[ CAS No. 166737-85-5 ] {[proInfo.proName]}

Name: 166737-85-5|H-Cys(Trt)-NH2|95%
Brand: Ambeed
SKU: A129329
Price: 9.0 USD
Availability: InStock
Rating: 95 (25 reviews)

,{[proInfo.pro_purity]}

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

2D 3D

Structure of 166737-85-5 * Storage: {[proInfo.prStorage]}

Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

For Research Only 110K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 166737-85-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 166737-85-5 ]

SDS Specification

Alternatived Products of [ 166737-85-5 ]

Product Details of [ 166737-85-5 ]

CAS No. :	166737-85-5	MDL No. :	MFCD22126061
Formula :	C₂₂H₂₂N₂OS	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	OHWBGKONMFYEKL-FQEVSTJZSA-N
M.W :	362.49	Pubchem ID :	44432703
Synonyms :

Calculated chemistry of [ 166737-85-5 ]

Physicochemical Properties

Num. heavy atoms :	26
Num. arom. heavy atoms :	18
Fraction Csp3 :	0.14
Num. rotatable bonds :	7
Num. H-bond acceptors :	2.0
Num. H-bond donors :	2.0
Molar Refractivity :	107.89
TPSA :	94.41 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-5.89 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.63
Log Po/w (XLOGP3) :	3.69
Log Po/w (WLOGP) :	3.42
Log Po/w (MLOGP) :	3.52
Log Po/w (SILICOS-IT) :	3.89
Consensus Log Po/w :	3.43

Druglikeness

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

Water Solubility

Log S (ESOL) :	-4.46
Solubility :	0.0125 mg/ml ; 0.0000345 mol/l
Class :	Moderately soluble
Log S (Ali) :	-5.36
Solubility :	0.00157 mg/ml ; 0.00000434 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-7.23
Solubility :	0.0000215 mg/ml ; 0.0000000594 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	3.64

Safety of [ 166737-85-5 ]

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

Application In Synthesis of [ 166737-85-5 ]

* 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 [ 166737-85-5 ]
Downstream synthetic route of [ 166737-85-5 ]

[ 166737-85-5 ] Synthesis Path-Upstream 1~4

1
[ 202752-01-0 ]
[ 166737-85-5 ]

Yield	Reaction Conditions	Operation in experiment
92%	With piperidine In N,N-dimethyl-formamide at 20℃; for 4 h;	A solution of the compound (R) - (9H-fluoren-9-yl) methyl (1-amino-1-oxo-3- (triphenylmethylthio) propan-2-yl) carbamate (4 g, 6.84 mmol )Was dissolved in N, N-dimethylformamide (20 ml)Piperidine (0.14 ml, 1.368 mmol) was added,Reaction at room temperature for 4 hours,TLC detection reaction is completed,The reaction mixture was washed with saturated brine,Extracted with dichloromethane,The organic phase was dried over sodium sulfate,concentrate,Column chromatography (methanol: dichloromethane = 1percent -5percent),The title product was obtained as a yellow oil (2.3 g, yield: 92percent).

Reference： [1] Patent: CN106432014, 2017, A, . Location in patent: Paragraph 0079; 0083; 0084; 0085; 0119; 0123; 0124; 0125
[2] Patent: WO2008/116302, 2008, A1, . Location in patent: Page/Page column 43-44

2
[ 58885-35-1 ]
[ 166737-85-5 ]

Yield	Reaction Conditions	Operation in experiment
57%	With ammonia In methanol at -78 - 20℃; for 14 h;	To 2.68g (7.37 mmol) of S-trityl-L-cysteine and 40 mL of methanol was added 7 mL (96 mmol) of thionyl chloride dropwise. After heating at reflux for 6h the solution was cooled to room temperature and then concentrated in vacuo. The resulting residue was taken up in 20 mL of methanol, treated with activated carbon, filtered and concentrated in vacuo yielding the methyl ester as an off-white foam. This material was dissolved in 6 mL of methanol in a sealable tube and cooled to -78°. After 30 mL of liquid ammonia was added, the tube was sealed and the reaction was stirred at room temperature for 14h After recooling to -78° the reaction tube was unsealed and the solution was carefully reduced to dryness. The residue was chromatographed on silica gel eluting with methylene chloride/methanol (10:1) furnishing 1.52g (57percent) of the primary amide as a white solid. Electrospray Mass Spec: 363.2 (M+H)+

Reference： [1] Patent: EP1149074, 2004, B1, . Location in patent: Page 23

3
[ 97802-29-4 ]
[ 166737-85-5 ]

Reference： [1] Patent: US6313123, 2001, B1,

4
[ 103213-32-7 ]
[ 166737-85-5 ]

Reference： [1] Patent: CN106432014, 2017, A,

[ 166737-85-5 ] Synthesis Path-Downstream 1~63

1
[ 166737-85-5 ]
3-{(4Z,10Z,15Z,19Z)-18-[2-(2,5-Dioxo-pyrrolidin-1-yloxycarbonyl)-ethyl]-3,8,13,17-tetramethyl-7,12-divinyl-22,24-dihydro-porphin-2-yl}-propionic acid [ No CAS ]
H-GGG-D(OtBu)PAALK(Boc)R(Pbf)AR(Pbf)N(Trt)T(tBu)E(OtBu)AAR(Pbf)R(Pbf)S(tBu)R(Pbf)AR(Pbf)K(Boc)LQ(Trt)R(Pbf)-NH-Novasyn TGR resin [ No CAS ]
protoporphyrin IX(-Cys-NH₂)(-GGG-DPAALKRARNTEAARRSRARKLQR-NH₂) [ No CAS ]

Reference： [1]Bulletin of the Chemical Society of Japan,2005,vol. 78,p. 1749 - 1756

2
[ 166737-85-5 ]
[ 286459-94-7 ]
(2R)-2-([14-(2-butynyloxy)phenyl]sulfonyl}amino)-3-(tritylsulfanyl)propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With triethylamine; In dichloromethane; for 13h;	Example 13 (2R)-2-([14-(2-Butynyloxy)phenyl]sulfonyl}amino)-3-(tritylsulfanyl)propanamide To a solution of 1.203g (3.685 mmol) of the primary amide product fromExample 12 and 1.39 ML (10 mmol) of triethylamine in 20 ML of methylene chloride was added in one portion 0.954g (3.9 mmol) of 4-but-2-ynyloxy-benzenesulfonyl chloride.. After stirring for 13h, 50 ML of dichloromethane and 50 ML of water were added.. The organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo and subjected to flash chromatography eluding with hexanes/ethyl acetate (1:1) to furnish 1.65g (79%) of the desired sulfonamide as a white solid.. Electrospray Mass Spec: 1139.6 (2M-H)

Reference： [1]Patent: EP1149074,2004,B1 .Location in patent: Page 23

3
[ 58885-35-1 ]
[ 166737-85-5 ]

Yield	Reaction Conditions	Operation in experiment
57%	With ammonia; In methanol; at -78 - 20℃; for 14h;	To 2.68g (7.37 mmol) of S-trityl-L-cysteine and 40 mL of methanol was added 7 mL (96 mmol) of thionyl chloride dropwise. After heating at reflux for 6h the solution was cooled to room temperature and then concentrated in vacuo. The resulting residue was taken up in 20 mL of methanol, treated with activated carbon, filtered and concentrated in vacuo yielding the methyl ester as an off-white foam. This material was dissolved in 6 mL of methanol in a sealable tube and cooled to -78. After 30 mL of liquid ammonia was added, the tube was sealed and the reaction was stirred at room temperature for 14h After recooling to -78 the reaction tube was unsealed and the solution was carefully reduced to dryness. The residue was chromatographed on silica gel eluting with methylene chloride/methanol (10:1) furnishing 1.52g (57%) of the primary amide as a white solid. Electrospray Mass Spec: 363.2 (M+H)+

Reference： [1]Patent: EP1149074,2004,B1 .Location in patent: Page 23

4
[ 166737-85-5 ]
(2R)-2-([14-(2-butynyloxy)phenyl]sulfonyl}amino)-3-(tritylsulfanyl)propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; water; 4-but-2-ynyloxybenzenesulfonyl chloride;	EXAMPLE 13 (2R)-2-([4-(2-Butynyloxy)phenyl]sulfonyl}amino)-3-(tritylsulfanyl)propanamide To a solution of 1.203 g (3.685 mmol) of the primary amide product from Example 12 and 1.39 mL (10 mmol) of triethylamine in 20 mL of methylene chloride was added in one portion 0.954 g (3.9 mmol) of 4-but-2-ynyloxy-benzenesulfonyl chloride. After stirring for 13 h, 50 mL of dichloromethane and 50 mL of water were added. The organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo and subjected to flash chromatography eluding with hexanes/ethyl acetate (1:1) to furnish 1.65 g (79%) of the desired sulfonamide as a white solid. Electrospray Mass Spec: 1139.6 (2M-H)-

Reference： [1]Patent: US6313123,2001,B1

5
[ 97802-29-4 ]
[ 166737-85-5 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; In methanol;	EXAMPLE 12 (2R)-2-Amino-3-(tritylsulfanyl)propanamide To 2.68 g (7.37 mmol) of S-trityl-L-cysteine and 40 mL of methanol was added 7 mL (96 mmol) of thionyl chloride dropwise. After heating at reflux for 6 h the solution was cooled to room temperature and then concentrated in vacuo. The resulting residue was taken up in 20 mL of methanol, treated with activated carbon, filtered and concentrated in vacuo yielding the methyl ester as an off-white foam. This material was dissolved in 6 mL of methanol in a sealable tube and cooled to -78.

Reference： [1]Patent: US6313123,2001,B1

6
[ 166737-85-5 ]
N-[1-(1-benzothien-2-yl)-4-[tert-butyl(dimethyl)silyl]oxy}-1-(trifluoromethyl)but-2-yn-1-yl]-L-leucine [ No CAS ]
N-[(1R)-1-(1-benzothien-2-yl)-4-hydroxy-1-(trifluoromethyl)but-2-yn-1-yl]-L-leucyl-S-trityl-L-cysteinamide [ No CAS ]
N-[(1S)-1-(1-benzothien-2-yl)-4-hydroxy-1-(trifluoromethyl)but-2-yn-1-yl]-L-leucyl-S-trityl-L-cysteinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; triethylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 3h;	To a solution of <strong>[166737-85-5]S-trityl-L-cysteinamide</strong> from Step 2, Example 2 (2.15 g, 6.15 mmol) in DMF (12.3 mL) was added 11ATU (2.28 g, 6 mol), HOBt (676 mg, 5 mmol) and N- [( 1 R)- 1 -( 1 -benzothien-2-yl)-4- { [tert-buty l(dimethyl)silyl]oxy }- 1 -(trifluoromethyl)but-2-yn- 1 -yl]- L-leucine (2.57 g, 5 mmol) from Step 3, Example 12. The mixture was cooled to 0C and Et3N (3.51 mL, 25 mmol) was added. The reaction was stirred at room temperature for 3 hours. Saturated aqueous NaHCO3, EtOAc:MTBE and water were added and the organic layer was separated. The aqueous layer was further extracted with 1 :1 EtOAc:MTBE. The combined organic layers were washed with brine, dried with magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel ehiting with ethyl acetate and hexanes (3:2) to afford the title compound (1.14 g) enriched in the desired isomer. <n="69"/>1H NMR delta (PPm)(CD3COCD3): 6.85 and 6.6 (2H, NH2), 3.65 (1H, m), 3.2 (1H, m), 0.95 (6H, m); other resonances complex.

Reference： [1]Patent: WO2008/116302,2008,A1 .Location in patent: Page/Page column 67-68

7
[ 166737-85-5 ]
[ 1064622-37-2 ]
[ 1064622-45-2 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-hydroxy-7-aza-benzotriazole; triethylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃;	To a solution of i<strong>[166737-85-5]S-trityl-L-cysteinamide</strong> from Step 2, Example 2 (235 mg, 0.65 mmol) in DMF (5 mL) was added HATU (209 mg, 0.55 mol), HOAt (68 mg, 0.5 mmol) and the N- [( 1 R)- 1 -(4-bromophenyl)-4-hy droxy- 1 -(trifluoromethyl)but-2-yn- 1 -y l]-4-fluoro-L-leucine from Step 4, Example 3 (220 mg, 0.5 mmol). The mixture was cooled to 0C and Et3N (0.35 mL, 2.5 mmol) was added. The reaction was stirred at room temperature overnight. Sat. aq. NaHCO3, EtOAc and water were added and the aqueous layer was extracted with EtOAc (3x). The combined organics were washed with brine (Ix), dried (MgSO4) and concentrated. The residue thus obtained was purified by column chromatography on silica gel eluting with 40% EtOAc/hexanes - > 60% EtOAc/hexanes - > 100% EtOAc to afford the title compound.1H NMR (500 MHz, d6-acetone) delta 7.8 (2H, d), 7.65-7.20 (17H, m), 6.6 and 6.8 (2H, 2 bs (NH2)), 4.5 (1H, m), 4.35 (2H, m), 4.25 (1H, m), 3.7 (1H, m), 3.3 (1H, m), 2.55-2.45 (2H, m), 2.25-2.15 (2H, m), 1.50-1.35 (6H, m).

Reference： [1]Patent: WO2008/116302,2008,A1 .Location in patent: Page/Page column 47

8
[ 202752-01-0 ]
[ 166737-85-5 ]

Yield	Reaction Conditions	Operation in experiment
92%	With piperidine; In N,N-dimethyl-formamide; at 20℃; for 4h;	A solution of the compound (R) - (9H-fluoren-9-yl) methyl (1-amino-1-oxo-3- (triphenylmethylthio) propan-2-yl) carbamate (4 g, 6.84 mmol )Was dissolved in N, N-dimethylformamide (20 ml)Piperidine (0.14 ml, 1.368 mmol) was added,Reaction at room temperature for 4 hours,TLC detection reaction is completed,The reaction mixture was washed with saturated brine,Extracted with dichloromethane,The organic phase was dried over sodium sulfate,concentrate,Column chromatography (methanol: dichloromethane = 1% -5%),The title product was obtained as a yellow oil (2.3 g, yield: 92%).
	With pyrrolidine; In N,N-dimethyl-formamide; at 20℃;	To a stirred solution of 9H-fluoren-9-ylmethyl {(li?)-2-amino-2-oxo-1-[(tritylthio)methyl]-ethyl} carbamate (380 mg, 0.65 mmol) in DMF (3 mL) was added pyrrolidine (11 muL, 0.13 mmol). The reaction was stirred at room temperature overnight. By TLC and mass spectrometry, the reaction was deemed complete. This DMF solution of the title compound was used as such in the next reaction (Step 5, Example 3).

Reference： [1]Patent: CN106432014,2017,A .Location in patent: Paragraph 0079; 0083; 0084; 0085; 0119; 0123; 0124; 0125
[2]Patent: WO2008/116302,2008,A1 .Location in patent: Page/Page column 43-44
[3]Journal of the American Chemical Society,2019,vol. 141,p. 1842 - 1846

9
[ 166737-85-5 ]
[ 225122-52-1 ]
[ 225122-70-3 ]

Yield	Reaction Conditions	Operation in experiment
		A. N-[3-methyl-N-(2,2-diphenylacetyl)-L-phenylalanyl]-<strong>[166737-85-5]S-trityl-L-cysteinamide</strong> To a solution of 3-methyl-N-(2,2-diphenylacetyl-L-phenylalanine (see example 302, 1.0 g, 2.68 mmol), 1-hydroxybenzotriazole hydrate (0.41 g, 2.68 mmol) and N-methylmorpholine (0.74 ML, 6.69 mmol) in CH2Cl2 (80 ML) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl (0.77 g, 4.02 mmol) in one portion.. After stirring 30 minutes at room temperature, <strong>[166737-85-5]S-trityl-L-cysteinamide</strong> (0.97 g, 2.68 mmol) is added to the solution in one portion, and the solution is stirred for 16 hours.. The solution is evaporated, and the residue partitioned between water (80 ML) and ethyl acetate (80 ML).. The aqueous layer is washed with EtOAc (280 ML), and the combined organic layers are then washed with 1 N HCl (100 ML), saturated aqueous NaHCO3 (150 ML), water (150 ML) and brine (150 ML), dried over MgSO4, and evaporated.. The residue is triturated with Et2O/hexane (1:1) to yield N-[3-methyl-N-(2,2-diphenylacetyl)-L-phenylalanyl]-<strong>[166737-85-5]S-trityl-L-cysteinamide</strong> as a white solid.

Reference： [1]Patent: US6353017,2002,B1 .Location in patent: Page column 116

10
[ 166737-85-5 ]
[ 27486-87-9 ]
[ 1129670-74-1 ]

Reference： [1]Tetrahedron,2009,vol. 65,p. 1257 - 1267

11
[ 166737-85-5 ]
C₅₅H₆₆N₉O₉PolS [ No CAS ]
[ 953424-20-9 ]

Yield	Reaction Conditions	Operation in experiment
		The peptide, prepared as described above, was cleaved from the resin at RT by washing with a solution of 1% TFA in DCM by three repeated washings (15 min each). The resulting solution was neutralized by addition of DIPEA and concentrated to about 10% peptide content. Modification of the C-terminus was achieved by activation of the carboxy terminus with TBTU/HOBt and coupling with Cys(Trt)-NH2 solution in DCM. After removal of the solvent, the protected peptide was precipitated in water and dried. The protecting groups were removed using a 95% TFA, 2.5% TIS, 2.5% EDT solution for 2 hours at room temperature. The product was precipitated by the addition of 10 volumes of MTBE, filtered and dried in vacuum to obtain 32 g product.

Reference： [1]Patent: US2006/276626,2006,A1 .Location in patent: Page/Page column 29

12
[ 166737-85-5 ]
[ 2799-07-7 ]
[ 81-30-1 ]
[ 1283599-82-5 ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 3338 - 3347

13
[ 166737-85-5 ]
[ 81-30-1 ]
[ 5680-79-5 ]
[ 1283599-84-7 ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 3338 - 3347

14
[ 166737-85-5 ]
[ 139-13-9 ]
C₇₂H₆₉N₇O₆S₃ [ No CAS ]

Reference： [1]Chemistry - A European Journal,2011,vol. 17,p. 4418 - 4428

15
[ 166737-85-5 ]
[ 15442-91-8 ]
C₃₂H₃₀Br₂N₂OS [ No CAS ]

Reference： [1]Organic Letters,2012,vol. 14,p. 1194 - 1197

16
[ 166737-85-5 ]
[ 752200-93-4 ]
C₇₆H₇₈N₈O₆S₃ [ No CAS ]

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

17
[ 166737-85-5 ]
[ 1417718-11-6 ]

Reference： [1]Patent: US8349899,2013,B1

18
[ 166737-85-5 ]
[ 1417718-07-0 ]

Reference： [1]Patent: US8349899,2013,B1

19
[ 166737-85-5 ]
[ 108-24-7 ]
[ 1417718-03-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	With sodium hydroxide; In water; N,N-dimethyl-formamide; at 20℃; for 1h;	Acetic anhydride (0.102 g, 0.92 mmol) was added to the mixture of compound 3.3 (STCC) (0.022 g, 0.061 mmol) and sodium hydroxide (0.0048 g, 0.12 mmol) in a mixture of DMF (0.25 mL) and water (0.5 mL) as is illustrated in Scheme L. The reaction was allowed to stir at rt for 1 h. The reaction mixture was diluted with water (20 mL), the product was extracted with ethyl acetate (3×25 mL), dried over anhydrous sodium sulfate, volatiles were evaporated under reduced pressure to obtain compound 3.6 ASTCC as a colorless solid (0.023 g, 94%). IR (KBr, cm-1): 3392, 3294, 1656, 1595, 1489. 1H NMR (300 MHz, CDCl3) delta 7.45-7.42 (m, 5H), 7.32-7.22 (m, 10H), 6.04 (s, 1H), 5.85 (d, J=7.42 Hz, 1H), 5.45 (bs, 1H), 4.19-4.12 (m, 1H), 2.74 (dd, J=13.08, 6.83 Hz, 1H), 2.56 (dd, J=13.08, 5.66 Hz, 1H), 1.89 (s, 3H); 13C NMR (75 MHz, CDCl3) delta 172.19, 170.22, 144.33, 129.53, 128.07, 127.90, 126.92, 51.76, 33.04, 23.08. HPLC-MS: Elution with 20-80% CH3CN in H2O (gradient 1.5% min-1), exhibited a single peak at 8.03 min. ESI-MS m/z [ES+] calcd for C24H26N2O2S [M+H]+405.22; found 405.16]

Reference： [1]Patent: US8349899,2013,B1 .Location in patent: Page/Page column 42-43

20
[ 166737-85-5 ]
[ 108-24-7 ]
[ 1417718-04-7 ]

Yield	Reaction Conditions	Operation in experiment
96%	In water; N,N-dimethyl-formamide; at 20℃; for 1h;Alkaline conditions;	Acetic anhydride (0.153 g, 1.5 mmol) was added to a mixture of compound 2.6 MSTLC (0.393 g, 1 mmol) and sodium carbonate (0.210 g, 2 mmol) in DMF (1 mL) and water (0.5 mL) as is illustrated in Scheme O. The reaction was allowed to stir at rt for 1 h. The reaction mixture was diluted with water (20 mL), the product was extracted with ethyl acetate (3×25 mL), dried over anhydrous sodium sulfate, volatiles were evaporated under reduced pressure to obtain compound 3.9 MASTC as a colorless solid (0.410 g, 96%). IR (KBr, cm-1): 3387, 3293, 1651, 1591, 1479. 1H NMR (300 MHz, CDCl3) delta 7.37-7.17 (m, 12H), 6.79 (d, J=8.7 Hz, 2H), 6.13 (d, J=7.61 Hz, 1H), 4.53-4.48 (m, 1H), 3.76 (s, 3H), 2.75 (dd, J=12.69, 5.69 Hz, 1H), 2.67 (dd, J=12.69, 4.68 Hz, 1H), 1.89 (s, 3H).

Reference： [1]Patent: US8349899,2013,B1 .Location in patent: Page/Page column 44-45

21
[ 166737-85-5 ]
4-[(4-{(2S)-3-(allyloxy)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}phenoxy)carbonyl]-amino}-2-[(tert-butoxycarbonyl)(methyl)amino]butanoic acid [ No CAS ]
allyl O-[(4-[(2R)-1-amino-1-oxo-3-(tritylsulfanyl)propan-2-yl]amino}-3-[(tert-butoxycarbonyl)-(methyl)amino]-4-oxobutyl)carbamoyl]-N-(tert-butoxycarbonyl)-L-tyrosinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 60℃; for 0.5h;Microwave irradiation; Sealed tube;	2.24 g (3.86 mmol) of the compound from example 8A was dissolved in 100 ml dichloromethane. 1.401 g (3.86 mmol) S-Trityl-L-cysteinamide, 0.67 ml (3.86 mmol) N,N-diisopropylethylamine and 1.47 g (3.86 mmol) HATU were added. The reaction mixture was split into 5 portions. The portions were heated for 30 min in a sealed tube at 60C in a microwave synthesizer. From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40C, approx. 200 mbar, approx. 30 min.). The raw product was purified by preparative RP-HPLC on a CI 8 column with a water methanol gradient from 9/1 to 1/9. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 3.26 g (2.75 mmol, 71 % of theory, 78% purity) of the desired product as a mixture of diastereomers. LC-MS (method 1 ): R, = 1.41 and 1.43 min., m z = 924 ( +H)+
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 60℃; for 0.5h;Sealed tube; Microwave irradiation;	Example 9A Allyl O-[(4-[(2R)-1-amino-1-oxo-3-(tritylsulfanyl)propan-2-yl]amino}-3-[(tert-butoxycarbonyl)-(methyl)amino]-4-oxobutyl)carbamoyl]-N-(tert-butoxycarbonyl)-L-tyrosinate 2.24 g (3.86 mmol) of the compound from example 8A was dissolved in 100 ml dichloromethane. 1.401 g (3.86 mmol) S-Trityl-L-cysteinamide, 0.67 ml (3.86 mmol) N,N-diisopropylethylamine and 1.47 g (3.86 mmol) HATU were added. The reaction mixture was split into 5 portions. The portions were heated for 30 min in a sealed tube at 60C in a microwave synthesizer. From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40C, approx. 200 mbar, approx. 30 min.). The raw product was purified by preparative RP-HPLC on a C18 column with a water methanol gradient from 9/1 to 1/9. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 3.26 g (2.75 mmol, 71% of theory, 78% purity) of the desired product as a mixture of diastereomers. LC-MS (method 1): Rt = 1.41 and 1.43 min., m/z = 924 (M+H)+

Reference： [1]Patent: WO2013/64508,2013,A1 .Location in patent: Page/Page column 32
[2]Patent: EP2773376,2016,B1 .Location in patent: Paragraph 0131; 0132

22
[ 166737-85-5 ]
N⁵-[(4-{(2S)-3-(allyloxy)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}phenoxy)carbonyl]-N²-(tert-butoxycarbonyl)-L-ornithine [ No CAS ]
N⁵-[(4-{(2S)-3-(allyloxy)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}phenoxy)carbonyl]-N²-(tert-butoxycarbonyl)-L-ornithyl-S-trityl-L-cysteinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 60℃; for 0.5h;Microwave irradiation; Sealed tube;	1.20 g (2.07 mmol) of the compound from example 11 A was dissolved in 48 ml dichloromethane. 0.750 g (2.07 mmol) S-Trityl-L-cysteinamide, 0.36 ml (2.07 mmol) Nu,Nu-diisopropylethylamine and 0.787 g (2.07 mmol) HATU were added. The reaction mixture was split into 3 portions. The portions were heated for 30 min in a sealed tube at 60C in a microwave synthesizer. From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40C, approx. 200 mbar, approx. 30 min.). The raw product was dissolved in dichloromethane and chromatographed over approx. 400 ml silica gel. Solvents used were dichloromethane/ethyl acetate 2/1, dichloromethane/ethyl acetate 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 1.30 g ( 1.5 mmol, 56% of theory, 82% purity) of the desired product. LC-MS (method 1 ): R, = 1.35 min., m/z = 924 (M+H)
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 60℃; for 0.5h;Sealed tube; Microwave irradiation;	Example 12A N5-[(4-{(2S)-3-(Allyloxy)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}phenoxy)carbonyl]-N2-(tert-butoxycarbonyl)-L-ornithyl-<strong>[166737-85-5]S-trityl-L-cysteinamide</strong> 1.20 g (2.07 mmol) of the compound from example 11A was dissolved in 48 ml dichloromethane. 0.750 g (2.07 mmol) S-Trityl-L-cysteinamide, 0.36 ml (2.07 mmol) N,N-diisopropylethylamine and 0.787 g (2.07 mmol) HATU were added. The reaction mixture was split into 3 portions. The portions were heated for 30 min in a sealed tube at 60C in a microwave synthesizer. From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40C, approx. 200 mbar, approx. 30 min.). The raw product was dissolved in dichloromethane and chromatographed over approx. 400 ml silica gel. Solvents used were dichloromethane/ethyl acetate 2/1, dichloromethane/ethyl acetate 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 1.30 g (1.5 mmol, 56% of theory, 82% purity) of the desired product. LC-MS (method 1): Rt = 1.35 min., m/z = 924 (M+H)+
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 60℃; for 0.5h;Sealed tube; Microwave irradiation;	Example 10A N5-[(4-{(2S)-3-(Allyloxy)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}phenoxy)carbonyl]-N2-(tert-butoxycarbonyl)-L-ornithyl-<strong>[166737-85-5]S-trityl-L-cysteinamide</strong> 1.20 g (2.07 mmol) of the compound from example 9A was dissolved in 48 ml dichloromethane. 0.750 g (2.07 mmol) S-Trityl-L-cysteinamide, 0.36 ml (2.07 mmol) N,N-diisopropylethylamine and 0.787 g (2.07 mmol) HATU were added. The reaction mixture was split into 3 portions. The portions were heated for 30 min in a sealed tube at 60 C. in a microwave synthesizer. From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40 C., approx. 200 mbar, approx. 30 min.). The raw product was dissolved in dichloromethane and chromatographed over approx. 400 ml silica gel. Solvents used were dichloromethane/ethyl acetate 2/1, dichloromethane/ethyl acetate 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 1.30 g (1.5 mmol, 56% of theory, 82% purity) of the desired product. LC-MS (method 1): Rt=1.35 min., m/z=924 (M+H)+

Reference： [1]Patent: WO2013/64508,2013,A1 .Location in patent: Page/Page column 35
[2]Patent: EP2773376,2016,B1 .Location in patent: Paragraph 0137; 0138
[3]Patent: US9315543,2016,B2 .Location in patent: Page/Page column 32

23
[ 166737-85-5 ]
(2S)-4-[(4-{(2S)-3-(allyloxy)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}phenoxy)carbonyl]-amino}-2-[(tert-butoxycarbonyl)amino]butanoic acid [ No CAS ]
allyl O-({(3S)-4-[(2R)-1-amino-1-oxo-3-(tritylsulfanyl)propan-2-yl]amino}-3-[(tert-butoxy-carbonyl)amino]-4-oxobutyl}carbamoyl)-N-(tert-butoxycarbonyl)-L-tyrosinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 60℃; for 0.5h;Microwave irradiation; Sealed tube;	2.50 g (4.42 mmol) of the compound from example 2A was dissolved in 100 ml dichloromethane. 1.602 g (4.42 mmol) S-Trityl-L-cysteinamide, 0.77 ml (4.42 mmol) N,N-diisopropylethylamine and 1.68 g (4.42 mmol) HATU were added. The reaction mixture was split into 5 portions. The portions were heated for 30 min in a sealed tube at 60C in a microwave synthesizer. From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40C, approx. 200 mbar, approx. 30 min.). The raw product was dissolved in dichloromethane and chromatographed over approx. 600 ml silica gel. Solvents used were dichloromethane/ethyl acetate 2/1, dichloromethane/ethyl acetate 1/1, dichloromethane/methanol 20/1 and dichloromethane/methanol 10/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 4.12 g (3.30 mmol, 75% of theory, 73% purity) of the desired product. LC-MS (method 1 ): R, = 1 .36 min., m z = 91 1 (M+H)+
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 60℃; for 0.5h;Sealed tube; Microwave irradiation;	Example 3A Allyl O-({(3S)-4-[(2R)-1-amino-1-oxo-3-(tritylsulfanyl)propan-2-yl]amino}-3-[(tert-butoxy-carbonyl)amino]-4-oxobutyl}carbamoyl)-N-(tert-butoxycarbonyl)-L-tyrosinate 2.50 g (4.42 mmol) of the compound from example 2A was dissolved in 100 ml dichloromethane. 1.602 g (4.42 mmol) S-Trityl-L-cysteinamide, 0.77 ml (4.42 mmol) N,N-diisopropylethylamine and 1.68 g (4.42 mmol) HATU were added. The reaction mixture was split into 5 portions. The portions were heated for 30 min in a sealed tube at 60C in a microwave synthesizer. From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40C, approx. 200 mbar, approx. 30 min.). The raw product was dissolved in dichloromethane and chromatographed over approx. 600 ml silica gel. Solvents used were dichloromethane/ethyl acetate 2/1, dichloromethane/ethyl acetate 1/1, dichloromethane/methanol 20/1 and dichloromethane/methanol 10/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 4.12 g (3.30 mmol, 75% of theory, 73% purity) of the desired product. LC-MS (method 1): Rt = 1.36 min., m/z = 911 (M+H)+
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 60℃; for 0.5h;Sealed tube; Microwave irradiation;	Example 3A Allyl O-({(3S)-4-[(2R)-1-amino-1-oxo-3-(tritylsulfanyl)propan-2-yl]amino}-3-[(tert-butoxy-carbonyl)amino]-4-oxobutyl}carbamoyl)-N-(tert-butoxycarbo-nyl)-L-tyrosinate 2.50 g (4.42 mmol) ofthe compound from example 2A was dissolved in 100 ml dichioromethane. 1.602 g (4.42 mmol) S-Trityl-L-cysteinamide, 0.77 ml (4.42 mmol) N,N-diisopropylethylamine and 1.68 g (4.42 mmol) HATU were added.The reaction mixture was split into 5 portions. The portions were heated for 30 mm in a sealed tube at 60 C. in a microwave synthesizet From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40 C., approx. 200 mbar, approx. 30 mm.). The raw product wasdissolved in dichloromethane and chromatographed over approx. 600 ml silica gel. Solvents used were dichloromethane/ethyl acetate 2/i, dichloromethane/ethyl acetate i/i, dichloromethane/methanol 20/i and dichloromethane/ methanol 10/i. The product-containing fractions were combined and concentrated to dryness under reduced pressure.This gave 4.12 g (3.30 mmol, 75% of theory, 73% purity) of the desired product.LC-MS (method 1): R=i.36 mi, mlz=9ii (M+H)

Reference： [1]Patent: WO2013/64508,2013,A1 .Location in patent: Page/Page column 27
[2]Patent: EP2773376,2016,B1 .Location in patent: Paragraph 0117; 0118
[3]Patent: US9315543,2016,B2 .Location in patent: Page/Page column 27; 28

24
[ 166737-85-5 ]
(2R,E)-tert-butyl 3-(2-(2-amino-3-(tritylthio)propanamido)vinyl)-5,6-dibromo-1H-indole-1-carboxylate [ No CAS ]

Reference： [1]Marine Drugs,2014,vol. 12,p. 1116 - 1130

25
[ 166737-85-5 ]
tert-butyl 5,6-dibromo-3-((6R,9R,Z)-2,2-dimethyl-4,7,10-trioxo-6,9-bis((tritylthio)methyl)-3-oxa-5,8,11-triazatridec-12-en-13-yl)-1H-indole-1-carboxylate [ No CAS ]

Reference： [1]Marine Drugs,2014,vol. 12,p. 1116 - 1130

26
[ 166737-85-5 ]
tert-butyl 5,6-dibromo-3-((6R,9R,E)-2,2-dimethyl-4,7,10-trioxo-6,9-bis((tritylthio)methyl)-3-oxa-5,8,11-triazatridec-12-en-13-yl)-1H-indole-1-carboxylate [ No CAS ]

Reference： [1]Marine Drugs,2014,vol. 12,p. 1116 - 1130

27
[ 166737-85-5 ]
(2R,Z)-tert-butyl 3-(2-(2-(((allyloxy)carbonyl)amino)-3-(tritylthio)propanamido)vinyl)-5, 6-dibromo-1H-indole-1-carboxylate [ No CAS ]

Reference： [1]Marine Drugs,2014,vol. 12,p. 1116 - 1130

28
[ 166737-85-5 ]
(2R,E)-tert-Butyl 3-(2-(2-(((allyloxy)carbonyl)amino)-3-(tritylthio)propanamido)vinyl)-5, 6-dibromo-1H-indole-1-carboxylate [ No CAS ]

Reference： [1]Marine Drugs,2014,vol. 12,p. 1116 - 1130

29
[ 166737-85-5 ]
(2R,Z)-tert-butyl 3-(2-(2-amino-3-(tritylthio)propanamido)vinyl)-5,6-dibromo-1H-indole-1-carboxylate [ No CAS ]

Reference： [1]Marine Drugs,2014,vol. 12,p. 1116 - 1130

30
[ 166737-85-5 ]
[ 2937-50-0 ]
[ 942057-11-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In tetrahydrofuran; water; at 0℃; for 2h;Inert atmosphere;	To a stirred solution of <strong>[166737-85-5]S-trityl-L-cysteine amide</strong> (500 mg, 1.38 mmol) in a mixture THF:H2O (2.5 mL:1.25 mL) at 0 C was added solid NaHCO3 (232 mg, 2.76 mmol) followed by allyloxycarbonyl chloride (0.14 mL, 1.65 mmol). After stirring for 2 h at 0 C, the mixture was quenched by slow addition of a 2 M solution of HCl until reached pH 2 and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure to afford 9 as a white solid (616 mg, 100% yield) that was used without further purification. 1H NMR (300 MHz, CDCl3) deltaH ppm: 7.43 (m, 5H), 7.33-7.19 (m, 10H), 5.88 (m, 1H), 5.81 (br s, 1H), 5.33 (br s, 1H), 5.29 (d, 1H, 16.0 Hz), 5.22 (d, 1H, J = 10.5 Hz), 5.06 (d, 1H, J = 7.2 Hz), 4.52 (dd, 2H, 5.7, J = 1.2 Hz), 3.87 (m, 1H), 2.76 (dd, 1H, J = 13.2, 7.2 Hz), 2.57 (dd, 1H, J = 13.2, 5.1 Hz). 13C NMR (75 MHz, CDCl3) deltaC ppm: 172.4, 156.0, 144.5, 132.5, 129.8, 128.3, 127.2, 118.2, 67.6, 66.3, 53.7, 33.9.

Reference： [1]Marine Drugs,2014,vol. 12,p. 1116 - 1130

31
[ 166737-85-5 ]
C₅₈H₅₇N₅O₇S [ No CAS ]

Reference： [1]Patent: WO2015/103643,2015,A2

32
[ 166737-85-5 ]
C₂₇H₂₉N₃O₂S [ No CAS ]

Reference： [1]Patent: WO2015/103643,2015,A2

33
[ 166737-85-5 ]
C₄₃H₄₇N₅O₅S [ No CAS ]

Reference： [1]Patent: WO2015/103643,2015,A2

34
[ 166737-85-5 ]
C₆₆H₇₀N₆O₁₀S [ No CAS ]

Reference： [1]Patent: WO2015/103643,2015,A2

35
[ 166737-85-5 ]
C₅₁H₆₀N₆O₈S [ No CAS ]

Reference： [1]Patent: WO2015/103643,2015,A2

36
[ 166737-85-5 ]
C₆₈H₇₃N₇O₁₁S [ No CAS ]

Reference： [1]Patent: WO2015/103643,2015,A2

37
[ 166737-85-5 ]
C₅₃H₆₃N₇O₉S [ No CAS ]

Reference： [1]Patent: WO2015/103643,2015,A2

38
[ 166737-85-5 ]
[ 71989-31-6 ]
C₄₂H₃₉N₃O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide;	Example 9. Synthesis of a modified eptifibatide A modified eptifibatide was prepared as shown in Scheme 2. Scheme 2. a) EDC, Hot, DMF, 98%; b) piperidine, DMF, 97%; c) Fmoc-D-Trp(Boc)-OH, EDC, HOAt, DMF, 95%; d) piperidine, DMF, 96%; e) Fmoc-L-Asp(tBu)-OH, EDC, HOAt, DMF, 98%; 1) piperidine, DMF, 96%; g) Fmoc-Gly-OH, EDC, HOAt, DMF, 95%; h) piperidine, 86%; i) Fmoc-L-Arg(Pbl)-OH, EDC, HOAt, DMF, 91%; j) piperidine, DMF, 89%; k) 3-(Tritylthio)propionic acid, EDC, HOAt, DMF, 97%; 1) h, DCM/MeOH, 42%; m) TFA, 78%. Briefly, protected cysteine amide 2 was coupled to Fmoc-proline 3 to give 4, which was de-protected and coupled to a diprotected R-tryptophan derivative to give 5. Several additional Fmoc-de-protection/coupling sequences were performed, including use of the t-butyl ester of aspartic acid and a Pbf-protected arginine derivative, to give 8. Next 3-(tritylthio) propionic acid was installed to give 9, and de- protective cyclization to form the disulfide was induced in presence of iodine (Kambes et al, Helv Chem Acta, 1980, 63: 899 - 915) followed by removal of the remaining three acid-sensitive protecting groups in the presence of TFA. All intermediates were purified by normal-phase silica gel chromatography, except the final product, which was purified by reverse-phase chromatography followed by lyophilization to give an amorphous white powder that was characterized by lH NMR and LC/MS, and demonstrated aqueous solubility characteristics similar to eptifibatide.

Reference： [1]Patent: WO2015/103643,2015,A2 .Location in patent: Page/Page column 145-146

39
[ 166737-85-5 ]
C₆₈H₉₇N₉O₁₆S₂ [ No CAS ]
C₉₀H₁₁₇N₁₁O₁₆S₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; for 1.5h;	Synthesis of DM1 conjugates100 mL RBF was charged with 57A (2.73 g, 2.01 mmol) and (2R)-2- amino-3-tritylsulfanyl-propanamide (728.60 mg, 2.01 mmol). Dichloromethane (27.00 mL) was added followed by diisopropylethylamine (519.54 mg, 4.02 mmol) and HATU (840.69 mg, 2.21 mmol). After 1.5 h, conversion was complete by HPLC/MS. 27 g silica gel (10 weighs) was charged in a fritted glass funnel. 40:60 TBME/DCM was used to wet silica. The DCM solution was added on top of the silica gel, then eluted with 40:60 TBME/DCM (250 mL), followed by 2% isopropanol in 40:60 TBME/DCM (250 mL). The filtrate was evaporated. The desired product 57B was obtained. (3.16 g, 92% yield). LCMS M/Z: 1705 [M + 1].

Reference： [1]Patent: WO2016/4048,2016,A2 .Location in patent: Paragraph 00395

40
[ 166737-85-5 ]
4-[(4-{(2S)-3-(allyloxy)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}phenoxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)(methyl)amino]butanoic acid [ No CAS ]
allyl O-[(4-[(2R)-1-amino-1-oxo-3-(tritylsulfanyl)propan-2-yl]amino}-3-[(tert-butoxycarbonyl)-(methyl)amino]-4-oxobutyl)carbamoyl]-N-(tert-butoxycarbonyl)-L-tyrosinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 60℃; for 0.5h;Sealed tube; Microwave irradiation;	Example 8A Allyl-O-[(4-[(2R)-1-amino-1-oxo-3-(tritylsulfanyl)propan-2-yl]amino}-3-[(tert-butoxycarbonyl)-(methyl)amino]-4-oxobutyl)carbamoyl]-N-(tert-butoxycarbonyl)-L-tyrosinate 2.24 g (3.86 mmol) of the compound from example 7A was dissolved in 100 ml dichloromethane. 1.401 g (3.86 mmol) S-Trityl-L-cysteinamide, 0.67 ml (3.86 mmol) N,N-diisopropylethylamine and 1.47 g (3.86 mmol) HATU were added. The reaction mixture was split into 5 portions. The portions were heated for 30 min in a sealed tube at 60 C. in a microwave synthesizer. From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40 C., approx. 200 mbar, approx. 30 min.). The raw product was purified by preparative RP-HPLC on a C18 column with a water methanol gradient from 9/1 to 1/9. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 3.26 g (2.75 mmol, 71% of theory, 78% purity) of the desired product as a mixture of diastereomers. LC-MS (method 1): Rt=1.41 and 1.43 min., m/z=924 (M+H)+

Reference： [1]Patent: US9315543,2016,B2 .Location in patent: Page/Page column 30; 31

41
[ 166737-85-5 ]
N²-[(4-{(2S)-3-(allyloxy)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}phenoxy)carbonyl]-N⁵-(tert-butoxycarbonyl)ornithine [ No CAS ]
N²-[(4-{(2S)-3-(allyloxy)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}phenoxy)carbonyl]-N⁵-(tert-butoxycarbonyl)-L-ornithyl-S-trityl-L-cysteinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 60℃; for 0.5h;Sealed tube; Microwave irradiation;	Example 12A N2-[(4-{(2S)-3-(Allyloxy)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}phenoxy)carbonyl]-N5-(tert-butoxycarbonyl)-L-ornithyl-<strong>[166737-85-5]S-trityl-L-cysteinamide</strong> 1.50 g (2.59 mmol) of the compound from example 11A was dissolved in 60 ml dichloromethane. 0.940 g (2.59 mmol) S-Trityl-L-cysteinamide, 0.45 ml (2.60 mmol) N,N-diisopropylethylamine and 0.984 g (2.59 mmol) HATU were added. The reaction mixture was split into 3 portions. The portions were heated for 30 min in a sealed tube at 60 C. in a microwave synthesizer. From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40 C., approx. 200 mbar, approx. 30 min.). The raw product was dissolved in dichloromethane and chromatographed over approx. 400 ml silica gel. Solvents used were dichloromethane/ethyl acetate 2/1, dichloromethane/ethyl acetate 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 1.72 g (1.64 mmol, 63% of theory, 88% purity) of the desired product. LC-MS (method 1): Rt=1.35 min., m/z=924 (M+H)+

Reference： [1]Patent: US9315543,2016,B2 .Location in patent: Page/Page column 33

42
[ 166737-85-5 ]
(2S)-2-[(4-{(2S)-3-(allyloxy)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}phenoxy)carbonyl]amino}-4-[(tert-butoxycarbonyl)amino]butanoic acid [ No CAS ]
allyl N-(tert-butoxycarbonyl)-O-[(4R,7S)-4-carbamoyl-13,13-dimethyl-6,11-dioxo-1,1,1-triphenyl-12-oxa-2-thia-5,10-diazatetradecan-7-yl]carbamoyl}-L-tyrosinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 60℃; for 0.5h;Sealed tube; Microwave irradiation;	Example 14A Allyl-N-(tert-butoxycarbonyl)-O-[(4R,7S)-4-carbamoyl-13,13-dimethyl-6,11-dioxo-1,1,1-triphenyl-12-oxa-2-thia-5,10-diazatetradecan-7-yl]carbamoyl}-L-tyrosinate 3.00 g (5.30 mmol) of the compound from example 13A was dissolved in 120 ml dichloromethane. 1.92 g (5.30 mmol) S-Trityl-L-cysteinamide, 0.92 ml (5.30 mmol) N,N-diisopropylethylamine and 2.02 g (5.30 mmol) HATU were added. The reaction mixture was split into 6 portions. The portions were heated for 30 min in a sealed tube at 60 C. in a microwave synthesizer. From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40 C., approx. 200 mbar, approx. 30 min.). The raw product was dissolved in dichloromethane and chromatographed over approx. 800 ml silica gel. Solvents used were dichloromethane/ethyl acetate 2/1, dichloromethane/ethyl acetate 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 4.91 g (3.73 mmol, 70% of theory, 69% purity) of the desired product. LC-MS (method 1): Rt=1.35 min., m/z=910 (M+H)+

Reference： [1]Patent: US9315543,2016,B2 .Location in patent: Page/Page column 35

43
[ 166737-85-5 ]
N-[(4-{(2S)-3-(allyloxy)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}phenoxy)carbonyl]-3-[(tert-butoxycarbonyl)amino]-L-alanine [ No CAS ]
N-[(4-{(2S)-3-(allyloxy)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}phenoxy)carbonyl]-3-[(tert-butoxycarbonyl)amino]-L-alanyl-S-trityl-L-cysteinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 3h;	Example 25A N-[(4-{(2S)-3-(Allyloxy)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}phenoxy)carbonyl]-3-[(tert-butoxycarbonyl)amino]-L-alanyl-<strong>[166737-85-5]S-trityl-L-cysteinamide</strong> 1.23 g (2.23 mmol) of the compound from example 24A was dissolved in 25 ml dichloromethane. 0.81 g (2.23 mmol) S-Trityl-L-cysteinamide, 0.39 ml (2.23 mmol) N,N-diisopropylethylamine and 0.85 g (2.23 mmol) HATU were added. The reaction mixture was stirred at room temperature for 3 h. From the reaction mixture the solvent was removed by rotary evaporation (approx. 40 C., approx. 200 mbar, approx. 30 min.). The raw product was dissolved in dichloromethane and chromatographed over approx. 70 ml silica gel. Solvents used were dicloromethane/methanol 20/1 to dichloromethane/methanol 5/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 2.38 g (2.03 mmol, 91% of theory, 76% purity) of the desired product. LC-MS (method 1): Rt=1.37 min., m/z=897 (M+H)+

Reference： [1]Patent: US9315543,2016,B2 .Location in patent: Page/Page column 41

44
[ 166737-85-5 ]
C₅₅H₇₃N₉O₁₄S₂ [ No CAS ]
C₇₇H₉₃N₁₁O₁₄S₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	[00305] To a solution of 60 (1.15 g, 1.00 mmol), <strong>[166737-85-5]S-trityl L-cysteine amide</strong> ( 1.09 g, 3.00 mmol), and HATU (1.14 g, 3.00 mmol) in DMF (15 mL) was added diisopropylethylamine (1.00 mmol, 5.7 mmol). The reaction w as stirred overnight at room temperature, then the reaction mixture loaded onto a 100 g C I 8 column. Eluting with 50% to 95% acetonitrile in water with 0.1 % AcOH provided 81 (1.24 g, 0.831 mol, 83% yield).
83%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;	1004051 To a solution of 5 (1.15 g, 1.00 mmol), <strong>[166737-85-5]S-trityl L-cysteine amide</strong> (1.09 g,3.00 mmol), and HATU (1.14 g, 3.00 mmol) in DMF (15 mL) was added diisopropylethylamine (1.00 mmol, 5.7 mmol). The reaction was stirred overnight at room temperature, then the reaction mixture loaded onto a 100 g Cl 8 column. Eluting with 50% to 95% acetonitrile in water with 0.1% AcOH provided 26 (1.24 g, 0.831 mol, 83% yield).

Reference： [1]Patent: WO2017/3940,2017,A1 .Location in patent: Paragraph 00305
[2]Patent: WO2017/210246,2017,A2 .Location in patent: Paragraph 00405

45
[ 166737-85-5 ]
C₇₂H₈₉N₁₁O₁₅S₂ [ No CAS ]
[ 64-19-7 ]
(x)C₂H₄O₂*C₇₉H₉₉N₁₃O₁₃S₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%		[00330] To a solution of 135 (61.2 mg, 0.0433 mmol), S-trityl cysteine amide (47.1 mg, 0.130 mmol) and HATU (49.2 mg, 0.130 mmol) in DMF (2 mL) was added diisopropylethylamine (0.20 mL). The reaction was stirred at room temperature for 18 h, then piperidine (1 mL) was added. The reaction was stirred at room temperature for 1 h, then most of the piperidine was removed in vacuo. Water (1 mL) and acetic acid (1 mL) were added, and the reaction mixture was loaded onto a 50 g CI 8 column. Elution with 5% to 70% acetonitrile in water with 0.1% AcOH provided 136 as the acetate salt (26.2 mg, 0.0164 mmol, 38% yield).

Reference： [1]Patent: WO2017/3940,2017,A1 .Location in patent: Paragraph 00330

46
[ 103213-32-7 ]
[ 166737-85-5 ]

Reference： [1]Patent: CN106432014,2017,A
[2]Journal of the American Chemical Society,2019,vol. 141,p. 1842 - 1846

47
[ 166737-85-5 ]
[ 103213-32-7 ]
(9H-fluoren-9-yl)methyl ((R)-1-(((R)-1-amino-1-oxo-3-(triphenylmethylthio)propan-2-yl)amino)-1-oxo-3-(triphenylmethylthio)propan-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99.76%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 0.583333h;	The compound (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(triphenylmethylthio)propionic acid (1.29 g, 2.21 mmol) was dissolved in dichloromethane (15 ml)1-hydroxybenzotriazole (448 mg, 3.315 mmol) was added,EDCI (635 mg, 3.315 mmol),Stirred at room temperature for 5 minutes, <strong>[166737-85-5](R)-2-amino-3-(triphenylmethylthio)propionamide</strong> (960 mg, 2.65 mmol),Room temperature reaction for 30 minutes,TLC detection reaction is completed,The mixture was washed with saturated brine,Extracted with dichloromethane,The organic phase was dried over sodium sulfate,concentrate,Column chromatography (methanol: dichloromethane 1% -5%),The product was obtained as a white solid (2.05 g, yield: 99.76%).

Reference： [1]Patent: CN106432014,2017,A .Location in patent: Paragraph 0079; 0086; 0087; 0088; 0119; 0126; 0127; 0128

48
[ 166737-85-5 ]
(R)-2-amino-N-((R)-1-amino-1-oxo-3-(triphenylmethylthio)propan-2-yl)-3-(triphenylmethylthio)propionamide [ No CAS ]

Reference： [1]Patent: CN106432014,2017,A

49
[ 166737-85-5 ]
C₆₈H₉₇N₉O₁₆S₂ [ No CAS ]
C₉₀H₁₁₇N₁₁O₁₆S₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; for 1.5h;	j00414J A flask was charged with 13 (2.73 g, 2.01 mmol) and (2R)-2-amino-3- tritylsulfanyl-propanamide (728.60 mg, 2.01 mmol). Dichloromethane (27.00 mL) was added followed by diisopropylethylamine (519.54 mg, 4.02 mmol) and HATU (840.69 mg, 2.21 mmol). After 1.5 h, conversion was complete by HPLC/MS. Silica gel (27 g) was charged in a fritted glass funnel. 40:60 MTBE/dichloromethane was used to wet silica. The DCM solution was added on top of the silica gel, then eluted with 40:60 MTBE/dichloromethane (250 mL), followed by 2% isopropanol in 40:60 MTBE/dichloromethane (250 mL). The filtrate was evaporated to yield 55 (3.16 g, 92% yield). LCMS MIZ: 1705 [M + 1].

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 2708 - 2719
[2]Patent: WO2017/210246,2017,A2 .Location in patent: Paragraph 00414

50
[ 166737-85-5 ]
C₃₂H₅₅N₁₅O₁₂S₂ [ No CAS ]
C₅₄H₇₅N₁₇O₁₂S₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23%	With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; diisopropyl-carbodiimide; In N,N-dimethyl-formamide; at 20℃; for 40h;	1004101 A vial was charged with 25 (246 mg, 0.27 1 mmol), S-trityl cysteine amide(174 mg, 0.406 mmol), diisopropylcarbodiimide (68 mg, 0.54 mmol), HOBt (73 mg,0.54 mmol), and DMF (5 mL) and diisopropylethylamine (105 mg, 0.813 mmol) wereadded. The reaction was stirred at room temperature for 40 h, and the resultingreaction mixture purified by preparative HPLC to give 51 (78.1 mg, 0.0625 mmol,23% yield). LCMS M/Z = 1250.3 [M + 1].

Reference： [1]Patent: WO2017/210246,2017,A2 .Location in patent: Paragraph 00410

51
[ 166737-85-5 ]
C₂₂H₂₇N₅O₃*(x)ClH [ No CAS ]
[ 7693-46-1 ]
C₄₅H₄₇N₇O₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%		A vial was charged with (4-nitrophenyl) carbonochloridate (37 mg, 183 umol) and dichloromethane (0.5 mL). <strong>[166737-85-5]S-trityl-L-cysteine amide</strong> (53 mg, 147 umol) was charged in a vial and dissolved in dichloromethane (0.5 mL). S-trityl-L- cysteine amide solution was added to (4-nitrophenyl) carbonochloridate solution. After 20 mins, solvent was evaporated, then 0.5 mL DMF was added. 3D (25 mg, 61 umol) was charged in a vial and suspended in DMF (1 mL). Carbamate solution was added, followed by diisopropylethylamine (24 mg, 183 umol, 32 uL). Solution was stirred at room temperature overnight. Crude was purified by preparative HPLC (40- 95% MeCN/water, 0.1% acetic acid). Pure fractions were pooled, frozen and lyophilized. 21 mg (43%) of white lyophilized powder was obtained (3.86 mins, M+H =

Reference： [1]Patent: WO2018/112176,2018,A1 .Location in patent: Paragraph 00370

52
[ 166737-85-5 ]
C₂₆H₃₁N₅O₃ [ No CAS ]
[ 7693-46-1 ]
C₄₉H₅₁N₇O₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%		A vial was charged with (4-nitrophenyl) carbonochloridate (65.5 mg, 325 umol) and dichloromethane (0.5 mL). <strong>[166737-85-5]S-trityl-L-cysteine amide</strong> (94 mg, 260 umol) was charged in a vial and dissolved in dichloromethane (0.5 mL). S-trityl-L- cysteine amide solution was added to (4-nitrophenyl) carbonochloridate solution. After 20 mins, solvent was evaporated, then 0.5 mL DMF was added. 1A (made according to procedures in WO2015038649) (100 mg, 217 umol) was charged in a vial and suspended in DMF (2 mL). Carbamate solution was added, followed by diisopropylethylamine (84 mg, 650 umol, 113 uL). Solution was stirred at room temperature overnight. Crude was purified by preparative FIPLC (40-95% MeCN/water, 0.1% acetic acid). Pure fractions were pooled, frozen and lyophilized. 61 mg (33%)) of white lyophilized powder was obtained (4.89 mins, M+H = 851).

Reference： [1]Patent: WO2018/112176,2018,A1 .Location in patent: Paragraph 00360

53
[ 166737-85-5 ]
[ 29022-11-5 ]
N-[(9H-fluoren-9-ylmethoxy)carbonyl]glycyl-S-trityl-L-cysteinamide [ No CAS ]