[ CAS No. 863971-53-3 ] {[proInfo.proName]}

Name: 863971-53-3|Fmoc-Val-Cit-PAB-PNP|98%
Brand: Ambeed
SKU: A157658
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Quality Control of [ 863971-53-3 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 863971-53-3 ]

SDS Specification

Alternatived Products of [ 863971-53-3 ]

Product Details of [ 863971-53-3 ]

CAS No. :	863971-53-3	MDL No. :	MFCD22200278
Formula :	C₄₀H₄₂N₆O₁₀	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	766.80	Pubchem ID :	-
Synonyms :

Calculated chemistry of [ 863971-53-3 ]

Physicochemical Properties

Num. heavy atoms :	56
Num. arom. heavy atoms :	24
Fraction Csp3 :	0.28
Num. rotatable bonds :	23
Num. H-bond acceptors :	10.0
Num. H-bond donors :	5.0
Molar Refractivity :	206.26
TPSA :	233.0 Å²

Pharmacokinetics

GI absorption :	Low
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.97 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.26
Log Po/w (XLOGP3) :	5.64
Log Po/w (WLOGP) :	5.4
Log Po/w (MLOGP) :	2.05
Log Po/w (SILICOS-IT) :	2.56
Consensus Log Po/w :	3.78

Druglikeness

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

Water Solubility

Log S (ESOL) :	-6.95
Solubility :	0.0000867 mg/ml ; 0.000000113 mol/l
Class :	Poorly soluble
Log S (Ali) :	-10.3
Solubility :	0.0000000387 mg/ml ; 0.0000000001 mol/l
Class :	Insoluble
Log S (SILICOS-IT) :	-10.58
Solubility :	0.0000000202 mg/ml ; 0.0 mol/l
Class :	Insoluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	4.0 alert
Leadlikeness :	3.0
Synthetic accessibility :	5.89

Safety of [ 863971-53-3 ]

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 [ 863971-53-3 ]

* 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 [ 863971-53-3 ]
Downstream synthetic route of [ 863971-53-3 ]

[ 863971-53-3 ] Synthesis Path-Upstream 1~7

1
[ 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

2
[ 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,

3
[ 68858-20-8 ]
[ 863971-53-3 ]

Reference： [1] Journal of Controlled Release, 2012, vol. 160, # 3, p. 618 - 629
[2] Patent: US2016/271270, 2016, A1,

4
[ 130878-68-1 ]
[ 863971-53-3 ]

Reference： [1] Journal of Controlled Release, 2012, vol. 160, # 3, p. 618 - 629
[2] Patent: KR2017/41562, 2017, A,

5
[ 159858-21-6 ]
[ 863971-53-3 ]

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

6
[ 623-04-1 ]
[ 863971-53-3 ]

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

7
[ 372-75-8 ]
[ 863971-53-3 ]

Reference： [1] Patent: KR2017/41562, 2017, A,

[ 863971-53-3 ] Synthesis Path-Downstream 1~88

1
2BrH*C₃₀H₃₀BrN₅O₃ [ No CAS ]
[ 863971-53-3 ]
[ 76-05-1 ]
[ 1037797-71-9 ]

Yield	Reaction Conditions	Operation in experiment
30%		Compound (3). A solution of HBr salt 1 (12 mg, 0.016 mmol) (see compound 10 of Example 6) and 2 (25 mg, 0.032 mmol) in DMF (1.5 mL) was treated with diisopropylethylamine (11 uL, 0.064 mmol) and was stirred at 25 C. under nitrogen for 48 h. The solvent was removed and crude product was purified by Prep HPLC to afforded 3 (6.4 mg, 30%). MS: calcd for C64H67BrN10O10 (M+H) m/z 1216.18 found 1216.40.

Reference： [1]Patent: US2010/145036,2010,A1 .Location in patent: Page/Page column 84-85; 86

2
[ 863971-53-3 ]
[ 33069-62-4 ]
C₈₁H₈₈N₆O₂₁ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; In dichloromethane; at 20℃; for 48h;Inert atmosphere;	To a stirred mixture of paclitaxel (100 mg, 0.1 17 mmol) and Fmoc-Val-Cit-PAB(74.8 mg, 0.00976 mmol) in dry DCM (10 ml) DMAP (14.3 mg, 0.1 17 mmol) is added and stirred at room temperature under nitrogen for 48 h. The solvent is evaporated to give a light-yellow crystalline solid which is purified by flash column chromatography [silica gel: 3-5% MeOH/Chloroform] giving the desired compound 45.

Reference： [1]Journal of Controlled Release,2012,vol. 160,p. 618 - 629
[2]Patent: WO2016/46574,2016,A1 .Location in patent: Page/Page column 80
[3]Nature Communications,2017,vol. 8

3
[ 68858-20-8 ]
[ 863971-53-3 ]

Reference： [1]Journal of Controlled Release,2012,vol. 160,p. 618 - 629
[2]Patent: US2016/271270,2016,A1

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 ]
[ 863971-53-3 ]

Reference： [1]Journal of Controlled Release,2012,vol. 160,p. 618 - 629
[2]Patent: KR2017/41562,2017,A
[3]Patent: WO2020/25108,2020,A1

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
[ 863971-53-3 ]
monomethyldolastatin hydrochloride salt [ No CAS ]
[ 1415329-11-1 ]

Yield	Reaction Conditions	Operation in experiment
58%	With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;	To a solution of 1.0 g (1.24 mmol) of monomethyldolastatin hydrochloride, 1.42 g (1.8575 mmol) of compound 16-9 and 95 mg (0.62 mmol) of HOBt in 10 mL of DMF was added 437 muL (2.48 mmol) of diisopropylethylamine. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was purified by HPLC to give 1.0 g (58%) of compound 16-10. MS (ESI) m/z 700 [M+2H], 1398 [M+H].
58%	With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;	To a solution of 1.0 g (1.24 mmol) of monomethyldolastatinhydrochloride, 1.42 g (1.8575 mmol) of compound 16-9 and 95 mg (0.62 mmol) ofHOBt in 10 mL20 of DMF was added 437 ~lL (2.48 mmol) of diisopropylethylamine. The reaction mixture was stirredat room temperature for 16 hours. The reaction mixture was purified by HPLC to give 1.0 g (58%) ofcompound 16-10. MS (ESI) m/z 700 [M+2H], 1398 [M+H].

Reference： [1]Patent: WO2012/166560,2012,A1 .Location in patent: Page/Page column 172
[2]Patent: WO2013/185117,2013,A1 .Location in patent: Paragraph 00482

8
[ 863971-53-3 ]
4-((S)-2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanamido)benzyl (2-(pyridin-2-yldisulfanyl)ethyl)carbamate [ No CAS ]

Reference： [1]Patent: WO2013/166155,2013,A1

9
[ 863971-53-3 ]
C₅₃H₈₈N₁₀O₁₈S₂ [ No CAS ]

Reference： [1]Patent: WO2013/166155,2013,A1

10
[ 863971-53-3 ]
C₃₈H₅₂N₈O₁₀S₂ [ No CAS ]

Reference： [1]Patent: WO2013/166155,2013,A1

11
[ 863971-53-3 ]
2-(2-pyridinyldisulfanyl)ethanamine hydrochloride [ No CAS ]
(9H-fluoren-9-yl)methyl ((S)-3-methyl-1-oxo-1-(((S)-1-oxo-1-((4-((((2-(pyridin-2-yldisulfanyl)ethyl)carbamoyl)oxy)methyl)phenyl)amino)-5-ureidopentan-2-yl)amino)butan-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; In N,N-dimethyl acetamide; at 20℃; for 6h;	Synthesis of 13 (Ex. 67) II (160 mg, 0.209 mmol) and 12 (48.8 mg, 0.219 mmol) were dissolved in DMA (1 mL) and were treated with N-methylmorpholine (46 mu, 0.417 mmol). The reaction was stirred at RT for 6 hours, then purified by RP-HPLC (95:5-20:80% A:B linear gradient (A = 0.1%) aqueous TFA; B = 0.1 %> TFA in acetonitrile) Waters C18 xbridge Column 19x250mm). Fractions containing 13 were extracted with 2: 1 DCM:MeOH, dried over Na2S04, filtered, and concentrated in vacuo to give the product. Measured mass = 814.3

Reference： [1]Patent: WO2013/166155,2013,A1 .Location in patent: Page/Page column 102

12
[ 863971-53-3 ]
monomethyldolastatin hydrochloride [ No CAS ]
C₇₅H₁₀₅N₁₁O₁₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;	Compound 16-10: To a solution of 1.0 g (1.24 mmol) of monomethyldolastatinhydrochloride, 1.42 g (1.8575 mmol) of compound 16-9 and 95 mg (0.62 mmol) of HOBt in10 mL of DMF was added 437 ~LL (2.48 mmol) of diisopropylethylamine. The reactionmixture was stirred at room temperature for 16 hours. The reaction mixture was purified by25 HPLC to give 1.0 g (58%) of compound 16-10. MS (ESI) m/z 700 [M+2H], 1398 [M+H].

Reference： [1]Patent: WO2013/192360,2013,A1 .Location in patent: Paragraph 00496

13
[ 863971-53-3 ]
[ 1609106-03-7 ]
[ 1609106-40-2 ]

Yield	Reaction Conditions	Operation in experiment
23%	With 2,6-dimethylpyridine; dmap; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 3.5h;	Example A67 Preparation of Ar-{7-[(2,5-dioxopyrrolidin-l-yl)oxy]-7-oxoheptanoyl}-L-valyl-N-[4-([(2- [(3Lambda,55,7Lambda,8Lambda)-7-{(1£,3^-5-[(25,35,5Lambda,^ dimethyltetrahydro-2H-pyran-2-yl]-3-methylpenta-l,3-dien-l-yl}-8-hydroxy-l,6- dioxaspiro[2.5]oct-5-yl]acetyl}hydrazinyl)carbonyl]oxy}methyl)phenyl]-A^-carbamoyl-L- ornithinamide (B190). Step 1. Synthesis of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valyl-N-[4-( [(2- [(3R,5S,7R,8R)-7-{(l£,3£)-5-[(2S,3S,5R,6R)-5-[(2Z,4S)-4-(acetyloxy)pent-2-enoyl]amino}-3,6- dimethyltetrahydro-2H-pyran-2-yl]-3-methylpenta-l,3-dien-l -yl}-8-hydroxy-l,6-dioxaspiro[2.5]oct-5- yl]acetyl}hydrazinyl)carbonyl]oxy}methyl)phenyl]-N5-carbamoyl-L-ornithinamide (B191). To a solution of B6 (19.4 mg, 0.035 mmol, 1 eq.) in NN-dimethylformamide (0.5 mL) at rt was added NN-diisopropylethylamine (24.7 muL, 0.14 mmol, 4 eq.), 2,6-lutidine (16.3 mu^, 0.14 mmol, 4 eq.), 4- NN-dimethylamino pyridine (4.3 mg, 0.035 mmol, 1 eq.) and N-[(9H-fluoren-9-ylmethoxy)carbonyl]- L-valyl-N5-carbamoyl-N-[4-([(4-nitrophenoxy)carbonyl]oxy}methyl)phenyl]-L-ornithinamide (40.6 mg, 0.053 mmol, 1.5 eq.), and the reaction was stirred for 2.5 h. More N-[(9H-fluoren-9- ylmethoxy)carbonyl]-L-valyl-N5-carbamoyl-N-[4-( [(4-nitrophenoxy)carbonyl]oxy}methyl)phenyl]-L- ornithinamide (13.5 mg, 0.018 mmol, 0.5 eq.) was added, and the reaction was stirred for another 1 h. The reaction was purified by reverse phase chromatography (Method A) to give B191 as a white solid. Yield: 9.4 mg, 0.0081 mmol, 23%. LCMS (Protocol D): m/z 1177.8 [M+H] , retention time = 0.90 minutes. Step 2. Synthesis of L-valyl-N-[4-( [(2-[(3R,5S,7R,8R)-7- {(l£',3£')-5-[(2S,3S,5R,6R)-5- [(2Z,4S)-4-(acetyloxy)pent-2-enoyl]amino}-3,6-dimethyltetrahydro-2H-pyran-2-yl]-3-methylpenta- 1 ,3 -dien- 1 -yl } - 8 -hydroxy- 1 ,6-dioxaspiro [2.5 ] oct-5 - yl]acetyl}hydrazinyl)carbonyl]oxy}methyl)phenyl]-N5-carbamoyl-L-ornithinamide acetate salt (B192). The title compound was prepared in 56% yield from 9.4 mg (0.008 mmol, 1.0 eq) of B191 and 13.6 mg (0.16 mmol, 20.0 eq) of piperidine using the procedure described for preparation of compound B47. LCMS (Protocol D): m/z 955.8 [M+H]+, retention time = 0.65 minutes. Step 3. Synthesis of N-{7-[(2,5-dioxopyrrolidin-l-yl)oxy]-7-oxoheptanoyl}-L-valyl-N-[4- ([(2-[(3R,5S,7R,8R)-7-{(l£,3£)-5-[(2S,3S,5R,6R)-5- [(2Z,4S)-4-(acetyloxy)pent-2-enoyl]amino}- 3,6-dimethyltetrahydro-2H-pyran-2-yl] -3 -methylpenta- 1 ,3-dien- 1 -yl} -8-hydroxy- 1 ,6- dioxaspiro [2.5] oct-5 -yl] acetyl} hydrazinyl)carbonyl] oxy } methyl)phenyl] -N5-carbamoyl-L- ornithinamide (B190). To a solution of B192 (4.5 mg, 0.004 mmol, 1 eq.) in NN- dimethylformamide (0.3 mL) at rt was added NN-diisopropylethylamine (3.5 muL, 0.02 mmol, 5 eq.) followed by l,l'-[(l,7-dioxoheptane-l,7-diyl)bis(oxy)]dipyrrolidine-2,5-dione (prepared as in J.Am.Chem.Soc. 2006, 128, 2802, 8.9 mg, 0.025 mmol) 6.2 eq.), and the reaction was allowed to stir for 35 min. The reaction was purified by reverse phase chromatography (Method A) to give B190 as a white solid. Yield: 1.65 mg, 0.0014 mmol, 34%. LCMS (Protocol D): m/z 1194.80 [M+H]+, retention time = 0.75 minutes. lH NMR (500 MHz, CD3CN) delta 9.06 (s, 1 H), 8.17 (s, 1 H), 7.71-7.63 (m, 2 H), 7.35-7.25 (m, 2 H), 7.19 (d, J= 7.6 Hz, 1 H), 6.73 (d, J= 6.6 Hz, 1 H), 6.47 (d, J= 8.8 Hz, 1 H), 6.41- 6.30 (m, 2 H), 5.96-5.85 (m, 2 H), 5.67-5.50 (m, 2 H), 5.33-5.24 (m, 1 H), 5.08-4.99 (m, 2 H), 4.74 (s, 1 H), 4.57-4.48 (m, 1 H), 4.39-4.25 (m, 2 H), 4.15-4.08 (m, 1 H), 3.82-3.75 (m, 1 H), 3.67-3.59 (m, 1 H), 3.55-3.47 (m, 1 H), 3.35-3.20 (m, 2 H), 3.12-2.99 (m, 2 H), 2.82-2.73 (m, 5 H), 2.66-2.52 (m, 6 H), 2.46-2.38 (m, 2 H), 2.36-2.20 (m, 4 H), 1.98 (s, 3 H), 1.77-1.57 (m, 11 H), 1.53-1.36 (m, 6 H), 1.30 (d, J= 6.6 Hz, 3 H), 1.06 (d, J= 6.6 Hz, 3 H), 1.00-0.91 (m, 9 H).

Reference： [1]Patent: WO2014/68443,2014,A1 .Location in patent: Page/Page column 188-190

14
[ 863971-53-3 ]
[ 1609106-04-8 ]
[ 1609131-81-8 ]

Yield	Reaction Conditions	Operation in experiment
59%	With 2,6-dimethylpyridine; dmap; 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 50℃; for 1.5h;	Example A15 Preparation of N-[3-(2-{2-[(bromoacetyl)amino]ethoxy}ethoxy)propanoyl]-L-valyl-N-[4-([(2- [(3S,5S,7S)-7-{(lE,3E)-5-[(2S,3S,5R,6R)-5-[(2Z,4S)-4-(acetyloxy)pent-2-enoyl]amino}-3,6- dimethyltetrahydro-2H-pyran-2-yl]-3-methylpenta-l,3-dien-l-yl}-l,6-dioxaspiro[2.5]oct-5- yl]acetyl}hydrazinyl)carbonyl]oxy}methyl)phenyl]-N~5- carbamoyl-L-ornithinamide( B43). Step 1. Synthesis of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valyl-N-[4-([(2- [(3S,5S,7S)- 7-{(lE,3E)-5-[(2S,3S,5R,6R)-5- [(2Z,4S)-4-(acetyloxy)pent-2-enoyl]amino}-3,6-dimethyltetrahydro- 2H-pyran-2-yl]-3-methylpenta-l,3-dien-l-yl}-l,6-dioxaspiro[2.5]oct-5- yl]acetyl}hydrazinyl)carbonyl]oxy}methyl)phenyl]-N~5- carbamoyl-L-ornithinamide (B41). To a solution of B7 of (56 mg, 0.1 mmol, 1 eq.) in NN-dimethylformamide (2.6 mL) was added N-[(9H- fluoren-9-ylmethoxy)carbonyl]-L-valyl-N~5- carbamoyl-N-[4-([(4- nitrophenoxy)carbonyl] oxy} methyl)phenyl] -L-ornithinamide (FMocValCitPABC-PNP, WO04010957, 121 mg, 0.15 mmol, 1.5 eq.) N,N'-diisopropylethylamine (56 mg, 0.4 mmol, 4.0 eq.), 2,6- Dimethylpyridine (45 mg, 0.4 mmol, 4.0 eq.,) and 3H-[l,2,3]triazolo[4,5-b]pyridin-3-ol (14.3 mg, 0.105 mmol, 1.05 eq.,). After stirring at 50 C for 1.5 hours, the reaction mixture was concentrated in vacuo and the crude material was purified by reverse phase chromatography (Method A) to provide B41 as a solid. Yield: 72 mg, 0.06 mmol, 59%. LCMS (Protocol D): m/z 1183.5 [M+Na]+, retention time = 0.95 minutes. Step 2. Synthesis of L-valyl-N-[4-([(2-[(3S,5S,7S)-7- {(lE,3E)-5-[(2S,3S,5R,6R)-5- [(2Z,4S)-4-(acetyloxy)pent-2-enoyl]amino} -3,6-dimethyltetrahydro-2H-pyran-2-yl]-3-methylpenta- 1 , 3 -dien- 1 -yl } - 1 , 6 -dioxaspiro [2.5 ] oct-5 -yl] acetyl } hydrazinyl)carbonyl] oxy } methyl)phenyl] -N~5- carbamoyl-L-ornithinamide (B42). To a solution of B41 (50 mg, 0.043 mmol, 1 eq.) in NN- dimethylformamide (0.7 mL) was added piperidine (66 mg, 0.78 mmol, 20 eq.) and the mixture stirred for 20 minutes. The reaction mixture was concentrated in vacuo and the crude material was purified by reverse phase chromatography (Method A) to provide B42. Yield: 31 mg, 0.033 mmol, 76%>. LCMS (Protocol D): m/z 939.3 [M+H]+, retention time = 0.66 minutes. Step 3. Synthesis of N-[3-(2-{2-[(bromoacetyl)amino]ethoxy} ethoxy)propanoyl]-L-valyl-N- [4-([(2- [(3S,5S,7S)-7-{(lE,3E)-5-[(2S,3S,5R,6R)-5- [(2Z,4S)-4-(acetyloxy)pent-2-enoyl]amino} - 3,6-dimethyltetrahydro-2H-pyran-2-yl]-3-methylpenta-l,3-dien-l-yl}-l,6-dioxaspiro[2.5]oct-5 yl]acetyl}hydrazinyl)carbonyl]oxy}methyl)phenyl]-N~5- carbamoyl-L-ornithinamide (B43). To a solution of B42 (10 mg, 0.011 mmol, 1 eq.) in NN-dimethylformamide (0.2 mL) was added 2-bromo- N-[2-(2- {3-[(2,5-dioxopyrrolidin-l -yl)oxy]-3-oxopropoxy}ethoxy)ethyl]acetamide (4.3 mg, 0.011 mmol, 1 eq.) and the mixture stirred at room temperature for 30 minutes. The reaction was diluted with dimethylsulfoxide (0.2 mL) and purified by reverse phase chromatography (Method A) to provide B43 as a solid. Yield: 8.8 mg, 0.007 mmol, 66%. HPLC (Protocol AA) retention time = 7.69 minutes (purity= 71%>). LCMS (Protocol A): m/z 1220.4 [M+H]+, retention time = 0.77 minutes.

Reference： [1]Patent: WO2014/68443,2014,A1 .Location in patent: Page/Page column 121; 122

15
[ 863971-53-3 ]
[ 1541195-53-2 ]
[ 1613321-11-1 ]

Yield	Reaction Conditions	Operation in experiment
63%	With triethylamine; In pyridine; at 20℃; for 23h;Inert atmosphere;	To a mixture of CN089 (1 12 mg, 0.131 mmol) and pNP-carbonate 60 (138 mg, 0.180 mmol) in anhydrous pyridine (1.8 mL) under Ar is added Et3N (24 mu, 0.17 mmol) and the mixture is stirred at rt. After 23 h, the mixture is concentrated to dryness under high vacuum, and the crude residue is purified by column chromatography on silica gel (MeOH/CH2CI2= 5:95 to 13:87) to afford the title compound 61 as a white solid (122 mg, 63%).1H NMR (500 MHz, 2:3 CDCI3/CD3OD) delta 0.87-0.90 (m, 6 H), 0.95-0.98 (m, 6 H), 1 .24-1.37 (m, 68 H), 1.51 -1.78 (m, 7 H), 1.89-1.96 (m, 1 H), 2.07-2.13 (m, 1 H), 2.32-2.42 (m, 2 H), 3.07-3.13 (m, 1 H), 3.20- 3.25 (m, 1 H), 3.66-3.81 (m, 8 H), 3.84-3.87 (m, 2 H), 3.99 (d, J = 6.7 Hz, 1 H), 4.24 (t, J = 6.9 Hz, 1 H), 4.37 (dd, J = 6.9, 10.5 Hz, 1 H), 4.45 (dd, J = 6.9, 10.5 Hz, 1 H), 4.54 (dd, J = 5.2, 8.6 Hz, 1 H), 4.84 (d, J = 3.7 Hz, 1 H), 4.97-5.03 (m, 2 H), 5.06-5.10 (m, 1 H), 7.30-7.33 (m, 4 H), 7.38-7.41 (m, 2 H), 7.58 (d, J = 8.1 Hz, 2 H), 7.63-7.65 (m, 2 H), 7.78 (d , J = 7.6 Hz, 2 H);13C NMR (126 MHz, 2:1 CDCI3/CD3OD) delta 14.3, 18.2, 19.4, 23.0, 25.5, 25.7, 26.7, 29.2, 29.6, 29.27, 29.74, 29.8, 29.93, 29.95, 29.98, 30.02, 30.05, 30.08, 30.10, 31 .4, 32.3, 35.0, 39.4, 47.6, 52.7, 53.8, 61.2, 62.3, 66.8, 67.4, 68.4, 69.4, 70.2, 70.7, 71 .0, 72.3, 75.1 , 100.4, 120.3, 120.5, 125.40, 125.44, 127.5, 128.2, 129.1 , 133.0, 138.2, 141.7, 144.2, 144.3, 157.1 , 157.6, 161.1 , 171 .1 , 173.2, 175.0; HRMS-ESI m/z calcd for C84H137N6016[M+H]+: 1486.0091 ; found 1486.0099.

Reference： [1]Patent: WO2014/88432,2014,A1 .Location in patent: Page/Page column 89; 90

16
[ 863971-53-3 ]
C₄₈H₇₅N₇O₁₁S [ No CAS ]
C₆₇H₁₀₂N₁₂O₁₆S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		[532] Fmoc-Val-Cit-PABA-PNP (0.027 mmol), tubulysin-A dimethyl-diamino ethyl carbamate (22.75 mg, 0.023 mmol, prepared using the procedure described in Example 23 except tert-butyl methyl(2-methylamino)ethylcarbamate can be used instead of tert-butyl 4- methylamino)butyl carbamate), 2,2,2-trifluoroacetic acid (1:1) and HOBt (0.025 mmol) in DMF (2 mL) are stirred at room temperature under argon. To the reaction mixture is added triethylamine (0.114 mmol). After 16 h the crude reaction mixture can be purified to give the title compound.

Reference： [1]Patent: WO2014/160360,2014,A1 .Location in patent: Paragraph 532

17
[ 863971-53-3 ]
C₃₇H₃₈N₂O₈Si [ No CAS ]
C₇₁H₇₅N₇O₁₅Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 3h;Inert atmosphere;	To a solution of compound 111 (0.041 g, 0.061 mmol) in DMF (1 mL), Hunig's base (0.032 mL, 0.183 mmol) and (9H-fluoren-9-yl)methyl ((S)-3 -methyl- l-(((S)-l-((4-((((4- nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-l-oxo-5-ureido-pentan-2-yl)amino)-l-oxobutan-2- yl)carbamate (0.056 g, 0.073 mmol) was added at RT. After 3 h, LCMS analysis showed 85% conversion to compound 112 ([M+H]: 1295.6). The crude reaction mixture was used in the next step without further purification.

Reference： [1]Patent: WO2015/23879,2015,A1 .Location in patent: Page/Page column 127; 128

18
[ 863971-53-3 ]
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

19
[ 863971-53-3 ]
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

20
[ 863971-53-3 ]
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

21
[ 863971-53-3 ]
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

22
[ 863971-53-3 ]
C₆₃H₈₁ClN₁₂O₁₄S₂ [ No CAS ]

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

23
[ 863971-53-3 ]
2-(biphenyl-4-yl)propan-2-yl methyl[2-(methylamino)ethyl]carbamate [ No CAS ]
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 ]

Yield	Reaction Conditions	Operation in experiment
52%	In N,N-dimethyl-formamide; at 20℃; for 3h;Inert atmosphere;	N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valyl-N5- carbamoyl-N-[4-([(4-nitrophenoxy)carbonyl]oxy}methyl)phenyl]-L-ornithinamide (310 mg, 0.404 mmol) and 2-(biphenyl-4-yl)propan-2-yl methyl[2-(methylamino)ethyl]carbamate (132 mg, 0.404 mmol) were dissolved in dry DMF (6 mL) and stirred under nitrogen atmosphere at room temperature for 3 hours. Solvent was evaporated and the resulting crude producy was purified by column chromatography (DCM / EtOH = 9 / 1) 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 (200 mg, 52% yield).ESI MS: m/z 954 (MH+)1H NMR (500 MHz, DMSO-de) delta 0.86 (m, 6 H), 1.21-1.64 (m, 4H), 1.69 (s., 6 H), 2.00 (m, 1 H), 2.62 - 3.08 (m, 10 H), 3.44 (m, 2 H), 3.93 (t, J = 7.6 Hz, 1 H), 4.22 (m, 1 H), 4.30 (m, 1 H), 4.42 (m, 1 H), 4.94 - 5.03 (m, 2 H), 5.39 (s, 2 H), 5.96 (m, 1 H), 7.25 - 7.46 (m, 11 H), 7.45 - 7.66 (m, 6 H), 7.74 (m, 2 H), 7.89 (m, 2 H), 8.11 (br.s., 1 H), 10.06 (br. s., 1 H)
52%	In N,N-dimethyl-formamide; at 20℃; for 3h;Inert atmosphere;	N-[(9H-fl uoren-9-yl methoxy)carbonyl]-L-valyl-N5-carbamoyl-N-[4-([(4-nitrophenoxy)carbonyljoxy}methyl)phenyl]-L-ornithinamide (310 mg, 0.404 mmol) and 2-(biphenyl-4-yl)propan-2-yl methyl[2-(methylamino)ethyl]carbamate (68)(132 mg, 0.404 mmol) were dissolved in dry DMF (6 ml) and stirred under nitrogen atmosphere at room temperaturefor 3 hours. Solvent was evaporated and the resulting crude producy was purified by column chromatography (DCM IEtCH = 9 I 1) affording N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valyl-N-{4-[1 0-(biphenyl-4-yl)-4,7,1 0-trimethyl-3,8-dioxo-2,9-dioxa-4,7-diazaundec-1 -yl]phenyl}-N5-carbamoyl-L-ornithinamide (69) (200 mg, 52% yield).MS (ESI): 954 [M+H].1H NMR (500 MHz, DMSO-d6) 0.86 (m, 6 H), 1.21-1.64 (m, 4H), 1.69 (s., 6 H), 2.00 (m, 1 H), 2.62-3.08 (m, 10 H),3.44 (m, 2 H), 393 (t, J 7.6 Hz, 1 H), 4.22 (m, 1 H), 4.30 (m, 1 H), 4.42 (m, 1 H), 4.94 - 5.03 (m, 2 H), 5.39 (s, 2 H),5.96 (m, 1 H), 725- 7.46 (m, 11 H), 7.45- 7.66 (m, 6 H), 7.74 (m, 2 H), 7.89 (m, 2 H), 8.11 (br.s., 1 H), 10.06 (br. s.,1 H)

Reference： [1]Patent: WO2015/44003,2015,A1 .Location in patent: Page/Page column 40
[2]Patent: WO2016/71418,2016,A1 .Location in patent: Page/Page column 67

24
[ 863971-53-3 ]
GLFGEIEELIEEGLENLIDWGNG [ No CAS ]
C₁₄₈H₂₀₉N₃₁O₄₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 20℃; for 1h;Inert atmosphere;	Into a 4-dram scintillation vial purged and maintained with an inert atmosphere of nitrogen was charged peptide (glfgeieelieeglenlidwgng all(D), SEQ ID NO: 1074, 20 mg, 1 equiv.) in dimethyl sulfoxide (100 ul). To the reaction was added (9H-fluoren-9-yl)methyl ((5)- 3-methyl-i -(((S)-i -((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)- 1 -oxo-5 - ureidopentan-2-yl)amino)- 1 -oxobutan-2-yl)carbamate (13.26mg, 2.2 equiv.) indimethylsulfoxide (100 ul). The resulting mixture was aged at room temperature for 1 hour and then, purified using Reverse-Phase Chromatography on Ci8 column, eluting with 0.05% TFA (v/v) in water and 0.05% (v/v) TFA in acetonitrile. After lyophilization, the product, FmocECL-peptide (C3a), was obtained as a solid. MS (mlz): 1587.7 (M+2, theoretical and observed)

Reference： [1]Patent: WO2015/69586,2015,A2 .Location in patent: Page/Page column 94; 95

25
[ 863971-53-3 ]
monomethyl auristatin D trifluoroacetate [ No CAS ]
[ 1415329-11-1 ]

Yield	Reaction Conditions	Operation in experiment
76%	With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 20 - 40℃; for 25h;	Preparation of 4-((S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3- methylbutanamido)-5-ureidopentanamido)benzyl ((S)-1-(((S)-1-(((3R,4S,5S)-3-methoxy- 1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-(((S)-2-phenyl-1-(thiazol-2- yl)ethyl)amino)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-3- methyl-1-oxobutan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamate (Fmoc- Val-Cit-PABC-MMAD)(Figure 64) To a dried scintillation vial containing a magnetic stir bar was added (9H-fluoren- 9-yl)methyl ((S)-3-methyl-1-(((S)-1-((4-((((4- nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxobutan-2- yl)carbamate (84 mg, 0.11 mmol), monomethyl auristatin D (TFA salt, 88 mg, 0.1 mmol), HOAt (5 mg, 0.004 mmol), DIPEA (35 muL, 0.2 mmol), and DMA (0.5 mL). The solution was stirred for 1 hour at room temperature. To the reaction mixture was added lutidine (35 muL, 0.3 mmol), additional (9H-fluoren-9-yl)methyl ((S)-3-methyl-1-(((S)-1-((4-((((4- nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxobutan-2- yl)carbamate (17 mg, 0.02 mmol), and DIPEA (35 muL, 0.2 mmol). The reaction mixture was heated to 40 C and stirred for 24 hours. The reaction mixture was purified by flash chromatography (elute 1-20% MeOH/DCM) to yield the title compound as a white solid (107 mg, 76% yield). ESI-MS calculated [MH]+: 1398.8; found 1399.1.

Reference： [1]Patent: WO2015/81282,2015,A1 .Location in patent: Paragraph 00116; 00968-00970

26
[ 863971-53-3 ]
(S)-1-((S)-3-maytansinyl) 2-(N-methyl-4-(methylamino)butanamido)propanoate [ No CAS ]
(S)-1-((S)-3-maytansinyl) 2-(N-methyl-4-(methylamino)butanamido)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 24h;	Preparation of (S)- 1-((S)-3-maytansinyl) 2-(4-((((4-((S)-2-((S)-2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-3-methylbutanamido)-5- ureidopentanamido)benzyl)oxy)carbonyl)(methyl)amino)-N-methylbutanamido)propanoate (FMOC Val Cit PABC NMC3 Maytansine) (Compound 31)(Figure 15) To a dried 4 mL glass scintillation vial containing a dried flea stir bar was added NMC3 Maytansine (39.8 mg, 0.05 mmol), FMOC Val Cit PABC PNO2P (42.0 mg, 0.06 mmol), HOAt (12.8 mg, 0.09 mmol), DIPEA (20.6 mg, 27.8 uL, 0.16 mmol), and anhydrous DMF (0.7 mL). The solution was stirred at room temperature for 24 h, adsorbed directly onto a Biotage KP C18 HS 1.2 g samplet, and purified on a Biotage KP C18 HS 12 g cartridge using a gradient of 0-100% CH3CN in H2O, giving the title compound as a pale yellow solid (46.9 mg, 64% yield). HPLC retention time 12.702 min. Method A.

Reference： [1]Patent: WO2015/81282,2015,A1 .Location in patent: Paragraph 0074; 00663; 00672; 00673

27
[ 863971-53-3 ]
MeVal-Val-dolaisoleucine-dolaproine-Phe-OtBu [ No CAS ]
Fmoc-Val-citrulline-para-aminobenzyl-N-methylvaline-valine-dolaisoleuine-dolaproine-phenylalanine-OtBu [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With pyridine; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; at 20℃;Sonication;	Compound 1 (300 mg, 0.38 mmol), Fmoc-Val-Cit-PAB-pNP (436 mg, 0.57 mmol, 1.5 eq.) were suspended inanhydrous pyridine, 5 mL. HOBt (10 mg, 0.076 mmol, 0.2 eq.) was added followed by DIEA (199 ml, 1.14 mmol, 3 eq.).Reaction mixture was sonicated for 10 min, and then stirred overnight at room temperature. Pyridine was removed underreduced pressure, residue was re-suspended in CH2Cl2. Mixture was separated by silica gel flash chromatography ina step gradient of MeOH, from 0 to 10%, in CH2Cl2. Product containing fractions were pulled, concentrated, dried in vacuum overnight to give 317 mg (59% yield) of Fmoc-Val-Cit-PAB-MMAF-OtBu. ES-MS m/z 1415.8 [M+H]+.

Reference： [1]Patent: EP2486933,2015,B1 .Location in patent: Paragraph 0574

28
[ 863971-53-3 ]
C₄₆H₇₅N₇O₈S*C₂HF₃O₂ [ No CAS ]
C₆₅H₁₀₂N₁₂O₁₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With benzotriazol-1-ol; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere;	Fmoc-Val-Cit-PABA-PNP (20.93 mg, 0.027 mmol), XMT-A4 dimethyl-diamino ethyl carbamate (22.75 mg, 0.023 mmol, prepared as described in Example 73 except tert-butyl methyl(2-methylamino)ethylcarbamate was used instead of tert-butyl 4-methylamino)butyl carbamate), m/z 886.4), 2,2,2-trifluoroacetic acid (1:1) and HOBt (3.83 mg, 0.025 mmol) in DMF (2 mL) were stirred at room temperature under argon. To the reaction mixture was added triethylamine (0.016 ml, 0.114 mmol). After 16 h the crude reaction mixture was purified to give the title compound as to a white amorphous solid (17.5 mg, 54% yield). M/z=1291.7.

Reference： [1]Patent: US9144615,2015,B2 .Location in patent: Page/Page column 565; 566

29
[ 863971-53-3 ]
duostatin-3 [ No CAS ]
C₆₁H₉₇N₁₁O₁₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Preparation of compound 7: To a solution of compound 5 (500 mg, 0.527 mmol) in 5 mL of DMF was added compound 6 (483 mg, 0.631 mmol), N-Hydroxybenzotriazole (HOBt, 40 mg, 0.296 mmol), and DIEA (0.27 mL). The mixture was stirred for 16 hours after which 0.4 mL of piperidine was added. After 1 hour, the mixture was diluted with 100 mL of ether and the precipitate was collected and dried to give compound 7 as HCI salt (640 mg, 95 %); MS m/z 1240.7 (M+H).

Reference： [1]Patent: WO2016/5593,2016,A1 .Location in patent: Page/Page column 114

30
[ 863971-53-3 ]
(R)-benzyl 3-methyl-2-(methylamino)butanoate [ No CAS ]
(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 ]

Yield	Reaction Conditions	Operation in experiment
65%	With 2,6-dimethylpyridine; benzotriazol-1-ol; In N,N-dimethyl-formamide; at 20℃; for 12h;	(0322) Compound 85 (0.11 g, 0.143 mmol) was dissolved in DMF (1 mL) and the resulting solution was then treated with compound 83 (hydrochloride, 0.11 g, 0.427 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (0.058 g, 0.430 mmol) and then with 2,6-dimethylpyridine (0.117 mL, 1.004 mmol) at RT. The resulting reaction mixture was stirred at RT for 12 h. The crude reaction mixture was wet loaded on to a C-18 reverse phase gold ISCO column eluting 50-100% aq CH3CN with 0.1% TFA over a 13 minute gradient. The appropriate fractions were isolated and freeze dried to afford (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 86 (0.08 gm, 65%) as a solid. 1H NMR (400 MHz, DMSO-d6) delta 8.10 (d, J=7.5 Hz, 1H), 7.88 (d, J=7.5 Hz, 3H), 7.73 (t, J=7.9 Hz, 3H), 7.60-7.51 (m, 3H), 7.43-7.11 (m, 9H), 5.95 (br. s., 1H), 5.39 (br. s., 1H), 5.16-4.86 (m, 4H), 4.50-4.12 (m, 5H), 3.93 (dd, J=8.9, 6.9 Hz, 1H), 3.08-2.88 (m, 2H), 2.84-2.72 (m, 3H), 2.15 (br. s., 1H), 2.05-1.93 (m, 1H), 1.73-1.54 (m, 2H), 1.46-1.24 (m, 2H), 0.98-0.67 (m, 12H); MS (ESI+) m/z 849.6 (M+H)+.

Reference： [1]Patent: US2016/130299,2016,A1 .Location in patent: Paragraph 0322

31
[ 863971-53-3 ]
(R)-benzyl 3-methyl-2-(methylamino)butanoate [ No CAS ]
(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
[ 863971-53-3 ]
C₂₇H₃₀N₄O₆*C₂HF₃O₂ [ No CAS ]
C₆₁H₆₇N₉O₁₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 24h;Inert atmosphere;	To a stirred solution of DNMEA-SN38 98 (80 mg, 0.13 mmol) and Fmoc-Val-Cit- PAB-PNP 13 (0.14 g, 0.19 mmol) in DMF (2 ml), was added HOBt (34 mg, 0.25 mmol), pyridine (52 muIota) and DIPEA (22 muIota). The reaction mixture was stirred under N2 atmosphere at room temperature for 24h. Solvents were evaporated in vacuo and the resulting residue was directly used for the next step. HRMS: ESI m/z Found 1 135.0803 [M+H]+ calculated 1135.2650 for C61H68N9O13.

Reference： [1]Patent: WO2016/46574,2016,A1 .Location in patent: Page/Page column 242

33
[ 863971-53-3 ]
C₄₆H₅₇N₉O₁₁ [ No CAS ]

Reference： [1]Patent: WO2016/46574,2016,A1

34
[ 863971-53-3 ]
C₆₀H₈₁N₉O₁₉ [ No CAS ]

Reference： [1]Patent: WO2016/46574,2016,A1

35
[ 474645-27-7 ]
[ 863971-53-3 ]
Fmoc-VC-PAB-MMAE [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 24h;	A 100 ml RB flask was charged with monomethyl auristatin E(MMAE) (200 mg, 0.279 mmcl), 1-hydroxybenzotriazole (23.34 mg, 0.173 mmol) and Fmoc-Val-Cit-PAB-pnp (269 mg, 0.351 mmol). N,NDimethylformamide (8 ml) was added then the mixture was stirred at rt upon which N,N-diisopropylethylamine (0.12 1 ml, 0.696 mmol) was slowly added via a syringe. After 1 day at rt, LCMS showed almost completion. The solvent was evaporated under high vacuum. The crude was dissolved in DMF, loaded on celite and dried. It was purified by Isco (12 g column, eluent: EtOAc/Hexanes:0-100% then 100% then DCM/MeOH: 0-20% then 20%) to give the title compound 4-7 as an off-white solid (256 mg, 68% yield). LCMS [M+H] 1346.
68%	With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	A 100 ml RB flask was charged with monomethyl auristatin E (MMAE) (200 mg,0.279 mmol),1-hydroxybenzotriazole(23.34 mg,0.173 mmol) and Fmoc-Val-Cit-PAB-pnp (269 mg,0.351 mmol). N,N-Dimethylformamide (8 ml) was added then the mixture was stirred at rt upon which A/,//-diisopropylethylamine (0.121 ml,0.696 mmol) was slowly added via a syringe. After 1 day at rt,LCMS showed almost completion. The solvent was evaporated under high vacuum. The crude was dissolved in a small volume of DMF,loaded on celite and dried. It was purified by Isco (12 g silica column,eluent: EtOAc/Hexanes: 0-100% then 100% followed by DCM/MeOH: 0-20% then 20%) to give the title compound as an off-white solid (256 mg,68% yield). LCMS [M+H]+ 1346.
	With pyridine; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 24h;Inert atmosphere;	To a solution of MMAE (0.15 g, 0.18 mmol) and Fmoc-Val-Cit-PAB-PNP 13 (0.152g, 0.19 mmol) in DMF (1.5 ml), was added HOBt (58 mg, 0.36 mmol), pyridine (0.12ml) and DIPEA (31 p1). The reaction mixture was stirred under N2 atmosphere at room temperature for 24h. Solvents were evaporated in vacuo and the residue triturated with ethyl acetate. The resulting solid was filtered, washed with ethyl acetate, dried to give 79. LC-MS ESI m/z 1367.7 [M+Na] This was used directlywithout further purification.

With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 25 - 30℃; for 16h;

To a 25 mL-round-bottom flask was added Fmocvc-PAB-PNP (2a) (0.33 g, 0.43 mmol) and anhydrous DMF (5 mL). To the solution were added MMAE (la, 0.21 g, 0.21 mmol), HOBt (38 mg, 0.28 mmol) and DIPEA (74 mg, 0.57 mmol) were added at 25 C. successively. The mixture was stirred at 25-30 C. for 16 hours until MMAE was totally consumed according to LCMS. The reaction mixture was filtered through membrane and the filtrate was purified by prep-HPLC (method A) to give Fmoc-3a as a white solid, which was dissolved in DMF (5 mL). To the solution was added diethylamine (0.3 mL). The reaction mixture was stirred at 30 C. for an hour until Fmoc was removed according to LCMS. The reaction mixture was filtered through membrane and the filtrate was purified by prepHPLC (method A) to give vcPAB-MMAE (3a) (0.20 g, 58% yield) as a white solid. ESI mlz: 562.5 (M/2+H).

Reference： [1]Organic and Biomolecular Chemistry,2016,vol. 14,p. 9501 - 9518
[2]Patent: WO2019/119141,2019,A1 .Location in patent: Paragraph 00212; 00277; 00278
[3]Patent: WO2019/109188,2019,A1 .Location in patent: Paragraph 00308; 00309
[4]Patent: WO2016/46574,2016,A1 .Location in patent: Page/Page column 144
[5]Patent: US2018/333504,2018,A1 .Location in patent: Paragraph 0373

36
[ 863971-53-3 ]
[ 25316-40-9 ]
C₆₁H₆₆N₆O₁₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;	To a suspension of Dox.HCI (25 mg, 0.043 mmol) and Fmoc-Val-Cit-PNP 13 (30 mg, 0.039 mmol) in dry DMF (1 ml) DIPEA (7.5 muIota, 0.043 mmol) was added, resulting in a dark-red solution. This was stirred at toom temperature under nitrogen for 24 h after which the solvent was evaporated under high vacuum and the residue triturated with dry diethyl ether to give a red solid Rf 0.22 [silica gel: 10% MeOH/DCM]. Purification by flash chromatography [silica gel: 5% MeOH/DCM] gave the desired product 14 as a red solid 25.2 mg (55 %); HRMS (m/z) calculated for C61H67N6O18[M + H] 1 171.4512 found: 1 171.4534

Reference： [1]Patent: WO2016/46574,2016,A1 .Location in patent: Page/Page column 65

37
[ 863971-53-3 ]
[ 25316-40-9 ]
[ 1022094-34-3 ]

Reference： [1]Patent: WO2016/46574,2016,A1

38
[ 159858-21-6 ]
[ 863971-53-3 ]

Reference： [1]Patent: US2016/271270,2016,A1
[2]Patent: WO2020/25108,2020,A1

39
[ 863971-53-3 ]
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

40
2,5-dioxopyrrolidin-1-yl (((9H-fluoren-9-yl)methoxy)carbonyl)-L-valinate [ No CAS ]
[ 863971-53-3 ]

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

41
[ 863971-53-3 ]
[ 112257-19-9 ]
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 ]

Yield	Reaction Conditions	Operation in experiment
81.9%	In N,N-dimethyl-formamide; at 20℃; for 3.5h;	In 500 ml of the single port in the bottle, adding 31.2 g of compound 17 (40.73 mmol, 1.0 eq), then adding 150 ml of DMF stirring and dissolves it, for added 50 ml of DMF dissolved 8.1 g methyl (2 - (methylamino) ethyl) tert-butyl carbamate (36.66 mmol, 1.1 eq), stirring at the room temperature reaction 3.5 h, TLC detection compound 17 reaction is complete, stopping the reaction. Post-processing: the reaction solution is added to the 2 L isopropyl ether stirring, precipitated [...] sticks the thick oil objects, leans the supernatant, then adding 1 L of isopropyl ether, the violent stirring, once again leans the supernatant, then adding 500 ml isopropyl ether stirring overnight, filtered, shall be 27.2 g ocher powdery solid, yield 81.9%.
		Step 5 Synthesis of 4-((S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamido)-5-ureidopentanamido)benzyl tert-butyl ethane-1,2-diylbis(methylcarbamate) (95) To a solution of compound 94 (1.7 g, 2.217 mmol) in DMA (15 mL) was added HOAT (332 mg, 2.44 mmol), 2,6-lutidine (950 mg, 8.87 mmol) at 0 C. The mixture was stirred at 0 C. for 5 minutes. Then tert-butyl methyl(2-(methylamino)ethyl)carbamate (38, 459 mg, 2.44 mmol,) was added to the mixture at 0 C. and followed by DIPEA (860 mg, 6.65 mmol) at 0 C. The mixture was stirred at rt for 1 h. and poured into TBME (800 mL) and stirred for 30 min, filtered and the filter cake was concentrated in vacuum to give the crude product (1.06 g) as a yellow solid. The crude product was purified by silica gel chromatography (Gradient: DCM:MeOH=100:1-10:1) to give the product 95 as a white solid 600 mg (33%).
395 mg	In N,N-dimethyl-formamide; at 20℃; for 0.0166667h;	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: CN109464654,2019,A .Location in patent: Paragraph 0071; 0090; 0093-0094
[2]Patent: US2016/271270,2016,A1 .Location in patent: Paragraph 0379; 0385
[3]Patent: US10086085,2018,B2 .Location in patent: Page/Page column 209-213

42
[ 623-04-1 ]
[ 863971-53-3 ]

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

43
[ 863971-53-3 ]
(S)-1-((S)-3-maytansinyl) 2-(N-methyl-4-(methylamino)butanamido)propanoate [ No CAS ]
(S)-1-((S)-3-maytansinyl) 2-(4-((((4-((S)-2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanamido)benzyl)oxy)carbonyl)(methyl)amino)-N-methylbutanamido)propanoate [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2016,vol. 7,p. 994 - 998

44
[ 863971-53-3 ]
6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(3-{2-[(2-carboxyethyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.1³'⁷]dec-1-yl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic acid [ No CAS ]
3-(1-((3-(2-((((4-((S)-2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanamido)benzyl)oxy)carbonyl)(2-carboxyethyl)amino)ethoxy)-5,7-dimethyladamantan-1-yl)methyl)-5-methyl-1H-pyrazol-4-yl)-6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		[0001042] A solution of Example 1.25.2 (0.059 g), (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 (0.053 g) and N,N-diisopropylethylamine (0.055 mL) in N,N- dimethylformamide (0.5 mL) was stirred at room temperature overnight. Diethylamine (0.066 mL) was added to the reaction, and stirring was continued for 30 minutes. The reaction was diluted with a 1 : 1 mixture of Nu,Nu-dimethylformamide and water (2 mL) and quenched by the addition of trifluoroacetic acid (0.073 mL). The mixture was purified by reverse phase HPLC using a Gilson system, eluting with 10-75% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound. MS (ESI) m/e 1223.8 (M+H)+.
		A solution of Example 1.25.2 (0.059 g), (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 (0.053 g) and N,N-diisopropylethylamine (0.055 mL) in N,N- dimethylformamide (0.5 mL) was stirred at room temperature overnight. Diethylamine (0.066 mL) was added to the reaction, and stirring was continued for 30 minutes. The reaction was diluted with a 1:1 mixture of N,N-dimethylformamide and water (2 mL) and quenched by the addition of trifluoroacetic acid (0.073 mL). The mixture was purified by reverse phase HPLC using a Gilson system, eluting with 10-75% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound. MS (ESI) m/e 1223.8 (M+H)+.
		A solution of Example 1.25.2 (0.059 g), <strong>[863971-53-3](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</strong> (0.053 g) and N,N-diisopropylethylamine (0.055 mL) in N,N-dimethylformamide (0.5 mL) was stirred at room temperature overnight. Diethylamine (0.066 mL) was added to the reaction, and stirring was continued for 30 minutes. The reaction was diluted with a 1:1 mixture of N,N-dimethylformamide and water (2 mL) and quenched by the addition of trifluoroacetic acid (0.073 mL). The mixture was purified by reverse phase HPLC using a Gilson system, eluting with 10-75% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound. MS (ESI) m/e 1223.8 (M+H)+.

Reference： [1]Patent: WO2016/94509,2016,A1 .Location in patent: Paragraph 0001042
[2]Patent: WO2017/214462,2017,A2 .Location in patent: Page/Page column 600
[3]Patent: US2017/355769,2017,A1 .Location in patent: Paragraph 2021

45
[ 863971-53-3 ]
6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(3,5-dimethyl-7-{2-[(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.1³'⁷]dec-1-yl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic acid [ No CAS ]
3-(1-((3-(2-((((4-((S)-2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanamido)benzyl)oxy)carbonyl)(2-sulfoethyl)amino)ethoxy)-5,7-dimethyladamantan-1-yl)methyl)-5-methyl-1H-pyrazol-4-yl)-6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		[000945] A solution of Example 1.2.9 (0.045 g) (9H-fluoren-9-yl)methyl ((S)-3-methyl-l-(((S)-l- ((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)- 1 -oxo-5 -ureidopentan-2-yl)amino)- 1 - oxobutan-2-yl)carbamate (0.043 g) and N,N-diisopropylethylamine (0.041 mL) were stirred together in N,N-dimethylformamide (1 mL) at room temperature. After stirring overnight, diethylamine (0.024 mL) was added to the reaction, and stirring was continued for 2 hours. The reaction was quenched with trifluoroacetic acid then purified by reverse phase HPLC using a Gilson system, eluting with 10-75% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound.
		A solution of Example 1.2.9 (0.045 g) (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 (0.043 g) and N,N-diisopropylethylamine (0.041 mL) were stirred together in N,N-dimethylformamide (1 mL) at room temperature. After stirring overnight, diethylamine (0.024 mL) was added to the reaction, and stirring was continued for 2 hours. The reaction was quenched with trifluoroacetic acid then purified by reverse phase HPLC using a Gilson system, eluting with 10-75% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound.
		To a mixture of Example 1.2.9 (57 mg) and <strong>[863971-53-3](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</strong> (54 mg) in N,N-dimethylformamide (2 mL) was added N,N-diisopropylethylamine (103 muL). The mixture was stirred overnight, and diethylamine (61.5 muL) was added. The resulting mixture was stirred for 4 hours and purified by reverse phase HPLC using a Gilson system and C18 column, eluting with 10-70% acetonitrile in water containing 0.1% v/v trifluoroacetic acid, to provide the title compound. MS (ESI) m/e 1257.4 (M-H).

Reference： [1]Patent: WO2016/94509,2016,A1 .Location in patent: Paragraph 000945
[2]Patent: WO2017/214462,2017,A2 .Location in patent: Page/Page column 563
[3]Patent: US2017/355769,2017,A1 .Location in patent: Paragraph 1966

46
[ 863971-53-3 ]
C₄₉H₇₇N₇O₁₁*C₂HF₃O₂ [ No CAS ]
C₈₃H₁₁₄N₁₂O₁₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57 mg	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;	The crude material from the previous step (46 mumol) was dissolved in DMF (5 mL). To the solution was added 35 mg (46 mumol) of Fmoc-Val-Cit-PABC-PNP and diisopropylethylamine (0.1 mL). The reaction mixture was stirred for overnight and 2 ml of 10% citric acid solution was added. The volatile material was removed in vacuo, and the residue was dissolved in ethyl acetate and 10% citric acid solution. The aqueous phase was extracted in ethyl acetate and the combined organic phase was washed with NaHCO3 solution and brine, then dried over NaSO4 and concentrated in vacuo. The residue was subjected to column chromatography to afford 57 mg of compound VI-3 (36 mumol, 78% yield over 2 steps) as a white solid.

Reference： [1]Patent: US2017/15710,2017,A1 .Location in patent: Paragraph 0665

47
[ 863971-53-3 ]
duostatin-3 trifluoroacetate [ No CAS ]
C₇₆H₁₀₇N₁₁O₁₆S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 16h;	To a solution of compound 5 (500 mg, 0.527 mmol) in 5 mL of DMFwas added compound 6 (483 mg, 0.631 mmol), N- Hydroxybenzotriazole (HOBt, 40 mg, 0.296 mmol), and DIEA (0.27 mL). The mixture was stirred for 16 hours after which 0.4 mL of piperidine was added. After 1 hour, the mixture was diluted with 100 mL of ether and the precipitate was collected and dried to give compound 7 as HCI salt (640 mg, 95 %); MS m/z 1240.7 (M+ H).

Reference： [1]Patent: WO2017/9258,2017,A1 .Location in patent: Page/Page column 109

48
[ 863971-53-3 ]
isopropyl 2-((((4-(2-(2-amino-3-methylbutanamido)-5-ureidopentanamido)benzyl)oxy)carbonyl)amino)-6-diazo-5-oxohexanoate [ No CAS ]

Reference： [1]Patent: WO2017/23774,2017,A1

49
[ 863971-53-3 ]
isopropyl 2-((((4-(2-(2-acetamido-3-methylbutanamido)-5-ureidopentanamido)benzyl)oxy)carbonyl)amino)-6-diazo-5-oxohexanoate [ No CAS ]

Reference： [1]Patent: WO2017/23774,2017,A1

50
[ 863971-53-3 ]
isopropyl 2-amino-6-diazo-5-oxohexanoate [ No CAS ]
isopropyl 2-((((4-(2-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamido)-5-ureidopentanamido)benzyl)oxy)carbonyl)amino)-6-diazo-5-oxohexanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	9-Fluorenylmethyloxycarbonyl-valyl-citrullyl-(4- aminobenzyl)-(4-nitrophenyl)carbonate (191 mg, 0.249 mmol, 1.2 equiv.), was dissolved in dry DMF (2.0 mL) and a solution of compound 3 (44 mg, 0.208 mmol) in dry DMF (1.0 mL) was added dropwise. To this reaction mixture was added diisopropylethyl amine (130 mu, 0.747 mmol, 3 equiv.) dropwise. The reaction mixture was stirred at room temperature overnight. The organic solvent was evaporated in vacuo. The residue was chromatographed on silica gel (chloroform: methanol, 15: 1) to yield the desired product 50 (110 mg, 53 %) as a white amorphous solid. *H NMR (400 MHz, DMSO): 0.85 (3H, d, J= 6.8), 0.88 (3H, d, J= 6.9), 1.16 (3H, d, J = 6.6), 1.18 (3H, d, J = 6.6), 1.31 - 1.49 (2H, m), 1.54 - 1.81 (3H, m), 1.89 - 2.03 (2H, m), 2.35 - 2.44 (2H, m), 2.89 - 3.05 (2H, m), 3.91 - 3.98 (2H, m), 4.20 - 4.34 (3H, m), 4.39 - 4.44 (1H, m), 4.86 - 5.00 (3H, m), 5.40 (2H, s), 5.97 (1H, t, J= 5.9), 6.05 (1H, s), 7.28 (2H, d, J= 8.7), 7.32 (2H, td, J = 7.5, 1.2), 7.39 - 7.44 (3H, m), 7.59 (2H, d, J= 8.3), 7.66 (1H, d, J = 7.7), 7.74 (2H, t, J = 7.8), 7.89 (2H, d, J= 7.6), 8.12 (1H, d, J = 7.5), 10.06 (1H, s). 13C NMR (101 MHz, DMSO): 18.28, 19.23, 21.45, 21.52, 25.78, 26.80, 29.48, 30.46, 36.32, 38.58, 46.69, 53.10, 53.42, 60.08, 65.29, 65.69, 68.04, 118.91 (2C), 120.10 (2C), 125.37 (2C), 127.07 (2C), 127.65 (2C), 128.61 (2C), 131.65, 138.64, 140.71 (2C), 143.77, 143.90, 156.13 (2C), 158.90, 170.60, 171.28, 171.55, 194.03. IR (KBr): 3400 s, br, sh, 3327 s, br, 3066 w, 2964 m, 2937 m, 2106 s, 1705 vs, br, 1651 vs, 1609 s, 1533 vs, 1517 vs, sh, 1479 m, 1466 m, 1450 s, 1415 m, 1386 s, sh, 1376 s, 1334 s, 1320 s, sh, 1248 s, 1183 m, 1145 m, 1106 s, 1047 m, 1020 m, sh, 826 w, 777 w, sh, 621 w, 427 w cm"1. Optical rotation: [a]22D - 15.6 (c 0.631, DMSO). ESI MS: 863 ([M + Na]+). HR ESI MS: calcd for C43H52N8OioNa 863.36986; found 863.36997.

Reference： [1]Patent: WO2017/23774,2017,A1 .Location in patent: Page/Page column 118; 119

51
[ 372-75-8 ]
[ 863971-53-3 ]

Reference： [1]Patent: KR2017/41562,2017,A
[2]Patent: WO2020/25108,2020,A1

52
[ 863971-53-3 ]
[ 253128-41-5 ]
C₅₉H₈₆N₆O₁₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%		[00347] Eribulin (ER-000086526) (61.5 mg, 0.074 mmol) was dissolved in N,N- dimethylformamide (DMF) (6.0 mL) and then mixed with Hunig Base (0.027 mL, 0.156 mmol) and Fmoc-Val-Cit-PAB-P P (86 mg, 0.112 mmol). The reaction was stirred at room temperature for 18 hours until the coupling was complete, as determined by high performance liquid chromatography (HPLC) analysis. Diethylamine (0.078 mL, 0.745 mmol) was added to the mixture, and the mixture was stirred for an additional 2 hours until the reaction was complete. The solvent was removed by evaporation, and the residue was purified by flash chromatography to obtain Val-Cit-PAB-eribulin (ER- 001228950) as a white solid (60 mg, 71% yield). 1HNMR (400 MHz, CD3OD) delta ppm 7.56 (d, J= 8.4 Hz, 2H), 7.32 (d, J= 8.4 Hz, 2H), 5.14 (s, 1H), 5.06 (d, J= 12.4 Hz, 1H), 5.03 (s, 1H), 5.01 (d, J= 12.4 Hz, 1H), 4.87 (s, 1H), 4.83 (s, 1H), 4.71 (t, J= 4.4 Hz, 1H), 4.62 (t, J= 4.4 Hz, 1H), 4.57 (dd, J= 4.8, 8.8 Hz, 1H), 4.47 (d, J= 10.8 Hz, 1H), 4.32-4.27 (m, 2H), 4.18 (dd, J= 4.8, 6.4 Hz, 1H), 4.13-4.07 (m, 2H), 3.98 (t, J = 10.4 Hz, 1H), 3.88-3.82 (m, 3H), 3.76-3.70 (m, 4H), 3.60 (d, J= 6.0 Hz, 1H), 3.38 (s, 3H), 3.26-3.10 (m, 3H), 2.93 (dd, J= 2.0, 11.2 Hz, 1H), 2.91-2.84 (m, 1H), 2.75-2.64 (m, 2H), 2.44-2.29 (m, 5H), 2.21-1.97 (m, 8H), 1.93-1.83 (m, 3H), 1.79-1.72 (m, 5H), 1.68-1.29 (m, 8H), 1.11 (d, J= 6.8 Hz, 3H), 1.07-1.01 (m, 1H), 1.06 (d, J= 7.2 Hz, 3H), 1.02 (d, J= 7.2 Hz, 3H). LCMS (M+H)=l 135.7.

Reference： [1]Patent: WO2017/151979,2017,A1 .Location in patent: Paragraph 00347

53
[ 863971-53-3 ]
C₅₉H₈₁IN₄O₂₂S₃ [ No CAS ]
C₇₈H₁₀₈IN₉O₂₇S₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21 mg		To compound 54 (23mg, 16 mumol) in 2 mL of DMF was added compound 57 (15 mg, 20 mumol), HOBt (2.5 mg), and 10 muL of DIEA. The mixture was stirred for 1 h, then 40 muL of piperidine was added. After 10 min the mixture was purified by HPLC to give compound 58 (21 mg). MS m/z 1826.5 (M+H).

Reference： [1]Patent: US2017/281758,2017,A1 .Location in patent: Paragraph 0126; 0127

54
[ 863971-53-3 ]
C₅₇H₇₈IN₃O₂₁S₃ [ No CAS ]
C₇₆H₁₀₅IN₈O₂₆S₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
11 mg		To compound 61 (22mg, 16 mumol) in 2 mL of DMF was added compound 57 (15 mg, 20 mumol), HOBt (2.5 mg), and 10 muL of DIEA. The mixture was stirred for 16 h, then 40 muL of piperidine was added. After 10 min the mixture was purified by HPLC to give compound 62 (11 mg). MS m/z 1769.5 (M+H).

Reference： [1]Patent: US2017/281758,2017,A1 .Location in patent: Paragraph 0130; 0132

55
[ 863971-53-3 ]
C₄₁H₄₈N₈O₁₀ [ No CAS ]

Reference： [1]Patent: WO2017/176648,2017,A1

56
[ 863971-53-3 ]
C₅₁H₅₉N₉O₁₃ [ No CAS ]

Reference： [1]Patent: WO2017/176648,2017,A1

57
[ 863971-53-3 ]
[ 529488-28-6 ]
C₅₆H₅₈N₈O₁₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 2,6-dimethylpyridine; benzotriazol-1-ol; In N,N-dimethyl-formamide;	2,3-Dimethoxy-12-(2-(methylamino)ethyl)-[l ,3]dioxolo[4',5':4,5]benzo[l,2- h]benzo[c][l ,6]naphthyridin-13(12H)-one (II) has a secondary amine that could be acylated by Val-Cit-PABA linker. This linker (developed by Seattle Genetics Inc.) has been extensively used in ADC projects. It represents the only enzyme cleavable linker component for FDA approved ADCs. Compound 7 was utilized for a maleimide-sulfhydryl coupling between the partially reduced mAb and the maleimide of compound 7. The chemical synthesis of 7 follows the route published by Seattle Genetics Inc. (Bioconjugate Chem. 2002, 13 :855-869; Blood 2003, 102:1458-1465; Nature Biotech, 2003, 21 :778-784). The cytotoxic TOP-1 targeting agent II was coupled to Fmoc-Val-Cit-PABA-PNP (1 eq) in the presence of HOBt (1 eq) in DMF-2,6-lutidine (4/1 , v/v) to provide compound 5. The reaction mixture was evaporated and treated with piperidine in DMF (20 v/v %) followed by semi -preparative reverse phase HPLC purification and lyophilization. Compound 6 was treated with 6-maleimidohexanoic acid succinate ester in DMF in the presence of DIPEA (2 eq). (0282) Compound 7 was purified by RP-HPLC and lyophilized. The final product was conjugated to the mAb previously reduced by dithiothreitol.

Reference： [1]Patent: WO2017/176648,2017,A1 .Location in patent: Page/Page column 48-50

58
[ 863971-53-3 ]
6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(3,5-dimethyl-7-{2-[(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.1³'⁷]dec-1-yl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic acid [ No CAS ]
3-(1-(((1r,3r)-3-(2-((((4-((S)-2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanamido)benzyl)oxy)carbonyl)(2-sulfoethyl)amino)ethoxy)-5,7-dimethyladamantan-1-yl)methyl)-5-methyl-1H-pyrazol-4-yl)-6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A solution of Example 1.2.9 (0.045 g) (9H-fluoren-9-yl)methyl ((S)-3-methyl-1-(((S)-1-30 ( ( 4-( ( ( ( 4-nitrophenoxy )carbonyl )oxy )methyl )phenyl )amino )-1-oxo-5-ureidopentan-2-yl )amino )-1-oxobutan-2-yl)carbamate (0.043 g) and N,N-diisopropylethylamine (0.041 mL) were stirred togetherin N,N-dimethylformamide (1 mL) at room temperature. After stirring overnight, diethylamine(0.024 mL) was added to the reaction, and stirring was continued for 2 hours. The reaction wasquenched with trifluoroacetic acid then purified by reverse phase HPLC using a Gilson system,35 eluting with 10-75% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desiredfractions were combined and freeze-dried to provide the title compound.

Reference： [1]Patent: WO2017/214282,2017,A1 .Location in patent: Page/Page column 521

59
[ 863971-53-3 ]
6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(3,5-dimethyl-7-{2-[(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.1³'⁷]dec-1-yl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic acid [ No CAS ]
3-(1-(((1r,3r)-3-(2-((((4-((S)-2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanamido)benzyl)oxy)carbonyl)(2-sulfoethyl)amino)ethoxy)-5,7-dimethyladamantan-1-yl)methyl)-5-methyl-1H-pyrazol-4-yl)-6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A solution of Example 1.2.9 (0.045 g) <strong>[863971-53-3](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</strong> (0.043 g) and N,N-diisopropylethylamine (0.041 mL) were stirred together in N,N-dimethylformamide (1 mL) at room temperature. After stirring overnight, diethylamine (0.024 mL) was added to the reaction, and stirring was continued for 2 hours. The reaction was quenched with trifluoroacetic acid then purified by reverse phase HPLC using a Gilson system, eluting with 10-75% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound.

Reference： [1]Patent: US2017/355769,2017,A1 .Location in patent: Paragraph 1924

60
[ 474645-27-7 ]
[ 863971-53-3 ]
{4-[(2S)-2-[(2S)-2-amino-3-methylbutanamido]-5-(carbamoylamino)pentanamido]phenyl}methyl N-[(1S)-1-[(1S)-1-[(3R,4S,5S)-1-[(2S)-2-[(1R,2R)-2-[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]carbamoyl}-1-methoxy-2-methylethyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl](methyl)carbamoyl}-2-methylpropyl]carbamoyl}-2-methylpropyl]-N-methylcarbamate [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2019,vol. 58,p. 6640 - 6644
Angew. Chem.,2019,vol. 131,p. 6712 - 6716,5
[2]Patent: WO2018/31690,2018,A1 .Location in patent: Paragraph 1020

61
[ 863971-53-3 ]
C₃₆H₅₁ClN₄O₁₀ [ No CAS ]
C₇₀H₈₈ClN₉O₁₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With 1-hydroxy-7-aza-benzotriazole; sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 20℃; for 24h;Inert atmosphere; Sealed tube;	The product of the preceding step (Compound 6, FIG. 19, 0.310 g, 0.390 mmol), 1-hydroxy-7-azabenzotriazole (HOAT, 0.164 g, 1.20 mmol), sodium bicarbonate (0.138 g, 1.64 mmol), and Fmoc-valine-citrulline-(p-amino)benzyl-(p-nitrophenyl)carbonate (0.595 g, 0.776 mmol, prepared by method known in the art, cf.-Gangwar et al., U.S. Pat. No. 7,714,016 B2) were dissolved in anhydrous DMF (10 mL), the reaction flask sealed with a rubber septum, purged with argon, and the mixture stirred at ambient temperature. After 24 hours the reaction was partially evaporated in vacuo to ca. 2-3 mL, treated with 10% aq. acetic acid and water (ca. 1 mL each), dissolved in acetonitrile (ca. 6 mL), and purified by flash chromatography on a 275 g C18 silica column (30-90% acetonitrile in water over 20 min, 0.05% acetic acid in both solvents). Partial evaporation, freezing, and lyophilization gave the title compound as a white solid (0.362 g, 68%). MS (ESI, pos.): calc'd for C70H88ClN9O17, 1361.6; found 1362.1 (M+H), 1384.1 (M+Na), 1344.1 (M-H2O+H).

Reference： [1]Patent: US2018/134794,2018,A1 .Location in patent: Paragraph 0316

62
[ 863971-53-3 ]
C₃₈H₄₉N₃O₉ [ No CAS ]
C₇₂H₈₆N₈O₁₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44 mg	With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at -20 - 20℃; for 106h;	To a solution of compound 4 (50 mg), Fmoc-Val-Cit-PAB-PNP (Levena Biopharma, 85 mg), and 1 -hydroxy-7-azabenzotriazole (HOAt) (11.5 mg) in DMF (3 mL), cooled to 0 C, was added DIPEA (40 mu). The reaction mixture was allowed to warm to room temperature and was stirred for 19 h. Additional HOAt (14 mg) was added and the mixture was stirred at room temperature for 9 h before storing at -20 C for 72 h. Further HOAt (18 mg) was then added, and the mixture was stirred at room temperature for 6 h. The reaction mixture was then directly purified by reverse phase C18-column chromatography, eluting with buffer A (v/v): water: (0556) 0.05% trifluoroacetic acid and buffer B (v/v): acetonitrile:0.05% trifluoroacetic acid (100:0 v/v to 0:100 v/v). The product fractions were combined and concentrated under reduced pressure and the aqueous solution was extracted with ethyl acetate (100 mL). The layers were separated and the organic layer was washed with brine. The ethyl acetate layer was then separated, dried over sodium sulfate, filtered and concentrated in vacuo. The product was further purified by normal phase chromatography eluting with dichloromethane:methanol (100:0 v/v to 85:15 v/v). The solvent was removed in vacuo to give compound 39 as a white solid (44 mg). 'H NMR (500 MHz,CD3OD) 5 ppm 0.83 - 1.03 (m, 14 H), 1.12 - 1.34 (m, 17 H), 1.46 - 1.67 (m, 7 H), 1.79 (s, 6 H), 1.92 (br. s., 2 H), 2.03 -2.14 (m, 2 H), 2.24 (d, J=14.17 Hz, 2 H), 2.69 (s, 4 H), 2.76 (dt, J=13.92, 6.72 Hz, 2 H), 2.87 (d, J=9.77 Hz, 2 H), 2.99 - 3.16 (m, 3 H), 3.16 - 3.24 (m,2 H), 3.37 (d, J=6.35 Hz, 8 H), 3.57 - 3.63 (m, 3 H), 3.82 (s, 4 H), 3.98 (d, J=7.33 Hz, 1 H), 4.17 - 4.27 (m, 3 H), 4.34 - 4.46 (m, 3 H), 4.50 - 4.61 (m, 1H), 4.74 (d, J=9.77 Hz, 2 H), 5.15 (s, 3 H), 5.55 (dd, J=15.14, 8.79 Hz, 1 H), 6.27 (d, J=10.75 Hz, 1 H), 6.67 (dd, J=15.63, 11.23 Hz, 1 H), 6.95 (s, 1 H), 7.04 - 7.15 (m, 4 H), 7.27 - 7.43 (m, 3 H), 7.49 (d, J=7.82 Hz, 5 H), 7.61 (d, J=8.3, 3 H), 7.67 (t, J=8.3, 3H), 7.80 (d, J=7.33 Hz, 3 H). LC/MS: (ES+) [M+H]+ (1320, 100%).

Reference： [1]Patent: WO2018/51109,2018,A1 .Location in patent: Page/Page column 94-95

63
[ 863971-53-3 ]
(1S,2S,4R,6R,8S,9S,11S,12R,13S,19S)-8-(2-aminoacetyl)-12,19-difluoro-11-hydroxy-9,13-dimethyl-6-propyl-5,7-dioxapentacyclo[10.8.0.0²^,⁹.0⁴^,⁸.0¹³^,¹⁸]icosa-14,17-dien-16-onetrifluoroacetic acid salt [ No CAS ]
{4-[(2S)-2-[(2S)-2-amino-3-methylbutanamido]-5-(carbamoylamino)pentanamido]phenyl}methyl N-{2-[(1S,2S,4R,8S,9S,11S,12R,13S,19S)-12,19-difluoro-11-hydroxy-9,13-dimethyl-16-oxo-6-propyl-5,7-dioxapentacyclo[10.8.0.0²^,⁹.0⁴^,⁸.0¹³^,1⁸]icosa-14,17-dien-8-yl]-2-oxoethyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%		Following the General Procedure D from compound 4b, (93 mg, 0.20 mmol), compound vcPAB-4b (0.13 g, 73% yield) was obtained after purification by reversed phase flash chromatography (50-80%) acetonitrile in aq. ammonium bicarbonate (10 mM)) as a white solid. ESI m/z: 871 (M + H)+.
73%		To a solution of Fmoc-VC-PAB-PNP (LP3-1, 0.17 g, 0.22 mmol) and compound P4 (93 mg, 0.20 mmol) in DMF (3 mL) was added with DIPEA (51 mg, 0.40 mmol) at RT by syringe. The mixture was stirred at RT for 3 hours and most of materials were consumed according to LCMS. To the resulting mixture was added piperidine (0.3 mL, excess) and it was stirred at RT for an hour until Fmoc was totally removed, which was monitored by LCMS. After filtering through a membrane, the filtrate was directly purified by prep-HPLC (method B) to give compound LP13-1 (0.13 g, 73% yield) as a white solid. ESI m/z: 871 (M + 1)+.

Reference： [1]Patent: WO2018/89373,2018,A2 .Location in patent: Paragraph 0907-0908; 0917-0920
[2]Patent: WO2019/217591,2019,A1 .Location in patent: Paragraph 0644

64
[ 863971-53-3 ]
(1R,2S,8S,10S,11S,13R,14R,15S,17S)-14-[2-(4-aminophenoxy)acetyl]-1,8-difluoro-14,17-dihydroxy-2,13,15-trimethyltetracyclo[8.7.0.02'7.011'15]heptadeca-3,6-dien-5-one [ No CAS ]
C₆₂H₇₀F₂N₆O₁₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.5h;	To a solution of Fmoc-vcPAB-PNP (73 mg, 96 muiotaetaomicron) in DMF (1 mL) were added compound 15-5 (40 mg, 80 muiotaetaomicron), DMAP (20 mg, 0.16 mmol), HOBt (23 mg, 0.16 mmol) and DIPEA (55 mg, 0.40 mmol) successively at RT. The reaction mixture was stirred at RT for half an hour until (15-5) was totally consumed according to LCMS. (ESI: 565.3 (M + H)+). To the resulting mixture was then added piperidine (34 mg, 0.40 mmol) at RT. After stirring at RT for further 30 minutes, which was monitored by LCMS, the resulting mixture was directly purified by reversed phase flash chromatography (0-30% acetonitrile in water) to (34f) (50 mg, yield 69%) as a pale yellow solid. ESI: 907 (M + H)+

Reference： [1]Patent: WO2018/89373,2018,A2 .Location in patent: Paragraph 0671; 0675

65
[ 863971-53-3 ]
C₂₉H₃₇NO₆ [ No CAS ]
C₆₃H₇₄N₆O₁₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 20℃;Inert atmosphere;	[00577] Compound 1014 - Starting compound 1013 (2 g, 2.61 mmol) and compound 1012 (1.36 g, 2.74 mmol) were added to the reaction flask. The reaction was evacuated and purged with argon three times. The starting material was dissolved by adding dimethyl sulfoxide, then N,N-diisopropylethylamine (0.909 rriL, 5.22 mmol) was added via syringe. The reaction was stirred at room temperature overnight. The reaction was checked by TLC (10% MeOH/DCM) and the reaction was diluted with dichloromethane, added to separation funnel and organic layer was washed with saturated sodium bicarbonate. The organic layer was separated and washed with a brine solution. The organic layer was separated and dried with sodium sulfate. The solid was filtered off and the mother liquor was concentrated on reduced pressure to yield 2.91 g, (99%) of 1014. NMR (400 MHz, DMSO-de): delta 10.12 (s, 1H), 7.94 - 7.80 (m, 2H), 7.57 (d, J = 8.4 Hz, 1H), 7.45 - 7.34 (m, 3H), 7.27 (m, 10H), 6.91 - 6.82 (m, 4H), 6.42 (d, J = 9.0 Hz, 1H), 6.27 (s, 1H), 5.41 (s, 1H), 4.91 (s, 1H), 3.72 (d, J = 2.5 Hz, 6H), 3.59 - 3.45 (m, 12H), 3.10 (m, J = 5.9 Hz, 2H), 3.06 - 2.86 (m, 5H), 2.53 (s, 37H), 1.22 (s, 1H), 0.87 (d, J = 6.9 Hz, 2H), 0.76 (d, J = 6.8 Hz, 2H).

Reference： [1]Patent: WO2018/136620,2018,A2 .Location in patent: Paragraph 00577

66
[ 863971-53-3 ]
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 trifluoroacetate [ No CAS ]

Reference： [1]Patent: US10086085,2018,B2

67
[ 863971-53-3 ]
5-(2-methoxy-4-(piperazin-1-ylmethyl)benzyl)-N⁴-pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine [ No CAS ]
4-((S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamido)-5-ureidopentanamido)benzyl 4-(4-((2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl)-3-methoxybenzyl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 4h;	A round bottom flask was charged with 5-(2-methoxy-5-(piperazin-1-ylmethyl)benzyl)-N4-pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine (lnt-1 , 1 .0 equiv.), HOAT (2.0 equiv.), Huenig's base (14.0 equiv.), <strong>[863971-53-3](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</strong> (1 .2 equiv.), and pyridine:DMF (1 :4, 0.02 M). The reaction mixture was stirred at room temperature for 4 hours, and the crude reaction mixture was then purified by RP-HPLC (0.035% TFA in ACN:0.05% TFA in H20, C18 column) to afford 4-((S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbutanamido)-5-ureidopentanamido)benzyl4-(4-((2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl)-3-methoxybenzyl)piperazine-1-carboxylate as a solid: LCMS [M+H] = 1065.5.

Reference： [1]Patent: WO2018/198091,2018,A1 .Location in patent: Page/Page column 256

68
[ 863971-53-3 ]
(1S,4aS,10aR)-6-(2-aminoethoxy)-N-((1S,4aS,10aR)-6-hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carbonyl)-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxamide [ No CAS ]
4-((S)-2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanamido)benzyl 2-((4bS,8S,8aR)-8-((1S,4aS,10aR)-6-hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carbonylcarbamoyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthren-3-yloxy)ethylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%		General procedure: To a solution of Fmoc-vc-PAB-PNP (2a, 0.68-1.0 equiv.) and a compound 1 (le, if, ig, ih, ii or im, 1.0 equiv.) in DMF was added with DIPEA (S equiv.) at RT by syringe. The mixture was stirred at 25 C. for 16-24 hours and most of 2a was consumed according to ECMS. To the resulting mixture was added piperidine (0.1-1 mE, excess) and it was stirred at 2S C. for 2 hours until Fmoc was totally removed, which was monitored by ECMS. Afier filtering through a membrane, the filtrate was directly purified by prep-HPEC (method B) to give a compound 3 (32-73% yield) as a white solid. Table 4 provides specific reaction conditions for making compounds 3e-3g, 3H and 31.
50%		To a solution of 9c (18 mg, 31 mumol) in DMF was added Fmoc-VC-PAB-PNP 19 (16 mg, 21 mumol) and DIPEA (20 mg, 0.16 mmol), and the mixture was stirred at 20-25 C. for 24 h. To the resulting mixture was added piperidine (0.1 mL), and the mixture was stirred at 25 C. for additional 2 h until Fmoc was removed from the intermediate as monitored by LC-MS. The mixture was filtered through a membrane, and the filtrate was directly purified by prep-HPLC (method B) to give 21c (14 mg, 50% yield) as a white solid. ESI m/z: 978 (M+1)+. 1H NMR (500 MHz, DMSO-d6) delta 10.22 (s, 1H), 9.04 (s, 1H), 8.71 (d, J=7.5 Hz, 1H), 8.12 (s, 2H), 7.59 (d, J=8.3 Hz, 2H), 7.42 (t, J=5.4 Hz, 1H), 7.29 (d, J=8.2 Hz, 2H), 6.94 (d, J=8.5 Hz, 1H), 6.84-6.76 (m, 2H), 6.67 (d, J=8.4 Hz, 1H), 6.64 (s, 1H), 6.51 (dd, J=8.1, 2.0 Hz, 1H), 6.12 (s, 1H), 5.52 (s, 2H), 4.96 (s, 2H), 4.51 (d, J=5.1 Hz, 1H), 3.92 (s, 2H), 3.66 (d, J=5.7 Hz, 1H), 3.32 (d, J=5.6 Hz, 2H), 3.13-2.93 (m, 2H), 2.85 (t, J=18.0 Hz, 2H), 2.77-2.63 (m, 2H), 2.26 (d, J=7.2 Hz, 2H), 2.22-2.03 (m, 4H), 1.89-1.82 (m, 4H), 1.79-1.69 (m, 1H), 1.68-1.53 (m, 4H), 1.46-1.40 (m, 2H), 1.27 (d, J=3.3 Hz, 8H), 1.19-1.08 (m, 4H), 1.03-0.89 (m, 12H) ppm

Reference： [1]Patent: US2018/333504,2018,A1 .Location in patent: Paragraph 0370; 0377
[2]Patent: US2018/334426,2018,A1 .Location in patent: Paragraph 0705

69
[ 863971-53-3 ]
C₂₅H₃₃F₂NO₅ [ No CAS ]
{4-[(2S)-2-[(2S)-2-amino-3-methylbutanamido]-5-(carbamoylamino)pentanamido]phenyl}methyl N-{2-[(1S,2S,4R,8S,9S,11S,12R,13S,19S)-12,19-difluoro-11-hydroxy-9,13-dimethyl-16-oxo-6-propyl-5,7-dioxapentacyclo[10.8.0.0²^,⁹.0⁴^,⁸.0¹³^,1⁸]icosa-14,17-dien-8-yl]-2-oxoethyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%		General procedure: To a solution of Fmoc-vc-PAB-PNP (2a, 0.68-1.0 equiv.) and a compound 1 (le, if, ig, ih, ii or im, 1.0 equiv.) in DMF was added with DIPEA (S equiv.) at RT by syringe. The mixture was stirred at 25 C. for 16-24 hours and most of 2a was consumed according to ECMS. To the resulting mixture was added piperidine (0.1-1 mE, excess) and it was stirred at 2S C. for 2 hours until Fmoc was totally removed, which was monitored by ECMS. Afier filtering through a membrane, the filtrate was directly purified by prep-HPEC (method B) to give a compound 3 (32-73% yield) as a white solid. Table 4 provides specific reaction conditions for making compounds 3e-3g, 3H and 31.

Reference： [1]Patent: US2018/333504,2018,A1 .Location in patent: Paragraph 0370; 0380; 0381

70
[ 863971-53-3 ]
C₂₅H₃₃F₂NO₅ [ No CAS ]
{4-[(2S)-2-[(2S)-2-[(2R)-2-amino-6-[2-(cyclooct-2-yn-1-yloxy)acetamido]hexanamido]-3-methylbutanamido]-5-(carbamoylamino)pentanamido]phenyl}methyl N-{2-[(1S,2S,4R,8S,9S,11S,12R,13S,19S)-12,19-difluoro-11-hydroxy-9,13-dimethyl-16-oxo-6-propyl-5,7-dioxapentacyclo[10.8.0.02'9.04.8.011,18]icosa-14,17-dien-8-yl]-2-oxoethyl}carbamate [ No CAS ]

Reference： [1]Patent: US2018/333504,2018,A1

71
[ 863971-53-3 ]
(1S,2S,4R,8S,9S,11S,12R,13S,19S)-8-[2-(4-aminophenoxy)acetyl]-12,19-difluoro-11-hydroxy-9,13-dimethyl-6-propyl-5,7-dioxapentacyclo[10.8.0.0²^,⁹.0⁴^,⁸.0¹³^,¹⁸]icosa-14,17-dien-16-one [ No CAS ]
{4-[(2S)-2-[(2S)-2-amino-3-methylbutanamido]-5-(carbamoylamino)pentanamido]phenyl}methyl N-(4-{2-[(1S,2S,4R,8S,9S,11S,12R,13S,19S)-12,19-difluoro-11-hydroxy-9,13-dimethyl-16-oxo-6-propyl-5,7-dioxapentacyclo[10.8.0.0²'⁹.0⁴'⁸.0^13,18]icosa-14,17-dien-8-yl]-2-oxoethoxy}phenyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%		General procedure: To a solution of Fmoc-vc-PAB-PNP (2a, 0.68-1.0 equiv.) and a compound 1 (le, if, ig, ih, ii or im, 1.0 equiv.) in DMF was added with DIPEA (S equiv.) at RT by syringe. The mixture was stirred at 25 C. for 16-24 hours and most of 2a was consumed according to ECMS. To the resulting mixture was added piperidine (0.1-1 mE, excess) and it was stirred at 2S C. for 2 hours until Fmoc was totally removed, which was monitored by ECMS. Afier filtering through a membrane, the filtrate was directly purified by prep-HPEC (method B) to give a compound 3 (32-73% yield) as a white solid. Table 4 provides specific reaction conditions for making compounds 3e-3g, 3H and 31.
64%		To a solution of Fmoc-vc-PAB-PNP (LP3-1, 100 mg, 0.13 mmol) and compound P3 (87 mg, 0.15 mmol) in DMF (5 mL) was added with DIPEA (67 mg, 0.52 mmol) at RT by syringe. The mixture was stirred at RT for 3 hours and most of LP3-1 was consumed according to LCMS. To the resulting mixture was added piperidine (1 mL, excess) and it was stirred at 25 C for 2 hours until Fmoc was totally removed, which was monitored by LCMS. After filtering through a membrane, the filtrate was directly purified by prep-HPLC (method B) to give a compound LP3-2 (80 mg, 64% yield) as a white solid. ESI m/z: 963 (M + 1)+.1H NMR (500 MHz, DMSOd6) t 10.22 (s, 1H), 9.57 (s, 1H), 8.69 (d, J = 7.5 Hz, 1H), 8.08 (s, 3H), 7.61 (d, J = 6.8 Hz, 2H), 7.36 (d, J = 6.8 Hz, 3H), 7.27 (d, J = 8.0 Hz, 1H), 7.22-7.00 (m, 1H), 6.84 (d, J = 7.2 Hz, 2H), 6.30 (dd, J = 8.0 Hz, 1.6Hz, 1H), 6.11 (s, 1H), 6.10-6.00 (m, 1H), 5.72-5.55 (m, 1H), 5.52 (s, 1H), 5.48 (s, 1H), 5.16-5.05 (m, 3H), 4.88-4.80 (m, 1H), 4.80-4.76 (m, 1H), 4.75- 4.70 (m, 1H), 4.55-4.48 (m, 1H), 4.25-4.20 (m, 1H), 3.70-3.60 (m, 1H), 3.12-2.90 (m, 2H), 2.70- 2.55 (m, 1H), 2.40-2.20 (m, 1H), 2.15-2.00 (m, 3H), 1.86-1.75 (m, 1H), 1.75-1.65 (m, 1H), 1.64- 1.54 (m, 5H), 1.49 (s, 4H), 1.46-1.34 (m, 4H), 0.97-0.91 (m,5H), 0.90-0.85 (m, 4H), 0.85-0.80 (m, 3H) ppm.

Reference： [1]Patent: US2018/333504,2018,A1 .Location in patent: Paragraph 0370; 0382; 0383
[2]Patent: WO2019/217591,2019,A1 .Location in patent: Paragraph 0642

72
[ 863971-53-3 ]
(1S,4aS,10aR)-6-((S)-2-amino-3-hydroxypropanamido)-N-((1S,4aS,10aR)-6-hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carbonyl)-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxamide [ No CAS ]
{4-[(2S)-2-[(2S)-2-amino-3-methylbutanamido]-5-(carbamoylamino)pentanamido]phenyl}methyl N-[(1S)-1-[(4bS,8S,8aR)-8-([(1S,4aS,10aR)-6-hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-yl]formamido}carbonyl)-4b,8- dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthren-3-yl]carbamoyl}-2-hydroxyethyl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%		{4-[(2S)-2-[(2S)-2-Amino-3-methylbutanamido]-5-(carbamoylamino)pentanamido]phenyl}methyl N-[(1S)-1-[(4bS,8S,8aR)-8-([(1S,4aS,10aR)-6-hydroxy-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-yl]formamido}carbonyl)-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydrophenanthren-3-yl]carbamoyl}-2-hydroxyethyl]carbamate (LP4-2) To a solution of Fmoc-vc-PAB-PNP (LP4-1, 58 mg, 76 mumol) and 9j (36 mg, 58 mumol) in DMF (3 mL) was added HOBt (7.9 mg, 58 mumol) and DIPEA (15 mg, 0.12 mmol), and the mixture was stirred at 30 C. for 16 hours. Compound 9j was then totally consumed according to LCMS. To the resulting mixture was added diethylamine (0.1 mL) and the reaction was stirred at RT for an hour until Fmoc was removed, as monitored by LCMS. After the reaction was filtered, the filtrate was directly purified by prep-HPLC (method B) to give compound LP4-2 (36 mg, 48% yield) as a light yellow solid. ESI m/z: 1021 (M+1)+. 1H NMR (400 MHz, DMSOd6) delta 10.02 (s, 1H), 9.82 (s, 1H), 9.00 (s, 1H), 8.69-8.65 (m, 1H), 8.11-8.00 (m, 4H), 7.65-7.53 (m, 3H), 7.40-7.30 (m, 3H), 7.30-7.20 (m, 1H), 6.96 (d, J=8.0 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 6.65-6.61 (m, 1H), 6.50 (dd, J=8.0 Hz, 2.0 Hz, 1H), 6.00-5.95 (m, 1H), 5.48 (s, 2H), 5.00-4.95 (m, 3H), 4.60-4.40 (m, 1H), 4.25-4.20 (m, 1H), 3.65-3.55 (m, 4H), 3.15-2.55 (m, 10H), 2.40-2.20 (m, 3H), 2.20-2.00 (m, 5H), 2.00-1.80 (m, 4H), 1.86-1.55 (m, 6H), 1.27 (d, J=4.8 Hz, 9H), 1.20-1.10 (m, 2H), 0.97-0.90 (m, 6H) ppm.
48%	With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 30℃; for 16h;	To a solution of Fmoc-vc-PAB-PNP (LP4-1, 58 mg, 76 mumol) and P5 (36 mg, 58 mumol) in DMF (3 mL) were added HOBt (7.9 mg, 58 mumol) and DIPEA (15 mg, 0.12 mmol), and the mixture was stirred at 30 C for 16 hours. Compound P5 was then totally consumed according to LCMS. To the resulting mixture was added diethylamine (0.1 mL), and the reaction was stirred at RT for an hour until Fmoc was removed, as monitored by LCMS. After the reaction was filtered, the filtrate was directly purified by prep-HPLC (method B) to give compound LP4-2 (36 mg, 48% yield) as a light yellow solid. ESI m/z: 1021 (M + 1)+.1H NMR (400 MHz, DMSOd6) t 10.02 (s, 1H), 9.82 (s, 1H), 9.00 (s, 1H), 8.69-8.65 (m, 1H), 8.11-8.00 (m, 4H), 7.65-7.53 (m, 3H), 7.40-7.30 (m, 3H), 7.30-7.20 (m, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.65-6.61 (m, 1H), 6.50 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 6.00-5.95 (m, 1H), 5.48 (s, 2H), 5.00-4.95 (m, 3H), 4.60-4.40 (m, 1H), 4.25-4.20 (m, 1H), 3.65-3.55 (m, 4H), 3.15-2.55 (m, 10H), 2.40-2.20 (m, 3H), 2.20-2.00 (m, 5H), 2.00-1.80 (m, 4H), 1.86-1.55 (m, 6H), 1.27 (d, J = 4.8 Hz, 9H), 1.20- 1.10 (m, 2H), 0.97-0.90 (m, 6H) ppm.

Reference： [1]Patent: US2018/334426,2018,A1 .Location in patent: Paragraph 0587; 0588
[2]Patent: WO2019/217591,2019,A1 .Location in patent: Paragraph 0609

73
[ 863971-53-3 ]
N-(2-aminoethyl)-3-(3-(3-ethyl-8-(trifluoromethyl)quinolin-4-yl)phenoxy)-N-methylbenzenesulfonamide [ No CAS ]
C₄₆H₅₃F₃N₈O₈S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%		To a mixture of 31 (0.14 g, 0.26 mmol) in DMF (5 mL) were subsequently added Fmoc-vc-PAB-PNP (0.26 g, 0.34 mmol), HOBt (46 mg, 0.34 mmol), and DIPEA (89 mg, 0.68 mmol) at rt. After the reaction was stirred at 20-25 C. for 24 h, 31 was totally consumed according to LC-MS analysis. To the reaction mixture was added Et2NH (0.5 mL) and the resulting mixture was stirred at 25 C. for additional 2 h. LC-MS showed the Fmoc group was totally removed at that time. The volatiles were removed in vacuo and the residue was purified by prep-HPLC (Method A) to give 32 (75 mg, 30% yield) as a white solid. ESI m/z: 935 (M+H)+. 1H NMR (400 MHz, methanol-d4) delta 8.97 (s, 1H), 8.06 (d, J=7.2 Hz, 1H), 7.71-7.52 (m, 7H), 7.40-7.37 (m, 2H), 7.31-7.27 (m, 3H), 7.18 (d, J=7.2 Hz, 1H), 7.06-7.04 (m, 1H), 5.00 (s, 2H), 4.55-4.52 (m, 1H), 3.25-3.06 (m, 7H), 2.74 (s, 3H), 2.73-2.60 (m, 2H), 2.06-1.54 (m, 5H), 1.18 (t, J=7.2 Hz, 3H), 0.98 (d, J=6.8 Hz, 3H), 0.93 (d, J=6.8 Hz, 3H) ppm.

Reference： [1]Patent: US2018/334426,2018,A1 .Location in patent: Paragraph 0795

74
[ 863971-53-3 ]
C₂₈H₄₇N₇O₇ [ No CAS ]

Reference： [1]Patent: CN109464654,2019,A

75
[ 863971-53-3 ]
C₃₈H₅₈N₈O₁₀ [ No CAS ]

Reference： [1]Patent: CN109464654,2019,A

76
[ 863971-53-3 ]
C₃₃H₅₀N₈O₈*C₂HF₃O₂ [ No CAS ]

Reference： [1]Patent: CN109464654,2019,A

77
[ 863971-53-3 ]
N-(4-((4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl)benzyl)tetradecanamide [ No CAS ]
C₇₀H₈₈N₁₀O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In N,N-dimethyl-formamide; at 20℃;	To a solution of Compound No. 6 (1.1 eq.) and Compound No. 64-10b (1.0 eq.) in DMF is added TEA (2.0 eq.), and the resulting solution is stirred at room temperature. Once LC/MS shows mostly the desired product Compound No. 52, and that all of Compound No. 64-10b is consumed the reaction mixture is directly used for the next step.

Reference： [1]Patent: US2019/151462,2019,A1 .Location in patent: Paragraph 0581; 0582

78
[ 863971-53-3 ]
N-(4-((4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl)benzyl)tetradecanamide [ No CAS ]
(9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-((((2-butyl-1-(4-(tetradecanamidomethyl)benzyl)-1H-imidazo[4,5-c]quinolin-4-yl)carbamoyl)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
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; trimethylamine; In N,N-dimethyl-formamide; at 20℃; for 15h;	9-Fluorenylmethyloxycarbonyl-valyl-citrullyl-(4-aminobenzyl)-(4-nitrophenyl)carbonate (1.2 eq) and trimethylamine are added to a solution of Compound No. 15 (1.0 eq) in anhydrous DMF, and and the slurry is mixed for 5 minutes followed by the addition of HBTU (1.25 eq). This reaction mixture is further stirred for 15 hours at room termperature. The solvent is removed under reduced pressure, the residue dissolved in ethyl acetate and washed with water, then dried using magnesium sulfate and concentrated under vacuum. This product is purified using column chromatography (6% methanol/dichloromethane) to yield Compound No. 16 ((9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-((((2-butyl-1-(4-(tetradecanamidomethyl)benzyl)-1H-imidazo[4,5-c]quinolin-4-yl)carbamoyl)oxy)methyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate).

Reference： [1]Patent: US2019/151462,2019,A1 .Location in patent: Paragraph 0617; 0624

79
[ 863971-53-3 ]
2-butyl-1-(4-(((2-cyclopropylethyl)amino)methyl)benzyl)-1H-imidazo[4,5-c]quinolin-4-amine [ No CAS ]
(9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-((((2-butyl-1-(4-(((2-cyclopropylethyl)amino)methyl)benzyl)-1H-imidazo[4,5-c]quinolin-4-yl)carbamoyl)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
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; trimethylamine; In N,N-dimethyl-formamide; at 20℃; for 15h;	9-Fluorenylmethyloxycarbonyl-valyl-citrullyl-(4-aminobenzyl)-(4-nitrophenyl)carbonate (1.2 eq) and trimethylamine are added to a solution of Compound No. 17 (1.0 eq) in anhydrous DMF, and and the slurry is mixed for 5 minutes followed by the addition of HBTU (1.25 eq). This reaction mixture is further stirred for 15 hours at room termperature. The solvent is removed under reduced pressure, the residue dissolved in ethyl acetate and washed with water, then dried using magnesium sulfate and concentrated under vacuum. This product is purified using column chromatography (6% MeOH/dichloromethane) to yield Compound No. 18 ((9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-((((2-butyl-1-(4-(((2-cyclopropylethyl)amino)methyl)benzyl)-1H-imidazo[4,5-c]quinolin-4-yl)carbamoyl)oxy)methyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate).

Reference： [1]Patent: US2019/151462,2019,A1 .Location in patent: Paragraph 0627

80
[ 863971-53-3 ]
2-butyl-1-(4-(((2-cyclopropylethyl)amino)methyl)benzyl)-1H-imidazo[4,5-c]quinolin-4-amine [ No CAS ]
C₆₁H₇₀N₁₀O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73 mg		To a solution of Compound No. 64-33b (33 mg, 1.0 eq) in DMF (1.5 mL) was added diisopropylethyl amine (0.1 mL) and the solution was stirred for 10 minutes under an argon atmosphere. Compound 10 (59 mg, 1 eq.) was added to the solution in two portions and the resulting clear yellow solution was stirred at 35 C. for 2 hours. Thin layer chromatography analysis, with 10% methanol in dichloromethane containing 1% trimethylamine, indicted that all of the Compound No. 64-33b had been consumed. The DMF was removed under reduced pressure, ethyl acetate (3 mL) was added to the yellow residue, the mixture triturated, the pale yellow solid formed allowed to settle and the supernatant was decanted. This process was repeated additional two times, and the product was dried under reduced pressure to yield 73 mg of an off-white solid. The off-white solid (70 mg, 0.066 mmol) was dissolved in ice-cold DMF (1.5 mL) and diisopropyl amine was added (0.1 mL). The resulting solution was stirred under an argon atmosphere, slowly warmed to room temperature and stirring was continued for 12 hours. Reverse-phase HPLC analysis of the reaction mixture indicated that removal of the Fmoc moiety was complete. The DMF was removed under reduced pressure, ethyl acetate (3 mL) was added to the yellow residue, the mixture triturated, the pale yellow solid formed allowed to settle and the supernatant was decanted. This process was repeated additional two times, and the product was dried under reduced pressure to yield 47 mg of Compound 40.

Reference： [1]Patent: US2019/151462,2019,A1 .Location in patent: Paragraph 0629; 0632

81
[ 863971-53-3 ]
2-butyl-1-(4-((((1-methylcyclobutyl)methyl)amino)methyl)benzyl)-1H-imidazo[4,5-c]quinoline-4-amine [ No CAS ]
C₆₂H₇₂N₁₀O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of Compound No. 64-60b (1.0 eq.) in DMF is added DIPEA, and the solution is stirred for 10 minutes under an argon atmosphere. Compound 10 (1.0 eq.) is added to the solution in two portions and the resulting clear yellow solution is stirred at 35 C. for 2 hours. Thin layer chromatography analysis, developed with 10% (v/v) methanol in DCM, containing 1% (v/v) TEA, indicates that all of the Compound No. 64-60b has been consumed. The DMF is removed under reduced pressure, ethyl acetate is added to the yellow residue, the mixture triturated, and the pale yellow solid formed allowed to settle and the supernatant is decanted. This process is repeated additional two times, and the product is dried under reduced pressure to yield an off-white solid. The off-white solid is dissolved in ice-cold DMF and diisopropyl amine is added. The resulting solution is stirred under an argon atmosphere, slowly warmed to room temperature, with stirring continued for 12 hours. Reverse-phase HPLC analysis of the reaction mixture indicates that removal of the Fmoc moiety is complete. The DMF is then removed under reduced pressure, ethyl acetate is added to the yellow residue, the mixture triturated, and the pale yellow solid formed is allowed to settle and the supernatant is decanted. This process is repeated an additional two times, and the product is dried under reduced pressure to yield Compound 43.

Reference： [1]Patent: US2019/151462,2019,A1 .Location in patent: Paragraph 0638

82
[ 863971-53-3 ]
2-butyl-1-(4-(((cyclobutylmethyl)amino)methyl)benzyl)-1H-imidazo[4,5-c]quinoline-4-amine [ No CAS ]
C₆₁H₇₀N₁₀O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of Compound No. 64-66b (1.0 eq.) in DMF is added DIPEA, and the solution is stirred for 10 minutes under an argon atmosphere. Compound 10 (1.0 eq.) is added to the solution in two portions and the resulting clear yellow solution is stirred at 35 C. for 2 hours. Thin layer chromatography analysis, developed with 10% (v/v) methanol in DCM, containing 1% (v/v) TEA, indicates that all of the Compound No. 64-66b has been consumed. The DMF is removed under reduced pressure, ethyl acetate is added to the yellow residue, the mixture triturated, and the pale yellow solid formed allowed to settle and the supernatant is decanted. This process is repeated additional two times, and the product is dried under reduced pressure to yield an off-white solid. The off-white solid is dissolved in ice-cold DMF and diisopropyl amine is added. The resulting solution is stirred under an argon atmosphere, slowly warmed to room temperature, with stirring continued for 12 hours. Reverse-phase HPLC analysis of the reaction mixture indicates that removal of the Fmoc moiety is complete. The DMF is then removed under reduced pressure, ethyl acetate is added to the yellow residue, the mixture triturated, and the pale yellow solid formed is allowed to settle and the supernatant is decanted. This process is repeated an additional two times, and the product is dried under reduced pressure to yield Compound 45.

Reference： [1]Patent: US2019/151462,2019,A1 .Location in patent: Paragraph 0642

83
[ 863971-53-3 ]
[ 1258457-59-8 ]
C₅₆H₆₂N₁₀O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 15h;	To a solution of Compound No. 6 (465 mg, 0.61 mmol) and Compound No. 5 (IMDQ; 190 mg, 0.53 mmol) in DMF (15 mL) was added triethylamine (0.13 mL, 0.94 mmol). The resulting yellow clear solution was stirred at room temperature for 15 hours. LC/MS showed mostly the desired product Compound No. 7, and that all of Compound No. 5 was consumed. The reaction mixture was directly used for next step. LC-MS: 987 [M+1]+.

Reference： [1]Patent: US2019/151462,2019,A1 .Location in patent: Paragraph 0547; 0548; 0552

84
[ 863971-53-3 ]
C₄₁H₅₂N₁₀O₅ [ No CAS ]

Reference： [1]Patent: US2019/151462,2019,A1

85
[ 863971-53-3 ]
C₅₂H₇₁N₁₃O₁₀ [ No CAS ]

Reference： [1]Patent: US2019/151462,2019,A1

86
[ 863971-53-3 ]
[ 1258457-58-7 ]
C₅₆H₆₂N₁₀O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
102 mg		To a solution of meta-IMDQ (46 mg, 1.0 eq.) in DMF (1.5 mL) was added diisopropylethyl amine (0.2 mL) and the solution was stirred for 10 minutes under an argon atmosphere. Compound 10 (98 mg, 1.0 eq.) was added to the solution in two portions. The resulting clear yellow solution was stirred at 0 C. for 2 hours, then slowly warmed to room temperature and stirring was continued for 12 hours. Thin layer chromatography analysis, with 10% methanol in dichloromethane containing 1% trimethylamine, indicted that all of the meta-IMDQ had been consumed. The DMF was removed under reduced pressure, ethyl acetate (3 mL) was added to the yellow residue, the mixture triturated, the pale yellow solid formed allowed to settle and the supernatant was decanted. This process was repeated additional two times, and the product was dried under reduced pressure to yield 102 mg of an off-white solid. The off-white solid (99 mg, 0.1 mmol) was dissolved in ice-cold DMF (1.5 mL) and diisopropyl amine was added (0.1 mL). The resulting solution was stirred under an argon atmosphere, slowly warmed to room temperature and stirring was continued for 12 hours. Reverse-phase HPLC analysis of the reaction mixture indicated that removal of the Fmoc moiety was complete. The DMF was distilled off under reduced pressure, ethyl acetate (3 mL) was added to the yellow residue, the mixture triturated, the pale yellow solid formed allowed to settle and the supernatant was decanted. This process was repeated additional two times, and the product was dried under reduced pressure to yield 68 mg of Compound 41.

Reference： [1]Patent: US2019/151462,2019,A1 .Location in patent: Paragraph 0634

87
[ 863971-53-3 ]
2-[(1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-9,13-dimethyl-16-oxo-6-propyl-5,7-dioxapentacyclo[10.8.0.0^2,9.0^4,8.0^13,18]icosa-14,17-dien-8-yl]-2-oxoethyl N-methyl-N-[2-(methylamino)ethyl]carbamate [ No CAS ]
2-[(1S,2S,4R,8S,9S,11S,12S,13R)-11-hydroxy-9,13-dimethyl-16-oxo-6-propyl-5,7-dioxapentacyclo[10.8.0.0^2,9.0^4,8.0^13,18]icosa-14,17-dien-8-yl]-2-oxoethyl N-(2-[({4-[(2S)-2-[(2S)-2-amino-3-methylbutanamido]-5-(carbamoylamino)pentanamido]phenyl}methoxy)carbonyl](methyl)amino}ethyl)-N-methylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
13%		To a solution of compound 1d (40 mg, 73 mumol) in DMF (3 mL) were added Fmoc-vcPAB-PNP (11d, 60 mg, 78 mumol), DMAP (9.0 mg, 74 mumol) and DIPEA (20 mg, 0.16 mmol) at room temperature. The mixture was stirred at room temperature for 3 hours until most of starting materials were consumed, which was monitored by LCMS. To the reaction mixture was then added piperidine (1 mL). After stirred at room temperature for an hour until the de-Fmoc reaction was completed, which was monitored by LCMS, the reaction mixture was directly purified by prep-HPLC (method B) to give compound 4c (9.0 mg, yield 13%, the 2nd peak in LC) as a white solid. ESI m/z: 951 (M + H)+, 973 (M + Na)+.
13%	With dmap; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 3h;	To a solution of compound 1d (40 mg, 73 mumol) in DMF (3 mL) were added Fmoc- vcPAB-PNP (11d, 60 mg, 78 mumol), DMAP (9.0 mg, 74 mumol) and DIPEA (20 mg, 0.16 mmol) at room temperature. The mixture was stirred at room temperature for 3 hours until most of starting materials were consumed, which was monitored by LCMS. To the reaction mixture was then added piperidine (1 mL). After stirred at room temperature for an hour until the de-Fmoc reaction was completed, which was monitored by LCMS, the reaction mixture was directly purified by prep-HPLC (method B) to give compound 4c (9.0 mg, yield 13%, the 2ndpeak in LC) as a white solid. ESI m/z: 951 (M + H)+, 973 (M + Na)+.

Reference： [1]Patent: WO2019/136487,2019,A2 .Location in patent: Paragraph 00336; 00338
[2]Patent: WO2019/217591,2019,A1 .Location in patent: Paragraph 0692

88
[ 863971-53-3 ]
2-[(1S,2S,4R,8S,9S,11S,12R,13S,19S)-12,19-difluoro-11-hydroxy-9,13-dimethyl-16-oxo-6-propyl-5,7-dioxapentacyclo[10.8.0.0^2,9.0^4,8.0^13,18]icosa-14,17-dien-8-yl]-2-oxoethyl N-[2-(methylamino)ethyl]carbamate trifluoroacetate [ No CAS ]
2-[(1S,2S,4R,8S,9S,11S,12R,13S,19S)-12,19-difluoro-11-hydroxy-9,13-dimethyl-16-oxo-6-propyl-5,7-dioxapentacyclo[10.8.0.0^2,9.0^4,8.0^13,18]icosa-14,17-dien-8-yl]-2-oxoethyl N-(2-[({4-[(2S)-2-[(2S)-2-amino-3-methylbutanamido]-5-(carbamoylamino)pentanamido]phenyl}methoxy)carbonyl](methyl)amino}ethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%		General procedure: To a solution of compound 101a, b or d (0.20 mmol) in DMF (3 mL) were added Fmoc-VC-PAB-PNP 11d (0.17 g, 0.22 mmol), HOBT (41 mg, 0.30 mmol) and DIPEA (77 mg, 0.60 mmol). The mixture was stirred at RT for 3 hours, which was monitored by LCMS. To the mixture was then added piperidine (0.3 mL). The reaction mixture was stirred at RT for an hour until Fmoc was totally removed according to LCMS. The resulting mixture was directly purified by reversed phase flash chromatography (50-80% acetonitrile in aq. NH4HCO3 (10 mM)) to give compound 101-3a, b or d as a white solid. Following the general procedure and using compound 101a, compound 101-3a (0.11 g, 57% yield) was obtained as a white solid. ESI m/z: 972 (M + H)+.
57%		General procedure: To a solution of compound 101a, b or d (0.20 mmol) in DMF (3 mL) were added Fmoc- VC-PAB-PNP 11d (0.17 g, 0.22 mmol), HOBT (41 mg, 0.30 mmol) and DIPEA (77 mg, 0.60 mmol). The mixture was stirred at RT for 3 hours, which was monitored by LCMS. To the mixture was then added piperidine (0.3 mL). The reaction mixture was stirred at RT for an hour until Fmoc was totally removed according to LCMS. The resulting mixture was directly purified by reversed phase flash chromatography (50-80% acetonitrile in aq. NH4HCO3 (10 mM)) to give compound 101-3a, b or d as a white solid.

Reference： [1]Patent: WO2019/136487,2019,A2 .Location in patent: Paragraph 00360; 00368-00369
[2]Patent: WO2019/217591,2019,A1 .Location in patent: Paragraph 0722; 0723

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[ CAS No. 863971-53-3 ] {[proInfo.proName]}

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