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[ CAS No. 150629-67-7 ] {[proInfo.proName]}

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Cat. No.: {[proInfo.prAm]}

2D 3D

Chemical Structure| 150629-67-7

Chemical Structure| 150629-67-7

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Quality Control of [ 150629-67-7 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 150629-67-7 ]

SDS Specification

Alternatived Products of [ 150629-67-7 ]

Product Details of [ 150629-67-7 ]

CAS No. :	150629-67-7	MDL No. :	MFCD00278818
Formula :	C₃₁H₃₆N₂O₆	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	AOHSSQNORWQENF-VWLOTQADSA-N
M.W :	532.63	Pubchem ID :	135404832
Synonyms :	Fmoc-L-Lys(Dde)-OH	Chemical Name :	Fmoc-L-Lys(Dde)-OH

Calculated chemistry of [ 150629-67-7 ]

Physicochemical Properties

Num. heavy atoms :	39
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.42
Num. rotatable bonds :	12
Num. H-bond acceptors :	6.0
Num. H-bond donors :	3.0
Molar Refractivity :	148.02
TPSA :	121.8 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 :	Yes
Log Kp (skin permeation) :	-5.62 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.11
Log Po/w (XLOGP3) :	5.54
Log Po/w (WLOGP) :	4.97
Log Po/w (MLOGP) :	2.41
Log Po/w (SILICOS-IT) :	5.41
Consensus Log Po/w :	4.29

Druglikeness

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

Water Solubility

Log S (ESOL) :	-6.07
Solubility :	0.000455 mg/ml ; 0.000000855 mol/l
Class :	Poorly soluble
Log S (Ali) :	-7.86
Solubility :	0.00000739 mg/ml ; 0.0000000139 mol/l
Class :	Poorly soluble
Log S (SILICOS-IT) :	-8.6
Solubility :	0.00000133 mg/ml ; 0.0000000025 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	3.0
Synthetic accessibility :	5.15

Safety of [ 150629-67-7 ]

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

Application In Synthesis of [ 150629-67-7 ]

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

Upstream synthesis route of [ 150629-67-7 ]
Downstream synthetic route of [ 150629-67-7 ]

[ 150629-67-7 ] Synthesis Path-Upstream 1~5

1
[ 94142-97-9 ]
[ 150629-67-7 ]

Yield	Reaction Conditions	Operation in experiment
70%	Stage #1: With N-ethyl-N,N-diisopropylamine In water at 20℃; Stage #2: With trifluoroacetic acid In ethanol; water for 60 h; Reflux	Synthesis of Fmoc-Lys(Dde)-OH Fmoc-Lys-OH.HCl (10.2 g, 25.2 mmol) was dissolved in H₂O, N,N-diisopropylethylamine (DIPEA 1.1 eq, 4.8 mL, 27.7 mmol) was added and the resulting solid was collected by filtration and dried in a vacuum oven overnight. To a stirred suspension of Fmoc-Lys-OH (7.9 g, 21.4 mmol, 1 eq) in ethanol (250 mL), Dde-OH (7.8 g, 42.8 mmol, 2 eq) and TFA (160 μL, 2.14 mmol, 0.1 eq) were added. The reaction was refluxed for 60 hours. After the reaction mixture was cooled to room temperature, the solvent was removed in vacuo and the residue was dissolved in EtOAc (300 mL), washed with 1M KHSO₄ (2200 mL) and 1M HCl (2200 mL). The organic phase was dried over MgSO₄, filtered, and evaporated in vacuo. Fmoc-Lys(Dde)-OH was isolated by flash column chromatography (elute with 10percent acetic acid/ethyl acetate) and crystallised from ethyl acetate/hexane as an off white solid (7.5 g, 70percent).

Reference： [1] Patent: US2014/134110, 2014, A1, . Location in patent: Paragraph 0155; 0157

2
[ 94142-97-9 ]
[ 71989-26-9 ]
[ 150629-67-7 ]

Yield	Reaction Conditions	Operation in experiment
41%	Stage #1: With hydrogenchloride In 1,4-dioxane at 20℃; for 2 h; Stage #2: With N-ethyl-N,N-diisopropylamine In ethanol for 17 h; Reflux	Fmoc-Lys(Boc)-OH (5.66 g, 12.1 mmol) was dissolved in 4 M HCl/dioxane (120 mL), and stirred at room temperature for 2 h to remove the side-chain Boc group. The solvent was removed under reduced pressure. The resulting residue was dissolved in EtOH(60 mL), and then 2-acetyldimedone (3.36 g, 18.4 mmol) and DIPEA (6.2 mL, 35.6 mmol) were added. The reaction mixture was refluxed for 17 h. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was dissolved in AcOEt (300 mL) and washed with 1 M HCl (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography(0.5percent–3percent MeOH/DCM) to give Fmoc-Lys(Dde)-OH (2.64 g,41percent) as a white solid. Spectroscopic data are identical to the published data.34 ¹H NMR (500 MHz, CDCl3): d 13.31 (brs, 1H), 7.75(d, J = 7.8 Hz, 2H), 7.59 (t, J = 7.8 Hz, 2H), 7.38 (t, J = 7.8 Hz, 2H),7.31–7.28 (m, 2H), 5.73 (d, J = 8.0 Hz, 1H), 4.48–4.45 (m, 1H),4.37 (d, J = 7.1 Hz, 2H), 4.20 (t, J = 7.1 Hz, 1H), 3.43–3.40 (m, 2H),2.55 (s, 3H), 2.36 (s, 4H), 2.00–1.50 (m, 6H), 1.01 (s, 6H). HR-MS(m/z, FAB): calcd for C31H37N2O6 ([M + H]+), 533.2652; found,533.2643.

Reference： [1] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 3, p. 1227 - 1234

3
[ 1755-15-3 ]
[ 105047-45-8 ]
[ 150629-67-7 ]

Reference： [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 22, p. 9290 - 9298
[2] Journal of the Chemical Society, Chemical Communications, 1993, # 9, p. 778 - 779

4
[ 126-81-8 ]
[ 150629-67-7 ]

Reference： [1] Patent: US2014/134110, 2014, A1,
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 22, p. 9290 - 9298

5
[ 94142-97-9 ]
[ 105047-45-8 ]
[ 150629-67-7 ]

Reference： [1] Tetrahedron Letters, 1998, vol. 39, # 12, p. 1603 - 1606

[ 150629-67-7 ] Synthesis Path-Downstream 1~88

1
[ 94142-97-9 ]
[ 105047-45-8 ]
[ 150629-67-7 ]

Reference： [1]Tetrahedron Letters,1998,vol. 39,p. 1603 - 1606

2
[ 93-10-7 ]
[ 2862-03-5 ]
[ 150629-67-7 ]
[ 292150-20-0 ]
Fmoc-L-Ala [ No CAS ]
(R)-2-{(S)-2-[(R)-2-((2S,3R,4R,5S,6R)-3-Acetylamino-2-benzyloxy-5-hydroxy-6-hydroxymethyl-tetrahydro-pyran-4-yloxy)-propionylamino]-propionylamino}-pentanedioic acid 1-amide 5-({(S)-1-carbamoyl-5-[(quinoline-2-carbonyl)-amino]-pentyl}-amide) [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 1361 - 1363

3
[ 2849-93-6 ]
[ 2862-03-5 ]
[ 150629-67-7 ]
[ 292150-20-0 ]
Fmoc-L-Ala [ No CAS ]
(R)-2-{(S)-2-[(R)-2-((2S,3R,4R,5S,6R)-3-Acetylamino-2-benzyloxy-5-hydroxy-6-hydroxymethyl-tetrahydro-pyran-4-yloxy)-propionylamino]-propionylamino}-pentanedioic acid 1-amide 5-({(S)-5-[(1H-benzoimidazole-2-carbonyl)-amino]-1-carbamoyl-pentyl}-amide) [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 1361 - 1363

4
[ 40525-29-9 ]
[ 2862-03-5 ]
[ 150629-67-7 ]
[ 292150-20-0 ]
Fmoc-L-Ala [ No CAS ]
C₄₁H₆₆N₈O₁₇ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 1361 - 1363

5
[ 82-07-5 ]
[ 2862-03-5 ]
[ 150629-67-7 ]
[ 292150-20-0 ]
Fmoc-L-Ala [ No CAS ]
(R)-2-{(S)-2-[(R)-2-((2S,3R,4R,5S,6R)-3-Acetylamino-2-benzyloxy-5-hydroxy-6-hydroxymethyl-tetrahydro-pyran-4-yloxy)-propionylamino]-propionylamino}-pentanedioic acid 1-amide 5-({(S)-1-carbamoyl-5-[(9H-xanthene-9-carbonyl)-amino]-pentyl}-amide) [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 1361 - 1363

6
[ 62558-67-2 ]
[ 2862-03-5 ]
[ 150629-67-7 ]
[ 292150-20-0 ]
Fmoc-L-Ala [ No CAS ]
2-{2-[2-(3-acetylamino-2-benzyloxy-5-hydroxy-6-hydroxymethyl-tetrahydro-pyran-4-yloxy)-propionylamino]-propionylamino}-pentanedioic acid 1-amide 5-({1-carbamoyl-5-[3-(4-hydroxy-phenylcarbamoyl)-propionylamino]-pentyl}-amide) [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 1361 - 1363

7
[ 102-14-7 ]
[ 2862-03-5 ]
[ 150629-67-7 ]
[ 292150-20-0 ]
Fmoc-L-Ala [ No CAS ]
(R)-2-{(S)-2-[(R)-2-((2S,3R,4R,5S,6R)-3-Acetylamino-2-benzyloxy-5-hydroxy-6-hydroxymethyl-tetrahydro-pyran-4-yloxy)-propionylamino]-propionylamino}-pentanedioic acid 1-amide 5-[(S)-1-carbamoyl-5-(3-phenylcarbamoyl-propionylamino)-pentyl]-amide} [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 1361 - 1363

8
[ 52986-22-8 ]
[ 2862-03-5 ]
[ 150629-67-7 ]
[ 292150-20-0 ]
Fmoc-L-Ala [ No CAS ]
2-{2-[2-(3-acetylamino-2-benzyloxy-5-hydroxy-6-hydroxymethyl-tetrahydro-pyran-4-yloxy)-propionylamino]-propionylamino}-pentanedioic acid 5-({5-[3-(adamantan-1-ylcarbamoyl)-propionylamino]-1-carbamoyl-pentyl}-amide) 1-amide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 1361 - 1363

9
3,4,5-trihydroxycyclohexane carboxylic acid [ No CAS ]
[ 2862-03-5 ]
[ 150629-67-7 ]
[ 292150-20-0 ]
Fmoc-L-Ala [ No CAS ]
2-{2-[2-(3-acetylamino-2-benzyloxy-5-hydroxy-6-hydroxymethyl-tetrahydro-pyran-4-yloxy)-propionylamino]-propionylamino}-pentanedioic acid 1-amide 5-({1-carbamoyl-5-[(3,4,5-trihydroxy-cyclohexanecarbonyl)-amino]-pentyl}-amide) [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 1361 - 1363

10
[ 23979-41-1 ]
[ 2862-03-5 ]
[ 150629-67-7 ]
[ 292150-20-0 ]
Fmoc-L-Ala [ No CAS ]
2-{2-[2-(3-acetylamino-2-benzyloxy-5-hydroxy-6-hydroxymethyl-tetrahydro-pyran-4-yloxy)-propionylamino]-propionylamino}-pentanedioic acid 1-amide 5-({1-carbamoyl-5-[2-(6-methoxy-naphthalen-2-yl)-propionylamino]-pentyl}-amide) [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 1361 - 1363

11
[ 2862-03-5 ]
[ 150629-67-7 ]
<i>N</i>-(4-acetylamino-phenyl)-succinamic acid [ No CAS ]
[ 292150-20-0 ]
Fmoc-L-Ala [ No CAS ]
2-{2-[2-(3-acetylamino-2-benzyloxy-5-hydroxy-6-hydroxymethyl-tetrahydro-pyran-4-yloxy)-propionylamino]-propionylamino}-pentanedioic acid 5-({5-[3-(4-acetylamino-phenylcarbamoyl)-propionylamino]-1-carbamoyl-pentyl}-amide) 1-amide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 1361 - 1363

12
[ 2862-03-5 ]
[ 150629-67-7 ]
3-(4-benzyloxy-phenyl)-4-oxo-1,2,3,4-tetrahydro-quinazoline-7-carboxylic acid [ No CAS ]
[ 292150-20-0 ]
Fmoc-L-Ala [ No CAS ]
C₅₄H₆₇N₉O₁₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 1361 - 1363

13
[ 2862-03-5 ]
[ 57-10-3 ]
[ 150629-67-7 ]
[ 292150-20-0 ]
Fmoc-L-Ala [ No CAS ]
(R)-2-{(S)-2-[(R)-2-((2S,3R,4R,5S,6R)-3-Acetylamino-2-benzyloxy-5-hydroxy-6-hydroxymethyl-tetrahydro-pyran-4-yloxy)-propionylamino]-propionylamino}-pentanedioic acid 1-amide 5-[((S)-1-carbamoyl-5-hexadecanoylamino-pentyl)-amide] [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 1361 - 1363

14
[ 2862-03-5 ]
[ 150629-67-7 ]
[ 4498-67-3 ]
[ 292150-20-0 ]
Fmoc-L-Ala [ No CAS ]
(R)-2-{(S)-2-[(R)-2-((2S,3R,4R,5S,6R)-3-Acetylamino-2-benzyloxy-5-hydroxy-6-hydroxymethyl-tetrahydro-pyran-4-yloxy)-propionylamino]-propionylamino}-pentanedioic acid 1-amide 5-({(S)-1-carbamoyl-5-[(1H-indazole-3-carbonyl)-amino]-pentyl}-amide) [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 1361 - 1363

15
[ 108-24-7 ]
[ 79-08-3 ]
[ 73724-43-3 ]
[ 88574-06-5 ]
[ 150629-67-7 ]
Ac-Lys(bromoacetyl)-6-aminohexanoic acid-Cys(S-tBu)-NH₂ [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2005,vol. 127,p. 17182 - 17183

16
[ 108-30-5 ]
[ 108-24-7 ]
[ 71989-23-6 ]
[ 71989-38-3 ]
[ 95753-55-2 ]
[ 150629-67-7 ]
N-(9-fluorenyl)methoxycarbonyl-Cys(Trt)-OHN-(9-fluorenyl)methoxycarbonyl-Tyr(t-Bu)-Wang resin [ No CAS ]
2-({12-[2-[2-(2-acetylamino-3-mercapto-propionylamino)-3-methyl-pentanoylamino]-3-(4-hydroxy-phenyl)-propionylamino]-3,6,13-trioxo-2,7,14-triaza-bicyclo[15.2.2]heneicosa-1⁽²⁰⁾,17⁽²¹⁾,18-triene-15-carbonyl}-amino)-3-(4-hydroxy-phenyl)-propionic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 3395 - 3401

17
[ 108-30-5 ]
[ 108-24-7 ]
[ 71989-23-6 ]
[ 71989-38-3 ]
[ 95753-55-2 ]
[ 150629-67-7 ]
N-(9-fluorenyl)methoxycarbonyl-Cys(Trt)-OHN-(9-fluorenyl)methoxycarbonyl-Tyr(t-Bu)-Wang resin [ No CAS ]
2-[2-({15-[2-(2-acetylamino-3-mercapto-propionylamino)-3-methyl-pentanoylamino]-3,6,14-trioxo-2,7,13-triaza-bicyclo[15.2.2]heneicosa-1⁽²⁰⁾,17⁽²¹⁾,18-triene-12-carbonyl}-amino)-3-(4-hydroxy-phenyl)-propionylamino]-3-(4-hydroxy-phenyl)-propionic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 3395 - 3401

18
[ 108-30-5 ]
[ 71989-23-6 ]
[ 71989-38-3 ]
[ 95753-55-2 ]
[ 150629-67-7 ]
N-(9-fluorenyl)methoxycarbonyl-Cys(Trt)-OHN-(9-fluorenyl)methoxycarbonyl-Tyr(t-Bu)-Wang resin [ No CAS ]
(S)-2-[(S)-2-[(3S,6S,9R,20S)-6-((S)-sec-Butyl)-3-(4-hydroxy-benzyl)-9-mercaptomethyl-2,5,8,11,14-pentaoxo-1,4,7,10,15-pentaaza-cycloicosane-20-carbonyl]-amino}-3-(4-nitro-phenyl)-propionylamino]-3-(4-hydroxy-phenyl)-propionic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 3395 - 3401

19
[ 108-24-7 ]
[ 71989-23-6 ]
[ 71989-38-3 ]
[ 95753-55-2 ]
[ 150629-67-7 ]
N-(9-fluorenyl)methoxycarbonyl-Cys(Trt)-OHN-(9-fluorenyl)methoxycarbonyl-Tyr(t-Bu)-Wang resin [ No CAS ]
2-[2-({19-[2-(2-acetylamino-3-mercapto-propionylamino)-3-methyl-pentanoylamino]-3,10,18-trioxo-2,11,17-triaza-bicyclo[19.2.2]pentacosa-1⁽²⁴⁾,21⁽²⁵⁾,22-triene-16-carbonyl}-amino)-3-(4-hydroxy-phenyl)-propionylamino]-3-(4-hydroxy-phenyl)-propionic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 3395 - 3401

20
[ 71989-23-6 ]
[ 71989-38-3 ]
[ 150629-67-7 ]
[ 77128-72-4 ]
N-(9-fluorenyl)methoxycarbonyl-Cys(Trt)-OH [ No CAS ]
Ac-Cys-Ile-Tyr-cyclo[Lys-Tyr-Tyr] [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 3395 - 3401

21
[ 313709-63-6 ]
[ 6946-15-2 ]
[ 150629-67-7 ]
[ 173963-93-4 ]
{3-[5-[1-carbamoyl-2-(4-cyano-phenyl)-ethylcarbamoyl]-5-(3-hydroxy-4-methyl-2-nitro-benzoylamino)-pentylcarbamoyl]-phenoxy}-acetic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 7413 - 7426

22
Fmoc-Lys(tBu)-OH [ No CAS ]
[ 123622-48-0 ]
[ 150629-67-7 ]
Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
(1N-Dde,8N-Mmt-spermidin-4-yl)carbonyl Wang resin [ No CAS ]
C₃₆H₇₆N₁₆O₅ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 3604 - 3617

23
[ 159751-47-0 ]
[ 19337-97-4 ]
[ 150629-67-7 ]
[ 162648-54-6 ]
2-(4-(1H-benzoimidazol-2-ylamino)phenyl)acetic acid [ No CAS ]
C₄₂H₅₁N₉O₇ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 5863 - 5867

24
[ 159751-47-0 ]
[ 19337-97-4 ]
[ 150629-67-7 ]
[ 162648-54-6 ]
2-(4-(1H-benzoimidazol-2-ylamino)phenyl)propanoic acid [ No CAS ]
C₄₃H₅₃N₉O₇ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 5863 - 5867

25
[ 159751-47-0 ]
[ 19337-97-4 ]
[ 150629-67-7 ]
[ 162648-54-6 ]
2-(4-(4-methyl-1H-benzoimidazol-2-ylamino)phenyl)acetic acid [ No CAS ]
C₄₃H₅₃N₉O₇ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 5863 - 5867

26
[ 159751-47-0 ]
[ 19337-97-4 ]
[ 150629-67-7 ]
[ 162648-54-6 ]
2-(4-(5-bromo-1H-benzoimidazol-2-ylamino)phenyl)acetic acid [ No CAS ]
C₄₂H₅₀BrN₉O₇ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 5863 - 5867

27
[ 159751-47-0 ]
[ 19337-97-4 ]
[ 150629-67-7 ]
[ 162648-54-6 ]
2-(o-tolylamino)-1H-benzoimidazole-5-carboxylic acid [ No CAS ]
C₄₂H₅₁N₉O₇ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 5863 - 5867

28
[ 159751-47-0 ]
[ 19337-97-4 ]
[ 150629-67-7 ]
[ 162648-54-6 ]
3-(1H-benzoimidazol-2-ylamino)benzoic acid [ No CAS ]
C₄₁H₄₉N₉O₇ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 5863 - 5867

29
[ 159751-47-0 ]
[ 19337-97-4 ]
[ 150629-67-7 ]
[ 162648-54-6 ]
3-(4-(1H-benzoimidazol-2-ylamino)phenyl)propanoic acid [ No CAS ]
C₄₃H₅₃N₉O₇ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 5863 - 5867

30
[ 159751-47-0 ]
[ 19337-97-4 ]
[ 150629-67-7 ]
[ 162648-54-6 ]
4-(1H-benzoimidazol-2-ylamino)benzoic acid [ No CAS ]
C₄₁H₄₉N₉O₇ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 5863 - 5867

31
[ 159751-47-0 ]
[ 19337-97-4 ]
[ 150629-67-7 ]
[ 162648-54-6 ]
4-(4-methyl-1H-benzoimidazol-2-ylamino)benzoic acid [ No CAS ]
C₄₂H₅₁N₉O₇ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 5863 - 5867

32
[ 123622-48-0 ]
[ 119831-72-0 ]
[ 150629-67-7 ]
[ 77205-61-9 ]
Fmoc-Ala-OH [ No CAS ]
Fmoc-Thr(But)-OH [ No CAS ]
HAEGTPTSDVSSYLEGQAAK[5-aminopentanoyl-CO-(CH₂)4NHCO-(CH₂)4CH₃]EFIAWLVRGRG [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 6126 - 6132

33
C₅₄H₅₂N₃O₉Pol [ No CAS ]
[ 29022-11-5 ]
[ 13734-38-8 ]
[ 71989-31-6 ]
[ 150629-67-7 ]
[ 80366-85-4 ]
[ 174653-61-3 ]
[ 882051-18-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 3880 - 3883

34
[ 159610-89-6 ]
[ 1008512-24-0 ]
[ 29022-11-5 ]
[ 71989-31-6 ]
[ 150629-67-7 ]
[ 1283189-10-5 ]

Reference： [1]Angewandte Chemie - International Edition,2011,vol. 50,p. 1901 - 1904

35
[ 29022-11-5 ]
[ 71989-31-6 ]
[ 71989-14-5 ]
[ 108-24-7 ]
[ 71989-26-9 ]
[ 109425-51-6 ]
[ 150629-67-7 ]
[ 59-05-2 ]
[ 143824-78-6 ]
[ 98-79-3 ]
C₈₄H₁₀₃N₂₇O₁₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: The linear protected GnRH-III derivatives (Glp-His(Trt)-Trp(Boc)-Ser(tBu)-His(Trt)-Asp(OtBu)-Trp(Boc)-Lys(Mtt)-Pro-Gly-R, Glp-His(Trt)-Trp(Boc)-Lys(Dde)-His(Trt)-Asp(OtBu)-Trp(Boc)-Lys(Mtt)-Pro-Gly-R, Glp-His(Trt)-Trp(Boc)-Lys(Dde)-His(Trt)-Asp(OtBu)-Trp(Boc)-Lys(Boc)-Pro-Gly-R; where R = resin) were prepared manually by solid phase peptide synthesis according to Fmoc/tBu chemistry on a Rink-Amide MBHA resin (0.38 mmol/g coupling capacity). The following Fmoc-protected amino acid derivatives were used: Fmoc-Gly-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, Fmoc-Lys(Mtt)-OH, Fmoc-Lys(Dde)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-His(Trt)-OH and Fmoc-Ser(tBu)-OH. Pyroglutamic acid (Glp or

Reference： [1]European Journal of Medicinal Chemistry,2012,vol. 52,p. 173 - 183

36
[ 29022-11-5 ]
[ 71989-31-6 ]
[ 71989-14-5 ]
[ 109425-51-6 ]
[ 150629-67-7 ]
[ 59-05-2 ]
[ 143824-78-6 ]
[ 98-79-3 ]
(S)-6-[(Diphenyl-p-tolyl-methyl)-amino]-2-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoic acid [ No CAS ]
2-(bis-tert-butoxycarbonylaminooxy)acetic acid [ No CAS ]
C₈₄H₁₀₄N₂₈O₁₉ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: The linear protected GnRH-III derivatives (Glp-His(Trt)-Trp(Boc)-Ser(tBu)-His(Trt)-Asp(OtBu)-Trp(Boc)-Lys(Mtt)-Pro-Gly-R, Glp-His(Trt)-Trp(Boc)-Lys(Dde)-His(Trt)-Asp(OtBu)-Trp(Boc)-Lys(Mtt)-Pro-Gly-R, Glp-His(Trt)-Trp(Boc)-Lys(Dde)-His(Trt)-Asp(OtBu)-Trp(Boc)-Lys(Boc)-Pro-Gly-R; where R = resin) were prepared manually by solid phase peptide synthesis according to Fmoc/tBu chemistry on a Rink-Amide MBHA resin (0.38 mmol/g coupling capacity). The following Fmoc-protected amino acid derivatives were used: Fmoc-Gly-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, Fmoc-Lys(Mtt)-OH, Fmoc-Lys(Dde)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-His(Trt)-OH and Fmoc-Ser(tBu)-OH. Pyroglutamic acid (Glp or

Reference： [1]European Journal of Medicinal Chemistry,2012,vol. 52,p. 173 - 183

37
H-Gly-2-chlorotrityl resin [ No CAS ]
[ 3057-74-7 ]
[ 86123-10-6 ]
[ 150629-67-7 ]
Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
[ 1414847-21-4 ]

Yield	Reaction Conditions	Operation in experiment
Ca. 100%		The linear protected peptide H-D(OBut)-f-K(Dde)-R(Pbf)-G-O-resin was first assembled from H-Gly-2-chlorotrityl resin using conventional Fmoc chemistry. The coupling reactions were carried out by adding a pre-activated solution of N-alpha-Fmoc-protected amino acid (3 equiv), 1-hydroxybenzotriazole (HOBt, 3 equiv), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU, 3 equiv), and DIEA (6 equiv) in anhydrous DMF to the resin (1 equiv) and swirled for 2 h. The progress of the coupling was monitored by the Kaiser test. The Fmoc protecting group was removed with a solution of 20% piperidine in DMF for 10 min (2X). The resin was washed with methanol (1 min, 2X) and DMF (1 min, 3X) and used in the subsequent reactions. The linear protected peptide H-D(OBut)-f-K(Dde)-R(Pbf)-G-O-resin was cleaved with with 1% TFA in DCM (8 times). The filtrate was added into a solution of methanol (80 mL) and pyridine (20 mL). After the resulting mixture was concentrated, 100 mL of water was added to precipitate the product i.e. H-D(OBut)-f-K(Dde)-R(Pbf)-G-OH in a nearly quantitative yield.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 5405 - 5409

38
[ 159751-47-0 ]
[ 19337-97-4 ]
[ 146982-27-6 ]
N-(tert-butoxycarbonyl)-S-trityl-D-cysteine [ No CAS ]
[ 150629-67-7 ]
[ 162648-54-6 ]
[ 181517-99-7 ]
[ 613245-91-3 ]
[ 1426413-17-3 ]

Yield	Reaction Conditions	Operation in experiment
		Rink amide MBHA resin (0.5 g, 0.325 mmol, loading 0.65 mmol/g) was swollen in DMF for 3 hours before Fmoc-deprotection with 20% 4-methylpiperidine in DMF twice (5 and 15 minutes, respectively). The beads were then washed with DMF (3x10 mL), methanol (MeOH) (3x10 mL) and DMF (3x10 mL), respectively. Fmoc-Lys(Dde)-OH ( 0.519 g, 0.975 mmol) was dissolved in a solution of N-Hydroxybenzotriazole (HOBt) (0.149 g, 0.975 mmol) and N,N'-diisopropylcarbidiimide (DIC) (152 uL, 0.975 mmol) in DMF (8 mL), which was then added to the suspension of the beads. The coupling was carried out at room temperature overnight. After filtration, the beads were washed with DMF (3x10 mL), MeOH (3x10 mL), and DMF (3x10 mL), respectively. After removal of Fmoc, the beads were then subjected to two cycles of coupling with and deprotection of the Fmoc-linker in the same manner as described above. The beads were washed with DMF (3x10 mL), MeOH (3x10 mL) and DMF (3x10 mL). Fmoc-Ach-OH (0.365 g, 0.975 mmol) was dissolved in a solution of HOBt (0.149 g, 0.975 mmol) and DIC (152 uL, 0.975 mmol) in DMF, and was then added into the beads. The coupling was carried out at room temperature for 2 hours. After filtration, the beads were washed with DMF (3x10 mL), MeOH (3x10 mL), and DMF (3x10 mL), respectively. The Fmoc deprotection group was removed with 20% 4-methylpiperidine twice ((5 and 15 minutes, respectively)). After washing with DMF, MeOH, and DMF respectively, the beads were then subjected to additional coupling and deprotection cycles stepwise with Fmoc-Aad(OtBu)-OH and Fmoc-Lys(Alloc)-OH in the same manner as described above. After removal of Fmoc, a solution of UPA (0.923 g, 3.25 mmol), HOBt (0.498 g, 3.25 mmol) and DIC (509 mu,, 3.25 mmol) in DMF was added to the beads. The reaction was conducted at room temperature until Kaiser test negative (3 hours to overnight). The beads were washed with DMF (3x10 mL), methanol (3x 10 mL), and DMF (3x10 mL). The Alloc protecting group was removed by treating with Pd(PPh3)4 (0.2 eq.) and PhSiH3 (20eq.) in dichloromethane (DCM), twice (30 minutes, each). A solution of trans-3-(3-pyridyl)acrylic acid (0.37 g, 1.3 mmol), HOBt (0.176 g, 1.3 mmol) and DIC (201 mu, 1 .3 mmol) in DMF (8 mL) was added to the beads. The coupling proceeded at room temperature 4 hours to overnight until Kaiser test was negative. The beads were washed with DMF (5 x 5 mL), MeOH (3 x 5 mL) and DCM (3 x 5 mL). The Dde protecting group was removed with 2% NH2NH2 in DMF twice (5 and 10 minutes, respectively). The beads were washed with DMF, MeOH and DMF, followed by coupling of (4 eq. to resin, 220 mg, 1.3 mmol) Boc-D-Cys(Trt)-OH, HOBt (0.176 g, 1.3 mmol) and DIC (201 iL, 1.3 mmol) in DMF (8 mL). The coupling reaction was conducted at room temperature until Kaiser test negative (4 hours to overnight). The beads were thoroughly washed with DMF, MeOH and DCM, respectively, and then dried under vacuum for 1 hour before adding a cleavage mixture of 82.5% trifluoroacetic acid (TFA): 5% thioanisole: 5% phenol:5% water: 2.5% triisopropylsilane (TIS) (v/v). The cleavage reaction was conducted at room temperature over 2-3 hours. The off-white crude product was precipitated out and washed with cold ether. The purity was determined by analytical reverse phase high performance liquid chromatography (RP-HPLC) and the crude product was used in the next step without further purification. LLP2A-Lys(D-Cys) MALDI-TOF MS [M+H]+: 1502.88 (calculated: 1502.77); [M+Na]+: 1524.88 (calculated: 1524.75).

Reference： [1]Patent: WO2013/32527,2013,A1 .Location in patent: Paragraph 0192-0196

39
Fmoc-Rink-(4-methylbenzhydrylamine) resin [ No CAS ]
[ 35661-60-0 ]
[ 84624-27-1 ]
[ 35661-40-6 ]
[ 144120-54-7 ]
[ 150629-67-7 ]
Fmoc-Lys(Boc)-Lys(Boc)-Leu-Lys(Boc)-Lys(ivDde)-Phe-Lys(Boc)-Lys(Boc)-Leu-Glu(Rink-MBHA)-OAll [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2013,vol. 11,p. 3365 - 3374

40
[ 94142-97-9 ]
α-Fmoc-L-lysine hydrochloride [ No CAS ]
[ 150629-67-7 ]

Yield	Reaction Conditions	Operation in experiment
70%		Synthesis of Fmoc-Lys(Dde)-OH Fmoc-Lys-OH.HCl (10.2 g, 25.2 mmol) was dissolved in H2O, N,N-diisopropylethylamine (DIPEA 1.1 eq, 4.8 mL, 27.7 mmol) was added and the resulting solid was collected by filtration and dried in a vacuum oven overnight. To a stirred suspension of Fmoc-Lys-OH (7.9 g, 21.4 mmol, 1 eq) in ethanol (250 mL), <strong>[94142-97-9]Dde-OH</strong> (7.8 g, 42.8 mmol, 2 eq) and TFA (160 muL, 2.14 mmol, 0.1 eq) were added. The reaction was refluxed for 60 hours. After the reaction mixture was cooled to room temperature, the solvent was removed in vacuo and the residue was dissolved in EtOAc (300 mL), washed with 1M KHSO4 (2200 mL) and 1M HCl (2200 mL). The organic phase was dried over MgSO4, filtered, and evaporated in vacuo. Fmoc-Lys(Dde)-OH was isolated by flash column chromatography (elute with 10% acetic acid/ethyl acetate) and crystallised from ethyl acetate/hexane as an off white solid (7.5 g, 70%).

Reference： [1]Patent: US2014/134110,2014,A1 .Location in patent: Paragraph 0155; 0157

41
[ 68858-20-8 ]
Ac-PFPQPELPY-NH<SUB>2</SUB> [ No CAS ]
[ 71989-14-5 ]
[ 71989-18-9 ]
[ 108-24-7 ]
[ 71989-23-6 ]
[ 71989-35-0 ]
[ 35661-60-0 ]
[ 71989-16-7 ]
[ 91000-69-0 ]
[ 135248-89-4 ]
[ 111061-56-4 ]
[ 150629-67-7 ]
C₁₁₆H₁₈₁N₂₉O₃₃S [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 1390 - 1399

42
[ 68858-20-8 ]
Ac-PQPELPYPQ-NH<SUB>2</SUB> [ No CAS ]
[ 71989-14-5 ]
[ 71989-18-9 ]
[ 108-24-7 ]
[ 71989-23-6 ]
[ 71989-35-0 ]
[ 35661-60-0 ]
[ 71989-16-7 ]
[ 91000-69-0 ]
[ 135248-89-4 ]
[ 111061-56-4 ]
[ 150629-67-7 ]
C₁₁₂H₁₈₀N₃₀O₃₄S [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 1390 - 1399

43
[ 68858-20-8 ]
Ac-PYPQPELPY-NH<SUB>2</SUB> [ No CAS ]
[ 71989-14-5 ]
[ 71989-18-9 ]
[ 108-24-7 ]
[ 71989-23-6 ]
[ 71989-35-0 ]
[ 35661-60-0 ]
[ 71989-16-7 ]
[ 91000-69-0 ]
[ 135248-89-4 ]
[ 111061-56-4 ]
[ 150629-67-7 ]
C₁₁₆H₁₈₁N₂₉O₃₄S [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 1390 - 1399

44
[ 2419-56-9 ]
C₄₃H₄₀ClN₂O₄Pol [ No CAS ]
[ 71989-31-6 ]
[ 71989-14-5 ]
[ 403-43-0 ]
[ 73724-45-5 ]
[ 150629-67-7 ]
cyclo(Ser-D-Pro-Lys(FBz)-Asp-Glu-Lys)*TFA [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2015,vol. 13,p. 1878 - 1896

45
[ 2419-56-9 ]
C₄₃H₃₉ClNO₅Pol [ No CAS ]
[ 71989-31-6 ]
[ 71989-14-5 ]
[ 403-43-0 ]
[ 73724-45-5 ]
[ 150629-67-7 ]
C₄₈H₇₄FN₇O₁₃ [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2015,vol. 13,p. 1878 - 1896

46
[ 2419-56-9 ]
C₄₃H₃₉ClNO₅Pol [ No CAS ]
[ 71989-31-6 ]
[ 71989-14-5 ]
[ 403-43-0 ]
[ 73724-45-5 ]
[ 150629-67-7 ]
C₃₆H₅₀FN₇O₁₃ [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2015,vol. 13,p. 1878 - 1896

47
[ 2419-56-9 ]
C₄₃H₄₀ClN₂O₄Pol [ No CAS ]
[ 71989-33-8 ]
[ 71989-14-5 ]
[ 403-43-0 ]
[ 150629-67-7 ]
cyclo(Ser-Lys(FBz)-Asp-Glu-Lys)*TFA [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2015,vol. 13,p. 1878 - 1896

48
[ 29022-11-5 ]
[ 35661-60-0 ]
Fmoc-L-Arg(Pbf)-OH [ No CAS ]
[ 35661-39-3 ]
[ 71989-31-6 ]
[ 35661-40-6 ]
[ 71989-33-8 ]
[ 71989-14-5 ]
[ 71989-18-9 ]
[ 71989-23-6 ]
[ 71989-38-3 ]
[ 71989-35-0 ]
[ 132388-59-1 ]
[ 109425-51-6 ]
[ 150629-67-7 ]
[ 59-05-2 ]
YPS(N^ε-(GFLG-MTX)K)PDFPGEDAPAEDLARYYSALRHYINLITRPRY [ No CAS ]

Reference： [1]ChemMedChem,2015,vol. 10,p. 804 - 814

49
[ 29022-11-5 ]
[ 35661-60-0 ]
Fmoc-L-Arg(Pbf)-OH [ No CAS ]
[ 35661-39-3 ]
[ 71989-31-6 ]
[ 35661-40-6 ]
[ 71989-33-8 ]
[ 71989-14-5 ]
[ 71989-18-9 ]
[ 71989-23-6 ]
[ 71989-38-3 ]
[ 71989-35-0 ]
[ 132388-59-1 ]
[ 109425-51-6 ]
[ 150629-67-7 ]
[ 59-05-2 ]
YPS-(N^ε-(MTX)K)-PDFPGEDAPAEDLARYYSALRHYINLITRPRY [ No CAS ]

Reference： [1]ChemMedChem,2015,vol. 10,p. 804 - 814

50
[ 68181-17-9 ]
[ 29022-11-5 ]
[ 35661-60-0 ]
Fmoc-L-Arg(Pbf)-OH [ No CAS ]
[ 35661-39-3 ]
[ 71989-31-6 ]
[ 35661-40-6 ]
[ 71989-33-8 ]
[ 71989-14-5 ]
[ 71989-18-9 ]
[ 71989-23-6 ]
[ 71989-38-3 ]
[ 71989-35-0 ]
[ 132388-59-1 ]
[ 109425-51-6 ]
[ 150629-67-7 ]
[ 60-23-1 ]
[ 59-05-2 ]
YPS-[N^ε-(3-[(2-(MTX)ethyl)disulfanyl]propanoyl)K]PDFPGEDAPAEDLARYYSALRHYINLITRPRY [ No CAS ]

Reference： [1]ChemMedChem,2015,vol. 10,p. 804 - 814

51
[ 68181-17-9 ]
[ 29022-11-5 ]
[ 35661-60-0 ]
Fmoc-L-Arg(Pbf)-OH [ No CAS ]
[ 35661-39-3 ]
[ 71989-31-6 ]
[ 35661-40-6 ]
[ 71989-33-8 ]
[ 71989-14-5 ]
[ 71989-18-9 ]
[ 71989-23-6 ]
[ 71989-38-3 ]
[ 71989-35-0 ]
[ 132388-59-1 ]
[ 109425-51-6 ]
[ 150629-67-7 ]
[ 59-05-2 ]
[ 60-24-2 ]
YPS-[N^ε-(3-[2-(MTX)oxoethyl]disulfanyl}propanoyl)K]PDFPGEDAPAEDLARYYSALRHYINLITRPRY [ No CAS ]

Reference： [1]ChemMedChem,2015,vol. 10,p. 804 - 814

52
[ 79-14-1 ]
[ 29022-11-5 ]
[ 35661-60-0 ]
Fmoc-L-Arg(Pbf)-OH [ No CAS ]
[ 35661-39-3 ]
[ 71989-31-6 ]
[ 35661-40-6 ]
[ 71989-33-8 ]
[ 71989-14-5 ]
[ 71989-18-9 ]
[ 71989-23-6 ]
[ 71989-38-3 ]
[ 71989-35-0 ]
[ 132388-59-1 ]
[ 109425-51-6 ]
[ 150629-67-7 ]
[ 59-05-2 ]
YPS(N^ε-(O-(MTX)glycolyl)K)PDFPGEDAPAEDLARYYSALRHYINLITRPRY [ No CAS ]

Reference： [1]ChemMedChem,2015,vol. 10,p. 804 - 814

53
[ 29022-11-5 ]
[ 35661-40-6 ]
[ 134978-97-5 ]
[ 144120-53-6 ]
[ 57-11-4 ]
[ 150629-67-7 ]
Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
C₇₅H₁₃₀N₁₄O₂₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		The interaction of cyclic and linear RGD peptide ligands withalpha v beta 3 integrin receptor were studied using MolecularOperating Environment software (Details in SupplementaryMaterial). The peptide amphiphiles were synthesized by followingstandard solid phase peptide synthesis procedure. Thecyclic RGD amphiphile (C18-ADA5-cRGDfK) was synthesizedentirely on solid support. Several protocols for synthesisof the cyclic RGD (cRGDfV or cRGDfK) peptide have beenreported and modified for improved yields. The cyclic RGDpeptide was built on solid phase using the protocol reported byMcCusker et al. with some modifications [20]. The O-allylprotected aspartic acid, Fmoc-Asp-OAll (2.5 equivalents)was loaded on the 2-chloro trityl chloride resin in the presenceof 10 equivalents of N,N-diisopropylethylamine (DIPEA) for5 h. After washing the resin with DMF (3 times) and DCM (3times), the amino group was deprotected by treatment with20% piperidine in DMF for 30 min and the wash steps wererepeated. The Fmoc-Gly-OH was added in the presence of 2equivalents of HOBT (hydroxybenzotriazole), 2 equivalentsof HATU (2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) and 4 equivalents of DIPEA.The subsequent amino acids in the order of Fmoc-Arg(Pbf)OH, Fmoc-Lys-Dde and Fmoc-Phe-OH were conjugatedusing the same deprotection and conjugation protocol.Each conjugation step was performed for 2 h. Allyldeprotection was performed using chloroform and Nmethylmorpholinein the presence of palladium catalyst in aN2 atmosphere for 4 hours followed by amino groupdeprotection using 20% piperidine in DMF. Cyclization wascarried out overnight in the presence of PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate),DIPEA and DMF. This step was repeated for an additional6 h. Further, the 1-(4,4-Dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde) group was specifically cleaved by using 2% hydrazinehydrate in DMF. For synthesis of the amphiphiles, the 8-amino-3,6 dioxaoctanoic acid (ADA) groups were conjugatedto the lysine side chain using the same protocol as for theamino acids. Finally, stearic acid was conjugated in the presenceof PyBOP (4 equivalents) and DIPEA (8 equivalents).The amphiphile was cleaved from the resin by treating withTFA:TIS: H2O (95:2.5:2.5) for 3 hrs. After removal of TFA,the amphiphile was precipitated using ether:hexane (50:50)mixture. The amphiphile was then separated by centrifugationand freeze dried before further analysis. The synthesis oflinear RGD amphiphile (C18-ADA5-RGD) was carried outusing the same protocol as previously reported [18] (SpecificDetails are provided in Supplementary Materials). All amphiphilessynthesized were characterized for molecular weightand purity using Matrix Assisted Laser Desorption/Ionization- Time of Flight (MALDI-TOF) and reversed phaseHPLC (RP-HPLC) respectively.

Reference： [1]Pharmaceutical Research,2015,vol. 32,p. 3087 - 3101

54
2-chlorotrityl chloride polystyrene resin [ No CAS ]
[ 29022-11-5 ]
[ 86123-10-6 ]
[ 144120-53-6 ]
[ 150629-67-7 ]
Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
C₆₈H₈₄N₉O₁₅PolS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: The synthesis of all the cyclic peptides was done by following a previously described procedure.41 Briefly, 2-chlorotrityl chloride resin (1.12 mmol/g) was placed in a reactor and suspended in DCM under nitrogen atmosphere. Then a mixture of Fmoc-Asp-OAll (2 equiv) and DIPA (8 equiv) in DCM was added. The resin loading reaction was allowed to proceed for 4-5 h and then the resin was capped by an addition of a few drops of methanol. The Fmoc protecting group was removed with 20% piperidine/DMF(3 x 7 min) and then a linear SPPS was applied using standard Fmoc procedures introducing the AA in the following order: Fmoc-Gly-OH, Fmoc-Asp(Pbf)-OH, Fmoc-Lys(Dde)-OH for 1a or Fmoc-Ser-OH for 1b, Fmoc-D-Phe-OH. All the couplings were performed in DMF with 3-fold excess of AA and 6 equiv of DIPA, using HATU for activation. Each coupling cycle was conducted for 2-3 h. The completion of each coupling reaction and Fmoc removal were monitored by the ninhydrin test. After the coupling of the last AA, the allyl ester was removed from the C-terminus with a mixture of Pd(PPh3)4 (0.3 equiv) and DMBA (6 equiv) in DCM for 4 h. The resin was thoroughly washed with a DMF solution of 0.5 M diethyldithiocarbamic acid sodium salt. Finally, the Fmoc protecting group was removed from the N-terminus and the cyclization reaction was performed by adding a mixture of PyBop (10 equiv), HOBT (10 equiv), DIPA (20 equiv) in NMP and shaking for 5 h.

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 294 - 303

55
[ 29022-11-5 ]
[ 35661-60-0 ]
[ 35661-39-3 ]
8-[(1-(carboxymethyl)-3-methylimidazolio-2-yl)methylthio]-8’-ethylthio-3,3’-commo-bis(undecahydro-1,2-dicarba-3-cobalta-closo-undecaborate) (1-) [ No CAS ]
[ 71989-31-6 ]
[ 35661-40-6 ]
[ 71989-33-8 ]
[ 71989-14-5 ]
[ 71989-18-9 ]
[ 71989-23-6 ]
[ 71989-35-0 ]
[ 47375-34-8 ]
[ 71989-16-7 ]
[ 71989-20-3 ]
[ 150629-67-7 ]
N_α-(Fluoren-9-ylmethoxycarbonyl)-N_(im)-(tert-butyloxycarbonyl)-L-histidine [ No CAS ]
[ 143824-77-5 ]
YPSXPDFPGEDAPAEDLARYYSALRHYINLITRPRY-NH2; X = Nε-[2-(8’-ethylthio-3,3’-commo-bis(undecahydro-1,2-dicarba-3-cobalta-closo-undecaboran-8-yl(1-))thiomethyl)-3-methylimidazolio-1]acetyl-L-lysyl [ No CAS ]

Reference： [1]ChemBioChem,2016,vol. 17,p. 308 - 317

56
[ 29022-11-5 ]
[ 35661-60-0 ]
[ 35661-39-3 ]
8-[(1-(carboxymethyl)-3-methylimidazolio-2-yl)methylthio]-8’-(1,2:3,4-di-O-isopropylidene-6-deoxy-α-D-galacto-pyranos-6-ylthio)-3,3’-commo-bis(undecahydro-1,2-dicarba-3-cobalta-closo-undecaborate) (1-) [ No CAS ]
[ 71989-31-6 ]
[ 35661-40-6 ]
[ 71989-33-8 ]
[ 71989-14-5 ]
[ 71989-18-9 ]
[ 71989-23-6 ]
[ 71989-35-0 ]
[ 47375-34-8 ]
[ 71989-16-7 ]
[ 71989-20-3 ]
[ 150629-67-7 ]
N_α-(Fluoren-9-ylmethoxycarbonyl)-N_(im)-(tert-butyloxycarbonyl)-L-histidine [ No CAS ]
[ 143824-77-5 ]
YPSXPDFPGEDAPAEDLARYYSALRHYINLITRPRY-NH2; X = Nε-[2-(8’-(1,2:3,4-di-O-isopropylidene-6-deoxy-α-D-galacto-pyranos-6-ylthio)-3,3’-commo-bis(undecahydro-1,2-dicarba-3-cobalta-closo-undecaboran-8-yl(1-))thiomethyl)-3-methylimidazolio-1]acetyl-L-lysyl [ No CAS ]

Reference： [1]ChemBioChem,2016,vol. 17,p. 308 - 317

57
[ 29022-11-5 ]
[ 35661-60-0 ]
[ 35661-39-3 ]
[ 71989-31-6 ]
[ 35661-40-6 ]
[ 71989-33-8 ]
[ 71989-14-5 ]
[ 71989-18-9 ]
[ 71989-23-6 ]
[ 71989-35-0 ]
[ 47375-34-8 ]
[ 71989-16-7 ]
[ 71989-20-3 ]
[ 150629-67-7 ]
N_α-(Fluoren-9-ylmethoxycarbonyl)-N_(im)-(tert-butyloxycarbonyl)-L-histidine [ No CAS ]
[ 143824-77-5 ]
YPSKPDFPGEDAPAEDLARYYSALRHYINLITRPRY-NH₂ [ No CAS ]

Reference： [1]ChemBioChem,2016,vol. 17,p. 308 - 317

58
[ 29022-11-5 ]
[ 35661-60-0 ]
[ 35661-39-3 ]
[ 71989-31-6 ]
[ 71989-33-8 ]
[ 71989-14-5 ]
[ 71989-18-9 ]
[ 71989-23-6 ]
[ 71989-35-0 ]
[ 47375-34-8 ]
[ 71989-16-7 ]
[ 71989-20-3 ]
[ 150629-67-7 ]
N_α-(Fluoren-9-ylmethoxycarbonyl)-N_(im)-(tert-butyloxycarbonyl)-L-histidine [ No CAS ]
[ 143824-77-5 ]
YPSKPDNPGEDAPAEDLARYYSALRHYINLITRQRY-NH₂ [ No CAS ]

Reference： [1]ChemBioChem,2016,vol. 17,p. 308 - 317

59
[ 29022-11-5 ]
[ 35661-60-0 ]
(2S,2S′)-6-[1′-(pyrid-2-ylmethyl)-[2,2′-bipyrrolidin]-1-ylmethyl]nicotinic acid [ No CAS ]
[ 35661-40-6 ]
[ 71989-23-6 ]
[ 71989-26-9 ]
[ 3301-79-9 ]
[ 150629-67-7 ]
BP₃₅₀ [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2016,vol. 14,p. 4061 - 4070

60
[ 35661-60-0 ]
[ 35737-10-1 ]
(2S,2S′)-6-[1′-(pyrid-2-ylmethyl)-[2,2′-bipyrrolidin]-1-ylmethyl]nicotinic acid [ No CAS ]
[ 35661-40-6 ]
[ 71989-23-6 ]
[ 71989-26-9 ]
[ 3301-79-9 ]
[ 150629-67-7 ]
BP₃₄₉ [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2016,vol. 14,p. 4061 - 4070

61
[ 867062-95-1 ]
[ 29022-11-5 ]
[ 68858-20-8 ]
[ 35661-60-0 ]
[ 882847-32-7 ]
[ 16937-99-8 ]
[ 71989-31-6 ]
[ 92122-45-7 ]
[ 71989-26-9 ]
[ 35661-38-2 ]
[ 71989-31-6 ]
[ 150629-67-7 ]
Fmoc-D-Asp(PG)-OH [ No CAS ]
Fmoc-D-Arg(PG)-OH [ No CAS ]
Fmoc-D-His(PG)-OH [ No CAS ]
Fmoc-D-Trp(PG)-OH [ No CAS ]
Fmoc-D-Ser(PG)-OH [ No CAS ]
Fmoc-Ser(PG)-OH [ No CAS ]
C₁₁₉H₁₉₆N₃₄O₃₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: The Rink amide resin (1 equiv) was washed with DCM and DMF in the reaction container, and deprotected twice with 20% piperidine in DMF for 10 min each time. The Fmoc-Lys(dde)-OH (5 equiv), HOBt (5 equiv) and DIC (5 equiv) were coupled with resinin 2 mL DMF for 4 h. For peptides 21-24, one PEG linker was coupled to the N-alpha position of the first lysine using Fmoc-NH-(PEG)3-CH2CH2-COOH (MW = 443.50). The DV3 sequence from the Cterminalto the N-terminal was coupled onto the PEG linker with the last D-amino acid protected by Boc group. After the coupling of the DV3 sequence was complete, the dde group of the first coupled lysine was deprotected with 2% hydrazine in DMF. Then, the other PEG linker was coupled onto the epsilon-amino group of the first coupled lysine and the sequence of CXCL121-8 from the C-terminal to N-terminal was coupled onto the PEG linker through Fmoc-L-aa (5 equiv), HOBt (5 equiv) and DIC (5 equiv) in 2 mL DMF. For peptide 20, the DV3 and CXCL121-8 sequences was directly coupled to the alpha and epsilon amino groups of the first lysine, respectively. The Fmoc groups of last amino acids acid was deprotected before washing with DMF and DCM, then the peptide was cleaved from the resin with a cocktail cleavage solution (TFA/H2O/Thiophenol = 90:5:5) for 2 h. The crude peptide was precipitated and washed twice with cold ethyl ether.

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 5393 - 5399

62
[ 867062-95-1 ]
[ 29022-11-5 ]
[ 68858-20-8 ]
[ 35661-60-0 ]
[ 16937-99-8 ]
[ 71989-31-6 ]
[ 92122-45-7 ]
[ 71989-26-9 ]
[ 35661-38-2 ]
[ 71989-31-6 ]
[ 150629-67-7 ]
Fmoc-D-Asp(PG)-OH [ No CAS ]
Fmoc-D-Arg(PG)-OH [ No CAS ]
Fmoc-D-His(PG)-OH [ No CAS ]
Fmoc-D-Trp(PG)-OH [ No CAS ]
Fmoc-D-Ser(PG)-OH [ No CAS ]
Fmoc-Arg(PG)-OH [ No CAS ]
Fmoc-Tyr(PG)-OH [ No CAS ]
Fmoc-Ser(PG)-OH [ No CAS ]
C₁₁₉H₁₉₆N₃₄O₃₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: The Rink amide resin (1 equiv) was washed with DCM and DMF in the reaction container, and deprotected twice with 20% piperidine in DMF for 10 min each time. The Fmoc-Lys(dde)-OH (5 equiv), HOBt (5 equiv) and DIC (5 equiv) were coupled with resinin 2 mL DMF for 4 h. For peptides 21-24, one PEG linker was coupled to the N-alpha position of the first lysine using Fmoc-NH-(PEG)3-CH2CH2-COOH (MW = 443.50). The DV3 sequence from the Cterminalto the N-terminal was coupled onto the PEG linker with the last D-amino acid protected by Boc group. After the coupling of the DV3 sequence was complete, the dde group of the first coupled lysine was deprotected with 2% hydrazine in DMF. Then, the other PEG linker was coupled onto the epsilon-amino group of the first coupled lysine and the sequence of CXCL121-8 from the C-terminal to N-terminal was coupled onto the PEG linker through Fmoc-L-aa (5 equiv), HOBt (5 equiv) and DIC (5 equiv) in 2 mL DMF. For peptide 20, the DV3 and CXCL121-8 sequences was directly coupled to the alpha and epsilon amino groups of the first lysine, respectively. The Fmoc groups of last amino acids acid was deprotected before washing with DMF and DCM, then the peptide was cleaved from the resin with a cocktail cleavage solution (TFA/H2O/Thiophenol = 90:5:5) for 2 h. The crude peptide was precipitated and washed twice with cold ethyl ether.

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 5393 - 5399

63
[ 867062-95-1 ]
[ 29022-11-5 ]
[ 68858-20-8 ]
[ 35661-60-0 ]
[ 16937-99-8 ]
[ 71989-31-6 ]
[ 92122-45-7 ]
[ 71989-26-9 ]
[ 35661-38-2 ]
[ 71989-31-6 ]
[ 150629-67-7 ]
Fmoc-D-Asp(PG)-OH [ No CAS ]
Fmoc-D-Arg(PG)-OH [ No CAS ]
Fmoc-D-His(PG)-OH [ No CAS ]
Fmoc-D-Trp(PG)-OH [ No CAS ]
Fmoc-D-Ser(PG)-OH [ No CAS ]
Fmoc-Ser(PG)-OH [ No CAS ]
C₁₀₁H₁₇₀N₂₈O₂₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: The Rink amide resin (1 equiv) was washed with DCM and DMF in the reaction container, and deprotected twice with 20% piperidine in DMF for 10 min each time. The Fmoc-Lys(dde)-OH (5 equiv), HOBt (5 equiv) and DIC (5 equiv) were coupled with resinin 2 mL DMF for 4 h. For peptides 21-24, one PEG linker was coupled to the N-alpha position of the first lysine using Fmoc-NH-(PEG)3-CH2CH2-COOH (MW = 443.50). The DV3 sequence from the Cterminalto the N-terminal was coupled onto the PEG linker with the last D-amino acid protected by Boc group. After the coupling of the DV3 sequence was complete, the dde group of the first coupled lysine was deprotected with 2% hydrazine in DMF. Then, the other PEG linker was coupled onto the epsilon-amino group of the first coupled lysine and the sequence of CXCL121-8 from the C-terminal to N-terminal was coupled onto the PEG linker through Fmoc-L-aa (5 equiv), HOBt (5 equiv) and DIC (5 equiv) in 2 mL DMF. For peptide 20, the DV3 and CXCL121-8 sequences was directly coupled to the alpha and epsilon amino groups of the first lysine, respectively. The Fmoc groups of last amino acids acid was deprotected before washing with DMF and DCM, then the peptide was cleaved from the resin with a cocktail cleavage solution (TFA/H2O/Thiophenol = 90:5:5) for 2 h. The crude peptide was precipitated and washed twice with cold ethyl ether.

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 5393 - 5399

64
[ 159610-89-6 ]
C₃₃H₃₁N₂O₆Pol [ No CAS ]
[ 29022-11-5 ]
[ 35737-10-1 ]
[ 71989-31-6 ]
[ 35661-40-6 ]
[ 92122-45-7 ]
[ 71989-26-9 ]
[ 77284-32-3 ]
[ 150629-67-7 ]
[ 166108-71-0 ]
C₁₄₈H₂₂₄N₂₅O₃₉Pol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Fmoc deprotection: In general, to the resin pre-swollen in DCM was added 20% piperidine in DMF and stirred at rt (2x10 min). The solution was drained and the resin washed with DMF (3x10 mL), DCM (3x10 mL) and MeOH (3x10 mL). In the cases were Fmoc 38 SUBSTITUTE SHEET RULE 26 deprotection was done in Cy5 containing peptides, a solution of 2% DBU in DMF (2 x 10 min, rt) was used instead. Aminoacid coupling: A solution of the appropriate D- or L-amino acid (3.0 eq per amine) and Oxyma (3.0 eq) in DMF (0.1 M) was stirred for 10 min. DIC (3.0 eq) was added and stirred for 1 min. The pre-activated mixture was then added to the resin pre-swollen in DCM and the reaction heated at 50C for 30 min. The solution was drained and washed with DMF (3x10 ml_), DCM (3x10 ml_) and MeOH (3x10 ml_). The completion of the coupling and deprotection reactions was monitored by Kaiser test or Chloranil test when secondary amines are involved. The side chain protecting group used was Boc for arginine, tryptophan and lysine. Fmoc-Lys(Dde)-OH was used as orthogonal reagent to introduce the dyes. Coupling of other carboxylic acids: Coupling of {2-[2-(Fmoc-amino)ethoxy]ethoxy}acetic acid (PEG), 5-Carboxyfluorescein (FAM), Fmoc-Lys(N3)-OH and MethylRed-Lys-(4- pentynoyl)-OH was done following the same procedure described for Aminoacid coupling.

Reference： [1]Patent: WO2016/151297,2016,A1 .Location in patent: Page/Page column 38-39; 47

65
[ 1257305-93-3 ]
C₃₃H₃₁N₂O₆Pol [ No CAS ]
[ 92122-45-7 ]
[ 150629-67-7 ]
[ 166108-71-0 ]
C₈₃H₁₁₅N₁₀O₁₉Pol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Fmoc deprotection: In general, to the resin pre-swollen in DCM was added 20% piperidine in DMF and stirred at rt (2x10 min). The solution was drained and the resin washed with DMF (3x10 mL), DCM (3x10 mL) and MeOH (3x10 mL). In the cases were Fmoc 38 SUBSTITUTE SHEET RULE 26 deprotection was done in Cy5 containing peptides, a solution of 2% DBU in DMF (2 x 10 min, rt) was used instead. Aminoacid coupling: A solution of the appropriate D- or L-amino acid (3.0 eq per amine) and Oxyma (3.0 eq) in DMF (0.1 M) was stirred for 10 min. DIC (3.0 eq) was added and stirred for 1 min. The pre-activated mixture was then added to the resin pre-swollen in DCM and the reaction heated at 50C for 30 min. The solution was drained and washed with DMF (3x10 ml_), DCM (3x10 ml_) and MeOH (3x10 ml_). The completion of the coupling and deprotection reactions was monitored by Kaiser test or Chloranil test when secondary amines are involved. The side chain protecting group used was Boc for arginine, tryptophan and lysine. Fmoc-Lys(Dde)-OH was used as orthogonal reagent to introduce the dyes. Coupling of other carboxylic acids: Coupling of {2-[2-(Fmoc-amino)ethoxy]ethoxy}acetic acid (PEG), 5-Carboxyfluorescein (FAM), Fmoc-Lys(N3)-OH and MethylRed-Lys-(4- pentynoyl)-OH was done following the same procedure described for Aminoacid coupling.

Reference： [1]Patent: WO2016/151297,2016,A1 .Location in patent: Page/Page column 38-39; 49

66
[ 94142-97-9 ]
[ 71989-26-9 ]
[ 150629-67-7 ]

Yield	Reaction Conditions	Operation in experiment
41%		Fmoc-Lys(Boc)-OH (5.66 g, 12.1 mmol) was dissolved in 4 M HCl/dioxane (120 mL), and stirred at room temperature for 2 h to remove the side-chain Boc group. The solvent was removed under reduced pressure. The resulting residue was dissolved in EtOH(60 mL), and then <strong>[94142-97-9]2-acetyldimedone</strong> (3.36 g, 18.4 mmol) and DIPEA (6.2 mL, 35.6 mmol) were added. The reaction mixture was refluxed for 17 h. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was dissolved in AcOEt (300 mL) and washed with 1 M HCl (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography(0.5%-3% MeOH/DCM) to give Fmoc-Lys(Dde)-OH (2.64 g,41%) as a white solid. Spectroscopic data are identical to the published data.34 1H NMR (500 MHz, CDCl3): d 13.31 (brs, 1H), 7.75(d, J = 7.8 Hz, 2H), 7.59 (t, J = 7.8 Hz, 2H), 7.38 (t, J = 7.8 Hz, 2H),7.31-7.28 (m, 2H), 5.73 (d, J = 8.0 Hz, 1H), 4.48-4.45 (m, 1H),4.37 (d, J = 7.1 Hz, 2H), 4.20 (t, J = 7.1 Hz, 1H), 3.43-3.40 (m, 2H),2.55 (s, 3H), 2.36 (s, 4H), 2.00-1.50 (m, 6H), 1.01 (s, 6H). HR-MS(m/z, FAB): calcd for C31H37N2O6 ([M + H]+), 533.2652; found,533.2643.

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 1227 - 1234

67
[ 150629-67-7 ]
[ 135112-27-5 ]
[ 292150-20-0 ]
C₂₅H₄₀N₅O₇Pol [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 7745 - 7763

68
[ 159610-89-6 ]
Fmoc-Gly-Wang resin [ No CAS ]
[ 209330-56-3 ]
[ 29022-11-5 ]
[ 35661-39-3 ]
[ 71989-31-6 ]
[ 150629-67-7 ]
C₈₁H₁₃₇N₂₁O₂₁ [ No CAS ]

Reference： [1]Chemistry - A European Journal,2017,vol. 23,p. 16283 - 16296

69
[ 75932-02-4 ]
[ 150629-67-7 ]
C₂₂H₃₇N₄O₄Pol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Fmoc-Lys (Dde) -OH (Nalpha-Fmoc-Nepsilon-Dde-L-lysine, Nalpha-Fmoc-Nepsilon-Lysine) was added to a reaction vessel of 800 ml in 2-chloro trityl chloride resin (100-200 mesh, Novabiochem 20 g, (21.3 g, 2 eq.) And DIPEA (29.9 ml, 8 eq.) Were added to DCM (700 ml) at room temperature and added to a solution of 12timeReaction during. The reaction solution was removed by filtration, and the synthesized resin was washed sequentially with 500 ml each of DCM (dichlormethane) and MeOH, DCM, and DMF (dimethylformamide).And dried in vacuo to obtain 23 g of compound 1a (Fmoc-Lys (Dde) -O-2-chloro trityl resin) in 99% yield in solid form. Compound 1a and 700 ml of 20% piperidine in DMF were placed in an 800 ml reaction vessel, reacted at room temperature for 5 minutes, and filtered to remove the reaction solution. 700 ml of 20% piperidine in DMF was added one more time and reacted at room temperature for 5 minutes. The reaction solution was removed by filtration, and the synthesized resin was sequentially washed with 500 ml each of DCM, MeOH, DCM and DMF. Fmoc-Lys (Fmoc) -OH (47.3g, 4eq), HOBt (10.8g, 4eq) and DIC (12.4ml, 4eq) were dissolved in 600ml of DMF And reacted at room temperature for 4 hours. The reaction solution was removed by filtration, and the synthesized resin was sequentially washed with 500 ml each of DCM, MeOH, DCM and DMF. And dried in vacuo to obtain 25 g of compound 1b (Fmoc-Lys (Fmoc) -Lys (Dde) -O-2-chloro trityl resin) in a 98% yield in solid phase form. Compound 1b and 700 ml of 20% piperidine in DMF were placed in an 800 ml reaction vessel, reacted at room temperature for 5 minutes, and filtered to remove the reaction solution. 700 ml of 20% piperidine in DMF was added and reacted at room temperature for 5 minutes. The reaction solution was removed by filtration, and the synthesized resin was sequentially washed with 500 ml each of DCM, MeOH, DCM and DMF.
		In a reaction vessel of 800 ml, 2-chloro trityl chloride resin (100-200mesh, 20 g of Novabiochem, 1 equivalent) and Fmoc-Lys (Dde) -OH (Nalpha-Fmoc-Nepsilon-Dde-L-lysine, Nalpha-Fmoc-Nepsilon- [1- (4,4-dimethyl-2,6-dioxocyclohexylidene) ethyl] (21.3 g, 2 eq.) And DIPEA (29.9 ml, 8 eq.) Were placed in DCM (700 ml) and reacted at room temperature for 12 hours. The reaction solution was removed by filtration, and the synthesized resin was sequentially washed with 500 ml each of DCM (dichloromethane) and MeOH, DCM, and DMF (dimethylformamide). And dried in vacuo to obtain 23 g of compound 1a (Fmoc-Lys (Dde) -O-2-chloro trityl resin) in 99% yield in solid phase form. Examples 1-2. Synthesis of compound 1b. Compound 1a and 700 ml of 20% piperidine in DMF were placed in an 800 ml reaction vessel, reacted at room temperature for 5 minutes, and filtered to remove the reaction solution. 700 ml of 20% piperidine in DMF was added one more time and reacted at room temperature for 5 minutes. The reaction solution was removed by filtration, and the synthesized resin was sequentially washed with 500 ml each of DCM, MeOH, DCM and DMF. Fmoc-Lys (Fmoc) -OH (47.3g, 4eq), HOBt (10.8g, 4eq) and DIC (12.4ml, 4eq) were dissolved in 600ml of DMF And reacted at room temperature for 4 hours. The reaction solution was removed by filtration, and the synthesized resin was sequentially washed with 500 ml each of DCM, MeOH, DCM and DMF. And dried in vacuo to obtain 25 g of compound 1b (Fmoc-Lys (Fmoc) -Lys (Dde) -O-2-chloro trityl resin) in a 98% yield in solid phase form. Examples 1-3. Compound 1c Synthesis Compound 1b and 700 ml of 20% piperidine in DMF were placed in an 800 ml reaction vessel, reacted at room temperature for 5 minutes, and then filtered to remove the reaction solution. 700 ml of 20% piperidine in DMF was added and reacted at room temperature for 5 minutes. The reaction solution was removed by filtration, and the synthesized resin was sequentially washed with 500 ml each of DCM, MeOH, DCM and DMF. Tert-butyl bromoacetate (59.1 ml, 20 eq.) And DIPEA (69.7 ml, 20 eq.) Were dissolved in 600 ml of DMF and reacted at room temperature for 12 hours. The reaction solution was removed by filtration, and the synthesized resin was washed with 500 ml of DMF. Then, 600 ml of DMF was added to dissolve 1,8-bis (dimethylamino) napthalene (85.7 g, 20 equivalents), tert-butyl bromoacetate (59.1 ml, 20 equivalents) and DIPEA (69.7 ml, 20 equivalents) Respectively. The reaction solution was removed by filtration, and the synthesized resin was sequentially washed with 500 ml of DCM and MeOH, DCM and DMF, respectively. And vacuum drying was conducted to obtain 31 g of tert-butoxycarbonylmethyl 2-Lys (Dde) -O-2-chloro trityl resin in 95% yield in solid form.
		In an 800 ml reaction vessel Fmoc-Nepsilon-Dde-L-lysine, Nalpha-Fmoc-Nepsilon- [1- (4,4-dimethyl- 2,6-dioxocyclohexylidene) ethyl] -L-lysine (21.3 g, 2 eq.) And DIPEA (29.9 ml, 8 eq.) Were placed in DCM (700 ml) and reacted at room temperature for 12 hours. The reaction solution was removed by filtration, and the synthesized resin was sequentially washed with 500 ml each of DCM (dichlormethane) and MeOH, DCM, and DMF (dimethylformamide). And dried in vacuo to obtain 23 g of compound 1a (Fmoc-Lys (Dde) -O-2-chloro trityl resin) in 99% yield in solid form. Compound 1a and 700 ml of 20% piperidine in DMF were placed in an 800 ml reaction vessel, reacted at room temperature for 5 minutes, and then filtered to remove the reaction solution. 700 ml of 20% piperidine in DMF was added one more time and reacted at room temperature for 5 minutes. The reaction solution was removed by filtration, and the synthesized resin was sequentially washed with 500 ml each of DCM, MeOH, DCM and DMF. Fmoc-Lys (Fmoc) -OH (47.3g, 4eq), HOBt (10.8g, 4eq) and DIC (12.4ml, 4eq) were dissolved in 600ml of DMF And reacted at room temperature for 4 hours. The reaction solution was removed by filtration, and the synthesized resin was sequentially washed with 500 ml each of DCM, MeOH, DCM and DMF. And dried in vacuo to obtain 25 g of compound 1b (Fmoc-Lys (Fmoc) -Lys (Dde) -O-2-chloro trityl resin) in a 98% yield in solid phase form. Compound 1b and 700 ml of 20% piperidine in DMF were placed in an 800 ml reaction vessel, reacted at room temperature for 5 minutes, and filtered to remove the reaction solution. 700 ml of 20% piperidine in DMF was added and reacted at room temperature for 5 minutes. The reaction solution was removed by filtration, and the synthesized resin was sequentially washed with 500 ml each of DCM, MeOH, DCM and DMF. Tert-butyl bromoacetate (59.1 ml, 20 eq.) And DIPEA (69.7 ml, 20 eq.) Were dissolved in 600 ml of DMF and reacted at room temperature for 12 hours. The reaction solution was removed by filtration, and the synthesized resin was washed with 500 ml of DMF. Then, 600 ml of DMF was added to dissolve 1,8-bis (dimethylamino) napthalene (85.7 g, 20 equivalents), tert-butyl bromoacetate (59.1 ml, 20 equivalents) and DIPEA (69.7 ml, 20 equivalents) Respectively. The reaction solution was removed by filtration, and the synthesized resin was sequentially washed with 500 ml each of DCM, MeOH, DCM and DMF. And vacuum dried to obtain 31 g of tert-butoxycarbonylmethyl 2-Lys (Dde) -O-2-chloro trityl resin in 95% yield in solid form.

Reference： [1]Patent: KR101796479,2017,B1 .Location in patent: Paragraph 0087-0097
[2]Patent: KR2018/118033,2018,A .Location in patent: Paragraph 0075-0086
[3]Patent: KR2018/117869,2018,A .Location in patent: Paragraph 0092-0104

70
2-chlorotrityl chloride polystyrene resin [ No CAS ]
[ 29022-11-5 ]
[ 35661-40-6 ]
[ 150629-67-7 ]
[ 146982-24-3 ]
Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
C₅₆H₇₀N₉O₁₂Pol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		CTC resin (250mg, loading capacity 0.25mmol) was swelled with DCM/DMF (1/1)for an hour and then put into a reaction flask of peptide synthesizer. A mixture of1mmol Fmoc-Asp-OAll, 2.5 ml 0.4 M HATU, 2.5ml 0.8 M DIPEA, and 2.5ml DMFwas added to the reaction flask containing resin. The residue was shaken for 45 mins.After washed three times with DMF, the resin was treated with 20% piperidine untilthe UV detector indicated no more Fmoc was released. Repeat procedures ofcoupling and deblocking were carried out following the above process until thetarget linear peptide H2N-fK(Dde)RGD-OAll is obtained on resin. The the resin wastreated with 730uL PhSiH3 (20eq) in 60mL DMF and 122mg Pd(PPh3)4 (0.35eq) in60mL DCM to remove Allyl protection group overnight. Then, 60mL couplingreagents of PyAOP (625.5mg, 1.2mmol, 4eq), HOBt (162mg,1.2mmol, 4eq) andDMM (216uL, 2.4mmol, 8eq) in 60mL DMF was added to perform theintramolecular cyclization for 12hours. The Dde protection group was removed with5% hydrazine monohydrate in DMF for 5mins twice. The peptide was cleavedfrom the resin using Cocktail R cleavage reagent to afford cyclo(KRGDf).

Reference： [1]Synlett,2017,vol. 28,p. 1966 - 1970

71
[ 29022-11-5 ]
[ 71989-31-6 ]
[ 35737-15-6 ]
[ 109425-51-6 ]
[ 35737-15-6 ]
[ 150629-67-7 ]
[ 98-79-3 ]
(S)-6-[(Diphenyl-p-tolyl-methyl)-amino]-2-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoic acid [ No CAS ]
C₁₃₇H₁₄₁N₂₀O₁₃Pol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: The Dau?GnRH-III derivatives were synthesized by solid phase peptide synthesis according to Fmoc/t-Bu chemistry on a RinkAmide MBHA resin (0.73 mmol/g coupling capacity) followed by ligation of Dau (oxime bond) in solution. All peptides were synthesized manually by usage of the following Fmoc-protected amino acid derivatives: Fmoc-Gly-OH, Fmoc-Pro-OH, Fmoc-Lys(Mtt)-OH, Fmoc-Lys(Dde)-OH, Fmoc-Trp-OH,Fmoc-D-Trp-OH, Fmoc-Asp(Ot-Bu)-OH, Fmoc-D-Asp(OtBu)-OH, Fmoc-D-Glu(Ot -Bu)-OH, Fmoc-His(Trt)-OH and Fmoc-Ser(t-Bu)-OH. Pyroglutamic acid (Glp or

Reference： [1]Beilstein Journal of Organic Chemistry,2018,vol. 14,p. 756 - 771

72
[ 29022-11-5 ]
[ 71989-31-6 ]
[ 35737-15-6 ]
[ 109425-51-6 ]
[ 71989-14-5 ]
[ 150629-67-7 ]
[ 98-79-3 ]
(S)-6-[(Diphenyl-p-tolyl-methyl)-amino]-2-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoic acid [ No CAS ]
C₁₃₄H₁₄₄N₁₉O₁₅Pol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: The Dau-GnRH-III derivatives were synthesized by solid phase peptide synthesis according to Fmoc/t-Bu chemistry on a RinkAmide MBHA resin (0.73 mmol/g coupling capacity) followed by ligation of Dau (oxime bond) in solution. All peptides were synthesized manually by usage of the following Fmoc-protected amino acid derivatives: Fmoc-Gly-OH, Fmoc-Pro-OH, Fmoc-Lys(Mtt)-OH, Fmoc-Lys(Dde)-OH, Fmoc-Trp-OH,Fmoc-D-Trp-OH, Fmoc-Asp(Ot-Bu)-OH, Fmoc-D-Asp(OtBu)-OH, Fmoc-D-Glu(Ot -Bu)-OH, Fmoc-His(Trt)-OH and Fmoc-Ser(t-Bu)-OH. Pyroglutamic acid (Glp or

Reference： [1]Beilstein Journal of Organic Chemistry,2018,vol. 14,p. 756 - 771

73
[ 544429-89-2 ]
C₂₁H₂₂O₇ [ No CAS ]
[ 84624-27-1 ]
[ 150629-67-7 ]
2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid [ No CAS ]
C₇₈H₁₀₉N₂₅O₂₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		(1) Weigh 1.0g wang resin (Wang Resin Tianjin Nankai Synthetic 1% DVB, 100-200mesh, 0.8- 1.0mmol/g) in a clean, dry reaction tube, Add an appropriate amount of DMF, swelling and activation for about 30 minutes, Then weigh the first amino acid Fmoc-Lys(Dde)-OH (N-fluorenylmethyloxycarbonyl-N'-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl]-lysine) 0.2mmol, 40 mg of DMAP (4-dimethylaminopyridine) and 0.3 ml of DIC were added to the reaction tube. DMF was used as a solvent at room temperature for 3.5 hours. After the reaction was completed, the mixture was washed with DMF for 4 to 6 times, and an appropriate amount of pyridine and acetic anhydride were added. The volume ratio was 1:1 and the reaction time was 30 minutes. The reaction was washed with DMF 4 to 6 times. The Fmoc of the amino acid was then removed with a 20% piperidine solution and taken twice for 15 min for 10 min + 5 min. Then wash with DMF 4 times, wash 2 times with methanol, remove a small amount of resin and detect with ninhydrin detection reagent, the test is blue, The next step can be performed. (2) Weigh 0.3mmol of tBu (t-butyl) protected DOTA raw material, HBTU (benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate) 0.3 mmol, DMF as a solvent, 0.5 ml of DIEA (N,N-diisopropylethylamine) was added for 1 hour at room temperature. After the reaction is completed, it is washed with DMF for 4-6 times. The colorless reaction can be detected by the next step. (3) Add 2% hydrazine hydrate in DMF solution to remove Dde (see Fmoc-Lys(Dde)-OH) for 30 min, 10min + 10min + 10min, then wash 4 times with DMF, wash twice with methanol, A small amount of resin was removed and detected with ninhydrin detection reagent. The test was blue, and the next reaction was performed. (4) Weigh FMOC-PEG2-COOH, 0.3mmol, HBTU 0.3mmol, DMF as solvent, 0.5ml of DIEA was added for 1h at room temperature, and the reaction was washed with DMF for 4-6 times. The Fmoc of the amino acid was then stripped off with a 20% piperidine solution for a total of 15 min, 10 min+5 min. After washing with DMF for 4 times and methanol 2 times, a small amount of resin was removed and detected with ninhydrin detection reagent. The test was blue. The next reaction can be performed. (5) Weigh FMOC-Lys(Dde)-COOH, 0.3mmol, HBTU 0.3mmol, DMF as solvent, 0.5ml of DIEA was added for 1h at room temperature, and the reaction was washed with DMF for 4-6 times. The Fmoc of the amino acid was then stripped off with 20% piperidine solution for a total of 15 min in 10 min + 5 min. Then wash with DMF 4 times, wash twice with methanol, remove a small amount of resin with ninhydrin detection reagent detection, detection is blue, The next reaction can be performed. (6) Weigh A (folate-NHS ester) 0.3mmol, DMSO as a solvent, add 5 drops of DIEA, and react at room temperature for 1 hour; After the reaction was complete, it was washed 4 to 6 times with DMF. (7) Remove Dde for 30 minutes by adding 2% hydrazine hydrate in DMF solution. 10min+10min+10min, Then wash four times with DMF, wash twice with methanol, remove a small amount of resin and detect with ninhydrin detection reagent. The test is blue and the next reaction can be performed. (8) Weigh BOC{tert-butyloxycarbonyl}-Lys(Fmoc)-COOH, 0.3mmol, HBTU 0.3mmol, DMF as solvent, add 0.5ml of DIEA for 1h at room temperature, and the reaction is washed with DMF for 4-6 times. The amino acid Fmoc{fluorenylmethyloxycarbonyl} was then stripped off with 20% piperidine solution for a total of 15 min, 10 min + 5 min. Then wash four times with DMF, wash twice with methanol, remove a small amount of resin and test with ninhydrin detection reagent. The test is blue and the next reaction can proceed. (9) Weigh A (folate-NHS ester) 0.3mmol, DMSO as a solvent, add 5 drops of DIEA, and react at room temperature for 1 hour; after completion of the reaction, wash with DMF 4-6 times; wash twice with methanol and drain. (10) Finally cut with 25% trifluoroacetic acid cutting fluid for 2 hours. The reaction solution is filtered by suction to obtain trifluoroacetic acid solution of folic acid. Ether precipitation, centrifugation, and then washed with ether 3 to 5 times, to give a white solid, purified by HPLC, freeze-dried, The target compound was subjected to mass analysis of molecular weight and chemical purity using a high performance liquid chromatography (HPLC) and mass spectrometry (MS). (11) Synthesis of different PEG content (PEGn) folic acid dimers, except in step (4) With FMOC-PEGn-COOH, other synthetic processes are exactly the same as those described above.

Reference： [1]Patent: CN104815336,2018,B .Location in patent: Paragraph 0062; 0067-0078

74
[ 21947-98-8 ]
[ 71989-26-9 ]
[ 111061-56-4 ]
[ 150629-67-7 ]
[ 139573-77-6 ]
C₇₄H₁₄₄N₁₄O₁₃S₂ [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2018,vol. 16,p. 3824 - 3830

75
[ 867062-95-1 ]
[ 71989-31-6 ]
[ 35661-40-6 ]
[ 71989-14-5 ]
[ 108-24-7 ]
[ 103213-32-7 ]
[ 71989-35-0 ]
[ 57-10-3 ]
[ 150629-67-7 ]
9-fluorenylmethoxycarbonyl-Nim-trityl-L-histidine [ No CAS ]
N-α-[(9H-fluoren-9-ylmethoxy)carbonyl]-N^G-(2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl)-D-arginine [ No CAS ]
C₈₈H₁₄₀N₂₂O₂₀S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		The synthesis of Example 33 (Ac-C+-DTHFPr-C+-rF-PEG2-K(Palmitoyl)-NH2) is representative: The following reagents were used:MB HA rink amide resin (1 equiv)Fmoc_Lys(Dde)-OH (3 equiv)Fmoc-Phe-OH (3 equiv)Fmoc-D-Arg(Pbf)-OH (3 equiv)Fmoc-Cys(Trt)-OH (3 equiv)Fmoc-D-Arg(Pbf)-OH (3 equiv)Fmoc-Pro-OH (3 equiv)Fmoc-Phe-OH (3 equiv)Fmoc-His(Trt)-OH (3 equiv)Fmoc-Thr(OtBu)-OH (3 equiv)Fmoc-Asp(OtBu)-OH (3 equiv)Fmoc-Cys(Trt)-OH (3 equiv)<strong>[867062-95-1]Fmoc-PEG2-OH</strong> (2.5 equiv)Palmitic acid (3 equiv)The peptide was synthesized using standard Fmoc chemistry by manual synthesis. 1. Swell the resin for 30 min in DMF and push out the DMF out of column with nitrogen.2. The Fmoc group was cleaved from the resin by adding 20% (v/v) piperidine in DMF.The resin was allowed to react with the 20% piperidine solution for 20 min. 3. After the Fmoc cleavage from the resin is complete, the 20% piperidine solution is pushed out of the column. The resin is washed 3 times with DMF:4. Preparing (or activating) the amino acid: 3 eq of the amino acid and 2.95 eq of HBTU were weighed and were then dissolved in DMF. 6 eq of DIEA was added to the above solution. The activated solution was then added to the column containing the resin and reacted for about 2 h.5. The resin was drained and the loaded resin was wasged 3 times with DMF. 6. Steps 2-5 were repeated for each amino acid coupling.7. The acetyl group protection was conducted by adding the cocktail of 5% Ac2O/10% NMM 85% DMF. The solution was reacted for about 0.5 h. 8. Boc group protection when necessary was conducted by adding the 3 eq of (Boc)20 and 6 eq of DIEA to the resin in DMF. The reaction mixture was reacted for about 0.5 h.9. The resin was drained and washed with DMF 3 times and with MeOH 3 times. Cleavage and disulfide bond formation:The resulting residue was treated with cocktail of 90%TFA/5%TIPS/2.5%H2O/2.5%EDT (10 mL) and swelled for about 2 h. The crude peptide was precipitated out by ether. Cleavage:The resulting residue was treated with cocktail of 90%TFA/5%TIPS/2.5%H2O/2.5%EDT (10 mL) and swelled for about 2 h. The crude peptide was precipitated out by ether. If no disulfide bond formation was required, the crude peptide was purified by reversed-phase HPLC.Optional Cyclization (disulfide bond formation):The crude peptide was dissolved in H20/ACN (1:1) to adjust the concentration to 1 mM. Then 1 M NH4HC03was added to the above solution to adjust the pH to about 8-9. The solution was allowed to react for about 8 h at room temperature. The reaction was monitored by LCMS. After the reaction was completed, the reaction was quenched by acetic acid to adjust the pH to about 6. The reaction mixure was lyophilized and the resulting solid was purified by reversed- phase HPLC.

Reference： [1]Patent: WO2018/128828,2018,A1 .Location in patent: Page/Page column 53-55; 61

76
[ 867062-95-1 ]
[ 71989-31-6 ]
[ 35661-40-6 ]
[ 71989-14-5 ]
[ 71989-35-0 ]
[ 57-10-3 ]
[ 150629-67-7 ]
9-fluorenylmethoxycarbonyl-Nim-trityl-L-histidine [ No CAS ]
N-α-[(9H-fluoren-9-ylmethoxy)carbonyl]-N^G-(2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl)-D-arginine [ No CAS ]
Fmoc-Ser(*)-OH [ No CAS ]
C₈₃H₁₃₅N₂₁O₁₉ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: The synthesis of Example 33 (Ac-C+-DTHFPr-C+-rF-PEG2-K(Palmitoyl)-NH2) is representative: The following reagents were used:MB HA rink amide resin (1 equiv)Fmoc_Lys(Dde)-OH (3 equiv)Fmoc-Phe-OH (3 equiv)Fmoc-D-Arg(Pbf)-OH (3 equiv)Fmoc-Cys(Trt)-OH (3 equiv)Fmoc-D-Arg(Pbf)-OH (3 equiv)Fmoc-Pro-OH (3 equiv)Fmoc-Phe-OH (3 equiv)Fmoc-His(Trt)-OH (3 equiv)Fmoc-Thr(OtBu)-OH (3 equiv)Fmoc-Asp(OtBu)-OH (3 equiv)Fmoc-Cys(Trt)-OH (3 equiv)<strong>[867062-95-1]Fmoc-PEG2-OH</strong> (2.5 equiv)Palmitic acid (3 equiv)The peptide was synthesized using standard Fmoc chemistry by manual synthesis. 1. Swell the resin for 30 min in DMF and push out the DMF out of column with nitrogen.2. The Fmoc group was cleaved from the resin by adding 20% (v/v) piperidine in DMF.The resin was allowed to react with the 20% piperidine solution for 20 min. 3. After the Fmoc cleavage from the resin is complete, the 20% piperidine solution is pushed out of the column. The resin is washed 3 times with DMF:4. Preparing (or activating) the amino acid: 3 eq of the amino acid and 2.95 eq of HBTU were weighed and were then dissolved in DMF. 6 eq of DIEA was added to the above solution. The activated solution was then added to the column containing the resin and reacted for about 2 h.5. The resin was drained and the loaded resin was wasged 3 times with DMF. 6. Steps 2-5 were repeated for each amino acid coupling.7. The acetyl group protection was conducted by adding the cocktail of 5% Ac2O/10% NMM 85% DMF. The solution was reacted for about 0.5 h. 8. Boc group protection when necessary was conducted by adding the 3 eq of (Boc)20 and 6 eq of DIEA to the resin in DMF. The reaction mixture was reacted for about 0.5 h.9. The resin was drained and washed with DMF 3 times and with MeOH 3 times. Cleavage and disulfide bond formation:The resulting residue was treated with cocktail of 90%TFA/5%TIPS/2.5%H2O/2.5%EDT (10 mL) and swelled for about 2 h. The crude peptide was precipitated out by ether. Cleavage:The resulting residue was treated with cocktail of 90%TFA/5%TIPS/2.5%H2O/2.5%EDT (10 mL) and swelled for about 2 h. The crude peptide was precipitated out by ether. If no disulfide bond formation was required, the crude peptide was purified by reversed-phase HPLC.Optional Cyclization (disulfide bond formation):The crude peptide was dissolved in H20/ACN (1:1) to adjust the concentration to 1 mM. Then 1 M NH4HC03was added to the above solution to adjust the pH to about 8-9. The solution was allowed to react for about 8 h at room temperature. The reaction was monitored by LCMS. After the reaction was completed, the reaction was quenched by acetic acid to adjust the pH to about 6. The reaction mixure was lyophilized and the resulting solid was purified by reversed- phase HPLC.

Reference： [1]Patent: WO2018/128828,2018,A1 .Location in patent: Page/Page column 51-53; 61

77
[ 29022-11-5 ]
[ 68858-20-8 ]
[ 35661-60-0 ]
[ 35661-39-3 ]
[ 864876-97-1 ]
[ 71989-31-6 ]
[ 71989-14-5 ]
[ 71989-26-9 ]
[ 132388-59-1 ]
[ 132327-80-1 ]
[ 135112-28-6 ]
[ 150629-67-7 ]
Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
[ 58-85-5 ]
H₂N-NK(Biotin)VPNLRGDLQV[norvaline]AQKVART-OH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8%		(0234) To enable investigation of introducing non-proteinogenic amino acids (listed in Figure 1) on A20FMDV2 binding activity, biotinylated peptides 1-15 (see Table 1), except for peptide 6, were synthesised by standard Fmoc SPPS on the acid liable (0235) hydroxymethylphenoxypropionic acid linker (HMPP) which delivers a C- terminal carboxylic acid using to the conditions depicted in Scheme 1. The desired peptide sequences were assembled using 20% (0236) piperidine/DMF to remove the Fmoc protecting group and 0- (0237) (benzotriazol-l-yl) -N, N, N ' , N '-tetramethyluronium hexafluorophosphate (HBTU) / DIPEA as coupling reagents. (0238) Since specific binding to the nubetabeta integrin was to be studied by flow cytometry, the native alanine at the second residue in A20FMDV2 (1) and all analogues thereof, were substituted with a biotinylated lysine residue. This substitution has previously been shown to be well tolerated [24,25] . We chose to install the D-biotin moiety by selective deprotection of a 1- ( 4 , 4-dimethyl-2 , 6-dioxocyclohex-l- ylidene ) ethyl (Dde) [19] group on the side chain group followed by condensation with D-biotin using HBTU/DIPEA. (0239) Trifluoroacetic acid (TFA) /H2O/3, 6-dioxa-l , 8-octanedithiol (0240) (DODT) /triisopropylsilane (TIPS) (94:2.5:2.5:1.0, v/v/v/v) effected cleavage of the synthesised peptides from the corresponding (0241) peptidyl-resins . Peptides 1-15 were obtained in good yields ranging from 2%-50% and purity exceeding 99% (see peptide characterization data) . (0242) For the synthesis of peptide 6 containing an i7-L-methyllysine modification we employed an on-resin i7-methylation protocol [22] which furnished peptide 6 in good yield (30%) following TFA-mediated peptide cleavage and RP-HPLC purification. (0243) The lead peptide, A20FMDV2, which contains all naturally-occurring amino acids would be susceptible to degradation by exopeptidases which act on the amino- and carboxy terminuses. To mitigate this, six N- and/or C-terminus-modified and biotinylated A20FDMV2 mimics were prepared wherein we systematically modified the amino and carboxy ends (peptides 16-18) and the N-terminal and C-terminal amino acids (Asnl and Thr20, respectively, peptides 19-21) . N- terminal/C-terminal modified peptides 16-18 were obtained by capping of the N-terminus with acetic anhydride (16) or by employing the Rink amide linker to afford the C-terminal carboxamide (17) or a combination of both (peptide 18) . (0244) Peptide 19, bearing the unnatural D-Asnl in place of the native Asnl at the N-terminus of biotinylated A20FMDV2 (1) was obtained using the synthetic route outlined in Scheme 1 except that the Fmoc-D- Asn(Trt)-OH building block was incorporated into the synthesis as the N-terminal residue. For the preparation of peptides 20 and 21, which contains the unnatural D-Thr at the C-terminus, HMP-anchored resin 27 (see Scheme 1, HMP = hydroxymethylphenoxyacetic acid) was first esterified with Fmoc-D-Thr (tBu) -OH using DIC/DMAP and the sequence then elongated by Fmoc SPPS . (0245) Table 1. List of prepared synthetic peptides [N-term] - XiK (Biotin) VPNLRGDLQVX2AQX3VARX4- [C-term] containing substitutions for the native Lysl6 (peptides 2-6) or Leul3 (peptides 7-15), C- terminal/N-terminal variants (peptides 16-21) and DTPA-modified peptides (22-26) . NB: nomenclature, particularly X position (0246) numbering used in this table is not the same as that used in the claims . (0247) Compound N- Xl X2 X3 X4 C- term. term. (0248) 1 NH2 Asn Leu Lys Thr C02H (0249) 2 NH2 Asn Leu D-Lys Thr C02H (0250) 3 NH2 Asn Leu L-Orn Thr C02H (0251) 1-2,4- (0252) 4 NH2 Asn Leu diaminobutyric Thr C02H acid (0253) 1-2,3- (0254) 5 NH2 Asn Leu diaminopropionic Thr C02H acid (0255) 6 NH2 Asn Leu ZV-L-meth llysine Thr C02H (0256) 7 NH2 Asn aminoisobutyric Lys Thr C02H acid (0257) 8 NH2 Asn L-norvaline Lys Thr C02H (0258) 9 NH2 Asn L-norleucine Lys Thr C02H (0259) 10 NH2 Asn L-allylglycine Lys Thr C02H (0260) L-tert- (0261) 11 NH2 Asn Lys Thr C02H butylalanine (0262) 12 NH2 Asn L-homoleucine Lys Thr C02H (0263) L-2-amino-3- (0264) 13 NH2 Asn ethylpentanoic Lys Thr C02H acid (0265) L- (0266) 14 NH2 Asn Lys Thr C02H cyclohexylalanine (0267) 15 L- (0268) NH2 Asn Lys Thr C02H adamantylglycine (0269) 16 Ac-NH Asn Leu Lys Thr C02H (0270) 17 NH2 Asn Leu Lys Thr CONH2 (0271) 18 Ac-NH Asn Leu Lys Thr CONH2 (0272) 19 D- (0273) NH2 Leu Lys Thr C02H (0274) Asn (0275) 20 D- (0276) NH2 Asn Leu Lys C02H (0277) Thr (0278) 21 D- D- (0279) NH2 Leu Lys C02H (0280) Asn Thr (0281) 22 DTPA- (0282) Asn Leu Lys Thr C02H NH (0283) 23 DTPA- (0284) Asn Leu Lys Thr C02H Gly-NH (0285) 24 DTPA- (0286) Asn Leu Lys Thr CONH2 NH (0287) 25 DTPA- D- (0288) Leu Lys Thr C02H NH Asn (0289) 26 DTPA- D- D- (0290) Leu Lys C02H NH Asn Thr (0291) 1 D -yr% -Q ^ (0292) - -^H Q - (0293) (0294) Scheme 1. Synthetic protocol for the preparation of the biotinylated A20FMDV2 peptide variants. (0295) The results obtained from the binding assays (Table 2, see later) s...

Reference： [1]Patent: WO2018/197490,2018,A1 .Location in patent: Page/Page column 21-25; 32-37

78
[ 29022-11-5 ]
[ 68858-20-8 ]
[ 35661-60-0 ]
[ 35661-39-3 ]
[ 864876-97-1 ]
[ 71989-31-6 ]
[ 71989-14-5 ]
[ 92122-45-7 ]
[ 132388-59-1 ]
[ 132327-80-1 ]
[ 150629-67-7 ]
Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
[ 58-85-5 ]
H<SUB>2</SUB>N-NK(Biotin)VPNLRGDLQVLAQkVART-OH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22%		(0234) To enable investigation of introducing non-proteinogenic amino acids (listed in Figure 1) on A20FMDV2 binding activity, biotinylated peptides 1-15 (see Table 1), except for peptide 6, were synthesised by standard Fmoc SPPS on the acid liable (0235) hydroxymethylphenoxypropionic acid linker (HMPP) which delivers a C- terminal carboxylic acid using to the conditions depicted in Scheme 1. The desired peptide sequences were assembled using 20% (0236) piperidine/DMF to remove the Fmoc protecting group and 0- (0237) (benzotriazol-l-yl) -N, N, N ' , N '-tetramethyluronium hexafluorophosphate (HBTU) / DIPEA as coupling reagents. (0238) Since specific binding to the nubetabeta integrin was to be studied by flow cytometry, the native alanine at the second residue in A20FMDV2 (1) and all analogues thereof, were substituted with a biotinylated lysine residue. This substitution has previously been shown to be well tolerated [24,25] . We chose to install the D-biotin moiety by selective deprotection of a 1- ( 4 , 4-dimethyl-2 , 6-dioxocyclohex-l- ylidene ) ethyl (Dde) [19] group on the side chain group followed by condensation with D-biotin using HBTU/DIPEA. (0239) Trifluoroacetic acid (TFA) /H2O/3, 6-dioxa-l , 8-octanedithiol (0240) (DODT) /triisopropylsilane (TIPS) (94:2.5:2.5:1.0, v/v/v/v) effected cleavage of the synthesised peptides from the corresponding (0241) peptidyl-resins . Peptides 1-15 were obtained in good yields ranging from 2%-50% and purity exceeding 99% (see peptide characterization data) . (0242) For the synthesis of peptide 6 containing an i7-L-methyllysine modification we employed an on-resin i7-methylation protocol [22] which furnished peptide 6 in good yield (30%) following TFA-mediated peptide cleavage and RP-HPLC purification. (0243) The lead peptide, A20FMDV2, which contains all naturally-occurring amino acids would be susceptible to degradation by exopeptidases which act on the amino- and carboxy terminuses. To mitigate this, six N- and/or C-terminus-modified and biotinylated A20FDMV2 mimics were prepared wherein we systematically modified the amino and carboxy ends (peptides 16-18) and the N-terminal and C-terminal amino acids (Asnl and Thr20, respectively, peptides 19-21) . N- terminal/C-terminal modified peptides 16-18 were obtained by capping of the N-terminus with acetic anhydride (16) or by employing the Rink amide linker to afford the C-terminal carboxamide (17) or a combination of both (peptide 18) . (0244) Peptide 19, bearing the unnatural D-Asnl in place of the native Asnl at the N-terminus of biotinylated A20FMDV2 (1) was obtained using the synthetic route outlined in Scheme 1 except that the Fmoc-D- Asn(Trt)-OH building block was incorporated into the synthesis as the N-terminal residue. For the preparation of peptides 20 and 21, which contains the unnatural D-Thr at the C-terminus, HMP-anchored resin 27 (see Scheme 1, HMP = hydroxymethylphenoxyacetic acid) was first esterified with Fmoc-D-Thr (tBu) -OH using DIC/DMAP and the sequence then elongated by Fmoc SPPS . (0245) Table 1. List of prepared synthetic peptides [N-term] - XiK (Biotin) VPNLRGDLQVX2AQX3VARX4- [C-term] containing substitutions for the native Lysl6 (peptides 2-6) or Leul3 (peptides 7-15), C- terminal/N-terminal variants (peptides 16-21) and DTPA-modified peptides (22-26) . NB: nomenclature, particularly X position (0246) numbering used in this table is not the same as that used in the claims . (0247) Compound N- Xl X2 X3 X4 C- term. term. (0248) 1 NH2 Asn Leu Lys Thr C02H (0249) 2 NH2 Asn Leu D-Lys Thr C02H (0250) 3 NH2 Asn Leu L-Orn Thr C02H (0251) 1-2,4- (0252) 4 NH2 Asn Leu diaminobutyric Thr C02H acid (0253) 1-2,3- (0254) 5 NH2 Asn Leu diaminopropionic Thr C02H acid (0255) 6 NH2 Asn Leu ZV-L-meth llysine Thr C02H (0256) 7 NH2 Asn aminoisobutyric Lys Thr C02H acid (0257) 8 NH2 Asn L-norvaline Lys Thr C02H (0258) 9 NH2 Asn L-norleucine Lys Thr C02H (0259) 10 NH2 Asn L-allylglycine Lys Thr C02H (0260) L-tert- (0261) 11 NH2 Asn Lys Thr C02H butylalanine (0262) 12 NH2 Asn L-homoleucine Lys Thr C02H (0263) L-2-amino-3- (0264) 13 NH2 Asn ethylpentanoic Lys Thr C02H acid (0265) L- (0266) 14 NH2 Asn Lys Thr C02H cyclohexylalanine (0267) 15 L- (0268) NH2 Asn Lys Thr C02H adamantylglycine (0269) 16 Ac-NH Asn Leu Lys Thr C02H (0270) 17 NH2 Asn Leu Lys Thr CONH2 (0271) 18 Ac-NH Asn Leu Lys Thr CONH2 (0272) 19 D- (0273) NH2 Leu Lys Thr C02H (0274) Asn (0275) 20 D- (0276) NH2 Asn Leu Lys C02H (0277) Thr (0278) 21 D- D- (0279) NH2 Leu Lys C02H (0280) Asn Thr (0281) 22 DTPA- (0282) Asn Leu Lys Thr C02H NH (0283) 23 DTPA- (0284) Asn Leu Lys Thr C02H Gly-NH (0285) 24 DTPA- (0286) Asn Leu Lys Thr CONH2 NH (0287) 25 DTPA- D- (0288) Leu Lys Thr C02H NH Asn (0289) 26 DTPA- D- D- (0290) Leu Lys C02H NH Asn Thr (0291) 1 D -yr% -Q ^ (0292) - -^H Q - (0293) (0294) Scheme 1. Synthetic protocol for the preparation of the biotinylated A20FMDV2 peptide variants. (0295) The results obtained from the binding assays (Table 2, see later) s...

Reference： [1]Patent: WO2018/197490,2018,A1 .Location in patent: Page/Page column 21-25; 32-37

79
[ 29022-11-5 ]
[ 68858-20-8 ]
[ 35661-60-0 ]
[ 35661-39-3 ]
[ 864876-97-1 ]
[ 71989-31-6 ]
[ 71989-14-5 ]
[ 132388-59-1 ]
[ 132327-80-1 ]
[ 150629-67-7 ]
[ 125238-99-5 ]
Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
[ 58-85-5 ]
NH₂-NK(Biotin)VPNLRGDLQVLAQ[diaminobutyric acid]VART-OH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29%		(0234) To enable investigation of introducing non-proteinogenic amino acids (listed in Figure 1) on A20FMDV2 binding activity, biotinylated peptides 1-15 (see Table 1), except for peptide 6, were synthesised by standard Fmoc SPPS on the acid liable (0235) hydroxymethylphenoxypropionic acid linker (HMPP) which delivers a C- terminal carboxylic acid using to the conditions depicted in Scheme 1. The desired peptide sequences were assembled using 20percent (0236) piperidine/DMF to remove the Fmoc protecting group and 0- (0237) (benzotriazol-l-yl) -N, N, N ' , N '-tetramethyluronium hexafluorophosphate (HBTU) / DIPEA as coupling reagents. (0238) Since specific binding to the nubetabeta integrin was to be studied by flow cytometry, the native alanine at the second residue in A20FMDV2 (1) and all analogues thereof, were substituted with a biotinylated lysine residue. This substitution has previously been shown to be well tolerated [24,25] . We chose to install the D-biotin moiety by selective deprotection of a 1- ( 4 , 4-dimethyl-2 , 6-dioxocyclohex-l- ylidene ) ethyl (Dde) [19] group on the side chain group followed by condensation with D-biotin using HBTU/DIPEA. (0239) Trifluoroacetic acid (TFA) /H2O/3, 6-dioxa-l , 8-octanedithiol (0240) (DODT) /triisopropylsilane (TIPS) (94:2.5:2.5:1.0, v/v/v/v) effected cleavage of the synthesised peptides from the corresponding (0241) peptidyl-resins . Peptides 1-15 were obtained in good yields ranging from 2percent-50percent and purity exceeding 99percent (see peptide characterization data) . (0242) For the synthesis of peptide 6 containing an i\7-L-methyllysine modification we employed an on-resin i\7-methylation protocol [22] which furnished peptide 6 in good yield (30percent) following TFA-mediated peptide cleavage and RP-HPLC purification. (0243) The lead peptide, A20FMDV2, which contains all naturally-occurring amino acids would be susceptible to degradation by exopeptidases which act on the amino- and carboxy terminuses. To mitigate this, six N- and/or C-terminus-modified and biotinylated A20FDMV2 mimics were prepared wherein we systematically modified the amino and carboxy ends (peptides 16-18) and the N-terminal and C-terminal amino acids (Asnl and Thr20, respectively, peptides 19-21) . N- terminal/C-terminal modified peptides 16-18 were obtained by capping of the N-terminus with acetic anhydride (16) or by employing the Rink amide linker to afford the C-terminal carboxamide (17) or a combination of both (peptide 18) . (0244) Peptide 19, bearing the unnatural D-Asnl in place of the native Asnl at the N-terminus of biotinylated A20FMDV2 (1) was obtained using the synthetic route outlined in Scheme 1 except that the Fmoc-D- Asn(Trt)-OH building block was incorporated into the synthesis as the N-terminal residue. For the preparation of peptides 20 and 21, which contains the unnatural D-Thr at the C-terminus, HMP-anchored resin 27 (see Scheme 1, HMP = hydroxymethylphenoxyacetic acid) was first esterified with Fmoc-D-Thr (tBu) -OH using DIC/DMAP and the sequence then elongated by Fmoc SPPS . (0245) Table 1. List of prepared synthetic peptides [N-term] - XiK (Biotin) VPNLRGDLQVX2AQX3VARX4- [C-term] containing substitutions for the native Lysl6 (peptides 2-6) or Leul3 (peptides 7-15), C- terminal/N-terminal variants (peptides 16-21) and DTPA-modified peptides (22-26) . NB: nomenclature, particularly X position (0246) numbering used in this table is not the same as that used in the claims . (0247) Compound N- Xl X2 X3 X4 C- term. term. (0248) 1 NH2 Asn Leu Lys Thr C02H (0249) 2 NH2 Asn Leu D-Lys Thr C02H (0250) 3 NH2 Asn Leu L-Orn Thr C02H (0251) 1-2,4- (0252) 4 NH2 Asn Leu diaminobutyric Thr C02H acid (0253) 1-2,3- (0254) 5 NH2 Asn Leu diaminopropionic Thr C02H acid (0255) 6 NH2 Asn Leu ZV-L-meth llysine Thr C02H (0256) 7 NH2 Asn aminoisobutyric Lys Thr C02H acid (0257) 8 NH2 Asn L-norvaline Lys Thr C02H (0258) 9 NH2 Asn L-norleucine Lys Thr C02H (0259) 10 NH2 Asn L-allylglycine Lys Thr C02H (0260) L-tert- (0261) 11 NH2 Asn Lys Thr C02H butylalanine (0262) 12 NH2 Asn L-homoleucine Lys Thr C02H (0263) L-2-amino-3- (0264) 13 NH2 Asn ethylpentanoic Lys Thr C02H acid (0265) L- (0266) 14 NH2 Asn Lys Thr C02H cyclohexylalanine (0267) 15 L- (0268) NH2 Asn Lys Thr C02H adamantylglycine (0269) 16 Ac-NH Asn Leu Lys Thr C02H (0270) 17 NH2 Asn Leu Lys Thr CONH2 (0271) 18 Ac-NH Asn Leu Lys Thr CONH2 (0272) 19 D- (0273) NH2 Leu Lys Thr C02H (0274) Asn (0275) 20 D- (0276) NH2 Asn Leu Lys C02H (0277) Thr (0278) 21 D- D- (0279) NH2 Leu Lys C02H (0280) Asn Thr (0281) 22 DTPA- (0282) Asn Leu Lys Thr C02H NH (0283) 23 DTPA- (0284) Asn Leu Lys Thr C02H Gly-NH (0285) 24 DTPA- (0286) Asn Leu Lys Thr CONH2 NH (0287) 25 DTPA- D- (0288) Leu Lys Thr C02H NH Asn (0289) 26 DTPA- D- D- (0290) Leu Lys C02H NH Asn Thr (0291) 1 D -yrpercent \?Q ^ (0292) ? -^H Q ? (0293) (0294) Scheme 1. Synthetic protocol for the preparation of the biotinylated A20FMDV2 peptide variants. (0295) The results obtained from th...

Reference： [1]Patent: WO2018/197490,2018,A1 .Location in patent: Page/Page column 21-25; 32-37

80
[ 29022-11-5 ]
[ 68858-20-8 ]
[ 35661-60-0 ]
[ 35661-39-3 ]
[ 864876-97-1 ]
[ 71989-31-6 ]
[ 71989-14-5 ]
[ 132388-59-1 ]
[ 132327-80-1 ]
[ 131570-56-4 ]
[ 150629-67-7 ]
Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
[ 58-85-5 ]
H₂N-NK(Biotin)VPNLRGDLQVLAQ[diaminopropionic acid]VART-OH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%		(0234) To enable investigation of introducing non-proteinogenic amino acids (listed in Figure 1) on A20FMDV2 binding activity, biotinylated peptides 1-15 (see Table 1), except for peptide 6, were synthesised by standard Fmoc SPPS on the acid liable (0235) hydroxymethylphenoxypropionic acid linker (HMPP) which delivers a C- terminal carboxylic acid using to the conditions depicted in Scheme 1. The desired peptide sequences were assembled using 20% (0236) piperidine/DMF to remove the Fmoc protecting group and 0- (0237) (benzotriazol-l-yl) -N, N, N ' , N '-tetramethyluronium hexafluorophosphate (HBTU) / DIPEA as coupling reagents. (0238) Since specific binding to the nubetabeta integrin was to be studied by flow cytometry, the native alanine at the second residue in A20FMDV2 (1) and all analogues thereof, were substituted with a biotinylated lysine residue. This substitution has previously been shown to be well tolerated [24,25] . We chose to install the D-biotin moiety by selective deprotection of a 1- ( 4 , 4-dimethyl-2 , 6-dioxocyclohex-l- ylidene ) ethyl (Dde) [19] group on the side chain group followed by condensation with D-biotin using HBTU/DIPEA. (0239) Trifluoroacetic acid (TFA) /H2O/3, 6-dioxa-l , 8-octanedithiol (0240) (DODT) /triisopropylsilane (TIPS) (94:2.5:2.5:1.0, v/v/v/v) effected cleavage of the synthesised peptides from the corresponding (0241) peptidyl-resins . Peptides 1-15 were obtained in good yields ranging from 2%-50% and purity exceeding 99% (see peptide characterization data) . (0242) For the synthesis of peptide 6 containing an i7-L-methyllysine modification we employed an on-resin i7-methylation protocol [22] which furnished peptide 6 in good yield (30%) following TFA-mediated peptide cleavage and RP-HPLC purification. (0243) The lead peptide, A20FMDV2, which contains all naturally-occurring amino acids would be susceptible to degradation by exopeptidases which act on the amino- and carboxy terminuses. To mitigate this, six N- and/or C-terminus-modified and biotinylated A20FDMV2 mimics were prepared wherein we systematically modified the amino and carboxy ends (peptides 16-18) and the N-terminal and C-terminal amino acids (Asnl and Thr20, respectively, peptides 19-21) . N- terminal/C-terminal modified peptides 16-18 were obtained by capping of the N-terminus with acetic anhydride (16) or by employing the Rink amide linker to afford the C-terminal carboxamide (17) or a combination of both (peptide 18) . (0244) Peptide 19, bearing the unnatural D-Asnl in place of the native Asnl at the N-terminus of biotinylated A20FMDV2 (1) was obtained using the synthetic route outlined in Scheme 1 except that the Fmoc-D- Asn(Trt)-OH building block was incorporated into the synthesis as the N-terminal residue. For the preparation of peptides 20 and 21, which contains the unnatural D-Thr at the C-terminus, HMP-anchored resin 27 (see Scheme 1, HMP = hydroxymethylphenoxyacetic acid) was first esterified with Fmoc-D-Thr (tBu) -OH using DIC/DMAP and the sequence then elongated by Fmoc SPPS . (0245) Table 1. List of prepared synthetic peptides [N-term] - XiK (Biotin) VPNLRGDLQVX2AQX3VARX4- [C-term] containing substitutions for the native Lysl6 (peptides 2-6) or Leul3 (peptides 7-15), C- terminal/N-terminal variants (peptides 16-21) and DTPA-modified peptides (22-26) . NB: nomenclature, particularly X position (0246) numbering used in this table is not the same as that used in the claims . (0247) Compound N- Xl X2 X3 X4 C- term. term. (0248) 1 NH2 Asn Leu Lys Thr C02H (0249) 2 NH2 Asn Leu D-Lys Thr C02H (0250) 3 NH2 Asn Leu L-Orn Thr C02H (0251) 1-2,4- (0252) 4 NH2 Asn Leu diaminobutyric Thr C02H acid (0253) 1-2,3- (0254) 5 NH2 Asn Leu diaminopropionic Thr C02H acid (0255) 6 NH2 Asn Leu ZV-L-meth llysine Thr C02H (0256) 7 NH2 Asn aminoisobutyric Lys Thr C02H acid (0257) 8 NH2 Asn L-norvaline Lys Thr C02H (0258) 9 NH2 Asn L-norleucine Lys Thr C02H (0259) 10 NH2 Asn L-allylglycine Lys Thr C02H (0260) L-tert- (0261) 11 NH2 Asn Lys Thr C02H butylalanine (0262) 12 NH2 Asn L-homoleucine Lys Thr C02H (0263) L-2-amino-3- (0264) 13 NH2 Asn ethylpentanoic Lys Thr C02H acid (0265) L- (0266) 14 NH2 Asn Lys Thr C02H cyclohexylalanine (0267) 15 L- (0268) NH2 Asn Lys Thr C02H adamantylglycine (0269) 16 Ac-NH Asn Leu Lys Thr C02H (0270) 17 NH2 Asn Leu Lys Thr CONH2 (0271) 18 Ac-NH Asn Leu Lys Thr CONH2 (0272) 19 D- (0273) NH2 Leu Lys Thr C02H (0274) Asn (0275) 20 D- (0276) NH2 Asn Leu Lys C02H (0277) Thr (0278) 21 D- D- (0279) NH2 Leu Lys C02H (0280) Asn Thr (0281) 22 DTPA- (0282) Asn Leu Lys Thr C02H NH (0283) 23 DTPA- (0284) Asn Leu Lys Thr C02H Gly-NH (0285) 24 DTPA- (0286) Asn Leu Lys Thr CONH2 NH (0287) 25 DTPA- D- (0288) Leu Lys Thr C02H NH Asn (0289) 26 DTPA- D- D- (0290) Leu Lys C02H NH Asn Thr (0291) 1 D -yr% -Q ^ (0292) - -^H Q - (0293) (0294) Scheme 1. Synthetic protocol for the preparation of the biotinylated A20FMDV2 peptide variants. (0295) The results obtained from the binding assays (Table 2, see later) s...

Reference： [1]Patent: WO2018/197490,2018,A1 .Location in patent: Page/Page column 21-25; 32-37

81
[ 29022-11-5 ]
C₁₉H₁₆ClN₂Pol [ No CAS ]
[ 86123-10-6 ]
[ 150629-67-7 ]
[ 146982-24-3 ]
Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
C₈₇H₉₉ClN₁₁O₁₄PolS [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 896 - 900

82
[ 15761-38-3 ]
N⁶-[4,6-bis(1,7-dicarba-closo-dodecaboran-9-ylthio)-1,3,5-triazin-2-yl]-N²-(tert-butoxycarbonyl)-L-lysine [ No CAS ]
[ 86123-10-6 ]
[ 150629-67-7 ]
1-tert-butoxycarbonyl-N-[(9-fluorenyl)methoxycarbonyl]-D-tryptophan [ No CAS ]
[ 32926-43-5 ]
[ 143824-78-6 ]
C₅₉H₈₉B₂₀N₁₇O₇S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.5 mg		General procedure: The first four amino acids (from the C-terminus) of peptide 13 were coupled by automated peptide synthesis as described in the general section. Following coupling scheme was used: The remaining two amino acids of peptide 13 were coupled manually using a 5-fold molar excess of amino acid, FIOBt and DIC (75 pmol each) in DMF as solvent. In addition, the whole sequence of peptide 15 was prepared by manual synthesis on a Rink amide AM resin using the same reagent conditions. Following coupling scheme was applied: In case of peptide 15, the resin was treated with a capping solution of 10 % DIPEA and 10 % acetic anhydride in DCM (15 min, 500 pi) after loading with the first C-terminal amino acid. Removal of Fmoc protecting groups after each manual coupling step was accomplished by using 20 % piperidine in DMF (2 x 10 min, 500 mI each). Peptides 14 and 16 were entirely prepared by automated peptide synthesis as described in the general section. The coupling scheme was as follows: The first two C-terminal amino acids of peptide 17 and 18 were coupled by automated peptide synthesis as described in the general section. Following coupling scheme was used:The remaining three amino acids of peptide 17 and 18 were coupled manually using a 3-fold or 5- fold molar excess of the amino acid and a 5-fold molar excess of FIOBt and DIC (75 pmol each) in DMF as solvent. The coupling scheme was as follows: Removal of Fmoc protecting groups after each manual coupling step was accomplished by using 20 % piperidine in DMF (2 x 10 min, 500 pi each). For the removal of the Mmt protecting group in peptide 13, the resin was treated with a cleavage mixture consisting of 2 % TFA, 5 % TIS in DCM (8 x 2 min, 1 ml each). After each deprotection step, the resin was washed with DCM. Finally, the resin was incubated with 5 % DIPEA in DCM (2 x 10 min, 1 ml each). For the cleavage of the Dde protecting group in all other peptides (14-18), the resin was treated with 2 % hydrazine in DMF (10 x 10 min, 1 ml each). In case of peptide 14, the building block Fmoc-L-Dap(Mtt)-OFI was coupled manually in 3-fold molar excess with a 5-fold molar excess of FIOBt and DIC (75 pmol each) to the e-amino group of the C- terminal lysine. DMF was used as solvent and the coupling time was approximately 16 h. For peptide 16, the building block Fmoc-L-Dap(Fmoc)-OFI was coupled manually in 5-fold molar excess with FIOBt and DIC (75 pmol each) in DMF to the C-terminal lysine side-chain. The coupling time was 4 h. Subsequently, removal of the Fmoc protecting groups was achieved by using 20 % piperidine in DMF (2 x 10 min, 500 mI each). 6-TAMRA was coupled manually to peptide 16 using a 2-fold molar excess of the fluorophore, FIATU and DIPEA (30 pmol each) in DMF as solvent for 5 h. Afterwards, removal of the Mtt protecting group in peptide 16 was performed as described for the Mmt deprotection above.The carbaboranes were coupled manually in 3-fold molar excess per free lysine or Dap amino group, except for mlJ9b, which was coupled in 1.5-fold molar excess per free amino group. Coupling reactions were prepared as follows: Peptides 13, 14 and 17: 3 eq. m9b, 5 eq. FIOBt and 5 eq. DIC in DMF as solvent. Peptide 15: 3 eq. bm9x, 4 eq. FIOBt and 4 eq. DIC in DMF. Peptide 16: 3 eq. mlJ9b, 4 eq. FIOBt and 4 eq. DIC in DMF. Peptide 18: 1.5 eq. mlJ9b, 2 eq. FIOBt and 2 eq. DIC in DMF. All coupling reactions were performed overnight for approximately 16 h. Cleavage of conjugates 13-15 and 17 from the resin and simultaneous side chain deprotection was accomplished using a mixture of TFA/TA/EDT (90:7:3, 1 ml) for 3 h. Cleavage of conjugates 16 and 18 from the resin was achieved using a mixture of TFA/FhO (95:5, 1 ml) for 3 h. The crude conjugates were precipitated and washed with an ice-cold mixture of hexane/diethyl ether (3:1, v/v), dissolved in ACN/FI2O and subsequently lyophilized. The first purification of the crude conjugate 13 was performed by preparative RP-HPLC using a C18- column (Phenomenex Jupiter 5u 300 A: 250 mm c 21.2 mm, 5 pm, 300 A) with a flow rate of 10 ml/min and a linear gradient of 50 % to 80 % eluent B in A over 30 min. Conjugate 13 had to be purified a second time using a XBridge C18-column (Waters XBridge Peptide BEH C18 OBD: 250 mm c 19 mm, 10 pm, 130 A) with a flow rate of 15 ml/min and a linear gradient of 50 % to 80 % eluent B in A over 30 min. For purification of conjugate 14, a XBridge C18-column (Waters XBridge Peptide BEH C18 OBD: 250 mm c 19 mm, 10 pm, 130 A) with a flow rate of 15 ml/min and a linear gradient of 30 % to 60 % eluent B in A over 30 min was applied. Purification of the conjugates 15-17 was achieved using a Kinetex C18-column (Phenomenex Kinetex 5u XB-C18: 250 mm c 21.2 mm, 5 pm, 100 A) with a flow rate of 15 ml/min. For conjugate 15 and 16, a linear gradient of 40 % to 70 % eluent B in A over 30 min was used, whereas for conjugate 17 a gradient of 50 % to 80 % eluent B in A over 30 min was applied. Purification of the...

Reference： [1]Patent: WO2019/115624,2019,A1 .Location in patent: Page/Page column 52-55; 57

83
[ 15761-38-3 ]
1-(1’,2’ :3’,4’-di-O-isopropylidene-6’-deoxy-a-D-galactopyranos-6’-yI)-9-(carboxymethylthio)-1,7-dicarba-closo-dodecaborane(12) [ No CAS ]
[ 86123-10-6 ]
[ 150629-67-7 ]
1-tert-butoxycarbonyl-N-[(9-fluorenyl)methoxycarbonyl]-D-tryptophan [ No CAS ]
[ 32926-43-5 ]
[ 143824-78-6 ]
N^α,N^β-di[(9-fluorenylmethyl)oxycarbonyl]-(S)-2,3-diaminopropionic acid [ No CAS ]
C₆₉H₁₀₆B₂₀N₁₄O₁₉S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
9.7 mg		General procedure: The first four amino acids (from the C-terminus) of peptide 13 were coupled by automated peptide synthesis as described in the general section. Following coupling scheme was used: The remaining two amino acids of peptide 13 were coupled manually using a 5-fold molar excess of amino acid, FIOBt and DIC (75 pmol each) in DMF as solvent. In addition, the whole sequence of peptide 15 was prepared by manual synthesis on a Rink amide AM resin using the same reagent conditions. Following coupling scheme was applied: In case of peptide 15, the resin was treated with a capping solution of 10 % DIPEA and 10 % acetic anhydride in DCM (15 min, 500 pi) after loading with the first C-terminal amino acid. Removal of Fmoc protecting groups after each manual coupling step was accomplished by using 20 % piperidine in DMF (2 x 10 min, 500 mI each). Peptides 14 and 16 were entirely prepared by automated peptide synthesis as described in the general section. The coupling scheme was as follows: The first two C-terminal amino acids of peptide 17 and 18 were coupled by automated peptide synthesis as described in the general section. Following coupling scheme was used:The remaining three amino acids of peptide 17 and 18 were coupled manually using a 3-fold or 5- fold molar excess of the amino acid and a 5-fold molar excess of FIOBt and DIC (75 pmol each) in DMF as solvent. The coupling scheme was as follows: Removal of Fmoc protecting groups after each manual coupling step was accomplished by using 20 % piperidine in DMF (2 x 10 min, 500 pi each). For the removal of the Mmt protecting group in peptide 13, the resin was treated with a cleavage mixture consisting of 2 % TFA, 5 % TIS in DCM (8 x 2 min, 1 ml each). After each deprotection step, the resin was washed with DCM. Finally, the resin was incubated with 5 % DIPEA in DCM (2 x 10 min, 1 ml each). For the cleavage of the Dde protecting group in all other peptides (14-18), the resin was treated with 2 % hydrazine in DMF (10 x 10 min, 1 ml each). In case of peptide 14, the building block Fmoc-L-Dap(Mtt)-OFI was coupled manually in 3-fold molar excess with a 5-fold molar excess of FIOBt and DIC (75 pmol each) to the e-amino group of the C- terminal lysine. DMF was used as solvent and the coupling time was approximately 16 h. For peptide 16, the building block Fmoc-L-Dap(Fmoc)-OFI was coupled manually in 5-fold molar excess with FIOBt and DIC (75 pmol each) in DMF to the C-terminal lysine side-chain. The coupling time was 4 h. Subsequently, removal of the Fmoc protecting groups was achieved by using 20 % piperidine in DMF (2 x 10 min, 500 mI each). 6-TAMRA was coupled manually to peptide 16 using a 2-fold molar excess of the fluorophore, FIATU and DIPEA (30 pmol each) in DMF as solvent for 5 h. Afterwards, removal of the Mtt protecting group in peptide 16 was performed as described for the Mmt deprotection above.The carbaboranes were coupled manually in 3-fold molar excess per free lysine or Dap amino group, except for mlJ9b, which was coupled in 1.5-fold molar excess per free amino group. Coupling reactions were prepared as follows: Peptides 13, 14 and 17: 3 eq. m9b, 5 eq. FIOBt and 5 eq. DIC in DMF as solvent. Peptide 15: 3 eq. bm9x, 4 eq. FIOBt and 4 eq. DIC in DMF. Peptide 16: 3 eq. mlJ9b, 4 eq. FIOBt and 4 eq. DIC in DMF. Peptide 18: 1.5 eq. mlJ9b, 2 eq. FIOBt and 2 eq. DIC in DMF. All coupling reactions were performed overnight for approximately 16 h. Cleavage of conjugates 13-15 and 17 from the resin and simultaneous side chain deprotection was accomplished using a mixture of TFA/TA/EDT (90:7:3, 1 ml) for 3 h. Cleavage of conjugates 16 and 18 from the resin was achieved using a mixture of TFA/FhO (95:5, 1 ml) for 3 h. The crude conjugates were precipitated and washed with an ice-cold mixture of hexane/diethyl ether (3:1, v/v), dissolved in ACN/FI2O and subsequently lyophilized. The first purification of the crude conjugate 13 was performed by preparative RP-HPLC using a C18- column (Phenomenex Jupiter 5u 300 A: 250 mm c 21.2 mm, 5 pm, 300 A) with a flow rate of 10 ml/min and a linear gradient of 50 % to 80 % eluent B in A over 30 min. Conjugate 13 had to be purified a second time using a XBridge C18-column (Waters XBridge Peptide BEH C18 OBD: 250 mm c 19 mm, 10 pm, 130 A) with a flow rate of 15 ml/min and a linear gradient of 50 % to 80 % eluent B in A over 30 min. For purification of conjugate 14, a XBridge C18-column (Waters XBridge Peptide BEH C18 OBD: 250 mm c 19 mm, 10 pm, 130 A) with a flow rate of 15 ml/min and a linear gradient of 30 % to 60 % eluent B in A over 30 min was applied. Purification of the conjugates 15-17 was achieved using a Kinetex C18-column (Phenomenex Kinetex 5u XB-C18: 250 mm c 21.2 mm, 5 pm, 100 A) with a flow rate of 15 ml/min. For conjugate 15 and 16, a linear gradient of 40 % to 70 % eluent B in A over 30 min was used, whereas for conjugate 17 a gradient of 50 % to 80 % eluent B in A over 30 min was applied. Purification of the...

Reference： [1]Patent: WO2019/115624,2019,A1 .Location in patent: Page/Page column 52-55; 58

84
[ 30992-29-1 ]
9‐(carboxymethylthio)‐1,7‐dicarba‐closododecaborane(12) [ No CAS ]
[ 86123-10-6 ]
[ 150629-67-7 ]
[ 32926-43-5 ]
N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine [ No CAS ]
Aib‐H‐(D‐2‐Nal)‐fK(9‐(carboxymethylthio)‐1,7‐dicarba‐closododecaborane(12))‐NH₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2 mg		General procedure: The first four amino acids (from the C-terminus) of peptide 13 were coupled by automated peptide synthesis as described in the general section. Following coupling scheme was used: The remaining two amino acids of peptide 13 were coupled manually using a 5-fold molar excess of amino acid, FIOBt and DIC (75 pmol each) in DMF as solvent. In addition, the whole sequence of peptide 15 was prepared by manual synthesis on a Rink amide AM resin using the same reagent conditions. Following coupling scheme was applied: In case of peptide 15, the resin was treated with a capping solution of 10 % DIPEA and 10 % acetic anhydride in DCM (15 min, 500 pi) after loading with the first C-terminal amino acid. Removal of Fmoc protecting groups after each manual coupling step was accomplished by using 20 % piperidine in DMF (2 x 10 min, 500 mI each). Peptides 14 and 16 were entirely prepared by automated peptide synthesis as described in the general section. The coupling scheme was as follows: The first two C-terminal amino acids of peptide 17 and 18 were coupled by automated peptide synthesis as described in the general section. Following coupling scheme was used:The remaining three amino acids of peptide 17 and 18 were coupled manually using a 3-fold or 5- fold molar excess of the amino acid and a 5-fold molar excess of FIOBt and DIC (75 pmol each) in DMF as solvent. The coupling scheme was as follows: Removal of Fmoc protecting groups after each manual coupling step was accomplished by using 20 % piperidine in DMF (2 x 10 min, 500 pi each). For the removal of the Mmt protecting group in peptide 13, the resin was treated with a cleavage mixture consisting of 2 % TFA, 5 % TIS in DCM (8 x 2 min, 1 ml each). After each deprotection step, the resin was washed with DCM. Finally, the resin was incubated with 5 % DIPEA in DCM (2 x 10 min, 1 ml each). For the cleavage of the Dde protecting group in all other peptides (14-18), the resin was treated with 2 % hydrazine in DMF (10 x 10 min, 1 ml each). In case of peptide 14, the building block Fmoc-L-Dap(Mtt)-OFI was coupled manually in 3-fold molar excess with a 5-fold molar excess of FIOBt and DIC (75 pmol each) to the e-amino group of the C- terminal lysine. DMF was used as solvent and the coupling time was approximately 16 h. For peptide 16, the building block Fmoc-L-Dap(Fmoc)-OFI was coupled manually in 5-fold molar excess with FIOBt and DIC (75 pmol each) in DMF to the C-terminal lysine side-chain. The coupling time was 4 h. Subsequently, removal of the Fmoc protecting groups was achieved by using 20 % piperidine in DMF (2 x 10 min, 500 mI each). 6-TAMRA was coupled manually to peptide 16 using a 2-fold molar excess of the fluorophore, FIATU and DIPEA (30 pmol each) in DMF as solvent for 5 h. Afterwards, removal of the Mtt protecting group in peptide 16 was performed as described for the Mmt deprotection above.The carbaboranes were coupled manually in 3-fold molar excess per free lysine or Dap amino group, except for mlJ9b, which was coupled in 1.5-fold molar excess per free amino group. Coupling reactions were prepared as follows: Peptides 13, 14 and 17: 3 eq. m9b, 5 eq. FIOBt and 5 eq. DIC in DMF as solvent. Peptide 15: 3 eq. bm9x, 4 eq. FIOBt and 4 eq. DIC in DMF. Peptide 16: 3 eq. mlJ9b, 4 eq. FIOBt and 4 eq. DIC in DMF. Peptide 18: 1.5 eq. mlJ9b, 2 eq. FIOBt and 2 eq. DIC in DMF. All coupling reactions were performed overnight for approximately 16 h. Cleavage of conjugates 13-15 and 17 from the resin and simultaneous side chain deprotection was accomplished using a mixture of TFA/TA/EDT (90:7:3, 1 ml) for 3 h. Cleavage of conjugates 16 and 18 from the resin was achieved using a mixture of TFA/FhO (95:5, 1 ml) for 3 h. The crude conjugates were precipitated and washed with an ice-cold mixture of hexane/diethyl ether (3:1, v/v), dissolved in ACN/FI2O and subsequently lyophilized. The first purification of the crude conjugate 13 was performed by preparative RP-HPLC using a C18- column (Phenomenex Jupiter 5u 300 A: 250 mm c 21.2 mm, 5 pm, 300 A) with a flow rate of 10 ml/min and a linear gradient of 50 % to 80 % eluent B in A over 30 min. Conjugate 13 had to be purified a second time using a XBridge C18-column (Waters XBridge Peptide BEH C18 OBD: 250 mm c 19 mm, 10 pm, 130 A) with a flow rate of 15 ml/min and a linear gradient of 50 % to 80 % eluent B in A over 30 min. For purification of conjugate 14, a XBridge C18-column (Waters XBridge Peptide BEH C18 OBD: 250 mm c 19 mm, 10 pm, 130 A) with a flow rate of 15 ml/min and a linear gradient of 30 % to 60 % eluent B in A over 30 min was applied. Purification of the conjugates 15-17 was achieved using a Kinetex C18-column (Phenomenex Kinetex 5u XB-C18: 250 mm c 21.2 mm, 5 pm, 100 A) with a flow rate of 15 ml/min. For conjugate 15 and 16, a linear gradient of 40 % to 70 % eluent B in A over 30 min was used, whereas for conjugate 17 a gradient of 50 % to 80 % eluent B in A over 30 min was applied. Purification of the...

Reference： [1]Patent: WO2019/115624,2019,A1 .Location in patent: Page/Page column 52-55; 58

85
[ 15761-38-3 ]
9‐(carboxymethylthio)‐1,7‐dicarba‐closododecaborane(12) [ No CAS ]
6-TAMRA [ No CAS ]
[ 86123-10-6 ]
[ 150629-67-7 ]
1-tert-butoxycarbonyl-N-[(9-fluorenyl)methoxycarbonyl]-D-tryptophan [ No CAS ]
[ 32926-43-5 ]
[ 143824-78-6 ]
N²-(9-fluorenylmethyloxycarbonyl)-N³-(4-methyltrityl)-2,3-diaminopropanoic acid [ No CAS ]
[K⁶(Dap(TAMRA/m9b))]-GHRP-6 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5.8 mg		General procedure: The first four amino acids (from the C-terminus) of peptide 13 were coupled by automated peptide synthesis as described in the general section. Following coupling scheme was used: The remaining two amino acids of peptide 13 were coupled manually using a 5-fold molar excess of amino acid, FIOBt and DIC (75 pmol each) in DMF as solvent. In addition, the whole sequence of peptide 15 was prepared by manual synthesis on a Rink amide AM resin using the same reagent conditions. Following coupling scheme was applied: In case of peptide 15, the resin was treated with a capping solution of 10 % DIPEA and 10 % acetic anhydride in DCM (15 min, 500 pi) after loading with the first C-terminal amino acid. Removal of Fmoc protecting groups after each manual coupling step was accomplished by using 20 % piperidine in DMF (2 x 10 min, 500 mI each). Peptides 14 and 16 were entirely prepared by automated peptide synthesis as described in the general section. The coupling scheme was as follows: The first two C-terminal amino acids of peptide 17 and 18 were coupled by automated peptide synthesis as described in the general section. Following coupling scheme was used:The remaining three amino acids of peptide 17 and 18 were coupled manually using a 3-fold or 5- fold molar excess of the amino acid and a 5-fold molar excess of FIOBt and DIC (75 pmol each) in DMF as solvent. The coupling scheme was as follows: Removal of Fmoc protecting groups after each manual coupling step was accomplished by using 20 % piperidine in DMF (2 x 10 min, 500 pi each). For the removal of the Mmt protecting group in peptide 13, the resin was treated with a cleavage mixture consisting of 2 % TFA, 5 % TIS in DCM (8 x 2 min, 1 ml each). After each deprotection step, the resin was washed with DCM. Finally, the resin was incubated with 5 % DIPEA in DCM (2 x 10 min, 1 ml each). For the cleavage of the Dde protecting group in all other peptides (14-18), the resin was treated with 2 % hydrazine in DMF (10 x 10 min, 1 ml each). In case of peptide 14, the building block Fmoc-L-Dap(Mtt)-OFI was coupled manually in 3-fold molar excess with a 5-fold molar excess of FIOBt and DIC (75 pmol each) to the e-amino group of the C- terminal lysine. DMF was used as solvent and the coupling time was approximately 16 h. For peptide 16, the building block Fmoc-L-Dap(Fmoc)-OFI was coupled manually in 5-fold molar excess with FIOBt and DIC (75 pmol each) in DMF to the C-terminal lysine side-chain. The coupling time was 4 h. Subsequently, removal of the Fmoc protecting groups was achieved by using 20 % piperidine in DMF (2 x 10 min, 500 mI each). 6-TAMRA was coupled manually to peptide 16 using a 2-fold molar excess of the fluorophore, FIATU and DIPEA (30 pmol each) in DMF as solvent for 5 h. Afterwards, removal of the Mtt protecting group in peptide 16 was performed as described for the Mmt deprotection above.The carbaboranes were coupled manually in 3-fold molar excess per free lysine or Dap amino group, except for mlJ9b, which was coupled in 1.5-fold molar excess per free amino group. Coupling reactions were prepared as follows: Peptides 13, 14 and 17: 3 eq. m9b, 5 eq. FIOBt and 5 eq. DIC in DMF as solvent. Peptide 15: 3 eq. bm9x, 4 eq. FIOBt and 4 eq. DIC in DMF. Peptide 16: 3 eq. mlJ9b, 4 eq. FIOBt and 4 eq. DIC in DMF. Peptide 18: 1.5 eq. mlJ9b, 2 eq. FIOBt and 2 eq. DIC in DMF. All coupling reactions were performed overnight for approximately 16 h. Cleavage of conjugates 13-15 and 17 from the resin and simultaneous side chain deprotection was accomplished using a mixture of TFA/TA/EDT (90:7:3, 1 ml) for 3 h. Cleavage of conjugates 16 and 18 from the resin was achieved using a mixture of TFA/FhO (95:5, 1 ml) for 3 h. The crude conjugates were precipitated and washed with an ice-cold mixture of hexane/diethyl ether (3:1, v/v), dissolved in ACN/FI2O and subsequently lyophilized. The first purification of the crude conjugate 13 was performed by preparative RP-HPLC using a C18- column (Phenomenex Jupiter 5u 300 A: 250 mm c 21.2 mm, 5 pm, 300 A) with a flow rate of 10 ml/min and a linear gradient of 50 % to 80 % eluent B in A over 30 min. Conjugate 13 had to be purified a second time using a XBridge C18-column (Waters XBridge Peptide BEH C18 OBD: 250 mm c 19 mm, 10 pm, 130 A) with a flow rate of 15 ml/min and a linear gradient of 50 % to 80 % eluent B in A over 30 min. For purification of conjugate 14, a XBridge C18-column (Waters XBridge Peptide BEH C18 OBD: 250 mm c 19 mm, 10 pm, 130 A) with a flow rate of 15 ml/min and a linear gradient of 30 % to 60 % eluent B in A over 30 min was applied. Purification of the conjugates 15-17 was achieved using a Kinetex C18-column (Phenomenex Kinetex 5u XB-C18: 250 mm c 21.2 mm, 5 pm, 100 A) with a flow rate of 15 ml/min. For conjugate 15 and 16, a linear gradient of 40 % to 70 % eluent B in A over 30 min was used, whereas for conjugate 17 a gradient of 50 % to 80 % eluent B in A over 30 min was applied. Purification of the...

Reference： [1]Patent: WO2019/115624,2019,A1 .Location in patent: Page/Page column 52-56

86
Fmoc-Rink resin [ No CAS ]
[ 29022-11-5 ]
[ 68858-20-8 ]
[ 35661-60-0 ]
[ 35661-39-3 ]
[ 1315449-94-5 ]
[ 35661-40-6 ]
[ 71989-33-8 ]
[ 71989-18-9 ]
[ 108-24-7 ]
[ 71989-23-6 ]
[ 71989-26-9 ]
[ 71989-35-0 ]
[ 94744-50-0 ]
[ 150629-67-7 ]
[ 159766-56-0 ]
Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
Ac-L-E(OtBu)-G-R(Pfb)-E(OtBu)-K(Boc)-V-R(Pfb)-A-K(Ac)-I-Aib-Aib-E(OtBu)-G-K(Dde)-S(tBu)-T(tBu)-F-S(tBu)-Mly(Boc)-R(Pfb)-A-K(Ac)-NH-Rink Amide Resin, Ac - acetyl, Aib - 2-amino-isobutyric acid, Boc - tert-butyloxycarbonyl, Dde - 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl, Mly - α-methyl-lysine, Pfb - 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl, tBu - tert-butyl [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		2.A Loading of Fmoc-Lys(Ac)-OH on Rink Amide Resin (0433) In a 100 ml reactor equipped with a sintered glass at the bottom, 6 g of Novabiochem or ChemImpex Rink amide AM resin (Low Loading 0.47 mmol/g) was swelled in 40 ml of DMF. The solvent was drained and 30 ml of 20% piperidine in DMF solution were added. After 15 min shaking, the solvent was drained. This was repeated twice to ensure complete Fmoc protecting group removal. The resin was washed with 5×30 ml DMF. (0434) In a separate flask a solution containing Fmoc-Lys(Ac)-OH (3.5 g, 8 mmol, 3 eq.) HOBT.H2O (1.3 g 8.5 mmol) in 30 ml DMF was prepared. Diisopropylcarbodiimide (DIC) (1 g, 8.5 mmol) was added to this solution and after 5 min the resulting mixture was added to the resin. The suspension was shaken on a stirring plate for 4 h or until completion of the reaction as judged by Kaiser Test (Ninhidrin test) on an aliquot part of the resin. (0435) The solvent was then drained and the resin washed 3 times with 30 ml DMF. Fmoc-Lys(Ac)-NH2 loaded resin was used immediately for subsequent steps or stored wet at 4 C. until needed. (0436) 2.B. Synthesis of Peptide Having the SEQ ID NO: 3 (0437) The following synthesis was performed using 5 times an amount of resin obtained at step 2.A. corresponding to 0.2 mmol of Fmoc-Lys(Ac)-NH2 each. The syntheses were performed separately on each individual batches using a CEM Liberty Blue microwave peptide synthesizer to assemble the second and third residue of the peptide sequence (starting from the C-terminus). (0438) Peptide synthesis was performed by using DIC 0.5M/Oxyma 1M in DMF. (0439) All amino acids were introduced with double couplings using standard heating protocol. (0440) The resin was removed from the synthesizer and Fmoc-alpha-methyl-lysine(Boc)-OH (3 eq.) was coupled manually using 3 eq. Oxyma and 3 eq. DIC with microwave heating (75 C. 15 sec. and 90 C. 110 sec). The completion of the reaction was controlled by Kaiser test. If positive, DIC 3 eq. was added followed by microwave heating as above. When coupling of Fmoc-alpha-methyl-lysine(Boc)-OH was complete the rest of the peptide sequence was assembled using a CEM Liberty Blue microwave peptide synthesizer. (0442) All amino acids were introduced with double couplings at 90 C. as above, with the exception of amino-isobutyric acid at position 21 and serine at position 29 for which a triple coupling at 90 for 2 minutes was performed. Fmoc-Lys(Dde)-OH was used at position 25. (0443) At the end of the 5 syntheses, the 5 batches of resin were combined and transferred into a 50 mL polypropylene syringe and the peptide was acetylated at N-terminus with acetic anhydride (944 10 mmol) in DMF (30 mL) for 20 minutes, repeating the cycle twice. (0444) Then, Dde protecting group on Lysine 25 side chain was removed by percolating 50 mL of a solution of hydrazine 5% w/v in DMF, followed by DMF washes (5×20 ml). The reaction was monitored by Kaiser Test and cleavage of an aliquot part of resin and UPLC/MS analysis. (0445) Three TTDS spacer units were introduced by single coupling by performing three times the following procedure: To the resin a solution of Fmoc-TTDS-OH (1.62 g, 3 mmol) in 30 mL of DMF were added followed by HOAt (5 ml of a 0.6 ml solution in DMF, 3 mmol) and DIC (1 ml, 6 mmol). The syringe was agitated on an orbital table for 18 h. The reaction was monitored by Kaiser Test. The resin was washed with DMF (2×30 mL). Then to the resin, 30 mL of 20% v/v of piperidine in DMF was added. The syringe was agitated on an orbital table for 20 min. This deprotection procedure was repeated a second time and the resin was washed with DMF (2×30 mL) and dichloromethane (3×30 mL). (0446) The three gamma-glutamic acids spacers were introduced by performing a double coupling of each Fmoc-Glu-OtBu. Thus the following procedure was applied three times: To the resin a solution (4S)-5-tert-butoxy-4-(9H-fluoren-9-yl methoxy carbonylamino)-5-oxo-pentanoic acid (Fmoc-Glu-OtBu) (1.275 g, 3 mmol) in of 30 mL of DMF were added followed by HOAt (5 ml of a 0.6 ml solution in DMF 3 mmol) and DIC (1 ml, 6 mmol). The syringe was agitated on an orbital table for 4 h. The resin was washed with DMF (2×20 mL) and the coupling was repeated a second time. The reaction was monitored by Kaiser Test. The resin was washed with DMF (2×30 mL). Then to the resin, 30 mL of 20% v/v of piperidine in DMF was added. The syringe was agitated on an orbital table for 20 min. This deprotection procedure was repeated a second time and the resin was washed with DMF (3×30 mL) and dichloromethane (3×30 mL). (0448) Finally, the peptide was acylated with palmitic acid (768 mg, 3 mmol), HOAt (5 ml of a 0.6 M solution in DMF, 3 mmol) and DIC (1 ml, 6 mmol) activation in DMF (30 mL) for 2.5 h. The resin was washed with DMF (2×30 mL) and dichloromethane (3×30mL) and dried under vacuum. (0449) The cleavage of the peptide from the resin was performed using a solution phenol (6.25 g), water (6.25 mL) and TIPS (3 mL) ...

Reference： [1]Patent: US2019/233494,2019,A1 .Location in patent: Paragraph 0347-0455

87
2-chlorotrityl chloride polystyrene resin [ No CAS ]
[ 75932-02-4 ]
[ 150629-67-7 ]
C₄₁H₅₀ClN₄O₅Pol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A 2-chloro trityl chloride resin (100-200 mesh, Novabiochem 100 mg, 1 eq.), Fmoc-Lys(Dde)-OH (Na-Fmoc-Nepsilon-Dde-L-lysine, Nalpha-Fmoc-Nepsilon-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl]-L-lysine) (106.5 mg, 2 eq.), and diisopropylamine (DIPEA, 69.7 mul, 4 eq.) dissolved in 5 ml of dichloromethane (DCM) were added to a 10 ml reaction vessel, and were reacted at room temperature (23 C.) for 12 hours. The reaction solution was removed by filtration, and the synthesized resin was subsequently washed using 10 ml of each of dichloromethane and methanol (MeOH), dichloromethane, and dimethylformamide (DMF), thereby quantitatively obtaining Compound 1a. Step 2. Synthesis of Compound 1b (Fmoc-Lys(Fmoc)-Lys(Dde)-O-2-chloro trityl Resin) (0147) (0148) 5 ml of 20% piperidine (in DMF) was added to the reaction vessel of step 1 (Compound 1a obtained in step 1), reacted at room temperature for 5 minutes, and filtered to remove the reaction solution. 5 ml of 20% piperidine (in DMF) was added once more, and reacted at room temperature for 5 minutes. The reaction solution was removed by filtration, the synthesized resin was sequentially washed with 10 ml of each of DCM and MeOH, DCM, and DMF, Fmoc-Lys(Fmoc)-OH (236.3 mg, 4 eq.), hydroxybenzotriazole (HOBt, 54.1 mg, 4 eq.), and N,N-diisopropylcarbodiimide (DIC, 61.9 mul, 4 eq.) dissolved in 5 ml of DMF were added, and reacted at room temperature for 2 hours. The reaction solution was removed by filtration, and the synthesized resin was subsequently washed using 10 ml of each of DCM and MeOH, DCM, and DMF, thereby quantitatively obtaining Compound 1b. Step 3. Synthesis of Compound 1c (tert-butoxycarbonylmethyl)2-Lys(tert-butoxycarbonylmethyl)2-Lys(Dde)-O-2-chloro trityl Resin) (0149) (0150) 5 ml of 20% piperidine (in DMF) was added to the reaction vessel of step 2 (Compound 1b obtained in step 2), reacted at room temperature for 5 minutes, and filtered to remove the reaction solution. 5 ml of 20% piperidine (in DMF) was added once more, and reacted at room temperature for 5 minutes. The reaction solution was removed by filtration, the synthesized resin was sequentially washed using 500 ml of each of DCM and MeOH, DCM, and DMF, t-butyl bromoacetate (147.7 mul, 10 eq.) and DIPEA (261.3 mul, 15 eq.) dissolved in 5 ml of DMF were added, and reacted at room temperature for 48 hours. The reaction solution was removed by filtration, and the synthesized resin was subsequently washed using 10 ml of each of DCM and MeOH, DCM, and DMF, thereby quantitatively obtaining Compound 1c.

Reference： [1]Patent: US2019/382340,2019,A1 .Location in patent: Paragraph 0145-0150

88
[ 159751-47-0 ]
[ 21947-98-8 ]
C₂₉H₃₁N₃O₅ [ No CAS ]
[ 150629-67-7 ]
[ 162648-54-6 ]
[ 181517-99-7 ]
[ 613245-91-3 ]
C₇₂H₁₀₉N₁₅O₁₈S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		The synthetic approach used to synthesize YLL8-Lys(D-Cys) is shown below in Scheme 2. Rink amide MBHA resin (0.5 g, 0.325 mmol, loading 0.65 mmol/g) was swollen in DMF for 3 hours. Fmoc was deprotected with 20% 4-methylpiperidine in DMF twice (5 and 15 minutes, respectively). After filtration, the beads were then washed with DMF (3x10 mL), methanol (MeOH) (3x10 mL) and DMF (3x10 mL), respectively. Fmoc-Lys(Dde)-OH (0.519 g, 0.975 mmol) was dissolved in a solution of 6-C1 HOBt (0.165 g, 0.975 mmol) and DIC (152 pL, 0.975 mmol) in DMF (8 mL), which was then added to the suspension of the beads. The coupling was carried out at room temperature overnight. After filtration, the beads were washed with DMF (3x10 mL), MeOH (3x10 mL), and DMF (3x10 mL), respectively. Fmoc was deprotected with 20% 4-methylpiperidine in DMF (8 mL) twice (5 and 15 minutes, respectively). Fmoc-Linker (0.612 g, 1.3 mmol) was dissolved in a solution of HOBt (0.22 g, 1.3 mmol) and DIC (201 pL, 1.3 mmol) in DMF (8 mL), which was then added to the suspension of the beads. The coupling was carried out at room temperature until Kaiser test is negative. After filtration, the beads were washed with DMF (3x10 mL), MeOH (3x10 mL), and DMF (3x10 mL), respectively. Fmoc was deprotected with 20% 4-methylpiperidine in DMF (8 mL) twice (5 and 15 minutes, respectively). Fmoc-Linker (0.612 g, 1.3 mmol) was dissolved in a solution of HOBt (0.22 g, 1.3 mmol) and DIC (201 pL, 1.3 mmol) in DMF (8 mL), which was then added to the suspension of the beads. The coupling was carried out at room temperature until Kaiser test is negative. After filtration, the beads were washed with DMF (3x10 mL), MeOH (3x10 mL), and DMF (3x10 mL), respectively. Fmoc was deprotected with 20% 4-methylpiperidine in DMF (8 mL) twice (5 and 15 minutes, respectively). After filtration, the beads were washed with DMF (3x10 mL), MeOH (3x10 mL), and DMF (3x10 mL), respectively. Fmoc-Ach-OH (0.365 g, 0.975 mmol) was dissolved in a solution of 6-C1 HOBt (0.165 g, 0.975 mmol) and DIC (152 pL, 0.975 mmol) in DMF, and was then added to the beads. The coupling was carried out at room temperature for 2 hours.After filtration, the beads were washed with DMF (3x10 mL), MeOH (3x10 mL), and DMF (3x10 mL), respectively. The Fmoc deprotection group was removed with 20% 4- methylpiperidine twice (5 and 15 minutes, respectively). After washing with DMF, MeOH, and DMF respectively, the beads were then subjected to additional coupling and deprotection cycles stepwise with Fmoc-Aad(0/Bu)-OH, Fmoc-Lys(Al2) and UPA in the same manner as described above.The Dde protecting group was removed with 2% hydrazine monohydrate in DMF twice (5 and 10 minutes, respectively) and the beads were again washed with DMF, MeOH and DMF, followed by coupling of Boc-D-Cys(Trt)-OH (4 eq. to resin, 220 mg, 1.3 mmol), HOBt (0T76g, 1.3 mmol), and DIC (201 pL, 1.3 mmol) in DMF (8 mL). The coupling reaction was conducted at room temperature until Kaiser test negative (4 hours to overnight). The beads were thoroughly washed with DMF, MeOH and DCM, respectively, and then dried under vacuum for 1 hour before adding a cleavage mixture (8 mL) of 82.5%trifluoroacetic acid (TFA): 5% thioanisole: 5% phenol:5% water: 2.5% triisopropylsilane (TIS) (v/v). The cleavage reaction was conducted at room temperature over 2-3 hours. The off-white crude product was precipitated out and washed with cold diethyl ether. The purity was determined by analytical HPLC and the crude product was used in the next step without further purification.

Reference： [1]Patent: WO2020/18941,2020,A1 .Location in patent: Paragraph 0185; 0188-0190

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Ghs Precautionary Statements

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Code	Phrase
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Code	Phrase
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Code	Phrase
P301	IF SWALLOWED:
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P320
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P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Ghs Hazard Statements

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere