[ CAS No. 53363-89-6 ] {[proInfo.proName]}

Name: 53363-89-6|Boc-N-Me-Leu-OH|95%
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Quality Control of [ 53363-89-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 53363-89-6 ]

Product Details of [ 53363-89-6 ]

CAS No. :	53363-89-6	MDL No. :	MFCD00038522
Formula :	C₁₂H₂₃NO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YXJFAOXATCRIKU-VIFPVBQESA-N
M.W :	245.32	Pubchem ID :	7010555
Synonyms :

Calculated chemistry of [ 53363-89-6 ]

Physicochemical Properties

Num. heavy atoms :	17
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.83
Num. rotatable bonds :	7
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	66.18
TPSA :	66.84 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.07 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.61
Log Po/w (XLOGP3) :	2.43
Log Po/w (WLOGP) :	2.35
Log Po/w (MLOGP) :	1.7
Log Po/w (SILICOS-IT) :	0.88
Consensus Log Po/w :	1.99

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-2.43
Solubility :	0.912 mg/ml ; 0.00372 mol/l
Class :	Soluble
Log S (Ali) :	-3.48
Solubility :	0.0819 mg/ml ; 0.000334 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.16
Solubility :	17.0 mg/ml ; 0.0692 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.9

Safety of [ 53363-89-6 ]

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 [ 53363-89-6 ]

* 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 [ 53363-89-6 ]
Downstream synthetic route of [ 53363-89-6 ]

[ 53363-89-6 ] Synthesis Path-Upstream 1~8

1
[ 13139-15-6 ]
[ 74-88-4 ]
[ 53363-89-6 ]

Yield	Reaction Conditions	Operation in experiment
98%	Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5 h; Inert atmosphere Stage #2: at 0 - 20℃; for 4.5 h; Inert atmosphere	To a solution of Boc-L-Leu (5.0 g, 21.6mmol) in THF (73 mL) wasadded NaH (60percent dispersion in mineral oil, 10.0 g, 0.13 mol) inportions at 0 oC. After stirring at 0 oC for 30 min, MeI (4.1 mL,66.0 mmol) and DMF (3.7 mL) were successively added. Thereaction was stirred for 30 min at 0 oC and additional 4 h atrt, until it was quenchedwith H2O (50 mL). The mixture was extracted by EtOAc (2×100 mL). The aqueoussolution was then acidified with 10percent aqueous KHSO4 solution to pH 5 and extractedwith ethyl acetate. The combined EtOAc extracts were washed with 5percent Na2S2O4solution and brine, and dried over Na2SO4, filtered and evaporated to give 13 (5.2 g,98percent yield) as a colorless oil.
95%	With sodium hydride In tetrahydrofuran at 0 - 20℃; for 26 h; Inert atmosphere	General procedure: (S)-2-(Tert-butoxycarbonyl(methyl)amino)-3-hydroxypropanoic acid(6a) Gummy substance (This compound was prepared byadding neat sodium hydride (10 equiv.) in portion wiseover a period of 2.0 h to a cooled (0 °C) solution of (S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (1equiv.) and iodomethane (10 equiv.) in dry THF under astream of nitrogen. The reaction mixture was stirred at room temperature for 24 h under nitrogen atmosphere andthen diluted with ether (20 mL) and quenched with water(30 mL). The layers were separated and the aqueous layerwas extracted with ether (2 x9 15 mL), acidified to pH 3with a 20 percent aqueous solution of citric acid and extractedwith EtOAc (3 x 20 mL). The combined organic phasewas dried over Na2SO4 and evaporated to afford thecorresponding N-methylated product in 90 percent yield asGummy substance.)
94%	Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 1 h; Inert atmosphere Stage #2: at 0 - 20℃; Inert atmosphere	Boc—Leu—OH (4.7 g, 30 mmol) was dissolved in 150 mL of THF in an inert atmosphere. Sodium hydride (3.2 g, 133 mmol, 4.0 equiv.) was added at 0°C in portions. The reaction mixture was agitated 1 hour at low temperature before adding iodomethane (14.2 g, 100 mmol, 5.0 equiv.). The reaction was left under agitationovernight at ambient temperature and then neutralised with 100 mL of water and washed 3 times with 200 mL of EtOAc. The aqueous phase was brought to pH 3 with iN HC1 and then extracted 3 times with 100 mL of EtOAc. The organic phases were combined, washed once with 300 mL of NaC1—saturated aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure yielding 4.7g (94 percent) of compound 52A in the form of a red oil.

Reference： [1] Tetrahedron Letters, 2014, vol. 55, # 44, p. 6109 - 6112
[2] Helvetica Chimica Acta, 1994, vol. 77, # 4, p. 1124 - 1165
[3] Medicinal Chemistry Research, 2016, vol. 25, # 6, p. 1148 - 1162
[4] Patent: WO2014/174060, 2014, A1, . Location in patent: Page/Page column 112
[5] International Journal of Molecular Sciences, 2017, vol. 18, # 3,
[6] Bioscience, Biotechnology, and Biochemistry, 1994, vol. 58, # 6, p. 1193 - 1194
[7] Tetrahedron, 2006, vol. 62, # 2-3, p. 264 - 284
[8] Canadian Journal of Chemistry, 1977, vol. 55, p. 906 - 910
[9] Tetrahedron, 1991, vol. 47, # 29, p. 5453 - 5462
[10] Tetrahedron Letters, 1998, vol. 39, # 40, p. 7373 - 7376
[11] Current Medicinal Chemistry, 2013, vol. 20, # 9, p. 1183 - 1194
[12] Journal of Organic Chemistry, 2014, vol. 79, # 17, p. 8491 - 8497

2
[ 13139-15-6 ]
[ 77-78-1 ]
[ 53363-89-6 ]

Reference： [1] Organic letters, 2003, vol. 5, # 2, p. 125 - 128
[2] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1995, vol. 34, # 1, p. 45 - 47

3
[ 130994-88-6 ]
[ 53363-89-6 ]

Reference： [1] Journal of Natural Products, 2011, vol. 74, # 4, p. 882 - 887
[2] Tetrahedron, 2012, vol. 68, # 35, p. 7070 - 7076

4
[ 172096-97-8 ]
[ 53363-89-6 ]

Reference： [1] Chemistry Letters, 1999, # 4, p. 299 - 300
[2] Tetrahedron Letters, 1998, vol. 39, # 14, p. 1985 - 1986

5
[ 61-90-5 ]
[ 53363-89-6 ]

Reference： [1] Tetrahedron, 1991, vol. 47, # 29, p. 5453 - 5462
[2] Medicinal Chemistry Research, 2016, vol. 25, # 6, p. 1148 - 1162
[3] International Journal of Molecular Sciences, 2017, vol. 18, # 3,

6
[ 24424-99-5 ]
[ 53363-89-6 ]

Reference： [1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1995, vol. 34, # 1, p. 45 - 47
[2] Medicinal Chemistry Research, 2016, vol. 25, # 6, p. 1148 - 1162
[3] International Journal of Molecular Sciences, 2017, vol. 18, # 3,

7
[ 58632-95-4 ]
[ 53363-89-6 ]

Reference： [1] Tetrahedron, 1991, vol. 47, # 29, p. 5453 - 5462

8
[ 13139-15-6 ]
[ 53363-89-6 ]

Reference： [1] Tetrahedron, 2012, vol. 68, # 35, p. 7070 - 7076

[ 53363-89-6 ] Synthesis Path-Downstream 1~59

1
[ 13139-15-6 ]
[ 74-88-4 ]
[ 53363-89-6 ]

Yield	Reaction Conditions	Operation in experiment
98%		To a solution of Boc-L-Leu (5.0 g, 21.6mmol) in THF (73 mL) wasadded NaH (60% dispersion in mineral oil, 10.0 g, 0.13 mol) inportions at 0 oC. After stirring at 0 oC for 30 min, MeI (4.1 mL,66.0 mmol) and DMF (3.7 mL) were successively added. Thereaction was stirred for 30 min at 0 oC and additional 4 h atrt, until it was quenchedwith H2O (50 mL). The mixture was extracted by EtOAc (2×100 mL). The aqueoussolution was then acidified with 10% aqueous KHSO4 solution to pH 5 and extractedwith ethyl acetate. The combined EtOAc extracts were washed with 5% Na2S2O4solution and brine, and dried over Na2SO4, filtered and evaporated to give 13 (5.2 g,98% yield) as a colorless oil.
95%	With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 26h;Inert atmosphere;	General procedure: (S)-2-(Tert-butoxycarbonyl(methyl)amino)-3-hydroxypropanoic acid(6a) Gummy substance (This compound was prepared byadding neat sodium hydride (10 equiv.) in portion wiseover a period of 2.0 h to a cooled (0 C) solution of (S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (1equiv.) and iodomethane (10 equiv.) in dry THF under astream of nitrogen. The reaction mixture was stirred at room temperature for 24 h under nitrogen atmosphere andthen diluted with ether (20 mL) and quenched with water(30 mL). The layers were separated and the aqueous layerwas extracted with ether (2 x9 15 mL), acidified to pH 3with a 20 % aqueous solution of citric acid and extractedwith EtOAc (3 x 20 mL). The combined organic phasewas dried over Na2SO4 and evaporated to afford thecorresponding N-methylated product in 90 % yield asGummy substance.)
94%		Boc-Leu-OH (4.7 g, 30 mmol) was dissolved in 150 mL of THF in an inert atmosphere. Sodium hydride (3.2 g, 133 mmol, 4.0 equiv.) was added at 0C in portions. The reaction mixture was agitated 1 hour at low temperature before adding iodomethane (14.2 g, 100 mmol, 5.0 equiv.). The reaction was left under agitationovernight at ambient temperature and then neutralised with 100 mL of water and washed 3 times with 200 mL of EtOAc. The aqueous phase was brought to pH 3 with iN HC1 and then extracted 3 times with 100 mL of EtOAc. The organic phases were combined, washed once with 300 mL of NaC1-saturated aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure yielding 4.7g (94 %) of compound 52A in the form of a red oil.

94%	With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 61.25h;	Sodium hydride (65.16g, 1.63mol) was added portion-wise over 1.25 hours to a mixture of Boc-L-leucine(125g, 0.50mol) and iodomethane (160ml_, 2.50mol) in THF (2L) cooled to 0C. The temperature was maintained below 5C during the addition and then allowed to warm up to room temperature and stirred for 2.5 days. The reaction mixture was cooled to 0C and quenched with water (2L); the temperature was maintained below 5C during the addition and then allowed to warm up to room temperature. The aqueous layer was extracted with EtOAc (2 750ml_), then the aqueous was acidified to pH 5 with 10% aqueous citric acid solution, extracted with EtOAc (3x1 L), dried over MgS04, filtered and the solvent removed in vacuo (50C) and azeotroped with DCM. The two batches were combined to yield 236.09 g, 94% yield. 1H NMR (CDCIs, 300 MHz): d 4.85 (t, 0.5H), 4.61 (dd, 0.5H), 2.81 (s, 1.5H), 2.78 (s, 1 .5H), 1.77-1.65 (m, 2H), 1 .57-1.51 (m, 1 H), 1.45 (s, 9H), 0.95-0.92 (m, 6H). Chiral analysis: 99.5% e.e. by GO
94%	With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 61.25h;	Sodium hydride (65.16g, 1 63mol) was added portion-wise over 1.25 hours to a mixture of Boc-L-leucine(125g, 0.50mol) and iodomethane (160mL, 2.50mol) in THF (2L) cooled to 0C. The temperature was maintained below 5C during the addition and then allowed to warm up to room temperature and stirred for 2.5 days. The reaction mixture was cooled to 0C and quenched with water (2L); the temperature was maintained below 5C during the addition and then allowed to warm up to room temperature. The aqueous layer was extracted with EtOAc (2c750mL), then the aqueous was acidified to pH 5 with 10% aqueous citric acid solution, extracted with EtOAc (3x1 L), dried over MgS04, filtered and the solvent removed in vacuo (50C) and azeotroped with DCM. The two batches were combined to yield 236.09 g, M1 , 94% yield.1H NMR (CDCIs, 300 MHz): d 4.85 (t, 0.5H), 4.61 (dd, 0.5H), 2.81 (s, 1.5H), 2.78 (s, 1.5H), 1.77-1.65 (m, 2H), 1.57-1.51 (m, 1 H), 1.45 (s, 9H), 0.95-0.92 (m, 6H). Chiral analysis: 99.5% e.e. by GC.

Reference： [1]Tetrahedron Letters,2014,vol. 55,p. 6109 - 6112
[2]Helvetica Chimica Acta,1994,vol. 77,p. 1124 - 1165
[3]Medicinal Chemistry Research,2016,vol. 25,p. 1148 - 1162
[4]Patent: WO2014/174060,2014,A1 .Location in patent: Page/Page column 112
[5]Patent: WO2019/108591,2019,A1 .Location in patent: Page/Page column 56; 57
[6]Patent: WO2019/217449,2019,A1 .Location in patent: Page/Page column 44; 45
[7]International Journal of Molecular Sciences,2017,vol. 18
[8]Bioscience, Biotechnology and Biochemistry,1994,vol. 58,p. 1193 - 1194
[9]Tetrahedron,2006,vol. 62,p. 264 - 284
[10]Canadian Journal of Chemistry,1977,vol. 55,p. 906 - 910
[11]Tetrahedron,1991,vol. 47,p. 5453 - 5462
[12]Tetrahedron Letters,1998,vol. 39,p. 7373 - 7376
[13]Current Medicinal Chemistry,2013,vol. 20,p. 1183 - 1194
[14]Journal of Organic Chemistry,2014,vol. 79,p. 8491 - 8497

2
[ 2666-93-5 ]
[ 53363-89-6 ]
[ 109745-86-0 ]

Reference： [1]Journal of Organic Chemistry,2007,vol. 72,p. 1980 - 2002
[2]Liebigs Annalen der Chemie,1987,p. 935 - 942
[3]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 4447 - 4449
[4]Organic Letters,2005,vol. 7,p. 3481 - 3484
[5]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 5625 - 5631
[6]Journal of Medicinal Chemistry,2008,vol. 51,p. 530 - 544
[7]eLife,2015,vol. 4

3
[ 53363-89-6 ]
[ 48168-99-6 ]
[ 89537-10-0 ]

Reference： [1]Tetrahedron Letters,1995,vol. 36,p. 4643 - 4646
[2]Journal of the American Chemical Society,1985,vol. 107,p. 4342 - 4343

4
[ 53363-89-6 ]
[ 3339-44-4 ]
<N-(tert-Butyloxycarbonyl)-N-methyl-L-leucyl>-N-methyl-L-valine methyl ester [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1994,vol. 59,p. 2437 - 2446

5
[ 53363-89-6 ]
[ 68641-49-6 ]
C₁₈H₃₀N₃O₉P [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1990,vol. 55,p. 2895 - 2903

6
[ 13139-15-6 ]
[ 77-78-1 ]
[ 53363-89-6 ]

Reference： [1]Organic letters,2003,vol. 5,p. 125 - 128
[2]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1995,vol. 34,p. 45 - 47

7
[ 53363-89-6 ]
[ 212117-40-3 ]
[ 212117-41-4 ]

Reference： [1]Tetrahedron Letters,1998,vol. 39,p. 5313 - 5316
[2]Journal of Medicinal Chemistry,2003,vol. 46,p. 2057 - 2073

8
[ 13734-36-6 ]
[ 53363-89-6 ]
[ 18942-49-9 ]
[ 5241-66-7 ]
Boc-Gln-OH, Boc-D-Pro-OH, Z-Arg(HCl)-OH, N^α-Boc-N^ε-Z-Lys-OH, CH3OH [ No CAS ]
[ 101835-71-6 ]

Reference： [1]Journal of medicinal chemistry,1986,vol. 29,p. 1171 - 1178

9
[ 13734-36-6 ]
[ 53363-89-6 ]
[ 18942-49-9 ]
[ 5241-66-7 ]
Boc-Gln-OH, Boc-D-Pro-OH, CH₃OH [ No CAS ]
[ 101835-72-7 ]

Reference： [1]Journal of medicinal chemistry,1986,vol. 29,p. 1171 - 1178

10
[ 53363-89-6 ]
[ 188908-64-7 ]
[ 188908-73-8 ]

Reference： [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 2057 - 2073

11
[ 53363-89-6 ]
L-allo-isoleucine-O-benzyl-L-serine allyl ester hydrochloride [ No CAS ]
[ 308279-69-8 ]

Reference： [1]Journal of the American Chemical Society,2000,vol. 122,p. 10214 - 10215

12
[ 53363-89-6 ]
[ 41979-39-9 ]
[ 1002750-48-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	With water; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 60℃; for 8h;	4-Piperidone monohydrate hydrochloride (1.10 g, 7.00 mmol) and N-Boc-N- methylleucine (1.89 g, 7.70 mmol) were suspended in N,N-dimethylformamide (70 ml). 1-Hydroxybenzotriazole (946 mg, 7.00 mmol), N- ethyldimethylaminopropylcarbodiimide hydrochloride (1.61 g, 8.40 mmol) and triethylamine (1.17 ml, 8.40 mmol) were added to the suspension, and the mixture was stirred at 60 C for 8 hours. The solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate (50 ml), poured into saturated aqueous NaHCO3 solution (50 ml) and extracted with ethyl acetate (100 ml x 2). The organic layer was washed with brine, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica (ethyl acetate/hexane, 40/60- 60/40) to give [(S)-l-(4,4-dihydroxypperidine-l-carbonyl)-3- methylbutyl]methylcarbamic acid tert-bnty ester (2.28 g, 94 %, pale yellow solid).

Reference： [1]Patent: WO2008/8398,2008,A2 .Location in patent: Page/Page column 373

13
[ 14051-46-8 ]
[ 53363-89-6 ]
t-butyl (1S)-1-[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]carbonyl}-3-methylbutyl(methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; at 20℃;	[0249] 389 mg (1.59 mmol) of t-butoxycarbonyl-N-methyl-L-leucine, 311 mg (1.62 mmol) of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride, 416 mg (1.52 mmol) of 4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidine and 0.22 ml (1.59 mmol) of triethylamine were stirred at room temperature overnight. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture. After extracting with dichloromethane, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane:ethyl acetate=3:1) to obtain the title compound. [0250] Yield: 368 mg (0.74 mmol), 48% MS (ESI, m/z) 501 (M+H)+ 1H-NMR (CDCl3): 0.86-0.98 (6H, dd), 1.34-1.65 (10H, m), 2.03-2.38 (4H, m), 2.64-2.84 (3H, m), 2.88-4.18 (6H, m), 4.78-5.12 (1H, m), 6.90-6.94 (2H, m), 7.11-7.38 (8H, m).
48%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;	389 mg (1.59 mmol) of t-butoxycarbonyl-N-methyl-L-leucine, 311 mg (1.62 mmol) of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride, 416 mg (1.52 mmol) of 4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidine and 0.22 ml (1.59 mmol) of triethylamine were stirred in 10 ml of dichloromethane at room temperature overnight. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture. After extracting with dichloromethane, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane : ethyl acetate = 3: 1) to obtain the title compound. Yield: 368 mg (0.74 mmol), 48 % MS (ESI, m/z) 501 (M+H)+ 1H-NMR (CDCl3): 0.86-0.98 (6H, dd), 1.34-1.65 (10H, m), 2.03-2.38 (4H, m), 2.64-2.84 (3H, m), 2.88-4.18 (6H, m), 4.78-5.12 (1H, m), 6.90-6.94 (2H, m), 7.11-7.38 (8H, m).

Reference： [1]Patent: US2004/167118,2004,A1 .Location in patent: Page 20-21
[2]Patent: EP1481673,2004,A1 .Location in patent: Page/Page column 29

14
[ 303-50-4 ]
[ 53363-89-6 ]
t-butyl (1S)-1-[[3-(5H-dibenzo[a,d][7]annulen-5-ylidene)propyl]-(methyl)amino]carbonyl}-3-methylbutyl(methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;	[0263] 280 mg (1.14 mmol) of t-butoxycarbonyl-N-methyl-L-leucine, 204 mg (1.06 mmol) of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride, 271 mg (1.04 mmol) of 3-(5H-dibenzo[a,d][7]annulen-5-ylidene)-N-methyl-1-propanamine and 0.15 ml (1.08 mmol) of triethylamine were stirred in 10 ml of dichloromethane at room temperature overnight. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture. After extracting with dichloromethane, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane:ethyl acetate=82:18) to obtain the title compound. [0264] Yield: 178 mg (0.37 mmol), 35%. MS (ESI, m/z) 489 (M+H)+ 1H-NMR (CDCl3): 0.63-0.96 (6H, m), 1.24-1.62 (11H, m), 2.22-2.91 (9H, m), 3.10-3.70 (2H, m), 4.66-5.08 (1H, m), 5.41-5.58 (1H, m), 6.79-6.91 (2H, m), 7.16-7.38 (8H, m).
35%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;	280 mg (1.14 mmol) of t-butoxycarbonyl-N-methyl-L-leucine, 204 mg (1.06 mmol) of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride, 271 mg (1.04 mmol) of 3-(5H-dibenzo[a,d][7]annulen-5-ylidene)-N-methyl-1-propanamine and 0.15 ml (1.08 mmol) of triethylamine were stirred in 10 ml of dichloromethane at room temperature overnight. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture. After extracting with dichloromethane, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane : ethyl acetate = 82:18) to obtain the title compound. Yield: 178 mg (0.37 mmol), 35 % MS (ESI, m/z) 489 (M+H)+ 1H-NMR (CDCl3): 0.63-0.96 (6H, m), 1.24-1.62 (11H, m), 2.22-2.91 (9H, m), 3.10-3.70 (2H, m), 4.66-5.08 (1H, m), 5.41-5.58 (1H, m), 6.79-6.91 (2H, m), 7.16-7.38 (8H, m).

Reference： [1]Patent: US2004/167118,2004,A1 .Location in patent: Page 21-22
[2]Patent: EP1481673,2004,A1 .Location in patent: Page/Page column 30

15
[ 53363-89-6 ]
[ 94790-37-1 ]
4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride [ No CAS ]
[ 248922-88-5 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In diethyl ether; N,N-dimethyl-formamide;	Step A. (S)-{1-[4,4-Bis-(4-fluoro-phenyl)-butylcarbamoyl]-3-methyl-butyl}-methyl-carbamic acid tert-butyl ester N-tert-Butoxycarbonyl-N-methyl-L-leucine (0.42 g, 1.7 mmol, Bachem Inc., Torrance, Calif.) was dissolved in dry DMF (5 mL) under nitrogen atmosphere and cooled to 0 C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.90 mL, 5.2 mmol) and solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.66 g, 1.7 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.51 g, 1.7 mmol) was then added. After additional 30 minutes stirring at 0 C., reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with 5% aqueous HCl solution, brine, saturated aqueous NaHCO3 solution, brine, and was dried over Na2SO4. Concentration in vacuo followed by drying under vacuum afforded the crude desired product which was used in the subsequent reaction without further purification.

Reference： [1]Patent: US6458781,2002,B1

16
[ 387350-79-0 ]
[ 53363-89-6 ]
[ 884308-85-4 ]

Yield	Reaction Conditions	Operation in experiment
78%	With dmap; benzotriazol-1-ol; diisopropyl-carbodiimide; In dichloromethane; at 20℃; for 8.25h;	To a mixture of N-cyclopropyl-N-piperidin-4-yl-3-trifluoromethyl-benzenesulfonamide (1.0 g, 2.9 mmol), BOC-L-Meleu-OH (0.72 g, 2.9 mmol), 1-hydroxybenzotriazole hydrate (HOBt, 50 mg, 0.37 mmol), 4-dimethylaminopyridine (DMAP, 20 mg, 0.16 mmol) in dichloromethane (20 mL) was added 1,3-diisopropylcarbodiimide (DIC, 0.44 mL, 2.9 mmol) at room temperature under argon over 15 minutes. The reaction mixture was shaken at room temperature for 8 hours. The reaction mixture was cooled to 0 C., and the solid was removed by filtration. The organic layer was washed with NaOH aqueous solution (2N, 15 mL). The solvent was removed under vacuum and the residue was purified by column (silica gel, EtOAc/hexanes 3/7) to give the intermediate (1-{4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)amino]piperidine-1-carbonyl}-3-methylbutyl)methyl-carbamic acid tert-butyl ester as sticky colorless oil (1.3 g, 78%).

Reference： [1]Patent: US2009/105249,2009,A1 .Location in patent: Page/Page column 32

17
[ 884308-83-2 ]
[ 53363-89-6 ]
[ 884308-84-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran;	N-Piperidin-4-yl-3-trifluoromethylbenzenesulfonamide (2) (6.3 g, 20.4 mmol), 1-hydroxybenzotriazole (3.32 g, 24.52 mmol), N-ethyl-dimethylaminopropyl carbodiimide hydrochloride (EDCI) (4.7 g, 24.52 mmol), and N-BOC-N-methylleucine (5.5 g, 22.44 mmol) were suspended in dry tetrahydrofuran (100 mL). Triethylamine (TEA) (8.5 ml, 61.2 mmol) was added to the suspension and the mixture stirred overnight. The mixture was poured into 1M sodium hydroxide solution (300 mL) and extracted with ethyl acetate (2*300 mL), dried (MgSO4), and the solvent was evaporated to dryness in vacuo to leave an off-white solid. The solid was triturated with ether (100 mL) to give the title compound 3 (yield 10.35 g, 95%) as a white solid. 1H NMR (400 MHz, CDCl3): delta (2:1 mixture of rotamers) 8.15 (1H, s), 8.07 (1H, d, J=12 Hz), 7.85 (1H, d, J=12 Hz), 7.66 (1H, m), 5.05-3.8 (4H, m), 3.55 (1H, m), 3.20-2.90 (1H, m), 2.65 (2s, 3H), 2.90-2.57 (1H, m), 1.74 (2H, m), 1.70-1.10 (15H, m), 0.90 (6H, d, J=15 Hz). LC: 100%. MS: m/z=558.3 (M+Na).

Reference： [1]Patent: US2009/105249,2009,A1 .Location in patent: Page/Page column 24-25

18
[ 53363-89-6 ]
[ 23707-37-1 ]
[ 1173807-57-2 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; for 4h;	Example 87 Preparation of (S)-tert-butyl 1-(isoquinolin-7-ylamino)-4-methyl-1-oxopentan-2-yl(methyl)carbamate (E86) To (S)-2-(tert-butoxycarbonyl(methyl)amino)-4-methylpentanoic acid in DMF was added EDC, DMAP and <strong>[23707-37-1]isoquinolin-7-amine</strong>. This mixture was stirred for 4 hours and the reaction was washed with NaHCO3 (sat), extracted with EtOAc, dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, Hexanes/EtOAc) gave pure (S)-tert-butyl 1-(isoquinolin-7-ylamino)-4-methyl-1-oxopentan-2-yl(methyl)carbamate (E87).

Reference： [1]Patent: US2009/186917,2009,A1 .Location in patent: Page/Page column 19

19
[ 53363-89-6 ]
[ 7517-19-3 ]
[ 109745-86-0 ]

Yield	Reaction Conditions	Operation in experiment
82%	With 6-chloro-3-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazol-3-ium-1-olatehexafluorophosphate(V); N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 2h;	To a stirred solution of 27 (504 mg,3.47 mmol) in dry CH2Cl2 (5 mL) was added Boc-NMe-l-Leu-OH(958 mg, 3.91 mmol) and HCTU (2.17 g, 5.25 mmol). After the solution was cooledto 0 C, DIPEA (2.40 mL,14.1 mmol) was dropwise added. The solution was warmed to room temperature and allowed to stir for 2h. The reaction was quenched with 5% KHSO4 aq.and extracted with EtOAc (5 mL x2). The extract was washed with saturated aqueous NaHCO3 (5 mL), with water (5 mL), and with brine (5 mL x2),dried with Na2SO4, and concentrated in vacuo. The resulting oil was purified by column chromatographyon silica-gel with hexane-EtOAc (2 : 1) to obtain 28 (1.06 g, 2.85 mmol, 82.0 %) as a colorless oil.1H-NMR (400MHz, CDCl3): dH 6.49 (br s, 1H), 4.47-4.41(m, 1H), 3.73 (s, 3H), 2.75 (s, 3H),1.68-1.49 (m, 6H), 1.49 (s, 9H), 0.95 (d, J = 6.9 Hz, 6H), 0.91 (d, J= 6.9 Hz, 6H) ppm.

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 5912 - 5914
[2]Tetrahedron Letters,2014,vol. 55,p. 4445 - 4447

20
[ 130994-88-6 ]
[ 53363-89-6 ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: Water (0.15 mL) and 2 M methanolic solution of NaOH (3.75 mL) were added to a solution of Nalpha-Boc-protected dipeptide alkyl ester (2.5 mmol) in methanol (5 mL). The mixture was stirred at rt for 4 h. The solvents were evaporated to dryness, the residue dissolved in water (20 mL), and washed with ether. The aqueous solution was then acidified with citric acid to pH 3, saturated with NaCl, and extracted with ethyl acetate. The organic phase was washed with saturated aqueous NaCl, dried over anhydrous MgSO4, and evaporated under vacuum. The residual product was dried in a vacuum desiccator over P4O10.

Reference： [1]Journal of Natural Products,2011,vol. 74,p. 882 - 887
[2]Tetrahedron,2012,vol. 68,p. 7070 - 7076

21
[ 36016-38-3 ]
[ 53363-89-6 ]
[ 1310366-75-6 ]

Yield	Reaction Conditions	Operation in experiment
58%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	[(tert-Butoxy)carbonyl]amino (2S)-2-[(tert-butoxy)carbonyl](methyl)amino}-4-methylpentanoate is prepared from (2S)-2-[(tert-butoxy)carbonyl](methyl)amino}-4-methylpentanoic acid and N-tert-butoxycarbonyl hydroxylamine according to Scheme 6. The compound exists as rotomers and is reported as such. (1.8 g, 58%), 1H NMR (500 MHz, CHLOROFORM-d) delta ppm 7.49-8.06 (1H, m), 4.75-5.10 (1H, m), 2.86 (3H, d, 7.8 Hz), 1.66-1.88 (2H, m), 1.54-1.64 (1H, m), 1.50 (9H, s), 1.47 (9H, d, 3.7 Hz), 0.96 (6H, dd, 10.7, 6.6 Hz).; To a stirred solution of N-tert-butoxycarbonyl hydroxylamine (1 equiv) and a carboxylic acid (1 equiv) in DCM (10 vol) is added EDCl.HCl (1 equiv). The reaction mixture is stirred at room temperature until complete consumption of the starting material is observed by tlc. The reaction mixture is washed with water (2×10 vol), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material is purified by column chromatography eluting with heptane: ethyl acetate.

Reference： [1]Patent: US2011/136827,2011,A1 .Location in patent: Page/Page column 44; 45

22
[ 320782-22-7 ]
[ 53363-89-6 ]
[ 1316821-86-9 ]

Yield	Reaction Conditions	Operation in experiment
94%		To a solution of Boc-N-methyl-L-leucine 11 (319 mg, 1.3 mmol) in dichloromethane-DMF (20 mL; 10:1) was added HATU (494 mg, 1.3 mmol), HOAt (179 mg, 1.3 mmol) and N,N-diisopropylethylamine (900 muL 5 mmol) and the reaction mixture stirred at room temperature for 5 min. 5,6-Dibromotryptamine hydrochloride 5·HCl (351 mg, 1 mmol) was added portionwise over 10 min and the reaction mixture stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (20 mL), washed with hydrochloric acid (1 M, 20 mL), saturated sodium hydrogen carbonate (20 mL), water (20 mL), brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography eluting with hexanes and ethyl acetate (1:1) to give Boc-alternatamide D as an yellow oil (510 mg, 0.94 mmol, 94 %) for use directly in the next step.

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 4042 - 4044

23
[ 1315050-51-1 ]
[ 53363-89-6 ]
[ 1357008-49-1 ]

Yield	Reaction Conditions	Operation in experiment
70%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h;Inert atmosphere;	General procedure: All peptide coupling reactions were carried out under argon with dry solvent, using methylene chloride and/or acetonitrile for dipeptide, tripeptide, and pentapeptide couplings. The amine (1.1 equiv) and acid (1 equiv) were weighed into a dry flask along with 4-8 equiv of DIPEA and 1.1 equiv of TBTU. *Anhydrous methylene chloride and/or acetonitrile were added to generate a 0.1 M solution. The solution was stirred at room temperature and reactions were monitored by TLC. Reactions were run for 1 h before checking via TLC. If reaction was not complete an additional 0.25 equiv of TBTU was added. If reaction was complete then work-up was done by washing with 10% aqueous hydrochloric acid and saturated sodium bicarbonate. After back extraction of aqueous layers with methylene chloride, organic layers were combined, dried over sodium sulfate, filtered, and concentrated. Flash column chromatography using a gradient of ethyl acetate/hexane gave our desired peptide.

Reference： [1]Tetrahedron,2012,vol. 68,p. 1029 - 1051

24
benzyl (R)-2-hydroxy-3-(4-morpholinophenyl)-propionate [ No CAS ]
[ 53363-89-6 ]
[ 168266-39-5 ]

Yield	Reaction Conditions	Operation in experiment
84%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃;	Into a 25 0-mL 3-necked round-bottom flask, was placed benzyl (2R)2-hydroxy-3 -[4-(morpholin-4-yl)phenyl]propanoate (10 g, 29.29 mmol, 1.00 equiv), (25)-2- [[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid (7.9 g, 32.20 mmol, 1.10 equiv), dichloromethane (180 mL). This was followed by the addition of DCC (6.6 g, 31.99 mmol, 1.10 equiv), 4-dimethylaminopyridine (3.9 g, 31.92 mmol, 1.10 equiv) and HOBT (4.3 g, 31.82 mmol, 11.10 equiv) respectively in portions with stirring at 0C. The resulting solution was stirred overnight at room temperature. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 14 g (84%) of (2R)1-(benzyloxy)-3-[4- (morpholin-4-yl)phenyl] -1 -oxopropan-2-yl-(2)-2-[ [(tert-butoxy)carbonyl] (methyl)amino] -4- methylpentanoate as a white solid. MS (ES, m/z): 569 (M+H); 1H NMR (300 IVIFIz, CDC13): 7.41-7.36 (m, 3H), 7.33-7.29 (m, 2H), 7.10 (d, J8.1 Hz, 2H), 6.85 (br, 2H), 5.26-5.23 (m, 1H),5.19-5.11 (m, 2H), 5.08-4.99 (m, 0.5H), 4.77-4.72 (m, 0.5H), 3.89 (br, 4H), 3.16-3.03 (m, 6H),2.67 (d, J8.4 Hz, 3H), 1.65-1.56 (m, 3H), 1.49 (d, J15.9 Hz, 9H), 0.92 (d, J6.0 Hz, 6H).
84%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃;	Into a 250-mL 3-necked round-bottom flask, was placed benzyl (2R)2-hydroxy-3-[4-(morpholin-4-yl)phenyl]propanoate (10 g, 29.29 mmol, 1.00 equiv), (2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid (7.9 g, 32.20 mmol, 1.10 equiv), dichloromethane (180 mL). This was followed by the addition of DCC (6.6 g, 31.99 mmol, 1.10 equiv), 4-dimethylaminopyridine (3.9 g, 31.92 mmol, 1.10 equiv) and HOBT (4.3 g, 31.82 mmol, 11.10 equiv) respectively in portions with stirring at 0oC. The resulting solution was stirred overnight at room temperature. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 14 g (84%) of (2R)1-(benzyloxy)-3-[4- (morpholin-4-yl)phenyl]-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4- methylpentanoate as a white solid. MS (ES, m/z): 569 (M+H); 1H NMR (300 MHz, CDCl3): delta 7.41-7.36 (m, 3H), 7.33-7.29 (m, 2H), 7.10 (d, J=8.1 Hz, 2H), 6.85 (br, 2H), 5.26-5.23 (m, 1H), 5.19-5.11 (m, 2H), 5.08-4.99 (m, 0.5H), 4.77-4.72 (m, 0.5H), 3.89 (br, 4H), 3.16-3.03 (m, 6H), 2.67 (d, J=8.4 Hz, 3H), 1.65-1.56 (m, 3H), 1.49 (d, J=15.9 Hz, 9H), 0.92 (d, J=6.0 Hz, 6H)
78.3%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20 - 25℃; for 3h;Inert atmosphere; Large scale;	Into a 50 L reactor purged and maintained with an inert atmosphere of nitrogen, was placed a solution of EMD-8 (1.96 kg, 5.75 mol, 1.0 eq) in dichloromethane (14.1 L, 10.V), N-(tert-butoxycarbonyl)-N-methyl-L-leucine (1.41 kg, 5.75 mol, 1.0 eq), DMAP (0.77 kg, 6.32 mol, 1.1 eq), EDCI (1.21 kg, 6.32 mol, 1.1 eq) at 20-25 C. The mixture was stirred at this temperature for at least 3 h and monitored by LCMS. The mixture was concentrated at below 40 C until no distillate drops out. The residue was dissolved in MTBE (14.1 L) and HC1 (aq, IN, 14.1 L) and filtered. The organic was washed with HC1 (aq, IN, 14.1 L), NaHC03 (sat, 14.1L x 2), and concentrated at below 40 C until no distillate drops out. Then the residue was resolved in heptane/MTBE (28.2 L, 8: 1, v/v), and concentrated at below 40 C until no distillate drops out. To the above residue was added heptane/MTBE (15.5 L, 8: 1, v/v) at 20-25 C and seed crystal (0.2%>, w/w), and kept stirring for overnight at 20-25 C. The mixture was filtered; the filter cake was washed with heptane (7.0 L). The solids were dried under vacuum at 40-45 C. This resulted in 2.56 kg (78.3%) of(R)-l -(benzyloxy)-3-(4-morpholinophenyl)-l-oxopropan-2-yl- N-(tertbutoxycarbonyl)-N-methyl-L-leucinate (EMD-9B) as a light yellow solid. MS (ES, m/z): 569 (M+H); NMR (DMSO-de, 300 MHz) 7.38-7.26 (m, 5H), 7.10 (d, J= 8.2 Hz, 2H), 6.96 (d, J = 8.1 Hz, 2H), 5.25-5.22 (m, 1H), 5.12-5.10 (m, 2H), 4.07-3.99 (m, 1 H), 3.79-3.76 (m? 4H), 3.19- 2.97 (m, 6H), 2.57 (s, 3H), 1.42-1.34 (m, 11H), 1.24-1.15 (m, 1H), 0.88-0.82 (m, 6H).

Reference： [1]European Journal of Organic Chemistry,2012,p. 1546 - 1553
[2]Patent: WO2016/187534,2016,A1 .Location in patent: Page/Page column 256; 257
[3]Patent: WO2018/93920,2018,A1 .Location in patent: Page/Page column 277; 278
[4]Patent: WO2019/91975,2019,A1 .Location in patent: Page/Page column 57; 58

25
[ 56777-24-3 ]
[ 53363-89-6 ]
[ 153052-68-7 ]

Yield	Reaction Conditions	Operation in experiment
99%	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;	Into a 2-L round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tetrahydrofuran (1.5 L), (2S)-2-[[(tert- butoxy)carbonyl] (methyl)amino] -4-methylpentanoic acid (50 g, 203.82 mmol, 1.00 equiv), benzyl (2)-2-hydroxypropanoate (36.7 g, 203.66 mmol, 1.00 equiv), triphenylphosphane (85 g, 324.07 mmol, 1.50 equiv). This was followed by the addition of DEAD (56.5 g, 324.43 mmol,1.20 equiv) dropwise with stirring at 0C. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50-1:10). This resulted in 82 g (99%) of (2R) 1 -(benzyloxy)- 1 -oxopropan-2-yl- (25)-2-[ [(tert-butoxy)carbonyl] (methyl)amino] - 4-methylpentanoate as pink oil. MS (ES, m/z): 408 (M+H); ?HNIVIR (300 IVIFIz, CDC13): 7.41-7.31 (m, 5H), 5.31-5.10 (m, 3H), 5.01-4.73 (m, 1H), 2.77-2.74 (m, 3H), 1.72-1.65 (m, 2H), 1.60-1.58 (m, 1H), 1.52-1.50 (m, 3H), 1.47(s, 9H), 0.96-0.94 (m, 6H).
99%	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;	Into a 2-L round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tetrahydrofuran (1.5 L), (2S)-2-[[(tert- butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid (50 g, 203.82 mmol, 1.00 equiv), benzyl (2S)-2-hydroxypropanoate (36.7 g, 203.66 mmol, 1.00 equiv), triphenylphosphine (85 g, 324.07 mmol, 1.50 equiv). This was followed by the addition of DEAD (56.5 g, 324.43 mmol, 1.20 equiv) dropwise with stirring at 0oC. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50-1:10). This resulted in 82 g (99%) of (2R)-1-(benzyloxy)-1-oxopropan-2-yl (2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]- 4-methylpentanoate as pink oil. MS (ES, m/z): 408 (M+H); 1HNMR(300 MHz, CDCl3, ppm): delta7.41-7.31 (m, 5H), 5.31-5.10 (m, 3H), 5.01-4.73 (m, 1H), 2.77-2.74 (m, 3H), 1.72-1.65 (m, 2H), 1.60-1.58 (m, 1H), 1.52-1.50 (m, 3H), 1.47(s, 9H), 0.96-0.94 (m, 6H).
99%	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;	Into a 2-L round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tetrahydrofuran (1.5 L), (2S)-2-[[(tert- butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid (50 g, 203.82 mmol, 1.00 equiv), benzyl (2S)-2-hydroxypropanoate (36.7 g, 203.66 mmol, 1.00 equiv), triphenylphosphane (85 g, 324.07 mmol, 1.50 equiv). This was followed by the addition of DEAD (56.5 g, 324.43 mmol, 1.20 equiv) dropwise with stirring at 0oC. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50-1:10). This resulted in 82 g (99%) of (2R)1-(benzyloxy)-1-oxopropan-2-yl- (2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]- 4-methylpentanoate as pink oil. MS (ES, m/z): 408 (M+H); 1HNMR (300 MHz, CDCl3): delta7.41- 7.31 (m, 5H), 5.31-5.10 (m, 3H), 5.01-4.73 (m, 1H), 2.77-2.74 (m, 3H), 1.72-1.65 (m, 2H), 1.60- 1.58 (m, 1H), 1.52-1.50 (m, 3H), 1.47(s, 9H), 0.96-0.94 (m, 6H).

62%	With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;	Triphenylphosphine (192g, 732mmol), Boc-Methyl-L-Leucine (165g, (0320) 672.6mmol), and benzyl-L-Lactate (120g, 666mmol) were dissolved in (0321) tetrahydrofuran (700mL). The resulting solution was cooled to 0C, then di- tertbutylazodicarboxylate (192g, 834mmol, 1.25eq.) was added portionwise, maintaining internal temperature < 5C. Once addition complete, mixture was allowed to stir and warm to room temperature overnight, during which time an off- white precipitate had formed. Heptane (500ml_) was added, and the resulting mixture filtered through Celite. The cake was washed with heptane (2x100ml_). The filtrate was concentrated in vacuo to yield a thick orange oil (602g). Heptane (500m L) was added, and the mixture was stirred vigorously for about 1 hour, resulting in further white precipitate forming. This was removed by filtration; the cake was washed with heptane (2x300ml_). The resulting filtrate was loaded directly onto silica (2kg), and eluted with EtOAc/hetane (1 % to 10%). First fraction (72.6g) still contained triphenylphosphine oxide; this was recolumned (about 700g silica, about 10% loading), using EtOAc/heptane (0% to 6%), to yield 68.2g (25.1 %) of Boc- MeLeu-DLac-OBn. The second fraction from the initial column was concentrated in vacuo to yield 100.1 g (combined = 168.3g, 62%) of (R)-1-(benzyloxy)-1 -oxopropan- 2-yl N-(tert-butoxycarbonyl)-N-methyl-L-leucinate as a straw coloured oil. 1H NMR (CDCIs): d 7.46-7.30 (m, 5H), 5.21-5.08 (m, 3H), 4.99-4.70 (ddd, 1 H), 2.73 (d, 3H), (0322) 1.73-1.40 (m, 18H), 0.92 (t, 6H). UPLC (CSH_C18, Short acid 2-95%): 1 .08 min, 308.5 Da [M-Boc+H]+.
62%	With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;	Triphenylphosphine (192g, 732mmol), Boc-Methyl-L-Leucine (165g,672.6mmol), and benzyl-L-Lactate (120g, 666mmol) were dissolved in tetrahydrofuran (700ml_). The resulting solution was cooled to 0C, then di- tertbutylazodicarboxylate (192g, 834mmol, 1 .25eq.) was added portionwise, maintaining internal temperature < 5C. Once addition complete, mixture was allowed to stir and warm to room temperature overnight, during which time an off- white precipitate had formed. Heptane (500m L) was added, and the resulting mixture filtered through Celite. The cake was washed with heptane (2x100ml_). The filtrate was concentrated in vacuo to yield a thick orange oil (602g). Heptane (500m L) was added, and the mixture was stirred vigorously for about 1 hour, resulting in further white precipitate forming. This was removed by filtration; the cake was washed with heptane (2x300ml_). The resulting filtrate was loaded directly onto silica (2kg), and eluted with EtOAc/hetane (1 % to 10%). First fraction (72.6g) still contained triphenylphosphine oxide; this was recolumned (about 700g silica, about 10% loading), using EtOAc/heptane (0% to 6%), to yield 68.2g (25.1 %) of Boc- MeLeu-DLac-OBn. The second fraction from the initial column was concentrated in vacuo to yield 100.1 g (combined = 168.3g, 62%) of (R)-1 -(benzyloxy)-1 -oxopropan- 2-yl N-(tert-butoxycarbonyl)-N-methyl-L-leucinate as a straw coloured oil. 1 H NMR (CDCl3 ): d 7.46-7.30 (m, 5H), 5.21 -5.08 (m, 3H), 4.99-4.70 (ddd, 1 H), 2.73 (d, 3H), 1 .73-1.40 (m, 18H), 0.92 (t, 6H). UPLC (CSH_C18, Short acid 2-95%): 1 .08 min, 308.5 Da [M-Boc+H]+.

Reference： [1]Patent: WO2016/187534,2016,A1 .Location in patent: Page/Page column 258; 259
[2]Patent: WO2017/116702,2017,A1 .Location in patent: Page/Page column 331
[3]Patent: WO2018/93920,2018,A1 .Location in patent: Page/Page column 279
[4]European Journal of Organic Chemistry,2012,p. 1546 - 1553
[5]Patent: WO2019/108591,2019,A1 .Location in patent: Page/Page column 61; 64; 65
[6]Patent: WO2019/217449,2019,A1 .Location in patent: Page/Page column 49; 52-53

26
[ 1393121-95-3 ]
[ 53363-89-6 ]
[ 1393122-05-8 ]

Yield	Reaction Conditions	Operation in experiment
91%		General procedure: NMM (15-20 mmol) was added to a solution of Nalpha-Boc amino acid (10 mmol) in THF (20 mL). The mixture was cooled to -15 C, then pivaloyl chloride (10 mmol) was added, and the mixture stirred for 10 min. After that, a solution of an amino component (9 mmol) and NMM (9 mmol) in 20 mL of a proper solvent (DCM, chloroform, or DMF) was added, and the resulting solution was stirred at 20 C for 1 h (for Pro, Sar, EtGly) or for 24 h (for MeAla, MeLeu, MePhe). The reaction mixture was then diluted with ethyl acetate (150 mL), washed with 10% solution of KHSO4 and with demineralized water, and dried over anhydrous MgSO4. The solvents were evaporated under vacuum to yield the solid material. In some cases the product was purified by column chromatography on silica gel.

Reference： [1]Tetrahedron,2012,vol. 68,p. 7070 - 7076

27
[ 53363-89-6 ]
[ 19460-86-7 ]
[ 1393121-81-7 ]

Yield	Reaction Conditions	Operation in experiment
96.3%		General procedure: NMM (15-20 mmol) was added to a solution of Nalpha-Boc amino acid (10 mmol) in THF (20 mL). The mixture was cooled to -15 C, then pivaloyl chloride (10 mmol) was added, and the mixture stirred for 10 min. After that, a solution of an amino component (9 mmol) and NMM (9 mmol) in 20 mL of a proper solvent (DCM, chloroform, or DMF) was added, and the resulting solution was stirred at 20 C for 1 h (for Pro, Sar, EtGly) or for 24 h (for MeAla, MeLeu, MePhe). The reaction mixture was then diluted with ethyl acetate (150 mL), washed with 10% solution of KHSO4 and with demineralized water, and dried over anhydrous MgSO4. The solvents were evaporated under vacuum to yield the solid material. In some cases the product was purified by column chromatography on silica gel.

Reference： [1]Tetrahedron,2012,vol. 68,p. 7070 - 7076

28
[ 53363-89-6 ]
[ 89536-89-0 ]
[ 89536-99-2 ]

Yield	Reaction Conditions	Operation in experiment
24%	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℃;	General procedure: Compound 1Y (50 mg, 0.08 mmol, 1.00 equiv) was dissolved in 2 mL of DMF in the presence of compound 1ZF (26.2 mg, 0.09 mmol, 1.20 equiv), DIEA (37.7 mL) and O-(7-azabenzotriazol-1-yl)-N,N,N?,N?-tetramethyluronium hexafluorophosphate(HATU, 43.3 mg, 0.11 mmol, 1.50 equiv). The reaction was left under agitation overnight at ambient temperature, then diluted with 10 mL of water and extracted 3 times with 5 mL of EtOAc. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to yield 100 mg of compound 1ZG in the form of a partly purified colourless oil. Compound 52B was prepared in similar manner as for compound 1ZG from the amine 1ZC (1.9 g, 7.4 mmol, 0.9 equiv.), the acid 52A (2.0 g, 8.1 mmol), HATU (4.7 g, 12 mmol, 1.5 equiv.) and DIEA (9 mL) in DMF (150 mL). After purification on a silicacolumn (EtOAc/EP = 1/10), compound 52B (0.8 g, 24 %) was obtained in the form of a white solid.

Reference： [1]Patent: WO2014/174060,2014,A1 .Location in patent: Page/Page column 41; 112; 113

29
[ 5407-57-8 ]
[ 53363-89-6 ]
C₂₃H₃₃ClN₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In N,N-dimethyl-formamide; at 0℃;	General procedure: (S)-2-Amino-N-(2-(7-chloroquinolin-4-ylamino) ethyl)-3-hydroxypropanamide (13) Gummy residue (1-hydroxybenzotriazoleHOBt (1.1 equiv.) and N,N0-dicyclohexylcarbodiimideDCC (1.5 equiv.) are added successively to asuspension of (S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoicacid (1 equiv.) in 15 mL of DMF. The mixturewas left under stirring for 30 min before adding N'-(7-chloroquinolin-4-yl) ethane-1,2-diamine, the stirring wascontinued for 4-6 h at 0 C temperature. The reactionmedium is then diluted with 40 mL of ethyl acetate andthen filtered, and washed with 40 mL of water saturatedwith NaCl. The organic phase is dried over Na2SO4, filteredand then evaporated. The crude product obtained ispurified by Column chromatography on silica gel (230-400mesh eluent: dichloromethane/Methanol 9:1). The fractionscontaining the desired compound according to TLCrevealed under UV are pooled and evaporated. The quantitativeyields were obtained for desired intermediates.Further Boc deprotection was done by TFA/DCM at roomtemperature for 4-6 h which leads to desired product ingood yield. It was obtained as gummy substance in 76 %yield);

Reference： [1]Medicinal Chemistry Research,2016,vol. 25,p. 1148 - 1162

30
[ 53363-89-6 ]
benzyl (2R)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-2-hydroxypropanoate [ No CAS ]
(2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-1-oxopropan-2-yl (2S)-2-[(tert-butoxy)carbonyl](methyl)amino}-4-methylpentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 2h;	Into a 1 000-mL round- bottom flask, was placed dichloromethane (200 mL), benzyl (2R)-3 -[4-(3 , 6-dihydro-2H-pyran-4- yl)phenyl]-2-hydroxypropanoate (12 g, 35.46 mmol, 1.00 equiv), (2S)-2-[[(tert- butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid (10.6 g, 43.21 mmol, 1.22 equiv), HOBT (6 g, 44.40 mmol, 1.25 equiv), DCC (9 g, 43.62 mmol, 1.23 equiv), 4- dimethylaminopyridine (6 g, 49.11 mmol, 1.38 equiv). The resulting solution was stirred for 2 h at room temperature. The solids were filtered out. The filtrate concentrated under vacuum. The filtrate was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 18.0 g (90%) of (2R)- 1 -(benzyloxy)-3 -[4-(3 , 6-dihydro-2H-pyran-4-yl)phenyl] -1- oxopropan-2-yl-(2)-2-[ [ (tert-butoxy)carbonyl ] (methyl)amino] -4-methylpentanoate as light yellow oil. MS (ES, m/z): 566 (M+H)
90%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃;	Into a 1000-mL round- bottom flask, was placed dichloromethane (200 mL), benzyl (2R)-3-[4-(3,6-dihydro-2H-pyran-4- yl)phenyl]-2-hydroxypropanoate (12 g, 35.46 mmol, 1.00 equiv), (2S)-2-[[(tert- butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid (10.6 g, 43.21 mmol, 1.22 equiv), HOBT (6 g, 44.40 mmol, 1.25 equiv), DCC (9 g, 43.62 mmol, 1.23 equiv), 4- dimethylaminopyridine (6 g, 49.11 mmol, 1.38 equiv). The resulting solution was stirred for 2 h at room temperature. The solids were filtered out. The filtrate concentrated under vacuum. The filtrate was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 18.0 g (90%) of (2R)-1-(benzyloxy)-3-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-1- oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate as light yellow oil. MS (ES, m/z): 566 (M+H)

Reference： [1]Patent: WO2016/187534,2016,A1 .Location in patent: Page/Page column 262
[2]Patent: WO2018/93920,2018,A1 .Location in patent: Page/Page column 282; 283

31
[ 53363-89-6 ]
benzyl (2R)-3-[4-(3,3-difluoropyrrolidin-1-yl)phenyl]-2-hydroxypropanoate [ No CAS ]
(2R)-1-(benzyloxy)-3-[4-(3,3-difluoropyrrolidin-1-yl)phenyl]-1-oxopropan-2-yl (2S)-2-[(tert-butoxy)carbonyl](methyl)amino}-4-fluoro-4-methylpentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃;	Into a 25 0-mL 3-necked round- bottom flask, was placed benzyl (2R)-3 -[4-(3 , 3 -difluoropyrrolidin- 1 -yl)phenyl] -2-hydroxypropanoate (1.5 g, 4.15 mmol, 1.00 equiv), (2S)-2-[[(tert-butoxy)carbonyl] (methyl)amino] -4-methylpentanoic acid (1 g, 4.08 mmol, 1.00 equiv), dichloromethane (80 mL). This was followed by the addition of DCC (1.1 g, 5.33 mmol, 1.20 equiv), 4-dimethylaminopyridine (600 mg, 4.91 mmol, 1.20 equiv) and HOBT (700 mg, 5.18 mmol, 1.20 equiv) respectively in portions with stirring at 0C. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:15). This resulted in 1.7 g (70%) of (2R)-1-(benzyloxy)-3-[4-(3,3-difluoropyrrolidin-1-yl)phenyl]-1- oxopropan-2-yl-(2)-2-[ [(tert-butoxy)carbonyl] (methyl)amino] -4-methylpentanoate as yellow oil. MS (ES, m/z): 589 (M+H).

Reference： [1]Patent: WO2016/187534,2016,A1 .Location in patent: Page/Page column 273

32
[ 53363-89-6 ]
benzyl (2R)-3-[4-(3,3-difluoropyrrolidin-1-yl)phenyl]-2-hydroxypropanoate [ No CAS ]
(2R)-1-(benzyloxy)-3-[4-(3,3-difluoropyrrolidin-1-yl)phenyl]-1-oxopropan-2-yl (2S)-2-[(tert-butoxy)carbonyl](methyl)amino}-4-methylpentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃;	Into a 25 0-mL 3-necked round-bottom flask, was placed benzyl (2R)-3 - [4-(3 ,3 -difluoropyrrolidin- 1 -yl)phenyl] -2-hydroxypropanoate (1.5 g, 4.15 mmol, 1.00 equiv), (2S)-2-[[(tert-butoxy)carbonyl] (methyl)amino] -4-methylpentanoic acid (1 g, 4.08 mmol, 1.00 equiv), dichloromethane (80 mL). This was followed by the addition of DCC (1.1 g, 5.33 mmol, 1.20 equiv), 4-dimethylaminopyridine (600 mg, 4.91 mmol, 1.20 equiv) and HOBT (700 mg, 5.18 mmol, 1.20 equiv) respectively in portions with stirring at 0C. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:15). This resulted in 1.7 g (70%) of (2R)-1-(benzyloxy)-3-[4-(3,3-difluoropyrrolidin-1-yl)phenyl]-1- oxopropan-2-yl (2)-2-[[(tert-butoxy)carbonyl](methyl)amino] -4-methylpentanoate as yellow oil. MS (ES, m/z): 589 (M+H).
70%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃;Inert atmosphere;	Into a 250-mL 3-necked round- bottom flask, was placed benzyl (2R)-3-[4-(3,3-difluoropyrrolidin-1-yl)phenyl]-2- hydroxypropanoate (1.5 g, 4.15 mmol, 1.00 equiv), (2S)-2-[[(tert- butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid (1 g, 4.08 mmol, 1.00 equiv), dichloromethane (80 mL). This was followed by the addition of DCC (1.1 g, 5.33 mmol, 1.20 equiv), 4-dimethylaminopyridine (600 mg, 4.91 mmol, 1.20 equiv) and HOBT (700 mg, 5.18 mmol, 1.20 equiv) respectively in portions with stirring at 0oC. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:15). This resulted in 1.7 g (70%) of (2R)-1-(benzyloxy)-3-[4-(3,3-difluoropyrrolidin-1-yl)phenyl]-1- oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate as yellow oil. MS (ES, m/z): 589 (M+H).

Reference： [1]Patent: WO2016/187534,2016,A1 .Location in patent: Page/Page column 289
[2]Patent: WO2018/93920,2018,A1 .Location in patent: Page/Page column 294

33
[ 53363-89-6 ]
benzyl (2R)-2-hydroxy-3-[5-(trifluoromethyl)pyridin-2-yl]propanoate [ No CAS ]
(2R)-1-(benzyloxy)-1-oxo-3-[5-(trifluoromethyl)pyridin-2-yl]propan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 25℃; for 12h;	Into a 5 0-mL round-bottom flask, was placed benzyl (2R)-2-hydroxy-3 -[5 -(trifluoromethyl)pyridin-2-yl]propanoate (500 mg, 1.54 mmol, 1.00 equiv), (25)-2- [[(tert-butoxy)carbonyl](methyl)amino] -4-methylpentanoic acid (489.9 mg, 2.00 mmol, 1.30 equiv), 4-dimethylaminopyridine (206.4 mg, 1.69 mmol, 1.10 equiv), HOBT (230.1 mg, 1.70 mmol, 1.11 equiv), dichloromethane (10 mL). This was followed by the addition of DCC (348.5 mg, 1.69 mmol, 1.10 equiv) in portions at 0C. The resulting solution was stirred for 12 h at 0-25C. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). The collected fractions were combined and concentrated under vacuum. This resulted in 281.2 mg (33%) of (2R)- 1 -(benzyloxy)- 1 -oxo-3 -[5 -(trifluoromethyl)pyridin-2-yl]propan-2-yl (2S)-2-[ [(tert-butoxy)carbonyl](methyl)amino] -4-methylpentanoate as light yellow oil. MS (ES, m/z): 553 (M+H).
33%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 25℃;	Into a 50-mL round-bottom flask, was placed benzyl (2R)-2-hydroxy-3-[5-(trifluoromethyl)pyridin-2-yl]propanoate (500 mg, 1.54 mmol, 1.00 equiv), (2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid (489.9 mg, 2.00 mmol, 1.30 equiv), 4-dimethylaminopyridine (206.4 mg, 1.69 mmol, 1.10 equiv), HOBT (230.1 mg, 1.70 mmol, 1.11 equiv), dichloromethane (10 mL). This was followed by the addition of DCC (348.5 mg, 1.69 mmol, 1.10 equiv) in portions at 0oC. The resulting solution was stirred for 12 h at 0-25oC. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). The collected fractions were combined and concentrated under vacuum. This resulted in 281.2 mg (33%) of (2R)-1-(benzyloxy)-1-oxo-3-[5-(trifluoromethyl)pyridin-2-yl]propan-2-yl (2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate as light yellow oil. MS (ES, m/z): 553 (M+H).

Reference： [1]Patent: WO2016/187534,2016,A1 .Location in patent: Page/Page column 268; 269
[2]Patent: WO2018/93920,2018,A1 .Location in patent: Page/Page column 290

34
[ 53363-89-6 ]
benzyl (2R)-2-hydroxy-3-[6-(trifluoromethyl)-3-pyridyl]propanoate [ No CAS ]
(2R)-1-(benzyloxy)-1-oxo-3-[6-(trifluoromethyl)pyridin-3-yl]propan-2-yl (2S)-2-[(tert-butoxy)carbonyl](methyl)amino}-4-methylpentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃;	To a stirred solution of N-tertbutoxycarbonyl-N-methyl-gamma-fluoro-L-leucine (0.46 g, 1.7 mmol), benzyl R-2-hydroxy-3 - [2-(trifluoromethyl)-5-pyridyl]propanoate (0.56 g, 1.7 mmol) and DMAP (cat.) in 6 mL DCM cooled to 0 C was added EDAC (0.51 g, 2.6 mmol) and the mixture stirred overnight allowing it to warm to room temperature. The mixture was diluted with 50 ml DCM, washed with 50 mL water, dried over sodium sulfate, filtered, concentrated and the residue purified on silica gel column eluting with ethyl acetate and heptanes to obtain the target compound as a clear oil. Yield: 0.80g, 81%. MS (CI, m/z): 553 (M+H).
81%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃;	To a stirred solution of N-tert- butoxycarbonyl-N-methyl-gamma-fluoro-L-leucine (0.46 g, 1.7 mmol), benzyl R-2-hydroxy-3- [2-(trifluoromethyl)-5-pyridyl]propanoate (0.56 g, 1.7 mmol) and DMAP (cat.) in 6 mL DCM cooled to 00C was added EDAC (0.51 g, 2.6 mmol) and the mixture stirred overnight allowing it to warm to room temperature. The mixture was diluted with 50 ml DCM, washed with 50 mL water, dried over sodium sulfate, filtered, concentrated and the residue purified on silica gel column eluting with ethyl acetate and heptanes to obtain the target compound as a clear oil. Yield: 0.80g, 81%. MS (CI, m/z): 553 (M+H).

Reference： [1]Patent: WO2016/187534,2016,A1 .Location in patent: Page/Page column 292
[2]Patent: WO2018/93920,2018,A1 .Location in patent: Page/Page column 313; 314

35
[ 53363-89-6 ]
tert-butyl N-[(1S)-1-(hydroxymethyl)-3-methyl-butyl]-N-methyl-carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With boron trifluoride diethyl etherate; In tetrahydrofuran; for 0.5h;	To a solution of N-boc-N-methyl-(L) leucine (4.0 g, 16 mmol) in 20 mL THF was added 18 mL of 1M boraneTHF complex in THF and the mixture stirred 30 mm. The mixture was quenched with 10 mL methanol and concentrated. The residue was dissolved in 150 mL ethyl acetate, washed with 100 mL water, washed with brine, dried over sodium sulfate, filtered and concentrated to obtain the target compound as a clear oil. Yield: 3.5 g, 93%. ?H NMR (CD2C12): 4.19 (m, 1H), 3.50 (d, J= 6.9 Hz, 2H), 2.68 (s, 3H), 1.86 (m, 1H), 1.51 (m, 1H), 1.44 (s, 9H), 1.39 (m, 1H), 1.1 (m, 1H), 0.92 (s, 3H), 0.91 (s, 3H).
93%	With borane-THF; In tetrahydrofuran; for 0.5h;	To a solution of N-boc-N-methyl-(L) leucine (4.0 g, 16 mmol) in 20 mL THF was added 18 mL of 1M borane- THF complex in THF and the mixture stirred 30 min. The mixture was quenched with 10 mL methanol and concentrated. The residue was dissolved in 150 mL ethyl acetate, washed with 100 mL water, washed with brine, dried over sodium sulfate, filtered and concentrated to obtain the target compound as a clear oil. Yield: 3.5 g, 93%.1H NMR (CD2Cl2): ^ 4.19 (m, 1H), 3.50 (d, J = 6.9 Hz, 2H), 2.68 (s, 3H), 1.86 (m, 1H), 1.51 (m, 1H), 1.44 (s, 9H), 1.39 (m, 1H), 1.1 (m, 1H), 0.92 (s, 3H), 0.91 (s, 3H).

Reference： [1]Patent: WO2016/187534,2016,A1 .Location in patent: Page/Page column 293; 294
[2]Patent: WO2018/93920,2018,A1 .Location in patent: Page/Page column 315

36
[ 53363-89-6 ]
benzyl (2R)-3-(4-cyanophenyl)-2-hydroxypropanoate [ No CAS ]
(2R)-1-(benzyloxy)-3-(4-cyanophenyl)-1-oxopropan-2-yl (2S)-2-[(tert-butoxy)carbonyl](methyl)amino}-4-methylpentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 17h;	Into a 100-mL 3-necked round-bottom flask, was placed benzyl (2R)-3-(4-cyanophenyl)-2-hydroxypropanoate (2 g, 7.11 mmol, 1.00 equiv), (25)- 2- [[(tert-butoxy)carbonyl](methyl)amino] -4-methylpentanoic acid (2.3 g, 9.38 mmol, 1.30 equiv), dichloromethane (40 mL). This was followed by the addition of DCC (1.6 g, 7.75 mmol, 1.10 equiv), 4-dimethylaminopyridine (960 mg, 7.86 mmol, 1.10 equiv) and HOBT (1.1 g, 8.14 mmol, 1.10 equiv) respectively in portions with stirring at 0C. The resulting solution was stirred for 17 h at room temperature. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 3.3 g (91%) of(2R)-1-(benzyloxy)-3-(4-cyanophenyl)-1-oxopropan-2-yl (25)-2-[ [(tert-butoxy)carbonyl](methyl)amino] -4-methylpentanoate as a white solid. MS (ES, m/z): 509 (M+H).
91%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃;	Into a 100-mL 3-necked round-bottom flask, was placed benzyl (2R)-3-(4-cyanophenyl)-2-hydroxypropanoate (2 g, 7.11 mmol, 1.00 equiv), (2S)- 2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid (2.3 g, 9.38 mmol, 1.30 equiv), dichloromethane (40 mL). This was followed by the addition of DCC (1.6 g, 7.75 mmol, 1.10 equiv), 4-dimethylaminopyridine (960 mg, 7.86 mmol, 1.10 equiv) and HOBT (1.1 g, 8.14 mmol, 1.10 equiv) respectively in portions with stirring at 0oC. The resulting solution was stirred for 17 h at room temperature. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 3.3 g (91%) of (2R)-1-(benzyloxy)-3-(4-cyanophenyl)-1-oxopropan-2-yl (2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate as a white solid. MS (ES, m/z): 509 (M+H).

Reference： [1]Patent: WO2016/187534,2016,A1 .Location in patent: Page/Page column 264
[2]Patent: WO2018/93920,2018,A1 .Location in patent: Page/Page column 285

37
[ 53363-89-6 ]
[ 30379-58-9 ]
2-(benzyloxy)-2-oxoethyl (2S)-2-[(tert-butoxy)carbonyl](methyl)amino}-4-methylpentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere;	Into a 250-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of benzyl 2-hydroxyacetate (3.5 g, 21.06 mmol, 1.00 equiv), dichloromethane (100 mL), (2S)-2- [(tert-butoxy)carbonyl] (methyl)amino-4- methylpentanoic acid (5.2 g, 21.20 mmol, 1.00 equiv). This was followed by the addition of DCC (5.21 g, 25.25 mmol, 1.20 equiv), HOBT (3.42 g, 25.31 mmol, 1.20 equiv) and 4- dimethylaminopyridine (3.1 g, 25.37 mmol, 1.20 equiv) respectively in portions with stirring at 0C. The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20-1:5). This resulted in 5.3 g (64%) of 2-(benzyloxy)-2-oxoethyl (2S)-2-[ [(tert-butoxy)carbonyl](methyl)amino] -4-methylpentanoate as colorless oil. MS (ES, m/z): 394 (M+H).
64%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃;Inert atmosphere;	Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of benzyl 2-hydroxyacetate (3.5 g, 21.06 mmol, 1.00 equiv), dichloromethane (100 mL), (2S)-2-[(tert-butoxy)carbonyl](methyl)amino-4- methylpentanoic acid (5.2 g, 21.20 mmol, 1.00 equiv). This was followed by the addition of DCC (5.21 g, 25.25 mmol, 1.20 equiv), HOBT (3.42 g, 25.31 mmol, 1.20 equiv) and 4- dimethylaminopyridine (3.1 g, 25.37 mmol, 1.20 equiv) respectively in portions with stirring at 0oC. The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20-1:5). This resulted in 5.3 g (64%) of 2-(benzyloxy)-2-oxoethyl (2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate as colorless oil. MS (ES, m/z): 394 (M+H).

Reference： [1]Patent: WO2016/187534,2016,A1 .Location in patent: Page/Page column 271; 272
[2]Patent: WO2018/93920,2018,A1 .Location in patent: Page/Page column 292; 293

38
[ 53363-89-6 ]
benzyl (2S)-3-[3-fluoro-4-(oxan-4-yl)phenyl]-2-hydroxypropanoate [ No CAS ]
(2R)-1-(benzyloxy)-3-[3-fluoro-4-(oxan-4-yl)phenyl]-1-oxopropan-2-yl (2S)-2-[(tert-butoxy)carbonyl](methyl)amino}-4-methylpentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃;	Into a 25 0-mL round-bottom flask, was placed (2S)-2- [[(tert-butoxy)carbonyl](methyl)amino] -4-methylpentanoic acid (900 mg, 3.67 mmol, 1.00 equiv), dichloromethane (30 mL), benzyl (2)-3-[3-fluoro-4-(oxan-4- yl)phenyl]-2-hydroxypropanoate (620 mg, 1.73 mmol, 1.00 equiv). This was followed by the addition of DCC (570 mg, 2.76 mmol, 1.10 equiv), HOBT (373 mg, 2.76 mmol, 1.10 equiv) and 4-dimethylaminopyridine (340 mg, 2.78 mmol, 1.10 equiv) respectively in portions with stirring at 0C. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 1.2 g (56%) of (2R)1-(benzyloxy)-3-[3-fluoro-4- (oxan-4-yl)phenyl]- 1 -oxopropan-2-yl-(2)-2- [ [(tert-butoxy)carbonyl] (methyl)amino] -4- methylpentanoate as colorless oil. MS (ES, m/z): 586 (M+H).Preparation Example 54: Preparation of dimer D27.

Reference： [1]Patent: WO2016/187534,2016,A1 .Location in patent: Page/Page column 272

39
[ 53363-89-6 ]
benzyl (2R)-2-hydroxy-3-[4-(trifluoromethyl)phenyl]propanoate [ No CAS ]
(2R)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethyl)phenyl]propan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃;	): Into a 1 00-mL round-bottom flask, was placed (25)-2- [[(tert-butoxy)carbonyl](methyl)amino] -4-methylpentanoic acid (200 mg, 0.82 mmol, 1.00 equiv), benzyl (2R)-2-hydroxy-3 - [4-(trifluoromethyl)phenyl]propanoate (152 mg, 0.47 mmol, 1.00 equiv), dichloromethane (10 mL). This was followed by the addition of DCC (140 mg, 0.68 mmol, 1.10 equiv), 4-dimethylaminopyridine (83 mg, 0.68 mmol, 1.10 equiv) and HOBT (116 mg, 0.86 mmol, 1.10 equiv) respectively in portions with stirring at 0C. The resulting solution was stirred overnight at room temperature. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20). This resulted in 159.3 mg (35%) of(2R)1-(benzyloxy)- 1 -oxo-3 - [4-(trifluoromethyl)phenyl]propan-2-yl-(2S)-2- [ [(tert-butoxy)carbonyl] (methyl)amino] -4-methylpentanoate as a light yellow solid. MS (ES, m/z): 552 (M+H); ?H NMR (300 IVIFIz, CDC13): 7.52-7.47 (m, 2H), 7.36-7.34 (m, 3H), 7.26-7.24 (m, 4H), 5.32 -5.28 (m, 1H), 4.18- 4.99 (m, 2H), 4.97-4.67 (m, 1H), 3.26-3.13 (m, 2H), 2.62 (d, J21.9 Hz, 3H), 1.60-1.14 (m, 12H), 0.93 (d, J12.0 Hz, 6H).
35%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃;	Into a 100-mL round-bottom flask, was placed (2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid (200 mg, 0.82 mmol, 1.00 equiv), benzyl (2R)-2-hydroxy-3-[4-(trifluoromethyl)phenyl]propanoate (152 mg, 0.47 mmol, 1.00 equiv), dichloromethane (10 mL). This was followed by the addition of DCC (140 mg, 0.68 mmol, 1.10 equiv), 4-dimethylaminopyridine (83 mg, 0.68 mmol, 1.10 equiv) and HOBT (116 mg, 0.86 mmol, 1.10 equiv) respectively in portions with stirring at 0oC. The resulting solution was stirred overnight at room temperature. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20). This resulted in 159.3 mg (35%) of (2R)1-(benzyloxy)- 1-oxo-3-[4-(trifluoromethyl)phenyl]propan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]- 4-methylpentanoate as a light yellow solid. MS (ES, m/z): 552 (M+H); 1H NMR (300 MHz, CDCl3): delta 7.52-7.47 (m, 2H), 7.36-7.34 (m, 3H), 7.26-7.24 (m, 4H), 5.32 -5.28 (m, 1H), 4.18- 4.99 (m, 2H), 4.97-4.67 (m, 1H), 3.26-3.13 (m, 2H), 2.62 (d, J=21.9 Hz, 3H), 1.60-1.14 (m, 12H), 0.93 (d, J=12.0 Hz, 6H).

Reference： [1]Patent: WO2016/187534,2016,A1 .Location in patent: Page/Page column 252; 253
[2]Patent: WO2018/93920,2018,A1 .Location in patent: Page/Page column 273; 274

40
benzyl (2R)-3-(4-fluorophenyl)-2-hydroxypropanoate [ No CAS ]
[ 53363-89-6 ]
(2R)-1-(benzyloxy)-3-(4-fluorophenyl)-1-oxopropan-2-yl (2S)-2-[(tert-butoxy)carbonyl](methyl)amino}-4-methylpentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 13h;	Into a 25 0-mL 3-necked round- bottom flask, was placed benzyl (2R)3-(4-fluorophenyl)-2-hydroxypropanoate (1.5 g, 5.47 mmol, 1.00 equiv), (2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid (1.5 g, 6.11 mmol, 1.10 equiv), dichloromethane (80 mL). This was followed by the addition of DCC (1.2 g, 5.82 mmol, 1.10 equiv), HOBT (0.8 g, 1.10 equiv) and 4-dimethylaminopyridine (0.7 g, 1.10 equiv) respectively in portions with stirring at 0C. The resulting solution was stirred for 13 h at room temperature. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 1.5 g (55%) of (2R)- 1 -(benzyloxy)-3 -(4-fluorophenyl)- 1 -oxopropan-2-yl-(2S)-2- [[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate as a white solid. MS (ES, m/z): 502 (M+H); ?H NMR (300 MHz, DMSO): 7.41-7.21 (m, 7H), 7.09-7.03 (m, 2H), 5.3 1-5.29 (m, 1H), 5.13 (s, 2H), 4.82-4.78 (m, 0.5H), 4.58-4.54 (m, 0.5H), 3.19-3.05 (m, 2H), 2.56 (s, 3H),1.52-1.23 (m, 12H), 0.90-0.79 (br, 6H).
55%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃;	Into a 250-mL 3-necked round- bottom flask, was placed benzyl (2R)3-(4-fluorophenyl)-2-hydroxypropanoate (1.5 g, 5.47 mmol, 1.00 equiv), (2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid (1.5 g, 6.11 mmol, 1.10 equiv), dichloromethane (80 mL). This was followed by the addition of DCC (1.2 g, 5.82 mmol, 1.10 equiv), HOBT (0.8 g, 1.10 equiv) and 4-dimethylaminopyridine (0.7 g, 1.10 equiv) respectively in portions with stirring at 0oC. The resulting solution was stirred for 13 h at room temperature. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 1.5 g (55%) of (2R)-1-(benzyloxy)-3-(4-fluorophenyl)-1-oxopropan-2-yl-(2S)-2- [[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate as a white solid. MS (ES, m/z): 502 (M+H); 1H NMR (300 MHz, DMSO): delta 7.41-7.21 (m, 7H), 7.09-7.03 (m, 2H), 5.31-5.29 (m, 1H), 5.13 (s, 2H), 4.82-4.78 (m, 0.5H), 4.58-4.54 (m, 0.5H), 3.19-3.05 (m, 2H), 2.56 (s, 3H), 1.52-1.23 (m, 12H), 0.90-0.79 (br, 6H).

Reference： [1]Patent: WO2016/187534,2016,A1 .Location in patent: Page/Page column 254; 255
[2]Patent: WO2018/93920,2018,A1 .Location in patent: Page/Page column 275; 276

41
[ 53363-89-6 ]
(2S)-1-(benzyloxy)-3-fluoropropan-2-ol [ No CAS ]
(2S)-1-(benzyloxy)-3-fluoropropan-2-yl (2S)-2-[(tert-butoxy)carbonyl](methyl)amino}-4-methylpentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 2h;	into a 500-mL round-bottom flask, was placed dichloromethane (200 mL),(2S)-2-[ [(tert-butoxy)carbonyl](methyl)amino] -4-methylpentanoic acid (14.6 g, 59.52 mmol,1.10 equiv), (2S)-1-(benzyloxy)-3-fluoropropan-2-ol (10 g, 54.29 mmol, 1.00 equiv), DCC (14 g,67.85 mmol, 1.25 equiv), 4-dimethylaminopyridine (8 g, 65.48 mmol, 1.21 equiv), HOBT (8.8 g,65.13 mmol, 1.20 equiv). The resulting solution was stirred for 2 h at room temperature. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 16 g (72%) of (25)-i -(benzyloxy)-3 -fluoropropan-2-yl-(2)-2-[ [(tert-butoxy)carbonyl] (methyl)amino] -4- methylpentanoate as colorless oil. MS (ES, m/z): 412(M+H).

Reference： [1]Patent: WO2016/187534,2016,A1 .Location in patent: Page/Page column 287; 288

42
[ 53363-89-6 ]
benzyl (2R)-3-(4-tert-butylphenyl)-2-hydroxypropanoate [ No CAS ]
(2R)-1-(benzyloxy)-3-(4-tert-butylphenyl)-1-oxopropan-2-yl (2S)-2-[(tert-butoxy)carbonyl](methyl)amino}-4-methylpentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃;	Into a 250-mL round-bottom flask, was placed a solution of benzyl (2R)-3-(4-tert-butylphenyl)-2-hydroxypropanoate (5.3 g, 16.97 mmol, 1.00 equiv) in dichloromethane (90 mL), (2S)-2- [[(tert-butoxy)carbonyl](methyl)amino]-4- methylpentanoic acid (4.2 g, 17.12 mmol, 1.00 equiv). This was followed by the addition of DCC (3.85 g, 18.66 mmol, 1.10 equiv), HOBT (2.52 g, 18.65 mmol, 1.10 equiv) and 4- dimethylaminopyridine (2.28 g, 18.66 mmol, 1.10 equiv) respectively in portions with stirring at 0C. The resulting solution was stirred overnight at room temperature. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:8). This resulted in 10 g (crude) of (2R)1- (benzyloxy)-3 -(4-tert-butylphenyl)- 1 -oxopropan-2-yl-(2S)-2-[ [(tert-butoxy)carbonyl] (methyl)amino]-4-methylpentanoate as light yellow oil. MS (ES, m/z): 562 (M+Na).
	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃;	Into a 250-mL round-bottom flask, was placed a solution of benzyl (2R)-3-(4-tert-butylphenyl)-2-hydroxypropanoate (5.3 g, 16.97 mmol, 1.00 equiv) in dichloromethane (90 mL), (2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4- methylpentanoic acid (4.2 g, 17.12 mmol, 1.00 equiv). This was followed by the addition of DCC (3.85 g, 18.66 mmol, 1.10 equiv), HOBT (2.52 g, 18.65 mmol, 1.10 equiv) and 4- dimethylaminopyridine (2.28 g, 18.66 mmol, 1.10 equiv) respectively in portions with stirring at 0oC. The resulting solution was stirred overnight at room temperature. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:8). This resulted in 10 g (crude) of (2R)1- (benzyloxy)-3-(4-tert-butylphenyl)-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl) amino]-4-methylpentanoate as light yellow oil. MS (ES, m/z): 562 (M+Na).

Reference： [1]Patent: WO2016/187534,2016,A1 .Location in patent: Page/Page column 262; 263
[2]Patent: WO2018/93920,2018,A1 .Location in patent: Page/Page column 283

43
[ 53363-89-6 ]
benzyl (2R)-2-hydroxy-3-[4-(trifluoromethoxy)phenyl]propanoate [ No CAS ]
(2R)-1-(benzyloxy)-1-oxo-3-[4-(trifluoromethoxy)phenyl]propan-2-yl (2S)-2-[(tert-butoxy)carbonyl](methyl)amino}-4-methylpentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃;	Into a 25 0-mL 3-necked round- bottom flask, was placed benzyl (2R)-2-hydroxy-3 - [4-(trifluoromethoxy)phenyl]propanoate (4.0 g, 11.75 mmol, 1.00 equiv), (2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid (2.94 g, 11.98 mmol, 1.00 equiv), dichloromethane (100 mL). This was followed by the addition of DCC (2.72 g, 13.18 mmol, 1.10 equiv), 4-dimethylaminopyridine (1.61 g, 13.18 mmol, 1.10 equiv) and HOBt (1.78 g, 13.17 mmol, 1.10 equiv) respectively in portions with stirring at 0C. The resulting solution was stirred overnight at room temperature. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:30). This resulted in 4.5 g (67%) of (2R)-1- (benzyloxy)- 1 -oxo-3 - [4-(trifluoromethoxy)phenyl]propan-2-yl-(2)-2-[ [(tert-butoxy)carbonyl] (methyl)amino]-4-methylpentanoate as yellow oil. MS (ES, m/z): 568 (M+H).
67%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃;	Into a 250-mL 3-necked round- bottom flask, was placed benzyl (2R)-2-hydroxy-3-[4-(trifluoromethoxy)phenyl]propanoate (4.0 g, 11.75 mmol, 1.00 equiv), (2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid (2.94 g, 11.98 mmol, 1.00 equiv), dichloromethane (100 mL). This was followed by the addition of DCC (2.72 g, 13.18 mmol, 1.10 equiv), 4-dimethylaminopyridine (1.61 g, 13.18 mmol, 1.10 equiv) and HOBt (1.78 g, 13.17 mmol, 1.10 equiv) respectively in portions with stirring at 0oC. The resulting solution was stirred overnight at room temperature. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:30). This resulted in 4.5 g (67%) of (2R)-1- (benzyloxy)-1-oxo-3-[4-(trifluoromethoxy)phenyl]propan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl] (methyl)amino]-4-methylpentanoate as yellow oil. MS (ES, m/z): 568 (M+H).

Reference： [1]Patent: WO2016/187534,2016,A1 .Location in patent: Page/Page column 263
[2]Patent: WO2018/93920,2018,A1 .Location in patent: Page/Page column 283; 284

44
[ 53363-89-6 ]
benzyl (2R)-2-hydroxy-3-[6-(morpholin-4-yl)pyridin-3-yl]propanoate [ No CAS ]
(2R)-1-(benzyloxy)-3-[6-(morpholin-4-yl)pyridin-3-yl]-1-oxopropan-2-yl (2S)-2-[(tert-butoxy)carbonyl](methyl)amino}-4-methylpentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃;	Into a 1 00-mL round-bottom flask, was placed a solution of benzyl (2R)-2-hydroxy-3 - [6-(morpholin-4-yl)pyridin-3 - yl]propanoate (1.36 g, 3.97 mmol, 1.00 equiv), (2S)-2-[(tert-butoxy)carbonyl](methyl)amino-4-methylpentanoic acid (980 mg, 3.99 mmol, 1.00 equiv) in dichloromethane (40 mL). This was followed by the addition of DCC (900 mg, 4.36 mmol, 1.10 equiv), 4-dimethylaminopyridine (540 mg, 4.42 mmol, 1.10 equiv) and HOBT (740 mg, 5.48 mmol, 1.10 equiv) respectively in portions with stirring at 0C. The resulting solution was stirred overnight at room temperature. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 1.2572 g (56%) of (2R)- 1 -(benzyloxy)-3 -[6-(morpholin-4-yl)pyridin-3 -yl]- 1 -oxopropan-2-yl-(2)-2- [[(tert-butoxy)carbonyl](methyl)amino] -4-methylpentanoate as a off-white solid. MS (ES, m/z):570 (M+H); ?H NMR (300 IVIFIz, CDC13): 8.01 (s, 1H), 7.39-7.33 (m, 4H), 7.30-7.28 (m, 2H),6.59-6.56 (m, 1H), 5.23-5.19 (m, 1H), 5.14 (s, 2H), 5.05-4.99 (m, 0.5H), 4.78-4.73 (m, 0.5H),3.85-3.82 (m, 4H), 3.49 (br, 4H), 3.10-2.95 (m, 2H), 2.68 (d, J10.8 Hz, 3H), 1.64-1.57 (m, 3H),1.48 (d, J12.9 Hz, 9H), 0.97-0.91 (m, 6H).
56%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃;	Into a 100-mL round-bottom flask, was placed a solution of benzyl (2R)-2-hydroxy-3-[6-(morpholin-4-yl)pyridin-3- yl]propanoate (1.36 g, 3.97 mmol, 1.00 equiv), (2S)-2-[(tert-butoxy)carbonyl](methyl)amino-4- methylpentanoic acid (980 mg, 3.99 mmol, 1.00 equiv) in dichloromethane (40 mL). This was followed by the addition of DCC (900 mg, 4.36 mmol, 1.10 equiv), 4-dimethylaminopyridine (540 mg, 4.42 mmol, 1.10 equiv) and HOBT (740 mg, 5.48 mmol, 1.10 equiv) respectively in portions with stirring at 0oC. The resulting solution was stirred overnight at room temperature. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 1.2572 g (56%) of (2R)-1-(benzyloxy)-3-[6-(morpholin-4-yl)pyridin-3-yl]-1-oxopropan-2-yl-(2S)-2- [[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate as a off-white solid. MS (ES, m/z): 570 (M+H); 1H NMR (300 MHz, CDCl3): delta 8.01 (s, 1H), 7.39-7.33 (m, 4H), 7.30-7.28 (m, 2H), 6.59-6.56 (m, 1H), 5.23-5.19 (m, 1H), 5.14 (s, 2H), 5.05-4.99 (m, 0.5H), 4.78-4.73 (m, 0.5H), 3.85-3.82 (m, 4H), 3.49 (br, 4H), 3.10-2.95 (m, 2H), 2.68 (d, J=10.8 Hz, 3H), 1.64-1.57 (m, 3H), 1.48 (d, J=12.9 Hz, 9H), 0.97-0.91 (m, 6H).

Reference： [1]Patent: WO2016/187534,2016,A1 .Location in patent: Page/Page column 263; 264
[2]Patent: WO2018/93920,2018,A1 .Location in patent: Page/Page column 284; 285

45
[ 53363-89-6 ]
[ 2441-07-8 ]
(2R)-1-(benzyloxy)-3-methyl-1-oxobutan-2-yl (2S)-2-[(tert-butoxy)carbonyl](methyl)amino}-4-methylpentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 22℃; for 48h;Inert atmosphere;	To a solution of a-D-hydroxyl acid 2 (1.37 g, 6.58 mmol) [15],L-N-Boc-Me-Leu-OH 3 (1.77 g, 7.22 mmol) [16], and 4-dimethylaminopyridine (DMAP) (1.04 g, 8.51 mmol) in CH2Cl2(20 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 1.51 g, 7.89 mmol) at 0 C (ice bath).The reaction mixture was allowed to stir at room temperaturefor 48 h under nitrogen gas and then acidified to pH 1 with 1 NHCl. The resulting solution was washed with CH2Cl2 (3 20 mL)and the combined organic layers were dried over MgSO4, filtered,and concentrated in vacuo. The crude product was purified by silicagel column chromatography (hexanes/EtOAc, 20:1), yielding thedesired product 4 (2.70 g, 6.20 mmol, 94% yield) as a colorless oil.The compound exists as a 1:1 mixture of rotamers [20]. 1H NMRof rotamer 1 (CDCl3, 400 MHz): d 7.45-7.30 (m, 5H, C6H5), 5.21 (d, J = 12.2 Hz, 1H, PhCH2-), 5.12 (d, J = 12.2 Hz, 1H, PhCH2-), 5.02(dd, J = 10.5, 4.9 Hz, 1H, COCHCN), 4.90 (t, J = 3.7 Hz, 1H,COOCHCO), 2.77 (s, 3H, NCH3), 2.33-2.13 (m, 1H, CH), 1.79-1.60(m, 3H, CH2 and CH), 1.47 (s, 9H, C(CH3)3), 0.99-0.92 (m, 12H,4 CH3); 1H NMR of rotamer 2 (CDCl3, 400 MHz): d 7.45-7.30(m, 5H, C6H5), 5.21 (d, J = 12.2 Hz, 1H, PhCH2-), 5.12 (d,J = 12.2 Hz, 1H, PhCH2-), 4.90 (t, J = 3.7 Hz, 1H, COOCHCO), 4.79(dd, J = 10.5, 4.9 Hz, 1H, COCHCN), 2.74 (s, 3H, NCH3), 2.33-2.13(m, 1H, CH), 1.79-1.60 (m, 3H, CH2 and CH), 1.46 (s, 9H, C(CH3)3), 0.99-0.92 (m, 12H, 4 CH3); 13C NMR of a 1:1 mixtureof rotamers (CDCl3, 100 MHz): d 172.2, 172.1, 169.2, 169.0, 156.2,155.5, 135.2, 135.1, 128.5, 128.3, 79.9, 79.5, 76.9, 76.8, 66.8, 66.7,56.5, 55.4, 37.3, 36.9, 29.8, 29.5, 28.1, 24.5, 24.3, 23.0, 21.0, 20.7,18.6, 18.5, 16.7; HRMS (ESI-TOF) m/z: [M+H]+ calcd. forC24H38NO6 436.2699; found, 436.2695.

Reference： [1]Bioorganic Chemistry,2016,vol. 69,p. 64 - 70

46
[ 917613-27-5 ]
[ 53363-89-6 ]
C₂₆H₄₁NO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 1h;Inert atmosphere;	Nitrogen atmosphere,1.2 g of (R) -2-hydroxyheptanoic acid benzyl ester was obtained at 0 CAnd 1.86 g of Boc-N-methyl-L-leucineWas dissolved in methylene chloride (50 ml), 1.46 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 32 mg of dimethylaminopyridine were added, and the mixture was stirred at 0 C After a minute,Followed by stirring at room temperature for 1 hour.After adding water to the reaction solution, the mixture was extracted twice with methylene chloride.The obtained organic phase was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine,Dried over anhydrous sodium sulfate and concentrated.The resulting crude product was subjected to rapid column chromatography(Eta-hexane: ethyl acetate = 10: 1 to 9: 1) to give N-Boc-N-Me-L-Ala- (R) -Etaep (OmicronBetaeta) 2.2g. yield: 96 %

Reference： [1]Patent: TW2016/9680,2016,A .Location in patent: Paragraph 0230

47
[ 53363-89-6 ]
[ 1738-77-8 ]
Boc-N-Me-L-Leu–L-Leu-OBn [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%		A reaction mixture containing Boc-N-Me-L-Leu-OH (6 mmol, 1.47 g) in THF (8 ml), DEPBT (9.0 mmol, 2.69 g), and DIEA (9.0 mmol, 1.6 ml) was stirred at 0C for 5 min. Then, L-Leu-OBn·TosOH (6.6 mmol, 2.59 g) was added and raised to room temperature naturally and stirred vigorously for 12 h. The solvent was evaporated in decompression. The residue was purified by column chromatography (silica gel, hexane/acetone=20 : 1). Finally, a 2.42 g product was obtained. Achromaticity crystalloid, yield 90%, [alpha]D24-64 (c=0.26, CH3OH); m.p.: 68-69C; 1H NMR (500 MHz, CDCl3) delta (ppm): 7.36 (m, 5H), 6.51 (s, 1H), 5.16 (m, 2H), 4.65 (s, 2H), 2.75(s, 3H), 1.63 (m, 4H), 1.54 (m, 2H), 1.48 (s, 9H), 0.93 (m, 12H); MS (ESI) m/z: 449.3 [M+H]+, 466.5 [M+NH4]+, 471.6 [M+Na]+.

Reference： [1]Anti-Cancer Drugs,2018,vol. 29,p. 503 - 512
[2]International Journal of Molecular Sciences,2017,vol. 18

48
[ 53363-89-6 ]
[ 17664-93-6 ]
C₂₅H₄₀N₂O₅ [ No CAS ]

Reference： [1]International Journal of Molecular Sciences,2017,vol. 18

49
[ 16937-99-8 ]
[ 16948-16-6 ]
[ 53363-89-6 ]
C₁₂H₂₁NO₄ [ No CAS ]
C₁₂H₂₁NO₄ [ No CAS ]
C₂₄H₄₀NO₄PolSi [ No CAS ]
[ 13734-31-1 ]
C₅₃H₈₈N₇O₇PolSi [ No CAS ]

Reference： [1]Patent: US2017/96454,2017,A1 .Location in patent: Paragraph 0197

50
[ 53363-89-6 ]
C₃₀H₄₁NO₅ [ No CAS ]
C₄₂H₆₂N₂O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 24h;	To a solution of 13 (59 mg, 0.12 mmol) and 5a (65 mg, 0.26 mmol) in CH2Cl2 (10 mL) was added sequentially TEA (0.21mL, 1.5 mmol), TCBC (0.11 mL, 0.7 mmol) and DMAP (180 mg, 1.5 mmol) at 0 C. The reaction mixture was slowlywarmed to room temperature and stirred for 24 h, and then quenched with saturated aqueous solution of NH4Cl (5 mL)and extracted with ethyl acetate (2 × 20 mL). The combined organic extracts were washed with brine (10 mL), dried overNa2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (ethylacetate/hexane, 1:4) to give rise to the desired product 3a (78 mg, 90%) as a colorless oil.

Reference： [1]Synlett,2018,vol. 29,p. 964 - 968

51
[ 53363-89-6 ]
N-Me-Leu-OBzl p-toluenesulfonic acid salt [ No CAS ]
[ 89537-10-0 ]

Yield	Reaction Conditions	Operation in experiment
81%		A solution of Boc-L-Me-Leu-OH (3.3 mmol, 0.81 g) in THF (5 ml) was prepared under an ice bath, and DEPBT (4.5 mmol, 1.35 g) and DIEA (4.5 mmol, 0.8 ml) were added in turn. After stirring for 5 min, H-N-Me-L-LeuOBn·TosOH (3 mmol, 1.27 g) was added to the mixture, raised to room temperature naturally, and stirred vigorously for 18 h. The solvent was evaporated in decompression. The residue was purified by column chromatography (silicagel, hexane/acetone=20:1). Finally, a 1.12 g product was obtained. Achromaticity oil, yield 81%, [alpha]D24-109.6 (c=0.7, CH3OH); 1H NMR (CDCl3) delta (ppm): 7.33 (m, 5H), 5.31 (m, 1H), 5.09 (m, 2H), 4.85 (m, 1H), 2.83 (s, 3H), 2.70 (s, 3H), 1.70 (m, 4H), 1.43 (s, 9H), 1.37 (m, 2H), 0.91 (m, 12H); MS (ESI) m/z: 463.3[M+H]+, 480.5 [M+NH4]+, 485.6[M+Na]+.

Reference： [1]Anti-Cancer Drugs,2018,vol. 29,p. 503 - 512

52
[ 13139-15-6 ]
hydriodic methane [ No CAS ]
[ 53363-89-6 ]

Yield	Reaction Conditions	Operation in experiment
87%		Hydriodic methane (15 mmol, 3.15 ml) was added to a solution of Boc-L-Leu-OH (10 mmol, 2.31 g) in THF (30 ml) slowly under an ice bath. The mixture was stirred vigorously for 30 min and 60% hydrid sodium (50 mmol, 1.2 g) was added smoothly. The mixture was stirred for 1h more in ice bath, and then be reacted overnight in room temperature. The reaction was cooled in an ice bath and a saturation aqueous solution of NH4Cl (10 ml) and saturation NaHCO3 was added in turn. The THF was evaporated in decompression. The aqueous solution were washed with petroleum ether (2×25 ml), 1 mol HCl was added to adjust the pH as 2-3, and extracted with EtOAc (4×50 ml). The combined organic layers were washed with sodium thiosulfate (5%, 75 ml) and saturation NaCl (75 ml), dried (Na2SO4), filtered, and concentrated. Finally, a 1.99 g product was obtained. Yellow oil, yield 87%, 1H NMR (400 MHz, CDCl3) delta (ppm): 4.82(m,0.5H), 4.62 (m,0.5H), 2.80 (s,3H), 1.71 (m,2H), 1.58 (m,1H), 1.46 (s,9H), 0.95 (d,J=6.4 Hz6H); MS (ESI) m/z: 246.2 [M+H]+, 263.2 [M+NH4]+, 268.3 [M+Na]+.

Reference： [1]Anti-Cancer Drugs,2018,vol. 29,p. 503 - 512

53
[ 56777-24-3 ]
[ 53363-89-6 ]
(2S)-1-(benzyloxy)-1-oxopropan-2-yl (2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 25℃; for 8h;	Into a 250-mL round-bottom flask, was placed (2S)-2-[[(tert- butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid (10 g, 40.76 mmol, 1.00 equiv), benzyl (2S)-2-hydroxypropanoate (7.2 g, 39.96 mmol, 1.00 equiv), and dichloromethane (150 mL). This was followed by the addition of DCC (10 g, 48.47 mmol, 1.20 equiv), HOBt (6.5 g, 48.11 mmol, 1.20 equiv) and 4-dimethylaminopyridine (5.8 g, 47.47 mmol, 1.20 equiv) in portions at 0oC. The resulting solution was stirred for 8 h at 25oC after which the solids were filtered out. The filtrate was concentrated under vacuum and the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 15.2 g (92%) of (2S)-1-(benzyloxy)-1- oxopropan-2-yl (2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate as brown oil. (ES, m/z): 408 [M+H]+.

Reference： [1]Patent: WO2018/93920,2018,A1 .Location in patent: Page/Page column 317; 318

54
[ 53363-89-6 ]
benzyl (2R)-3-[3-fluoro-4-(oxan-4-yl)phenyl]-2-hydroxypropanoate [ No CAS ]
(2R)-1-(benzyloxy)-3-[3-fluoro-4-(oxan-4-yl)phenyl]-1-oxopropan-2-yl (2S)-2-[(tert-butoxy)carbonyl](methyl)amino}-4-methylpentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃;Inert atmosphere;	Into a 250-mL round-bottom flask, was placed (2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid (900 mg, 3.67 mmol, 1.00 equiv), dichloromethane (30 mL), benzyl (2S)-3-[3-fluoro-4-(oxan-4- yl)phenyl]-2-hydroxypropanoate (620 mg, 1.73 mmol, 1.00 equiv). This was followed by the addition of DCC (570 mg, 2.76 mmol, 1.10 equiv), HOBT (373 mg, 2.76 mmol, 1.10 equiv) and 4-dimethylaminopyridine (340 mg, 2.78 mmol, 1.10 equiv) respectively in portions with stirring at 0oC. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 1.2 g (56%) of (2R)1-(benzyloxy)-3-[3-fluoro-4- (oxan-4-yl)phenyl]-1-oxopropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4- methylpentanoate as colorless oil. MS (ES, m/z): 586 (M+H).

Reference： [1]Patent: WO2018/93920,2018,A1 .Location in patent: Page/Page column 293; 294

55
[ 53363-89-6 ]
(2S)-1-(benzyloxy)-3-fluoropropan-2-ol [ No CAS ]
(2S)-1-(benzyloxy)-3-fluoropropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With dmap; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 2h;	Into a 500-mL round-bottom flask, was placed dichloromethane (200 mL), (2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4-methylpentanoic acid (14.6 g, 59.52 mmol, 1.10 equiv), (2S)-1-(benzyloxy)-3-fluoropropan-2-ol (10 g, 54.29 mmol, 1.00 equiv), DCC (14 g, 67.85 mmol, 1.25 equiv), 4-dimethylaminopyridine (8 g, 65.48 mmol, 1.21 equiv), HOBT (8.8 g, 65.13 mmol, 1.20 equiv). The resulting solution was stirred for 2 h at room temperature. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 16 g (72%) of (2S)-1-(benzyloxy)-3-fluoropropan-2-yl-(2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-4- methylpentanoate as colorless oil. MS (ES, m/z): 412(M+H).

Reference： [1]Patent: WO2018/93920,2018,A1 .Location in patent: Page/Page column 309

56
[ 53363-89-6 ]
[ 155030-63-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 2 h / 10 - 25 °C / Inert atmosphere 2: hydrogenchloride / ethyl acetate / 1 h / 20 - 25 °C / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 2.5 h / 10 - 25 °C / Inert atmosphere 4: hydrogenchloride / ethyl acetate / 1 h / 20 - 25 °C / Inert atmosphere 5: N-ethyl-N,N-diisopropylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 2.5 h / 10 - 25 °C / Inert atmosphere 6: hydrogenchloride / ethyl acetate / 1 h / 20 - 25 °C / Inert atmosphere 7: 5% Pd/C; hydrogen / ethanol / 4 h / 20 - 25 °C 8: N-ethyl-N,N-diisopropylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 2.5 h / 10 - 25 °C / Inert atmosphere
	Multi-step reaction with 8 steps 1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 2 h / 10 - 25 °C / Inert atmosphere 2: hydrogenchloride / ethyl acetate / 1 h / 20 - 25 °C / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 2.5 h / 10 - 25 °C / Inert atmosphere 4: 5% Pd/C; hydrogen / ethanol / 4 h / 20 - 25 °C 5: N-ethyl-N,N-diisopropylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 2.5 h / 10 - 25 °C / Inert atmosphere 6: hydrogenchloride / ethyl acetate / 1 h / 20 - 25 °C / Inert atmosphere 7: 5% Pd/C; hydrogen / ethanol / 4 h / 20 - 25 °C 8: N-ethyl-N,N-diisopropylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / ethyl acetate / 2.5 h / 10 - 25 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: ELANCO ANIMAL HEALTH INC - WO2019/91975, 2019, A1
[2]Current Patent Assignee: ELANCO ANIMAL HEALTH INC - WO2019/91975, 2019, A1

57
[ 1158076-89-1 ]
[ 53363-89-6 ]
C₂₆H₄₁NO₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 16h;	Compound 18 (0.35 g, 1.59 mmol) and amino acid 9 (0.40 g, 1.67 mmol) were dissolved in CH2Cl2 (20 mL) Add EDCI·HCl (0.37 mg, 1.90 mmol) and DMAP (10 mg) was stirred at room temperature overnight.Quenched with 1N HCl (15 mL).Extraction with ethyl acetate and purification by column (9:1 PE: EtOAc, Rf = 0.6)Target 19 (0.62 g, 88%):

Reference： [1]Patent: CN109553589,2019,A .Location in patent: Paragraph 0119; 0128; 0130; 0133

58
[ 53363-89-6 ]
benzyl (R)-2-hydroxy-3-(4-((methoxycarbonyl)amino)phenyl)propanoate [ No CAS ]
(R)-1-(benzyloxy)-3-(4-((methoxycarbonyl)amino)phenyl)-1-oxopropan-2-yl N-(tert-butoxycarbonyl)-N-methyl-L-leucinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With 4-methyl-morpholine; dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; for 5h;	EDC.HCI (134.8g, 703mmol), was added in one portion to a mixture of (R)- benzyl 2-hydroxy-3-(4-((methoxycarbonyl)amino)phenyl)propanoate (178.2g, (0314) 541 mmol), Boc-Methyl-L-Leucine (146. Og, 595mmol), DMAP (6.60g, 54mmol), 4- methylmorpholine (154.6ml_, 406mmol) and DCM (3.4L). EDC.HCI slowly dissolves forming an orange solution; a mild exotherm was controlled by cooling after about15 minutes. After 5 hours the reaction was washed with water (2x2 L), 10% aqueous citric acid solution (2x1 L), 5% aqueous citric acid solution (1 x1 L), saturated aqueous NaHCOs, water (1 L), dried over MgS04, filtered and the solvent removed in vacuo to yield an oil 296.1 g, 98%. 1 H NMR (CDCIs, 400 MHz): d 7.44-6.95 (m, 9H), 6.67-6.45 (m, 1 H), 5.36-4.64 (m, 4H), 4.14-3.63 (m, 3H), 3.22-2.92 (m, 2H), 2.74-2.50 (m, 3H), 1.69-1.32 (m, 12H), 1.01 -0.79 (m, 6H). UPLC (CSH_C18, Short acid, 2-95%): 1.06 min, 457.6 Da, [M-Boc+H]+.
98%	With 4-methyl-morpholine; dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; for 5.25h;Cooling;	EDC.HCI (134.8g, 703mmol), was added in one portion to a mixture of (R)- benzyl 2-hydroxy-3-(4-((methoxycarbonyl)amino)phenyl)propanoate (178.2g,541 mmol), Boc-Methyl-L-Leucine (146.0g, 595mmol), DMAP (6.60g, 54mmol), 4- methylmorpholine (154.6mL, 406mmol) and DCM (3.4L). EDC.HCI slowly dissolves forming an orange solution; a mild exotherm was controlled by cooling after about15 minutes. After 5 hours the reaction was washed with water (2x2 L), 10% aqueous citric acid solution (2x1 L), 5% aqueous citric acid solution (1 x1 L), saturated aqueous NaHCCb, water (1 L), dried over MgSC , filtered and the solvent removed in vacuo to yield an oil 296.1 g, 98%.1H NMR (CDCl3, 400 MHz): d 7.44-6.95 (m, 9H), 6.67-6.45 (m, 1 H), 5.36-4.64 (m, 4H), 4.14-3.63 (m, 3H), 3.22-2.92 (m, 2H), 2.74-2.50 (m, 3H), 1 .69-1.32 (m, 12H), 1.01 -0.79 (m, 6H). UPLC (CSH_C18, Short acid, 2-95%): 1 .06 min, 457.6 Da, [M-Boc+H]+.

Reference： [1]Patent: WO2019/108591,2019,A1 .Location in patent: Page/Page column 61; 63; 64
[2]Patent: WO2019/217449,2019,A1 .Location in patent: Page/Page column 49; 52

59
[ 53363-89-6 ]
[ 66866-69-1 ]

Yield	Reaction Conditions	Operation in experiment
62.1 g	With hydrogenchloride; In dichloromethane; at 15℃;	(3) Put 880mL of dichloromethane and 88.3g of N-methyl-Boc-L-leucine into a 2L reaction flask equipped with a thermometer at 15C, stir to dissolve and clear,Pass in hydrogen chloride gas very slowly. As the reaction progresses, the system slowly becomes turbid.A white solid precipitates out. After the raw material has reacted completely, filter it.Obtain 62.1g of N-methyl-L-leucine hydrochloride;

Reference： [1]Patent: CN112876502,2021,A .Location in patent: Paragraph 0078; 0082; 0096; 0100

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H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 53363-89-6 ] {[proInfo.proName]}

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[ 53363-89-6 ] Synthesis Path-Upstream 1~8

[ 53363-89-6 ] Synthesis Path-Downstream 1~59

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Amino Acid Derivatives

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[ 53363-89-6 ]