H-Met-OtBu·HCl | H-Met-OtBu.HCl

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Quality Control of [ 91183-71-0 ] Purity: 97% SDS Specification

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Product Details of [ 91183-71-0 ]

CAS No. :	91183-71-0
Formula :	C₉H₂₀ClNO₂S
M.W :	241.78
SMILES Code :	O=C(OC(C)(C)C)[C@@H](N)CCSC.[H]Cl
Synonyms :	H-Met-OtBu.HCl
MDL No. :	MFCD00038896
InChI Key :	KZJQROCWHZGZBJ-FJXQXJEOSA-N
Pubchem ID :	13141795

Safety of [ 91183-71-0 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 91183-71-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	14
Num. arom. heavy atoms	0
Fraction Csp3	0.89
Num. rotatable bonds	6
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	63.96
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	77.62 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.0
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	2.03
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.21
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.	1.7
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	1.26
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.44

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.22
Solubility	1.45 mg/ml ; 0.006 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-3.29
Solubility	0.125 mg/ml ; 0.000516 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	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	-1.78
Solubility	3.98 mg/ml ; 0.0165 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	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	No
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	No
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	No
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	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.33 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<1.0
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)	2.99

Application In Synthesis of [ 91183-71-0 ]

* 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 [ 91183-71-0 ]

[ 91183-71-0 ] Synthesis Path-Downstream 1~42

1
[ 50-00-0 ]
[ 73400-26-7 ]
[ 91183-71-0 ]
[ 136789-10-1 ]

References: [1]Journal of Organic Chemistry USSR (English Translation),1991,vol. 27,p. 357 - 358.
Zhurnal Organicheskoi Khimii,1991,vol. 27,p. 417 - 419.

2
[ 91183-71-0 ]
[ 530-62-1 ]
[ 106015-56-9 ]

References: [1]Heterocycles,1986,vol. 24,p. 3079 - 3085.

3
[ 83896-44-0 ]
[ 91183-71-0 ]
glycyrrhizic acid L-methionine tert-butyl ester triamide [ No CAS ]

References: [1]Russian Journal of Bioorganic Chemistry,1994,vol. 20,p. 778 - 785.

4
[ 91183-71-0 ]
[ 166169-36-4 ]
[ 166169-37-5 ]

References: [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 224 - 236.

5
[ 50-00-0 ]
[ 91183-71-0 ]
2-methyleneamino-4-methylsulfanyl-butyric acid tert-butyl ester [ No CAS ]

References: [1]Pharmaceutical Chemistry Journal,1998,vol. 32,p. 132 - 135.

6
[ 138-41-0 ]
[ 91183-71-0 ]
4-methylsulfanyl-2-(4-sulfamoyl-benzoylamino)-butyric acid tert-butyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 1787 - 1791.

7
[ 1205-30-7 ]
[ 91183-71-0 ]
2-(4-chloro-3-sulfamoyl-benzoylamino)-4-methylsulfanyl-butyric acid tert-butyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 1787 - 1791.

8
[ 91183-71-0 ]
[ 501-52-0 ]
N-methyl-L-phenylalanine allyl ester hydrochloride [ No CAS ]
N,O-dimethyl-L-tyrosine allyl ester hydrochloride [ No CAS ]
Fmoc-D-Tyr(O-Wang resin)-OAll [ No CAS ]
N-3-phenylpropionyl-D-tyrosyl-N,O-dimethyl-L-tyrosyl-N-methyl-L-phenylalanyl-L-methionine methyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2003,vol. 11,p. 2591 - 2615.

9
[ 91183-71-0 ]
[ 4457-32-3 ]
N-methyl-L-phenylalanine allyl ester hydrochloride [ No CAS ]
N,O-dimethyl-L-tyrosine allyl ester hydrochloride [ No CAS ]
Fmoc-D-Tyr(O-Wang resin)-OAll [ No CAS ]
(S)-2-[(S)-2-[(R)-3-(4-Hydroxy-phenyl)-2-(4-nitro-benzyloxycarbonylamino)-propionyl]-methyl-amino}-3-(4-methoxy-phenyl)-propionyl]-methyl-amino}-3-phenyl-propionic acid [ No CAS ]
N-4-nitrobenzyloxycarbonyl-D-tyrosyl-N,O-dimethyl-L-tyrosyl-N-methyl-L-phenylalanyl-L-methionine [ No CAS ]
N-4-nitrobenzyloxycarbonyl-D-tyrosyl-N,O-dimethyl-L-tyrosyl-N-methyl-L-phenylalanyl-L-methionine sulfoxide [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2003,vol. 11,p. 2591 - 2615.

10
[ 852325-32-7 ]
[ 91183-71-0 ]
[ 852325-33-8 ]

References: [1]Journal of Organic Chemistry,2005,vol. 70,p. 3720 - 3723.

11
[ 91183-71-0 ]
[ 150841-01-3 ]
3-oxo-17β-(O-tert-butyl-L-methionin-N-yl)carbonyl-28-norlup-20(29)-ene [ No CAS ]

References: [1]Russian Journal of Bioorganic Chemistry,2004,vol. 30,p. 80 - 88.

12
[ 91183-71-0 ]
[ 136789-10-1 ]

References: [1]Pharmaceutical Chemistry Journal,1998,vol. 32,p. 132 - 135.

13
[ 91183-71-0 ]
2-[3-(1-tert-Butoxycarbonyl-3-methylsulfanyl-propyl)-1-(4-[2-(dimethylamino-methyleneamino)-5-methyl-4-oxo-3,4,5,6,7,8-hexahydro-pteridin-6-ylmethyl]-amino}-benzoyl)-ureido]-pentanedioic acid dibutyl ester [ No CAS ]

References: [1]Heterocycles,1986,vol. 24,p. 3079 - 3085.

14
[ 91183-71-0 ]
[ 106044-01-3 ]

References: [1]Heterocycles,1986,vol. 24,p. 3079 - 3085.

15
[ 223761-08-8 ]
[ 91183-71-0 ]
tert-butyl (2S)-2-{2-(4-fluorophenyl)-6-[1-(4-fluorophenyl)-2-(1-methylimidazol-5-yl)ethoxymethyl]pyrid-3-oylamino}-4-methylsulfanylbutyrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In DMF (N,N-dimethyl-formamide); at 20℃; for 16h;	2-(4-Fluorophenyl)-6-[1-(4-fluorophenyl)-2-(1-methylimidazol-5-yl)ethoxymethyl]pyrid-3-carboxylic acid (0.39 g) and <strong>[91183-71-0]L-methionine-tert-butyl-ester.HCl</strong> (0.42 g) were dissolved in DMF (50 ml) then DMAP (0.63 g), EDC (0.25 g) and HOBT (0.12 g) were added under an inert atmosphere at ambient temperature. After 16 hours the solution was evaporated under reduced pressure, the residue obtained was diluted with 1M citric acid (10 ml) and extracted with 2% methanol/dichloromethane (1×100 ml, 1×60 ml). The combined extracts were dried, filtered and concentrated under reduced pressure to give a yellow oil. Purification by flash column chromatography eluting with methanol/ethyl acetate (9:1) gave tert-butyl (2S)-2-{2-(4-fluorophenyl)-6-[1-(4-fluorophenyl)-2-(1-methylimidazol-5-yl)ethoxymethyl]pyrid-3-oylamino}-4-methylsulfanylbutyrate as a colourless foam (0.34 g). 1H NMR (CDCl3) delta 1.43 (9H, s), 1.82-1.95 (2H, m), 2.04 (3H, s), 2.20-2.29 (2H, m), 2.88-2.99 (1H, m), 3.02-3.14 (1H, m), 3.20 (2H, s), 4.41-4.49 (1H, m), 4.55-4.66 (3H, m), 6.48 (1H, dd), 6.76 (1H, s), 7.00-7.15 (4H, m), 7.23-7.31 (4H, m), 7.58-7.66 (2H, m), 7.90(1H, dd). Anal. Calculated allowing for 0.5 H2O: C, 63.2; H, 6.1; N, 8.7; Found: C, 63.0; H, 5.8; N, 8.7; MS (MH+) 637.4.

References: [1]Patent: US6342765,2002,B1 .Location in patent: Page column 53.

16
[ 223761-14-6 ]
[ 91183-71-0 ]
tert-butyl (2S)-2-{3-(4-fluorophenethyl)-6-[1-(4-fluorophenyl)-2-(1-methylimidazol-5-yl)ethoxy]pyrid-2-oylamino}-4-methylsulfanylbutyrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In dichloromethane; at 20℃; for 16h;	3-(4-Fluorophenethyl)-6-[1-(4-fluorophenyl)-2-(1-methylimidazol-5-yl)ethoxy]pyridin-2-carboxylic acid (0.61 g) and <strong>[91183-71-0]L-methionine-tert-butyl-ester.HCl</strong> (0.64 g) were dissolved in dichloromethane (50 ml) then DMAP (0.96 g) and EDC (0.38 g) were added under an inert atmosphere at ambient temperature. After stirring for 16 hours the solution was washed with 1M citric acid (60 ml) and the organic layer dried and concentrated under reduced pressure. Purification on a silica flash column eluting with ethyl acetate gave tert-butyl (2S)-2-{3-(4-fluorophenethyl)-6-[1-4-fluorophenyl)-2-(1-methylimidazol-5-yl)ethoxy]pyrid-2-oylamino}-4-methylsulfanylbutyrate as a colourless foam (0.27 g). 1H NMR (CDCl3) delta: 1.54 (9H, d), 1.75-1.98 (2H, m), 2.05 (3H, s), 2.12-2.29 (1H, m), 2.33-2.63 (1H, m), 2.76-2.88 (2H, m), 3.06-3.30 (4H, m), 3.42 (3H, s), 4.63-4.73 (1H, m), 6.05-6.21 (1H, m), 6.76-7.03 (5H, m), 7.06-7.16 (2H, m), 7.26-7.42 (4H, m), 8.06-8.14 (1H, m). Anal. Calculated allowing for 1.5 HCl: C, 59.6; H, 5.9; N, 7.9. Found: C, 59.8; H, 5.9; N, 7.7; MS(MH+) 651.

References: [1]Patent: US6342765,2002,B1 .Location in patent: Page column 55.

17
[ 223761-21-5 ]
[ 91183-71-0 ]
[ 223761-22-6 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In DMF (N,N-dimethyl-formamide); at 20℃; for 16h;	A mixture of 2-(4-fluorophenethyl)-5-[2-(1-methylimidazol-5-yl)-1-(thiazol-2-yl)ethoxy]benzoic acid (0.74 g, 1.63 mmol), DMAP (1.0 g, 8.2 mmol), L-methionine tert-butyl ester HCl (1.0 g, 4.92 mmol), EDC (0.63 g, 3.27 mmol) and HOBT (0.22 g, 1.63 mmol) in DMF (50 ml) was stirred at ambient temperature under a nitrogen atmosphere for 16 hours. The reaction was evaporated to dryness and washed with aqueous citric acid (1M, 20 ml) and extracted with dichloromethane (20 ml). The extracts were washed with saturated brine and dried and applied directly onto a silica flash column which was eluted with ethyl acetate/methanol (9:1 and 4:1) to give tert-butyl (2S)-2- {2-(4-fluorophenethyl)-5-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxy]benzoylamino}-4-methylsulfanylbutyrate. The product was dissolved in ethyl acetate and treated with 1M ethereal HCl (10 ml). The resulting solid was isolated by centrifuging, flirther washing with diethyl ether and finally drying under high vacuum to give tert-butyl (2S)-2-{2-(4-fluorophenethyl)-5-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxy]benzoylamino}-4-methylsulfanylbutyrate as a white solid, (0.57 g, 54% Yield). 1H NMR (CDCl3) delta: 1.45-1.53 (9H, s), 1.99-2.10 (1H, m), 2.08 (3H, s), 2.16-2.31 (1H, m), 2.51-2.63 (2H, t), 2.78-2.97 (2H, m), 2.92-3.00 (2H, m), 3.30-3.4 (2H, m), 3.57 (3H, s), 4.66-4.78 (1H, m), 5.68-5.73 (1H, m), 6.47-6.55 (1H, t), 6.77-7.13 (8H, m), 7.40-7.45 (2H, m), 7.80 (1H, d). Anal. Calculated allowing for: 2 HCl 2H2O C, 53.00; H, 6.07; N, 7.49; S, 8.58; Found: C, 53.00; H, 6.20; N, 7.00; S, 8.70; MS (MH+). 439.4.

References: [1]Patent: US6342765,2002,B1 .Location in patent: Page column 59-60.

18
[ 223761-25-9 ]
[ 91183-71-0 ]
[ 223760-23-4 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In DMF (N,N-dimethyl-formamide); at 20℃; for 16h;	A mixture of 2-(4-fluorophenethyl)-5-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxymethyl]benzoic acid (0.47 g, 1.06 mmol) (from Example 63), DMAP (0.62 g, 5.05 mmol), L-methionine tert-butyl ester HCl (0.62 g, 3.02 mmol), EDC (0.39 g, 2.02 mmol) and HOBT (0.137 g, 1.01 mmol) in DMF (25 ml) was stirred at ambient temperature under a nitrogen atmosphere for 16 hours. The reaction was evaporated to dryness and washed with aqueous citric acid (1M, 10 ml) and extracted with dichloromethane (20 ml). The extracts were washed with saturated brine, dried and filtered. Purification by flash column chromatography eluting with dichloromethanel methanol (95:5, 9:1 and 85:15) gave a gum. This was dissolved in ethyl acetate and treated with 1M ethereal HCl (10 ml). The resulting solid precipitate was isolated by centrifuging, further washing with diethyl ether and drying under high vacuum to give tert-butyl (2S)-2- (2-(4-fluorophenethyl)-5-[1-(thiazol-2-yl)-2-(1 -methylimidazol-5-yl)ethoxymethyl]benzoylamino}-4-methylsulfanylbutyrate as a white solid, (0.366 g, 55%). 1H NMR (CDCl3) delta: 1.51(9H, s), 1.92-2.08 (1H, m), 2.15-2.33 (1H, m), 2.59-2.70 (2H, m), 2.85-2.98 (5H, m), 3.00-3.23 (4H, m), 3.46 (3H, d), 4.34 (1H, d), 4.52 (1H, dd), 4.70-4.83 (1H, m), 4.83-4.90 (1H, m), 6.77 (1H, d), 6.99-7.08 (3H, m), 7.12-7.21 (5H, m), 7.38 (1H, d), 7.80 (1H, d). Anal. Calculated allowing for: 2.75 H2O,1 HCl C, 55.27; H, 6.48; N, 7.58; S, 8.68; Found: C, 55.00; H, 6.70; N, 7.50; S, 9.00; MS (MH+). 653.4.

References: [1]Patent: US6342765,2002,B1 .Location in patent: Page column 60-61.

19
[ 223761-27-1 ]
[ 91183-71-0 ]
[ 223760-25-6 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In DMF (N,N-dimethyl-formamide); at 20℃; for 16h;	A mixture of 2-(4-fluorophenyl)-4-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxymethyl]benzoic acid (0.44 g, 1.07 mmol) (from Example 65), DMAP (0.62 g, 5.03 mmol), L-methionine tert-butyl ester HCl (0.62 g, 5.03 mmol), EDC (0.39 g, 2.01 mmol) and HOBT (0.138 g, 1.01 mmol) in DMF (25 ml) was stirred at ambient temperature under a nitrogen atmosphere for 16 hours. The reaction was evaporated to dryness, the residue treated with aqueous citric acid (1M, 10 ml) and then extracted with dichloromethane (20 ml). The extracts were washed with saturated brine, dried and applied directly to a silica flash column eluting with dichloromethane/methanol (95:5, 9:1 and 85:15) to give a gum. This was dissolved in ethyl acetate and treated with ethereal 1M HCl (10 ml). The resulting solid was isolated by centrifuging, further washing with diethyl ether and drying under high vacuum to give tert-butyl (2S)-2-{2-(4-fluorophenyl)-4-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxymethyl]benzoylamino}-4-methylsulfanylbutyrate as a white solid, (0.373 g, 59%). 1H NMR (DMSO-d6) delta: 1.49 (9H, s), 1.80-2.00 (2H, m), 2.06 (3H, s), 2.20-2.40 (2H, m), 3.13-3.31 (4H, m), 4.22-4.32 (1H, m), 4.70 (2H, q), 5.11 (1H, q), 6.63 (1H, s), 7.20-7.30 (2H, m), 7.30-7.51(7H, m), 7.80 (1H, d), 7.80 (1H, d), 7.89 (1H, d), 8.53 (1H, d). Anal. Calculated allowing for: 1.5 H2O, 1.5 HCl C, 54.40; H, 5.92; N, 7.93; S, 9.08; Found: C, 54.40; H, 6.00; N, 7.80; S, 9.00; MS (MH+). 625.4.

References: [1]Patent: US6342765,2002,B1 .Location in patent: Page column 62.

20
[ 223761-27-1 ]
[ 91183-71-0 ]
[ 223760-26-7 ]

Yield	Reaction Conditions	Operation in experiment
62%	With dmap; benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In DMF (N,N-dimethyl-formamide); at 20℃; for 16h;	A mixture of 2-(4-fluorophenyl)-4-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxymethyl]benzoic acid (0.44 g, 1.07 mmol), DMAP (0.61 g, 5.04 mmol), L-methionine tert-butyl ester HCl (0.71 g, 3.03 mmol), EDC (0.39 g, 2.01 mmol) and HOBT (0.138 g, 1.01 mmol) in DMF (25 ml) was stirred at ambient temperature under a nitrogen atmosphere for 16 hours. The reaction was evaporated to dryness and washed with aqueous citric acid (1M, ml) and extracted with dichloromethane (20 ml). The extracts were washed with saturated brine, dried and filtered. Purification by flash column chromatography eluting with dichloromethane/methanol (95:5, 9:1 and 85:15) gave a gum. This was dissolved in ethyl acetate and treated with ethereal 1M HCl (10 ml). The resulting solid was isolated by centrifuging, further washing with diethyl ether and drying under high vacuum to give tert-butyl (2S)-2-{2-(4-fluorophenyl)-4-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxymethyl]benzoylamino}-4-methylsulfonylbutyrate as a white solid, (0.406 g, 62%). 1H NMR (DMSO-d6) delta: 1.40 (9H, s),1.82-2.02 (1H, m), 2.02-2.12 (1H, m), 2.73-2.89 (1H, m), 2.93 (3H, s), 2.95-3.10 (2H, m), 3.10-3.25 (2H, m), 3.45 (3H, s), 4.18 4.28 (1H, m),4.63 (2H, q), 5.02 (1H, q0, 6.60 (1H, s), 7.10-7.25 (2H, m),7.25-7.50 (7H, m), 7.71 (1H, d), 7.81 (1H, d), 8.79 (1H, d). Anal. Calculated allowing for 1.5 HCl, 1.5 H2O: C, 52.04; H, 5.66; N, 7.59; S, 8.68; Found: C, 51.90; H, 5.40; N, 7.40; S, 8.70; MS (MH+). 657.4.

References: [1]Patent: US6342765,2002,B1 .Location in patent: Page column 62-63.

21
C₁₃H₁₀N₃O₂PolS [ No CAS ]
[ 91183-71-0 ]
C₁₈H₁₉N₄O₃PolS₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With N-ethyl-N,N-diisopropylamine; 3-hydroxy-3,4-dihydrobenzotriazine-4-one; diisopropyl-carbodiimide; In dichloromethane; at 20℃; for 18h;	Resin 1F (500 mg; 2.24 mmol) is swollen with CH2Cl2 (2×80 ml) and H-Met-O-tert-Bu hydrochloride (540 mg; 2.24 mmol), dichloromethane (11 ml), DIPEA (0.39 ml; 2.2 mmol), 3-hydroxy-1,2,3-benzotriazin-4-(3H)-one (HOOBT; 360 mg; 2.24 mmol) and 1,3-diisopropylcarbodiimide (DIC) (0.35 ml; 2.4 mmol) are then added. The mixture is stirred for 18 hours at room temperature. The resin is then filtered off, washed successively with DMF (2×), CH2Cl2 (2×), MeOH (2×), CH2Cl2 (2×) and finally dried (572 mg; 94%). [0109] A sample of this resin (100 mg) is cleaved by treatment with a 50/50/10 TFA/CH2Cl2/Et3SiH solution (3 ml) for 2.5 hours. The suspension is filtered and the resin is rinsed with CH2Cl2 (2×). The filtrates are combined and concentrated to give the desired product 1 (22 mg; 37%). [0110] HPLC (C18, lambda 220 nM), 100% H2O to 100% CH2CN (+0.1% TFA) over 8 minutes): purity: 87%. [0111] Mass spectrum (ESI): m/z 405 (MH+).

References: [1]Patent: US2004/204417,2004,A1 .Location in patent: Page 8-9.

22
[ 858104-55-9 ]
[ 91183-71-0 ]
N-[4-((2R,3R)-1-(4-fluorophenyl)-3-[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-L-methionine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%		Method 9; N-1 [4- ( (2R, 3R)-l- (4-fluorophenyl)-3-1 [2- (4-fluorophenyl)-2-oxoethyl] thio}-4-oxoazetidin- 2-yl) phenoxy]acetyl}glycyl-L-methionine; A mixture of 3- (R)-4- (R)-l- (4-Fluorophenyl)-3- [ (4-fluorobenzoyl) methylthio]-4-14- [N- (carboxymethyl) carbamoylmethoxy] phenyl} azetidin-2-one (0.0197g, 0.036 mmol), tert-butyl L-methioninate hydrochloride (0.0144 g, 0.060 mmol) and N-methylmorpholine (0.012 ml, 0. 111 mmol) in DCM (2ml) was stirred at room temperature. TBTU (0.018 g, 0.056 mmol) was added and the mixture was stirred overnight. Trifluoroacetic acid (0.65 ml) was added and after a couple of hours the hydrolysis was complete according to LC-MS. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on a Kromasil C8-column using a gradient of 5-100% MeCN in 0.15% trifluoroacetic acid buffer as eluent. The solvent was removed under reduced pressure and 0.015 g (61 %) of the title product was obtained. M/z 672.10.

References: [1]Patent: WO2005/61452,2005,A1 .Location in patent: Page/Page column 132.

23
[ 5070-13-3 ]
[ 91183-71-0 ]
C₁₆H₂₂N₂O₆S [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 1164 - 1171.

24
[ 858103-94-3 ]
[ 91183-71-0 ]
[ 13518-40-6 ]
C₃₉H₄₅F₂N₃O₇S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 55; N-[4-((2R, 3R)-1-(4-fluorophenyl)-3-[2-(4-fluorophenyl)-2-hydroxyethyl] thio}-4- oxoazetidin-2-yl) phenoxy] acetyl}-D-valyl-L-methionine; N-[4-((2R,3R)-1-(4-Fluorophenyl)-3-[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2- yl) phenoxy] acetyl}-D-valine (13.3 mg, 0.023 mmol), tert-butyl L-methioninate hydrochloride (7.4 mg, 0.031 mmol) and N-methylmorpholine (10, ul, 0.091 mmol) were dissolved in 1 ml. After 5 minutes, TBTU (8.9 mg, 0.028 mmol) was added and the resulting suspension was stirred overnight. Additional tert-butyl L-methioninate hydrochloride (2.1 mg, 0087 mmol), N-methylmorpholine (5, ul, 45, umol) and TBTU (2.1 mg, 6.54 jumol) were added and the mixture was stirred for 2 h. The formation of the ester was confirmed. M/z 768.1 (M-H) and 770.0 (M+H). The yellow suspension was purified on silica gel (1g) and eluted with EtOAc: DCM (15: 85). The pure fractions were concentrated and formic acid (1.5 ml) was added. The solution was stirred at 50C overnight. The solvent was removed under reduced pressure. Toluene was added and removed under reduced pressure. The residue was dissolved in methanol (1 ml) and sodium borohydride (9.9 mg, 0.26 mmol) was added. The resulting reaction mixture was stirred for 10 minutes. Ammonium acetate (18.9 mg) was added and the solvent was removed under reduced pressure. The residue was purified with preparative HPLC on a C8 column. A gradient from 20% to 40 % MeCN in 0.1 M ammonium acetate buffer was used as eluent. After lyophilisation, the title compound was obtained as a white solid was obtained (4.6 mg, 28%). 1H-NMR (400 MHz, DMSO-d6) : 0.75 (d, 3H), 0.79 (d, 3H), 1.79-1. 97 (m, 3H), 1.99 (s, 3H), 2.36-2. 44 (m, 2H), 2.86-2. 92 (m, 2H), 2.24-4. 35 (m, 3H), 4.58 (d, 2H), 4.67-4. 76 (m, 1H), 5.03 (d, 0.5H), 5.5 (d, 0. 5H), 5.63 (t, 1H), 6.95 (d, 2H), 7.05-7. 16 (m, 4H), 7.18-7. 24 (m, 2H), 7.30-7. 38 (m, 2H), 7.82 (d, 1H), 7.37 (d, 1H). M/z : 714.0 (M-1) and 716.1 (M+H).

References: [1]Patent: WO2005/61452,2005,A1 .Location in patent: Page/Page column 96-97.

25
[ 91183-71-0 ]
[ 1405-86-3 ]
[ 1200807-15-3 ]

References: [1]Russian Journal of Bioorganic Chemistry,2009,vol. 35,p. 510 - 517.

26
[ 91183-71-0 ]
[ 7432-21-5 ]
[ 1610768-79-0 ]

References: [1]Angewandte Chemie - International Edition,2014,vol. 53,p. 5389 - 5393.
Angew. Chem.,2014,vol. 126,p. 5493 - 5497,5.

27
[ 91183-71-0 ]
[ 53100-44-0 ]
C₁₉H₃₂N₂O₆S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 12h;	To a solution of HCl·Met-OtBu (242 mg, 1.0 mmol) in DMF (10 ml)was added Et3N (0.15 ml, 1.1 mmol) and Boc-pyroGlu-OH (229 mg,1.0 mol) at 0 C. HOBt (271 mg, 2.0 mmol) and EDC·HCl (287 mg,1.5 mmol) were added and the reaction mixture was stirred for 12 hat room temperature. After the removal of the solvent under reducedpressure, the residue was dissolved in ethyl acetate, and washed with5% NaHCO3 and 10% citric acid, and dried over anhydrous sodiumsulfate. After filtration, the resulting filtrate was concentrated underreduced pressure and white product was precipitated by diethyl etherto give 248 mg of protected dipeptide in 59% yield. The protected dipeptide (198 mg) was treated with 4 M HCl/dioxane at room temperaturefor 3 h to remove the protected groups. After the removal of excessHCl/dioxane, white solid was precipitated by ether to give 90 mg ofdesired product in 73% yield. MS (ESI) m/z: 261.09 [M + H]+ (calcd.261.09).

References: [1]Life Sciences,2014,vol. 117,p. 1 - 6.

28
C₆₆H₇₁N₃O₂₂ [ No CAS ]
[ 91183-71-0 ]
C₆₇H₁₁₁N₃O₁₉S₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; at 20 - 22℃; for 24h;	General procedure: N-Hydroxyphthalimide (3.0-3.5 mmol) and N,N-dicyclohexylcarbodiimide (3.0-3.5 mmol) were added to a solution of glycyrrhizic acid (1.0 mmol) in 20 mL of dioxane or THF at 0-5 C and the mixture was stirred for 1 h at this temperature, then at 20-22 C for 4 h. The precipitated dicyclohexylurea was filtered off, and tert-butyl ester of amino acid hydrochloride (4 mmol) and triethylamine (5-6 mmol) were added to the filtrate. The mixture was kept for 24 h at 20-22 C with occasional stirring. Then the mixture was poured in cold 5% solution of NaHCO3, the precipitate was filtered off, washed with water, dried, and reprecipitated from aqueous ethanol to provide carboxylprotectedconjugates 3, 5, 7, and 9 in 60-65% yield. To remove the ester tert-butyl group the obtained products (0.6-0.8 g) were dissolved in a mixture of methylene chloride and trifluorocetic acid (1 : 1, 10 mL). The mixture was kept for 1 h at 20-22 C, then evaporated in a vacuum and purified by column chromatography on silica gel eluting with a mixture chloroform-methanol-water (300 : 10 : 1, 200 : 10 : 1, 100 : 10 : 1, 50 : 10 : 1, vol). The individual fractions (by TLC) were combined and evaporated.

References: [1]Russian Journal of General Chemistry,2015,vol. 85,p. 2735 - 2738.
Zh. Obshch. Khim.,2015,vol. 85,p. 2003 - 2006,4.

29
C₉H₁₃N₃O₃ [ No CAS ]
[ 91183-71-0 ]
(S)-tert-butyl 2-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-4-(methylthio)butanoate [ No CAS ]

References: [1]Journal of Organic Chemistry,2016,vol. 81,p. 9802 - 9809.

30
[ 91183-71-0 ]
[ 530-62-1 ]
[ 106015-56-9 ]

References: [1]Advanced Synthesis and Catalysis,2017,vol. 359,p. 1963 - 1968.

31
[ 91183-71-0 ]
[ 1610768-79-0 ]

References: [1]Advanced Synthesis and Catalysis,2017,vol. 359,p. 1963 - 1968.

32
[ 199434-50-9 ]
[ 91183-71-0 ]
C₁₂H₂₂N₂O₄S [ No CAS ]

References: [1]ACS Catalysis,2018,vol. 8,p. 2181 - 2187.

33
[ 91183-71-0 ]
C₁₂H₂₄N₂O₃S [ No CAS ]
C₁₂H₂₄N₂O₃S [ No CAS ]

References: [1]ACS Catalysis,2018,vol. 8,p. 2181 - 2187.

34
[ 402-43-7 ]
[ 91183-71-0 ]
C₁₆H₂₂F₃NO₂S [ No CAS ]
C₁₆H₂₂F₃NO₂S [ No CAS ]

References: [1]Journal of the American Chemical Society,2019,vol. 141,p. 6392 - 6402.

35
[ 91183-71-0 ]
FmocHN-L-(NHBoc)Lys-L-Val-L-Met-OtBu [ No CAS ]

References: [1]Journal of the American Chemical Society,2019,vol. 141,p. 17361 - 17369.

36
[ 91183-71-0 ]
H₂N-L-(NHBoc)Lys-L-Val-L-Met-OtBu trifluoroacetate [ No CAS ]

References: [1]Journal of the American Chemical Society,2019,vol. 141,p. 17361 - 17369.

37
[ 68858-20-8 ]
[ 91183-71-0 ]
FmocHN-L-Val-L-Met-OtBu [ No CAS ]