in patent: Paragraph 00309-00310

36
[ 159858-22-7 ]
C₇₀H₉₂N₁₀O₁₃ [ No CAS ]

Reference： [1]Patent: WO2016/123582,2016,A1

37
[ 159858-22-7 ]
C₇₂H₉₆N₁₀O₁₃ [ No CAS ]

Reference： [1]Patent: WO2016/123582,2016,A1

38
[ 159858-22-7 ]
C₆₅H₈₄N₁₀O₁₁ [ No CAS ]

Reference： [1]Patent: WO2016/123582,2016,A1

39
[ 75-44-5 ]
ethyl (6S,9S,12S,E)-6-(2-(3-aminophenyl)propan-2-yl)-9-(tert-butyl)-12-isopropyl-2,2,5,11,14-pentamethyl-4,7,10-trioxo-3-oxa-5,8,11-triazapentadec-13-en-15-oate [ No CAS ]
[ 159858-22-7 ]
C₆₈H₉₃N₉O₁₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To an argon-flushed solution of A9a (27 mg, 0.04 mmol) in 1 mL CH2Cl2 is added 15 % w/v phosgene in toluene (0.6 mL, 0.06 mmol). The reaction mixture is heated to 50 oC in a sealed tube for 4h, cooled to ambient temperature, and the volatiles removed in vacuo. To the residue is added a vacuum-dried solution of Fmoc-valine-citruline-p- aminobenzyl alcohol (26 mg, 0.04 mmol) in 1 mL DMF. The reaction mixture is stirred at 45 oC under argon for 6 h, then at ambient temperature for 24 hr. After removal of all volatiles in vacuo the residue is purified on silica gel (90:10 CH2Cl2:MeOH eluent) to give A10a

Reference： [1]Patent: WO2016/123582,2016,A1 .Location in patent: Paragraph 00340-00341

40
[ 159858-22-7 ]
(9H-fluoren-9-yl)methyl ((2S)-1-(((2S)-1-((4-((((2-cyanoethoxy)(2-((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-6a,8a-dimethyl-4-oxo-10-propyl-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-8b-yl)-2-oxoethoxy)phosphoryl)oxy)methyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate [ No CAS ]

Reference： [1]Bioconjugate Chemistry,2016,vol. 27,p. 2081 - 2088

41
[ 159858-22-7 ]
4-((2S)-2-((2S)-2-(2-(cyclooct-2-yn-1-yloxy)acetamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl (2-((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-6a,8a-dimethyl-4-oxo-10-propyl-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12bdodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]-dioxol-8b-yl)-2-oxoethyl) hydrogen phosphate [ No CAS ]

Reference： [1]Bioconjugate Chemistry,2016,vol. 27,p. 2081 - 2088

42
[ 159858-22-7 ]
C₆₁H₇₅N₆O₁₃P [ No CAS ]

Reference： [1]Bioconjugate Chemistry,2016,vol. 27,p. 2081 - 2088

43
[ 159858-22-7 ]
4-((S)-2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanamido)benzyl (2-((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-6a,8a-dimethyl-4-oxo-10-propyl-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-8b-yl)-2-oxoethyl) hydrogenphosphate [ No CAS ]

Reference： [1]Bioconjugate Chemistry,2016,vol. 27,p. 2081 - 2088

44
[ 102691-36-1 ]
[ 159858-22-7 ]
C₄₂H₅₆N₇O₇P [ No CAS ]

Reference： [1]Bioconjugate Chemistry,2016,vol. 27,p. 2081 - 2088

45
2,5-dioxopyrrolidin-1-yl (((9H-fluoren-9-yl)methoxy)carbonyl)-L-valinate [ No CAS ]
[ 159858-22-7 ]

Reference： [1]Patent: US2016/271270,2016,A1

46
[ 159858-22-7 ]
C₅₀H₆₃N₇O₁₂ [ No CAS ]

Reference： [1]Patent: WO2017/66668,2017,A1
[2]Patent: WO2017/66668,2017,A1
[3]Patent: WO2017/66668,2017,A1

47
[ 159858-22-7 ]
C₃₇H₆₂N₁₀O₈ [ No CAS ]

Reference： [1]Patent: WO2017/66668,2017,A1
[2]Patent: WO2017/66668,2017,A1

48
[ 159858-22-7 ]
C₅₉H₈₄N₁₀O₁₄ [ No CAS ]
C₅₉H₈₄N₁₀O₁₄ [ No CAS ]

Reference： [1]Patent: WO2017/66668,2017,A1
[2]Patent: WO2017/66668,2017,A1

49
[ 159858-22-7 ]
C₅₅H₇₂N₈O₁₄ [ No CAS ]

Reference： [1]Patent: WO2017/66668,2017,A1
[2]Patent: WO2017/66668,2017,A1

50
[ 159858-22-7 ]
C₄₉H₆₁N₇O₁₂ [ No CAS ]

Reference： [1]Patent: WO2017/66668,2017,A1
[2]Tetrahedron Letters,2018,vol. 59,p. 3594 - 3599

51
[ 159858-22-7 ]
(9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-(bromomethyl)phenyl)amino)-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With brominating agent; In tetrahydrofuran; at 0 - 20℃; for 2h;Inert atmosphere;	It the flask which was flame dried the die peptide Fmoc -Val - Cit - PAB (9(/b), 75 mg, 125 mumol) under N 2 added and it cooled to 0. In addition, 33% HBr solution among the acetic acid (1.3 mL) was added the drop by drop. The solution was stirred for 2 hours after it was warmed at the room temperature. Next, the HBr remaining was blown through N 2 stream and reaction the additionally was condensated under the reduced pressure. Next, after the residue of the result was put in into THF and it 3 times recondensed it used without the additional refinement in the next experimen

Reference： [1]Patent: KR2017/53648,2017,A .Location in patent: Paragraph 0626; 1215

52
[ 159858-22-7 ]
4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl((S)-1-(((S)-1-(((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamate [ No CAS ]

Reference： [1]International Journal of Molecular Sciences,2017,vol. 18
[2]Patent: CN107789630,2018,A
[3]Patent: CN108743968,2018,A
[4]Patent: CN109200291,2019,A
[5]Patent: WO2019/108797,2019,A1

53
C₁₈H₂₈N₄O₅ [ No CAS ]
[ 159858-22-7 ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 989 - 1000

54
[ 159858-22-7 ]
4-((R)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl ((2S)-1-(((2S)-1-(((4S,5S)-1-((S)-2-((1R,2R)-3-(((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3-methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 989 - 1000

55
[ 623-04-1 ]
[ 159858-22-7 ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 989 - 1000

56
C₇₀H₁₀₄N₄O₁₁S₂Si₃ [ No CAS ]
[ 159858-22-7 ]
C₁₀₄H₁₄₁N₉O₁₈S₂Si₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14%		To a solution of triphosgene (54.0 mg, 0.180 mmol) in DCM (10 mL) was added amixture of compound A3 (500 mg, 0.450 mmol) and triethylamine (50.0 mg, 0.490 mmol) inDCM (5.0 mL) at 0C under N2. The reaction mixture was stirred at 0C for 30 mm. To thereaction mixture was added a solution of Fmoc-VC PAB (260.0 mg, 0.450 mmol) andtriethylamine (78.0 mg, 0.770 mmol) in DMF (3.0 mL). The mixture was stirred at 40C for 8 h, concentrated, and purified by column chromatography (0-8% MeOH in DCM) to givecompound A4 (130 mg, 14%) as a yellow solid. LCMS (5-95, AB, 1.5 mm): RT =1.474 mm,m/z=978.l [M12+l]+

Reference： [1]Patent: WO2018/31662,2018,A1 .Location in patent: Page/Page column 163; 164; 165

57
[ 32315-10-9 ]
C₇₀H₁₀₄N₄O₁₁S₂Si₃ [ No CAS ]
[ 159858-22-7 ]
C₁₀₄H₁₄₁N₉O₁₈S₂Si₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14%		To a solution of triphosgene (54.0 mg, 0.180 mmol) in DCM (10 mL) was added amixture of compound A3 (500 mg, 0.450 mmol) and triethylamine (50.0 mg, 0.490 mmol) inDCM (5.0 mL) at 0C under N2. The reaction mixture was stirred at 0C for 30 mm. To thereaction mixture was added a solution of Fmoc-VC PAB (260.0 mg, 0.450 mmol) andtriethylamine (78.0 mg, 0.770 mmol) in DMF (3.0 mL). The mixture was stirred at 40C for 8 h, concentrated, and purified by column chromatography (0-8% MeOH in DCM) to givecompound A4 (130 mg, 14%) as a yellow solid. LCMS (5-95, AB, 1.5 mm): RT =1.474 mm,m/z=978.l [M12+l]+

Reference： [1]Patent: WO2018/31662,2018,A1 .Location in patent: Page/Page column 163; 164; 165

58
[ 159858-22-7 ]
ethyl 7-(((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)amino)-7-oxoheptanoate [ No CAS ]

Reference： [1]Chemical Science,2018,vol. 9,p. 6490 - 6496
[2]Patent: WO2018/178060,2018,A1

59
[ 159858-22-7 ]
ethyl 7-(((S)-3-methyl-1-oxo-1-(((S)-1-oxo-1-((4-((((S)-7-oxo-6-((R)-5-oxo-pyrrolidine-2-carboxamido)-7-(phenylamino)heptyl)thio)methyl)phenyl)amino)-5-ureidopentan-2-yl)amino)butan-2-yl)amino)-7-oxoheptanoate [ No CAS ]

Reference： [1]Chemical Science,2018,vol. 9,p. 6490 - 6496
[2]Patent: WO2018/178060,2018,A1

60
[ 159858-22-7 ]
7-(((S)-3-methyl-1-oxo-1-(((S)-1-oxo-1-((4-((((S)-7-oxo-6-((R)-5-oxopyrrolidine-2-carboxamido)-7-(phenylamino)heptyl)thio)methyl)phenyl)amino)-5-ureidopentan-2-yl)amino)butan-2-yl)amino)-7-oxoheptanoic acid [ No CAS ]

Reference： [1]Chemical Science,2018,vol. 9,p. 6490 - 6496
[2]Patent: WO2018/178060,2018,A1

61
C₂₀H₁₆N₂O₂ [ No CAS ]
[ 159858-22-7 ]
C₅₃H₅₅N₇O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;	A two phase of mixture of ICQO-1 (30 mg, 103.3 pmol) in dichioromethane (10.1 mL) and saturated aqueous sodium hydrogen carbonate (10.1 mL) was cooled to 000. A solution of 20 % phosgene in toluene (1 .5 mol eq.) was quickly added to the organic layer under N2 and the reaction mixture was stirred vigorously for 1 h at room temperature. The layers were separated and the aqueous layer was extracted with dichloromethane (3 x 10 mL). The combined organic layers were dried (MgSO4) and concentrated to five the isocyanate as oil. This oil was dissolved in anhydrous DMF (2.25 mL), Fmoc-Val-Cit-PAB (1.3 mol eq.) was added and the mixture was stirred overnight at room temperature under N2. The resulting mixture was dry- loaded onto silica and the purified using automated normal phase chromatography eluting with a gradient of 4 to 32 % methanol in dichloromethane gave 28 mg (30 %) of Fmoc-Val- Cit-PAB-ICQO-1.

Reference： [1]Patent: WO2018/178277,2018,A1 .Location in patent: Paragraph 00155

62
[ 159858-22-7 ]
C₄₃H₆₀N₈O₁₁ [ No CAS ]