[ CAS No. 1093192-07-4 ]

Name: 1093192-07-4|(S)-Methyl 2-amino-3-((tert-butoxycarbonyl)amino)-3-methylbutanoate|95%
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SKU: A461085
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Quality Control of [ 1093192-07-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1093192-07-4 ]

SDS Specification

Alternatived Products of [ 1093192-07-4 ]

Product Details of [ 1093192-07-4 ]

CAS No. :	1093192-07-4	MDL No. :	MFCD16293742
Formula :	C₁₁H₂₂N₂O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UTWVEOUYCGZORL-SSDOTTSWSA-N
M.W :	246.30	Pubchem ID :	45382265
Synonyms :

Calculated chemistry of [ 1093192-07-4 ]

Physicochemical Properties

Num. heavy atoms :	17
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.82
Num. rotatable bonds :	7
Num. H-bond acceptors :	5.0
Num. H-bond donors :	2.0
Molar Refractivity :	63.54
TPSA :	90.65 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.4 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.68
Log Po/w (XLOGP3) :	0.56
Log Po/w (WLOGP) :	0.79
Log Po/w (MLOGP) :	0.61
Log Po/w (SILICOS-IT) :	0.11
Consensus Log Po/w :	0.95

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.26
Solubility :	13.6 mg/ml ; 0.0552 mol/l
Class :	Very soluble
Log S (Ali) :	-2.04
Solubility :	2.27 mg/ml ; 0.00921 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.43
Solubility :	9.21 mg/ml ; 0.0374 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.96

Safety of [ 1093192-07-4 ]

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 [ 1093192-07-4 ]

* 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 [ 1093192-07-4 ]
Downstream synthetic route of [ 1093192-07-4 ]

[ 1093192-07-4 ] Synthesis Path-Upstream 1~10

1
[ 1093192-06-3 ]
[ 1093192-07-4 ]

Yield	Reaction Conditions	Operation in experiment
95%	With hydrogen In tetrahydrofuran for 2 h; Inert atmosphere	Methyl (2S)-2-amino-3-[(tert-butoxy)carbonyl]amino}-3-methylbutanoate (136): 135 (0.50 g, 1 .4 mmol) is dissolved in anhydrous THF (10 mL) in 50 mL flask and placed under argon. Palladium hydroxide catalyst (0.18 g, 20 wtpercent) is rapidly weight and added to the flask. The flask is then filled with hydrogen and refilled. (-101 kpa). After 2 h, LC/MS showed the reaction is completed. The mixture is filtered through a celite pad, and the filtrate is condensed to dryness. The residue is purified by CombiFlash (eluting with 0-5percent MeOH in DCM) to afford 34 as white solid (330 mg, 95percent yield). ¹ H NMR (300 MHz, CDCI₃) 51 .30 (s, 3H), 1 .37 (s, 3H), 1 .39 (s, 9H), 3.26 (br s, 2H), 3.71 (s, 3H), 3.87 (s, 1 H), 4.95 (s, 1 H); ¹³C NMR (75 MHz, CDCI₃) δ 24.15, 24.23, 28.55, 52.28, 54.77, 60.55, 79.77, 155.26, 173.41 .
59.3%	With hydrogen In tetrahydrofuran at 20℃; for 9 h;	Compound III-07 (2.4 g, 6.848 mmol) was dissolved in THF (50 mL), then Pb(OH)₂ 20percent, 1.3 g) was added. The solution was stirred at room temperature under hydrogen (intensity of pressure: 3.0KG) for 9 h, then filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel with DCM/MeOH (100/1~50/1) to give III-08 (1.0 g, 59.3percent) as a colorless oil. ¹H NMR (400 MHz, Chloroform-d) δ 5.03-4.90 (s, 1H), 3.97-3.80 (s, 1H), 3.79-3.70 (s, 3H), 1.52-1.42 (s, 9H), 1.42-1.35 (s, 3H), 1.35-1.28 (s, 3H). MS(EI) m/z: (M⁺, 246).

Reference： [1] Patent: WO2012/31298, 2012, A2, . Location in patent: Page/Page column 121-122
[2] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 2, p. 94 - 102
[3] Patent: WO2008/154642, 2008, A2, . Location in patent: Page/Page column 245-246

2
[ 1093192-03-0 ]
[ 1093192-07-4 ]

Reference： [1] Patent: WO2012/31298, 2012, A2,
[2] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 2, p. 94 - 102
[3] Patent: WO2008/154642, 2008, A2,

3
[ 1093192-04-1 ]
[ 1093192-07-4 ]

Reference： [1] Patent: WO2012/31298, 2012, A2,
[2] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 2, p. 94 - 102
[3] Patent: WO2008/154642, 2008, A2,

4
[ 1093192-05-2 ]
[ 1093192-07-4 ]

Reference： [1] Patent: WO2012/31298, 2012, A2,
[2] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 2, p. 94 - 102
[3] Patent: WO2008/154642, 2008, A2,

5
[ 1093192-00-7 ]
[ 1093192-07-4 ]

Reference： [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 12, p. 5002 - 5014

6
[ 1093191-99-1 ]
[ 1093192-07-4 ]

Reference： [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 12, p. 5002 - 5014

7
[ 170454-20-3 ]
[ 1093192-07-4 ]

Reference： [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 12, p. 5002 - 5014

8
[ 1219366-49-0 ]
[ 1093192-07-4 ]

Reference： [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 12, p. 5002 - 5014

9
[ 1093192-01-8 ]
[ 1093192-07-4 ]

Reference： [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 12, p. 5002 - 5014

10
[ 1219366-76-3 ]
[ 1093192-07-4 ]

Reference： [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 12, p. 5002 - 5014

[ 1093192-07-4 ] Synthesis Path-Downstream 1~69

1
[ 1093192-06-3 ]
[ 1093192-07-4 ]

Yield	Reaction Conditions	Operation in experiment
95%	With hydrogen;palladium(II) hydroxide; In tetrahydrofuran; under 757.576 Torr; for 2.0h;Inert atmosphere;	Methyl (2S)-2-amino-3-[(tert-butoxy)carbonyl]amino}-3-methylbutanoate (136): 135 (0.50 g, 1 .4 mmol) is dissolved in anhydrous THF (10 mL) in 50 mL flask and placed under argon. Palladium hydroxide catalyst (0.18 g, 20 wt%) is rapidly weight and added to the flask. The flask is then filled with hydrogen and refilled. (-101 kpa). After 2 h, LC/MS showed the reaction is completed. The mixture is filtered through a celite pad, and the filtrate is condensed to dryness. The residue is purified by CombiFlash (eluting with 0-5% MeOH in DCM) to afford 34 as white solid (330 mg, 95% yield). 1 H NMR (300 MHz, CDCI3) 51 .30 (s, 3H), 1 .37 (s, 3H), 1 .39 (s, 9H), 3.26 (br s, 2H), 3.71 (s, 3H), 3.87 (s, 1 H), 4.95 (s, 1 H); 13C NMR (75 MHz, CDCI3) delta 24.15, 24.23, 28.55, 52.28, 54.77, 60.55, 79.77, 155.26, 173.41 .
59.3%	With hydrogen; In tetrahydrofuran; at 20℃; for 9.0h;	Compound III-07 (2.4 g, 6.848 mmol) was dissolved in THF (50 mL), then Pb(OH)2 20%, 1.3 g) was added. The solution was stirred at room temperature under hydrogen (intensity of pressure: 3.0KG) for 9 h, then filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel with DCM/MeOH (100/1~50/1) to give III-08 (1.0 g, 59.3%) as a colorless oil. 1H NMR (400 MHz, Chloroform-d) delta 5.03-4.90 (s, 1H), 3.97-3.80 (s, 1H), 3.79-3.70 (s, 3H), 1.52-1.42 (s, 9H), 1.42-1.35 (s, 3H), 1.35-1.28 (s, 3H). MS(EI) m/z: (M+, 246).
	With hydrogen;18% Pd(OH)2/C; In tetrahydrofuran; under 3620.13 Torr; for 11.0h;	Synthesis of (2S)-2-Amino-3-(tert-butoxycarbonylamino)-3 -methyl-butyric acid methyl ester (E-(S)). The combined BOC-diamino-ester D-(S) (6.30 g, 17.98 mmol) was dissolved in THF (5 % soln, 125 mL) in Parr shaker bottle and placed under nitrogen.The palladium hydroxide catalyst (2.27 g, 18 wt %) was rapidly weighed and added to the shaker flask with a following flush with nitrogen. The shaker flask was then connected to hydrogen and evacuated and refilled 3 times. The flask was then filled with hydrogen (70 psi) and shaking was commenced. The pressure was kept above 60 psi as the hydrogen was consumed. After 1 h, check of a sample by HPLC-MS showed incomplete deprotection. After 11 h, check of a sample by HPLC-MS showed a major product peak (2.55 min (MS-TIC), 2.59 (ELSD), MH+- 247.5) with no other peaks visible by UV (254 nm), MS, or ELSD. This mixture was then carefully flushed with nitrogen and filtered through a celite pad with additional MeOH (-250 mL) washing. This clear solution was rotary evaporated under reduced pressure (to 35 C) followed with addition of heptane (50 mL) and evaporation to yield a "water" clear oil (4.2 g) that was kept under vacuum. LC-MS [M+H] 247.5 (C11H22N2O4+H, requires 247.31).

Reference： [1]Patent: WO2012/31298,2012,A2 .Location in patent: Page/Page column 121-122
[2]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 94 - 102
[3]Patent: WO2008/154642,2008,A2 .Location in patent: Page/Page column 245-246

2
[ 1093192-07-4 ]
[ 1093192-08-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogenchloride; In diethyl ether; at 0℃; for 0.08333330000000001h;	Synthesis of (2S)-2-Amino-3-(tert-butoxycarbonylamino)-3 -methyl -butyric acid methyl ester HCl salt (E-(S)-HCl). The BOC-Me2DAP methyl ester (E-(S)) (506 mg, 2.05 mmol) under nitrogen was dissolved in diethyl ether (3 mL), cooled in a 0 C bath and rapidly stirred as a 2 M in Et2O hydrochloric acid soln (1.05 mL, 2.10 mmol, 1.02 eq) was added over 1 min. After stirring an additional 4 min, hexanes (25 mL) was added, and the suspension shaken, centrifuged and decanted. Additional hexanes (-20 mL) was added and the suspension shaken, cooled in a 0 C bath, centrifuged and decanted. The white precipitate was dried under full vacuum to yield the BOC-diamino-ester hydrochloride salt (E-(S)-HCl) (592 mg, 101.9% yield). Check of the sample by HPLC-MS showed the major product peak (2.89 min (MS-TIC), 2.92 (ELSD), MH+= 247.5) with no other peaks visible by UV (254 nm), MS, or ELSD. LC-MS [M+H] 247.5 (Cl 1H22N2O4+H, requires 247.31). * - [HPLC method: Onyx monolithic Cl 8 column, 50 x 4.6 mm; 1.5 mL/min; 9.10 min gradient of 5%-60% MeCN in H2O with 0.1% TFA; UV (254 ran); MS; ELSD. Retention times reported for UV (254 nm).]

Reference： [1]Patent: WO2008/154642,2008,A2 .Location in patent: Page/Page column 246-247

4
[ 1093192-07-4 ]
[ 1219366-78-5 ]
[ 1219366-79-6 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃;	Step H-E; A mixture of He (50 mg, 0.206 mmol), lib (56 mg, 0.227 mmol), HATU (86 mg, 0.227 mmol) and DIPEA (80 mg, 0.619 mmol) in DCM (3 mL) is stirred at rt overnight. Volatiles are removed under redu?ed pressure and the residue is purified with silica-gel chromatography (30% EtOAc/Heptane) to afford Hf (82 mg). Found m/z ES+ - 471 and ES- = 469.

Reference： [1]Patent: WO2010/31750,2010,A1 .Location in patent: Page/Page column 71

5
[ 1093192-03-0 ]
[ 1093192-07-4 ]

Reference： [1]Patent: WO2012/31298,2012,A2
[2]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 94 - 102
[3]Patent: WO2008/154642,2008,A2

6
[ 1093192-04-1 ]
[ 1093192-07-4 ]

Reference： [1]Patent: WO2012/31298,2012,A2
[2]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 94 - 102
[3]Patent: WO2008/154642,2008,A2

7
[ 1093192-05-2 ]
[ 1093192-07-4 ]

Reference： [1]Patent: WO2012/31298,2012,A2
[2]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 94 - 102
[3]Patent: WO2008/154642,2008,A2

8
[ 1093192-07-4 ]
[ 1363368-24-4 ]

Reference： [1]Patent: WO2012/31298,2012,A2

9
[ 1093192-07-4 ]
[ 1363373-89-0 ]

Reference： [1]Patent: WO2012/31298,2012,A2

10
[ 1093192-07-4 ]
[ 1363373-87-8 ]
[ 1363373-88-9 ]

Yield	Reaction Conditions	Operation in experiment
68%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 16.0h;Inert atmosphere;	To a solution of 103 (180 mg, 0.69 mmol) in anhydrous DMF (5 mL) is added 104 (237 mg, 0.97 mmol, 1 .4 equiv), EDC.HCI (185 mg, 0.97 mmol, 1 .2 equiv), HOBt (131 mg, 0.97 mmol, 1 .4 equiv) at room temperature under argon. The mixture is cooled to 0C, DIEA (0.5 mL, 2.76 mmol, 5.00 equiv) is added. The reaction mixture is stirred at 0 C for 2 hours, then is allowed to warm to room temperature for 14 hours. The yellow solution is then concentrated to dryness. The residue is treated with water (30 mL), extracted with EtOAc (3x50 mL). The combined extracts are washed with water (30 mL), brine (30 mL), and dried (anhydrous Na2SO4). The crude product is purified by CombiFlash (eluting with MeOH in DCM 0-1 .5 %) to give 105 (230 mg, 68% yield) as yellow solid. 1 H NMR (300 MHz, CDCI3) 51 .45 (s, 9H), 1 .47 (s, 3H), 1 .51 (s, 3H), 4.35 (s, 1 H), 4.73 (t, J=8.1 Hz, 2H), 6.64-6.70 (m, 2H), 7.12- 7.18 (m, 1 H), 7.33 (d, J=8.1 Hz, 1 H), 7.59 (d, J=8.1 Hz, 2H), 7.91 (d, J=8.4 Hz, 2H), 9.14 (br, s, 1 H); 13C NMR (75 MHz, CDCI3); 524.87, 28.22, 28.54, 52.44, 54.54, 62.47, 76.28, 79.04, 80.03, 80.70, 82.13, 106.12, 1 14.67, 1 18.15, 125.38, 127.65, 131 .09, 132.67, 133.36, 134.20, 145.00, 156.65, 166.34, 170.77; LC/MS m/s [M+H]+490.3.

Reference： [1]Patent: WO2012/31298,2012,A2 .Location in patent: Page/Page column 87

11
[ 1093192-07-4 ]
[ 1410809-83-4 ]

Reference： [1]Patent: WO2012/154204,2012,A1

12
[ 1093192-07-4 ]
[ 1410809-37-8 ]

Reference： [1]Patent: WO2012/154204,2012,A1

13
[ 1093192-07-4 ]
[ 1410809-88-9 ]

Reference： [1]Patent: WO2012/154204,2012,A1

14
[ 1093192-07-4 ]
[ 1410809-39-0 ]

Reference： [1]Patent: WO2012/154204,2012,A1

15
[ 1093192-07-4 ]
4-(((cis)-3-(hydroxymethyl)cyclobutyl)buta-1,3-diynyl)benzoic acid [ No CAS ]
(S)-methyl 3-(tert-butoxycarbonylamino)-2-(4-(((1,3-cis)-3-(hydroxymethyl)cyclobutyl)buta-1,3-diynyl)benzamido)-3-methylbutanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 16.0h;	<strong>[1093192-07-4](S)-methyl 2-amino-3-(tert-butoxycarbonylamino)-3-methylbutanoate</strong> (387 mg, 1 .573 mmol, 1.0 equiv) and 4-(((1 ,3-c/'s)-3-(hydroxymethyl)cyclobutyl)buta- 1 ,3-diynyl)benzoic acid (400 mg, 1.573 mmol, 1.0 equiv) were dissolved in DMF (3 mL). To this was added DIPEA (0.687 mL, 3.93 mmol, 2.5 equiv) then HATU (718 mg, 1 .888 mmol, 1 .2 equiv). This stirred at room temperature for -16 h. The reaction was partitioned between 1 M citric acid and ethyl acetate. The organics were washed with semi-saturated sodium chloride, saturated sodium bicarbonate then saturated sodium chloride, dried over magnesium sulfate and evaporated to dryness. Yielded 1.035 g crude (S)-methyl 3-(tert-butoxycarbonylamino)-2-(4-(((1 ,3-c/'s)-3-(hydroxymethyl)cyclobutyl)buta-1 ,3-diynyl)benzamido)-3-methylbutanoate. LCMS M+1 expected = 483.2, observed = 483.2.

Reference： [1]Patent: WO2012/154204,2012,A1 .Location in patent: Page/Page column 74; 75

16
[ 1093192-07-4 ]
4-(((trans)-3-(hydroxymethyl)cyclobutyl)buta-1,3-diynyl)benzoic acid [ No CAS ]
(S)-methyl 3-(tert-butoxycarbonylamino)-2-(4-(((1,3-trans)-3-(hydroxymethyl)cyclobutyl)buta-1,3-diynyl)benzamido)-3-methylbutanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 16.0h;	<strong>[1093192-07-4](S)-methyl 2-amino-3-(tert-butoxycarbonylamino)-3-methylbutanoate</strong> (329 mg, 1 .377 mmol, 1.0 equiv) and 4-(((1 ,3-£rans)-3-(hydroxymethyl)cyclobutyl)buta- 1 ,3-diynyl)benzoic acid (340 mg, 1.377 mmol, 1.0 equiv) were dissolved in DMF (3 ml_). To this was added DIPEA (0.584 mL, 3.34 mmol, 2.5 equiv) then HATU (610 mg, 1 .605 mmol, 1.2 equiv). This stirred at room temperature for ~16 h. The reaction was partitioned between 1 M citric acid and ethyl acetate. The organics were washed with semi-saturated sodium chloride, saturated sodium bicarbonate then saturated sodium chloride, dried over magnesium sulfate and evaporated to dryness. Yielded 990 mg crude (S)-methyl 3-(tert-butoxycarbonylamino)-2-(4-(((1 ,3-trans)-3-(hydroxymethyl)cyclobutyl)buta-1 ,3-diynyl)benzamido)-3-methylbutanoate. LCMS M+1 expected = 483.2, observed = 483.2.

Reference： [1]Patent: WO2012/154204,2012,A1 .Location in patent: Page/Page column 76

17
[ 1093192-07-4 ]
[ 1410810-59-1 ]
[ 1410810-62-6 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 16.0h;	<strong>[1093192-07-4](S)-methyl 2-amino-3-(tert-butoxycarbonylamino)-3-methylbutanoate</strong> (100 mg, 0.406 mmol, 1.0 equiv) and 4-((3-(hydroxymethyl)cyclopentyl)buta-1 ,3- diynyl)benzoic acid (crude) (theoretical 109 mg, 0.406 mmol, 1.0 equiv) were dissolved in DMF (1 ml_). To this was added DIPEA (0.177 ml_, 1.016 mmol, 2.5 equiv) then HATU (185 mg, 0.488 mmol, 1 .2 equiv). This stirred at room temperature for ~16 h. The reaction was partitioned between 1 M citric acid and ethyl acetate. The organics were washed with semi-saturated sodium chloride, saturated sodium bicarbonate then saturated sodium chloride, dried over magnesium sulfate and evaporated to dryness. Yielded 500 mg crude (S)-methyl 3-(tert-butoxycarbonylamino)-2-(4-((3- (hydroxymethyl)cyclopentyl)buta-1 ,3-diynyl)benzamido)-3-methylbutanoate. LCMS M+1 expected = 497.3, observed = 497.2.

Reference： [1]Patent: WO2012/154204,2012,A1 .Location in patent: Page/Page column 82

18
[ 1093192-07-4 ]
[ 1410810-76-2 ]
[ 1411940-98-1 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 5.0h;	To a solution of 4-((4-(hydroxymethyl)cyclohexyl)buta-1 ,3-diynyl)benzoic acid 2 (1 .05g, 3.72mmol), HATU (1.55g, 4.1 mmol) in DMF (25mL) was added (S)- methyl 2-amino-3-(tert-butoxycarbonylamino)-3-methylbutanoate (915 mg, 3.72mmoL) and DIPEA (1.44 g, 1 1 .2mmoL). The mixture was kept stirring at r.t. for 5 hours. After this time, the reaction was diluted with water (20mL), then extracted with ethyl acetate (60ml_ x 3). The combined organic layers were washed with water then brine, dried and concentrated, the residue was purified with silica-gel chromatography (PE:EA 2: 1 ) to give (S)-methyl 3-(tert-butoxycarbonylamino)-2-(4-((4-(hydroxymethyl)cyclohexyl)buta-1 ,3-diynyl)benzamido)-3-methylbutanoate 3 as a yellow solid. (1.6 g, 85%). LC-MS:51 1 [M+H]+.455 [M-56]

Reference： [1]Patent: WO2012/154204,2012,A1 .Location in patent: Page/Page column 87; 88; 89

19
[ 1093192-07-4 ]
4-4-[(1R,2R)-2-(hydroxymethyl)cyclopropyl]buta-1,3-diyn-1-ylbenzoic acid [ No CAS ]
[ 1410809-82-3 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 5.0h;	To a solution of 4-(((1 R,2R)-2-(hydroxymethyl)cyclopropyl)buta-1 ,3- diynyl)benzoic acid 11 (1.20g, S.Ommol), HATU (2.34 g , 6 mmol) in DMF 50mL, treated with <strong>[1093192-07-4](S)-methyl 2-amino-3-(tert-butoxycarbonylamino)-3-methylbutanoate</strong> (1.48g, 6.0mmoL) and DIPEA (3.58g, 20mmoL). The mixture was kept stirring at r.t. for 5 hours. When LCMS showed little compound 11 remaining, the reaction was diluted with EtOAc (100 mL), washed with 5% lithium chloride (3x50mL), the organic layer was dried and concentrated to give 12 as a yellow oil. Purification by silica gel column chromatography PE:EA=2: 1 gave 2.0g 12 as a colorless oil, yield: 70%, LCMS:CP- 0005065-091 -3 (ESI) m I z = 469 (M+1 ) purity:95 % (214nm).

Reference： [1]Patent: WO2012/154204,2012,A1 .Location in patent: Page/Page column 38; 44
[2]ChemMedChem,2019,vol. 14,p. 1560 - 1572

20
[ 1093192-07-4 ]
[ 1410809-86-7 ]
[ 1410809-87-8 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 5.0h;	To a solution of 4-(((1 S,2S)-2-(hydroxymethyl)cyclopropyl)buta-1 ,3- diynyl)benzoic acid 11 (1.05g, 4.38mmol), HATU (1.83g, 4.81 mmol) in DMF (25mL) was added <strong>[1093192-07-4](S)-methyl 2-amino-3-(tert-butoxycarbonylamino)-3-methylbutanoate</strong> (1 .076g, 4.38mmoL) and DIPEA (1.69g,' 13.1 mmoL). The mixture was kept stirring at r.t. for 5 hours. After this time, the reaction was diluted with water (20ml_), then extracted with ethyl acetate (60ml_ x 3). The combined organic layers were washed with water and brine, then dried and concentrated to give Compound 12 as a yellow oil. (1.35g, 65%) LC-MS:469 [M+H]+.

Reference： [1]Patent: WO2012/154204,2012,A1 .Location in patent: Page/Page column 46; 50; 51

21
[ 1093192-07-4 ]
4'-(((1,2-trans)-2-(hydroxymethyl)cyclopropyl)ethynyl)biphenyl-4-carboxylic acid [ No CAS ]
[ 1410809-91-4 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 48.0h;	<strong>[1093192-07-4](S)-methyl 2-amino-3-(tert-butoxycarbonylamino)-3-methylbutanoate</strong> (150 mg, 0.609 mmol, 1.0 equiv) and 4'-(((1 ,2-frans)-2- (hydroxymethyl)cyclopropyl)ethynyl)biphenyl-4-carboxylic acid (178 mg, 0.609 mmol, 1 .0 equiv) were dissolved in DMF (2 ml_). To this was added DIPEA (0.266 ml_, 1.523 mmol, 2.5 equiv) then HATU (278 mg, 0.731 mmol, 1.2 equiv). This stirred at room temperature for ~48 h. The reaction was partitioned between 1 M citric acid and ethyl acetate. The organics were washed with semi-saturated sodium chloride, saturated sodium bicarbonate then saturated sodium chloride, dried over magnesium sulfate and evaporated to dryness. Yielded 370 mg crude (S)-methyl 3-(tert-butoxycarbonylamino)- 2-(4'-(((1 S,2S)-2-(hydroxymethyl)cyclopropyl)ethynyl)biphenyl-4-ylcarboxamido)-3- methylbutanoate. LCMS M+1 expected = 521.3, observed = 521.3.

Reference： [1]Patent: WO2012/154204,2012,A1 .Location in patent: Page/Page column 54

22
[ 1093192-07-4 ]
[ 1410810-08-0 ]
[ 1410810-09-1 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 16.0h;	<strong>[1093192-07-4](S)-methyl 2-amino-3-(tert-butoxycarbonylamino)-3-methylbutanoate</strong> (347 mg, 1.408 mmol, 1.0 equiv) and 4-(((1 S,2R)-2-(hydroxymethyl)-2- methylcyclopropyl)buta-1 ,3-diynyl)benzoic acid (358 mg, 1.408 mmol, 1.0 equiv) were dissolved in DMF (3 mL). To this was added DIPEA (0.615 ml_, 3.52 mmol, 2.5 equiv) then HATU (642 mg, 1.689 mmol, 1.2 equiv). This stirred at room temperature for ~16 h. The reaction was partitioned between 1 M citric acid and ethyl acetate. The organics were washed with semi-saturated sodium chloride, saturated sodium bicarbonate then saturated sodium chloride, dried over magnesium sulfate and evaporated to dryness. Yielded 912 mg crude (S)-methyl 3-(tert-butoxycarbonylamino)-2-(4-(((1 S,2R)-2- (hydroxymethyl)-2-methylcyclopropyl)buta-1 ,3-diynyl)benzamido)-3-methylbutanoate. LCMS M+1 expected = 483.2, observed = 483.2.

Reference： [1]Patent: WO2012/154204,2012,A1 .Location in patent: Page/Page column 66

23
[ 1093192-07-4 ]
[ 1410809-81-2 ]
[ 1410809-82-3 ]

Yield	Reaction Conditions	Operation in experiment
2 g	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 5.0h;	(S)-methyl-2-(4-(((lR,2R)-2-(acetoxymethyl)cyclopropyl)buta-l,3-diynyl)benzamido)- 3-(tert-butoxycarbonylamino)-3-methylbutanoate (12)To a solution of 11 (1.20 g, 5. Ommol), HATU (2.34 g , 6 mmol) in DMF50mL, treated with (S)-methyl-2-amino-3-(tert-butoxycarbonylamino)-3- methylbutanoate (1.48 g, 6.0 mmoL) and DIPEA (3.58 g, 20 mmoL). The mixture was stirred at ambient temperature for 5 hours. When LCMS showed little compound 11 remaining, the reaction was diluted with EtOAc (100 mL), washed with 5% lithium chloride (3x50mL), the organic layer was dried and concentrated to give 12 as a yellow oil. Purification by silica gel column chromatography PE:EA=2:1 gave 2.0 g 12 as a colorless oil, yield: 70%, LCMS:CP-0005065-091-3 (ESI) m / z = 469 (M+l) purity: 95 % (214nm).

Reference： [1]Patent: WO2013/39947,2013,A1 .Location in patent: Page/Page column 28; 29

24
[ 1093192-07-4 ]
4-((5-oxopyrrolidin-3-yl)buta-1,3-diynyl)benzoic acid [ No CAS ]
(2S)-methyl 3-(tert-butoxycarbonylamino)-3-methyl-2-(4-((5-oxopyrrolidin-3-yl)buta-1,3-diynyl)benzamido)butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide;	To a stirring solution of (S)-methyl 2-amino-3-{tert-butoxycarbonylamino)-3- methylbutanoate (461 mg, 1.87 mmol) and compound 29.17(474 mg, 1.87 mmol) in DMF (4 ml) was added DIPEA (0.82 ml,4.7 mmol) followed by HATU (854 mg, 2.25 mmol) and the10 reaction was stirred overnight. The reaction mixture was partitioned between1M citric acid andethyl acetate. The organicswerewashedwithsemi-saturated sodium chloride, saturated sodium bicarbonate then saturated sodium chloride, dried over magnesiumsulfate, filtered and concentrated under reduced pressureto yield compound29.18, which was carriedthrough to the next stepwithout further purification. MS:m/z calcd for C26H31N306 481.2, found [M-15 Boc+Hr382.1.

Reference： [1]Patent: WO2014/165075,2014,A1 .Location in patent: Page/Page column 113; 114

25
[ 1093192-07-4 ]
4-((1-methyl-5-oxopyrrolidin-3-yl)buta-1,3-diyn-1-yl)benzoic acid [ No CAS ]
(2S)-methyl 3-((tert-butoxycarbonyl)amino)-3-methyl-2-(4-((1-methyl-5-oxopyrrolidin-3-yl)buta-1,3-diyn-1-yl)benzamido)butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide;	To a stirring solution of compound 30.2 (251 mg, 0.94 mmol) in DMF (40 ml) were added INT-1.6 (231 mg, 0.94 mmol), HATU (393 mg, 1.034 mmol) and DIPEA (364 mg, 2.82 mmol) and the reactionwas stirred overnight. The reactionmixture was dilutedwith H20, 5 andextractedwithEA. The organic layer was washedwithbrine,dried,filteredand concentrated underreducedpressure togive a crude, which waspurified by flash chromatography (silicagel MeOH/DCM) to yield compound30.3 as a yellow solid.MS: m/z calcd for C27H33N306495.2, found [M+Hf496.

Reference： [1]Patent: WO2014/165075,2014,A1 .Location in patent: Page/Page column 116; 117

26
(S)-methyl 2-amino-3-(tert-butoxycarbonylamino)-3-methylbutanoate oxalate [ No CAS ]
[ 1093192-07-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In water; ethyl acetate; for 0.166667h;Cooling with ice;	(S)-methyl 2-amino-3-(tert-butoxycarbonylamino)-3-methylbutanoate oxalate (9.34 g, 27.8 mmol) (synthesizedas described in WO 2008/154642 at pages 240-6) wassuspended in ethyl acetate (80 mL) and water (80 mL). Whilecooling in an ice bath, potassiumcarbonate (7.67 g, 55.5 mmol) wasadded and the reaction was stirred for 10min. The aqueous5 layer was separated and extracted with ethyl acetate (2 x 75 mL) and the combined organic extracts were dried over sodium sulfate,and concentrated under reduced pressure to give a clear oil.

Reference： [1]Patent: WO2014/165075,2014,A1 .Location in patent: Page/Page column 42; 43

27
[ 1093192-07-4 ]
(S)-4-((1-acetylazetidin-3-yl)buta-1,3-diynyl)-N-(3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)benzamide-2,2,2 trifluoroacetate [ No CAS ]