166737-85-5|H-Cys(Trt)-NH2| Ambeed

Structure of H-Cys(Trt)-NH2
CAS No.: 166737-85-5

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Quality Control of [ 166737-85-5 ] Purity: 95% SDS Specification

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Product Details of [ 166737-85-5 ]

CAS No. :	166737-85-5
Formula :	C₂₂H₂₂N₂OS
M.W :	362.49
SMILES Code :	O=C(N)[C@@H](N)CSC(C1=CC=CC=C1)(C2=CC=CC=C2)C3=CC=CC=C3
MDL No. :	MFCD22126061
InChI Key :	OHWBGKONMFYEKL-FQEVSTJZSA-N
Pubchem ID :	44432703

Safety of [ 166737-85-5 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 166737-85-5 ] Show Less

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 ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	94.41 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.63
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	3.69
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.42
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	3.52
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	3.89
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.43

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-4.46
Solubility	0.0125 mg/ml ; 0.0000345 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-5.36
Solubility	0.00157 mg/ml ; 0.00000434 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-7.23
Solubility	0.0000215 mg/ml ; 0.0000000594 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Poorly soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	Yes
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	Yes
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	Yes
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	Yes
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.89 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<2.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	3.64

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.

Downstream synthetic route of [ 166737-85-5 ]

[ 166737-85-5 ] Synthesis Path-Downstream 1~35

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 ]

References: [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)

References: [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)+

References: [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)-

References: [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.

References: [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.

References: [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).

References: [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).

References: [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.

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

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

References: [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.

References: [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 ]

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

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

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

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

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

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

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

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

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

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

References: [1]Patent: US8349899,2013,B1 .

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

References: [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]

References: [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).

References: [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)+

References: [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)+

References: [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)

References: [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 ]