[ CAS No. 94994-39-5 ] {[proInfo.proName]}

Name: 94994-39-5|4-((tert-Butoxycarbonyl)(methyl)amino)butanoic acid|98%
Brand: Ambeed
SKU: A352699
Price: 14.0 USD
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2D 3D

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Quality Control of [ 94994-39-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 94994-39-5 ]

SDS Specification

Alternatived Products of [ 94994-39-5 ]

Product Details of [ 94994-39-5 ]

CAS No. :	94994-39-5	MDL No. :	MFCD09831984
Formula :	C₁₀H₁₉NO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PXAKQDWAISFHCM-UHFFFAOYSA-N
M.W :	217.26	Pubchem ID :	10656390
Synonyms :

Calculated chemistry of [ 94994-39-5 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.8
Num. rotatable bonds :	7
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	56.56
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) :	-6.94 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.03
Log Po/w (XLOGP3) :	0.97
Log Po/w (WLOGP) :	1.72
Log Po/w (MLOGP) :	1.13
Log Po/w (SILICOS-IT) :	0.38
Consensus Log Po/w :	1.25

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.34
Solubility :	10.0 mg/ml ; 0.0461 mol/l
Class :	Very soluble
Log S (Ali) :	-1.96
Solubility :	2.37 mg/ml ; 0.0109 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.1
Solubility :	17.3 mg/ml ; 0.0796 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.13

Safety of [ 94994-39-5 ]

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

Application In Synthesis of [ 94994-39-5 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 94994-39-5 ]
Downstream synthetic route of [ 94994-39-5 ]

[ 94994-39-5 ] Synthesis Path-Upstream 1~8

1
[ 24424-99-5 ]
[ 6976-17-6 ]
[ 94994-39-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine In dichloromethane at 20℃; for 72 h;	Example 12; Preparation of 4-(ter*-Butoxycarbonylmethylamino)butyric Acid To a stirred mixture of 4-(methylamino)butyric acid hydrochloride (1.00 g, 6.51 mmol) and triethylamine (2.72 mL, 19.5 mmol) in DCM (60 mL) at room temperature was added di-tert-butyldicarbonate (1.56 g, 7.16 mmol). The resulting mixture was stirred for about 72 h. LC-MS showed product was present (Rt 4.11 min; m/z 216.2 [M + H]⁺). DCM and water were added and the pH of the aqueous layer was adjusted to pH 4.5 to 6 with aqueous hydrochloric acid (1 M). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (1.5 g, 100 percent yield) as light yellow thick oil.¹H NMR (CDCl₃) δ 3.28 (br s); 2.85 (s); 2.35 (t); 1.84 (t); 1.46 (s).
96%	With triethylamine In methanol at 20℃; for 1.16667 h;	Di-t-butyl dicarbonate (7 g, 32.1 mmol) was added dropwise over 10 minutes to a mixture of 4-(methylamino)butyric acid hydrochloride (5 g, 32.5 mmole) in MeOH (50 mL) and 3 eq. Et₃N (5 mL). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was dissolved in EtOAc (150 mL), and washed with an ice-cold 0.1 N aqueous HCl solution (2.x.70 mL). The organic layer was then washed with water (2.x.100 mL) to neutral pH, and then washed with sat. NaCl (1.x.100 mL). The EtOAc layer was dried over Na₂SO₄and concentrated to give the Boc-protected product (6.8 g, 96percent yield).
70%	Stage #1: With sodium hydrogencarbonate In 1,4-dioxane; water Stage #2: at 0 - 20℃; for 22.3333 h;	[0335] To a stirred solution of 4-(methylamino)-butyric acid hydrochloride (303 mg, 1.97 mmol) and dioxane (2 mL) in saturated aqueous NaHCO3 (2 mL) was added added di-tert-butyl di-carbonate (523 mg, 2.40 mmol) and the mixture was stirred at 0° C. for 20 minutes followed by stirring at room temperature for 22 hours. The reaction was concentrated under reduced pressure and the residue was diluted with water (20 mL). The aqueous phase was extracted with ethyl acetate (2.x.15 mL). The aqueous phase was treated with 5percent w/v aqueous citric acid until a pH of 4 was obtained. The aqueous phase was then again extracted with ethyl acetate (4.x.15 mL). The combined organic phase was dried (MgSO4), filtered and concentrated under reduced pressure to give a colourless oil (300 mg, 70percent). [0336] To a stirred solution of the N-protected acid from above (143 mg, 0.659 mmol) in THF (5 mL) was added BH3.THF (1.0M in THF, 2.5 mmol) and the mixture was stirred at 50° C. for 64 hours. Dry CH3OH (5 mL) was added, and the mixture stirred at 70° C. for 1 hour. The reaction was concentrated under reduced pressure. The crude yellow oil (148 mg) was purified by column chromatography (2 cm OD, 20 g silica, 1:1 EtOAc: hexanes) to afford the N-protected alcohol (71 mg, 53percent). [0337] To a suspension of the N-protected alcohol from above (71 mg, 0.35 mmol), NMO (65 mg, 0.56 mmol) and 3 molecular sieves (186 mg) in CH2Cl2 (2.55 mL) was added TPAP (13 mg, 0.04 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was filtered through a silica gel plug with ethyl acetate. The filtrate was concentrated under reduced pressure to give a yellow oil (46 mg, 65percent). [0338] Using the General Procedure B: To a stirred solution of the N-protected aldehyde from above (46 mg, 0.229 mmol) and [1-(tert-butyloxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydroquinolin-8-yl)-amine (89 mg, 0.229 mmol) in CH2Cl2 (2.55 mL) was added NaBH(OAc)3 (100 mg, 0.47 mmol) and the mixture was stirred for 19 hours. Purification of the crude yellow oil (126 mg) by flash chromatography (12 g silica, 50:1:1 CH2Cl2: CH3OH: NH4OH) afforded the N-protected tertiary amine (80 mg, 62percent). [0339] Using the General Procedure D: The N-protected tertiary amine from above (76 mg, 0.135 mmol) was converted to COMPOUND 34 as a white solid (71 mg, 75percent). 1H NMR (D2O) δ 1.54 (br s, 4H), 1.74-1.90 (m, 1H), 1.95-2.09 (m, 1H), 2.13-2.23 (m, 1H), 2.32-2.42 (m, 1H), 2.50-2.64 (m, 4H) containing 2.61 (s, 3H), 2.77-2.94 (m, 3H), 2.97-3.04 (m, 2H), 4.39 (d, 1H, J=17.1 Hz), 4.47-4.60 (m, 2H) containing 4.53 (d, 1H, J=17.2 Hz), 7.60 (dd, 2H, J=6.1, 3.0 Hz), 7.80 (dd, 2H, J=6.1, 3.0 Hz), 7.86 (dd, 1H, J=7.9, 6.2 Hz), 8.34 (d, 1H, J=7.9 Hz), 8.62 (d, 1H, J=5.0 Hz). 13C NMR (D2O) δ 20.42 (2 carbons), 23.69, 25.40, 27.64, 33.05, 48.23, 49.00, 51.68, 60.66, 114.25 (2 carbons), 125.93, 126.93 (2 carbons), 130.97, 139.31, 140.61, 148.10, 151.25, 151.77. ES-MS m/z 364 (M+H). Anal Calc. for C21H25N5O.3.2HBr.1.9H2O: C, 38.41; H, 4.91; N, 10.67; Br, 38.94. Found: C, 38.53; H, 5.02; N, 10.42; Br, 38.79.

Reference： [1] Patent: WO2010/123766, 2010, A1, . Location in patent: Page/Page column 59
[2] Patent: US2009/48147, 2009, A1, . Location in patent: Page/Page column 41
[3] Patent: US2003/220341, 2003, A1, . Location in patent: Page/Page column 32-33
[4] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 3, p. 1376 - 1392
[5] Patent: EP881220, 1998, A1,
[6] Patent: US2010/317697, 2010, A1, . Location in patent: Page/Page column 54
[7] Patent: US2011/178053, 2011, A1, . Location in patent: Page/Page column 28-29

2
[ 1119-48-8 ]
[ 24424-99-5 ]
[ 94994-39-5 ]

Reference： [1] Journal of Organic Chemistry, 1985, vol. 50, # 8, p. 1302 - 1304

3
[ 24424-99-5 ]
[ 94994-39-5 ]

Reference： [1] Journal of Medicinal Chemistry, 1985, vol. 28, # 1, p. 1 - 2

4
[ 57294-38-9 ]
[ 74-88-4 ]
[ 94994-39-5 ]

Reference： [1] Journal of Medicinal Chemistry, 1985, vol. 28, # 1, p. 1 - 2

5
[ 6976-17-6 ]
[ 94994-39-5 ]

Reference： [1] Patent: EP1043319, 2000, A1,

6
[ 57294-38-9 ]
[ 94994-39-5 ]

Reference： [1] Organic and Biomolecular Chemistry, 2011, vol. 9, # 6, p. 1846 - 1854

7
[ 133171-74-1 ]
[ 94994-39-5 ]

Reference： [1] Organic and Biomolecular Chemistry, 2011, vol. 9, # 6, p. 1846 - 1854

8
[ 94994-39-5 ]
[ 99207-32-6 ]

Yield	Reaction Conditions	Operation in experiment
53%	at 50℃; for 64 h;	[0335] To a stirred solution of 4-(methylamino)-butyric acid hydrochloride (303 mg, 1.97 mmol) and dioxane (2 mL) in saturated aqueous NaHCO3 (2 mL) was added added di-tert-butyl di-carbonate (523 mg, 2.40 mmol) and the mixture was stirred at 0° C. for 20 minutes followed by stirring at room temperature for 22 hours. The reaction was concentrated under reduced pressure and the residue was diluted with water (20 mL). The aqueous phase was extracted with ethyl acetate (2.x.15 mL). The aqueous phase was treated with 5percent w/v aqueous citric acid until a pH of 4 was obtained. The aqueous phase was then again extracted with ethyl acetate (4.x.15 mL). The combined organic phase was dried (MgSO4), filtered and concentrated under reduced pressure to give a colourless oil (300 mg, 70percent). [0336] To a stirred solution of the N-protected acid from above (143 mg, 0.659 mmol) in THF (5 mL) was added BH3.THF (1.0M in THF, 2.5 mmol) and the mixture was stirred at 50° C. for 64 hours. Dry CH3OH (5 mL) was added, and the mixture stirred at 70° C. for 1 hour. The reaction was concentrated under reduced pressure. The crude yellow oil (148 mg) was purified by column chromatography (2 cm OD, 20 g silica, 1:1 EtOAc: hexanes) to afford the N-protected alcohol (71 mg, 53percent). [0337] To a suspension of the N-protected alcohol from above (71 mg, 0.35 mmol), NMO (65 mg, 0.56 mmol) and 3 molecular sieves (186 mg) in CH2Cl2 (2.55 mL) was added TPAP (13 mg, 0.04 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was filtered through a silica gel plug with ethyl acetate. The filtrate was concentrated under reduced pressure to give a yellow oil (46 mg, 65percent). [0338] Using the General Procedure B: To a stirred solution of the N-protected aldehyde from above (46 mg, 0.229 mmol) and [1-(tert-butyloxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydroquinolin-8-yl)-amine (89 mg, 0.229 mmol) in CH2Cl2 (2.55 mL) was added NaBH(OAc)3 (100 mg, 0.47 mmol) and the mixture was stirred for 19 hours. Purification of the crude yellow oil (126 mg) by flash chromatography (12 g silica, 50:1:1 CH2Cl2: CH3OH: NH4OH) afforded the N-protected tertiary amine (80 mg, 62percent). [0339] Using the General Procedure D: The N-protected tertiary amine from above (76 mg, 0.135 mmol) was converted to COMPOUND 34 as a white solid (71 mg, 75percent). 1H NMR (D2O) δ 1.54 (br s, 4H), 1.74-1.90 (m, 1H), 1.95-2.09 (m, 1H), 2.13-2.23 (m, 1H), 2.32-2.42 (m, 1H), 2.50-2.64 (m, 4H) containing 2.61 (s, 3H), 2.77-2.94 (m, 3H), 2.97-3.04 (m, 2H), 4.39 (d, 1H, J=17.1 Hz), 4.47-4.60 (m, 2H) containing 4.53 (d, 1H, J=17.2 Hz), 7.60 (dd, 2H, J=6.1, 3.0 Hz), 7.80 (dd, 2H, J=6.1, 3.0 Hz), 7.86 (dd, 1H, J=7.9, 6.2 Hz), 8.34 (d, 1H, J=7.9 Hz), 8.62 (d, 1H, J=5.0 Hz). 13C NMR (D2O) δ 20.42 (2 carbons), 23.69, 25.40, 27.64, 33.05, 48.23, 49.00, 51.68, 60.66, 114.25 (2 carbons), 125.93, 126.93 (2 carbons), 130.97, 139.31, 140.61, 148.10, 151.25, 151.77. ES-MS m/z 364 (M+H). Anal Calc. for C21H25N5O.3.2HBr.1.9H2O: C, 38.41; H, 4.91; N, 10.67; Br, 38.94. Found: C, 38.53; H, 5.02; N, 10.42; Br, 38.79.

Reference： [1] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 3, p. 1376 - 1392
[2] Patent: US2003/220341, 2003, A1, . Location in patent: Page/Page column 32-33
[3] Journal of Medicinal Chemistry, 1985, vol. 28, # 1, p. 1 - 2

[ 94994-39-5 ] Synthesis Path-Downstream 1~81

1
[ 42137-80-4 ]
[ 94994-39-5 ]
[ 94994-43-1 ]

Reference： [1]Journal of Organic Chemistry,1985,vol. 50,p. 1302 - 1304

2
[ 1119-48-8 ]
[ 24424-99-5 ]
[ 94994-39-5 ]

Reference： [1]Journal of Organic Chemistry,1985,vol. 50,p. 1302 - 1304

3
[ 53907-28-1 ]
[ 94994-39-5 ]
[ 95018-02-3 ]

Reference： [1]Journal of Organic Chemistry,1985,vol. 50,p. 1302 - 1304

4
[ 94994-39-5 ]
[ 99207-32-6 ]

Yield	Reaction Conditions	Operation in experiment
53%	With borane-THF; at 50℃; for 64h;	[0335] To a stirred solution of 4-(methylamino)-butyric acid hydrochloride (303 mg, 1.97 mmol) and dioxane (2 mL) in saturated aqueous NaHCO3 (2 mL) was added added di-tert-butyl di-carbonate (523 mg, 2.40 mmol) and the mixture was stirred at 0 C. for 20 minutes followed by stirring at room temperature for 22 hours. The reaction was concentrated under reduced pressure and the residue was diluted with water (20 mL). The aqueous phase was extracted with ethyl acetate (2×15 mL). The aqueous phase was treated with 5% w/v aqueous citric acid until a pH of 4 was obtained. The aqueous phase was then again extracted with ethyl acetate (4×15 mL). The combined organic phase was dried (MgSO4), filtered and concentrated under reduced pressure to give a colourless oil (300 mg, 70%). [0336] To a stirred solution of the N-protected acid from above (143 mg, 0.659 mmol) in THF (5 mL) was added BH3.THF (1.0M in THF, 2.5 mmol) and the mixture was stirred at 50 C. for 64 hours. Dry CH3OH (5 mL) was added, and the mixture stirred at 70 C. for 1 hour. The reaction was concentrated under reduced pressure. The crude yellow oil (148 mg) was purified by column chromatography (2 cm OD, 20 g silica, 1:1 EtOAc: hexanes) to afford the N-protected alcohol (71 mg, 53%). [0337] To a suspension of the N-protected alcohol from above (71 mg, 0.35 mmol), NMO (65 mg, 0.56 mmol) and 3 molecular sieves (186 mg) in CH2Cl2 (2.55 mL) was added TPAP (13 mg, 0.04 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was filtered through a silica gel plug with ethyl acetate. The filtrate was concentrated under reduced pressure to give a yellow oil (46 mg, 65%). [0338] Using the General Procedure B: To a stirred solution of the N-protected aldehyde from above (46 mg, 0.229 mmol) and [1-(tert-butyloxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydroquinolin-8-yl)-amine (89 mg, 0.229 mmol) in CH2Cl2 (2.55 mL) was added NaBH(OAc)3 (100 mg, 0.47 mmol) and the mixture was stirred for 19 hours. Purification of the crude yellow oil (126 mg) by flash chromatography (12 g silica, 50:1:1 CH2Cl2: CH3OH: NH4OH) afforded the N-protected tertiary amine (80 mg, 62%). [0339] Using the General Procedure D: The N-protected tertiary amine from above (76 mg, 0.135 mmol) was converted to COMPOUND 34 as a white solid (71 mg, 75%). 1H NMR (D2O) delta 1.54 (br s, 4H), 1.74-1.90 (m, 1H), 1.95-2.09 (m, 1H), 2.13-2.23 (m, 1H), 2.32-2.42 (m, 1H), 2.50-2.64 (m, 4H) containing 2.61 (s, 3H), 2.77-2.94 (m, 3H), 2.97-3.04 (m, 2H), 4.39 (d, 1H, J=17.1 Hz), 4.47-4.60 (m, 2H) containing 4.53 (d, 1H, J=17.2 Hz), 7.60 (dd, 2H, J=6.1, 3.0 Hz), 7.80 (dd, 2H, J=6.1, 3.0 Hz), 7.86 (dd, 1H, J=7.9, 6.2 Hz), 8.34 (d, 1H, J=7.9 Hz), 8.62 (d, 1H, J=5.0 Hz). 13C NMR (D2O) delta 20.42 (2 carbons), 23.69, 25.40, 27.64, 33.05, 48.23, 49.00, 51.68, 60.66, 114.25 (2 carbons), 125.93, 126.93 (2 carbons), 130.97, 139.31, 140.61, 148.10, 151.25, 151.77. ES-MS m/z 364 (M+H). Anal Calc. for C21H25N5O.3.2HBr.1.9H2O: C, 38.41; H, 4.91; N, 10.67; Br, 38.94. Found: C, 38.53; H, 5.02; N, 10.42; Br, 38.79.

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 1376 - 1392
[2]Patent: US2003/220341,2003,A1 .Location in patent: Page/Page column 32-33
[3]Journal of Medicinal Chemistry,1985,vol. 28,p. 1 - 2

5
[ 57294-38-9 ]
[ 74-88-4 ]
[ 94994-39-5 ]

Reference： [1]Journal of Medicinal Chemistry,1985,vol. 28,p. 1 - 2

6
[ 762302-94-3 ]
[ 94994-39-5 ]
[ 876028-83-0 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;	b.2 (4-r4-(2-terf-Butvl-6-cvclobutvl-pvrimidin-4-vl)-piperazin-1-vn-butvl)-methyl-amine hydrochloride; b.2.1: (4-r4-(2-ferf-Butvl-6-cvclobutvl-pyrimidin-4-vl)-piperazin-1-vll-4-oxo-butvl)-methvl-carbamic acid tert-butyl ester; 6 g of 4-(terf-butoxycarbonyl-methyl-amino)-butyric acid (27.6 mmol) and 5.53 g of triethylamine (54.6 mmol) were dissolved in 100 ml of dimethylformamide. 4.1 g of hydroxybenzotriazole (HOBt, 30.35 mmol), 7.6 g of 2-tert-butyl-4-(piperazin-1-yl)-6-cyclobutyl-pyrimidine (27.7 mmol), and 5.8 g of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimid hydrochloride (EDCI, 30.26 mmol) were added at room temperature, and the reaction mixture was stirred for 16 h. The reaction mixture was partitioned between water and ethyl acetate, the organic phase dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using dichloromethane. Fractions containing the product were combined and the solvent evaporated to yield 13.1 g of the title compound.MS (ESI) m/z: 474.4 [M+H]+1H-NMR (CDCI3): 5 [ppm] 6.1 (s, 1H), 3.7 (m, 4H), 3.5-3.6 (m, 4H), 3.45 (m, 1H),3.3 (m, 2H), 2.95 and 2.9 (d, 3H, Me), 2.2-2.4 (m, 6H), 2.0 (m, 1H), 1.9 (m, 3H), 1.45 (s,9H), 1.35 (s,9H).

Reference： [1]Patent: WO2006/15842,2006,A1 .Location in patent: Page/Page column 40

7
[ 94994-39-5 ]
[ 174138-01-3 ]
7-[4-(tert-butoxycarbonyl-methyl-amino)-butyryl]-[1,4,7]triazonane-1,4-dicarboxylic acid di-tert-butyl ester [ No CAS ]

Reference： [1]Tetrahedron Letters,2003,vol. 44,p. 5699 - 5701

8
[ 94994-39-5 ]
[ 530-62-1 ]
(4-imidazol-1-yl-4-oxo-butyl)-methyl-carbamic acid tert-butyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 5515 - 5524

9
[ 6638-79-5 ]
[ 94994-39-5 ]
[ 761456-79-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 5147 - 5160

10
[ 94994-39-5 ]
[ 120984-59-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 5147 - 5160

11
[ 94994-39-5 ]
2,3-dimethoxy-6-methyl-12-(4-methylamino-butylidene)-6H,12H-8,10-dioxa-6-aza-benzo[a]cyclopenta[h]fluoren-5-one [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 5147 - 5160

12
[ 94994-39-5 ]
[ 799279-16-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 5515 - 5524

13
[ 94994-39-5 ]
{3-[1-(3-chloro-phenyl)-5-(4-phenoxy-phenyl)-1H-pyrazol-3-yl]-propyl}-methyl-amine; compound with GENERIC INORGANIC NEUTRAL COMPONENT [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 5515 - 5524

14
[ 94994-39-5 ]
4-dimethylamino-1-(4,7-dimethyl-[1,4,7]triazonan-1-yl)-butan-1-one [ No CAS ]

Reference： [1]Tetrahedron Letters,2003,vol. 44,p. 5699 - 5701

15
[ 24424-99-5 ]
[ 94994-39-5 ]

Reference： [1]Journal of Medicinal Chemistry,1985,vol. 28,p. 1 - 2

16
[ 94994-39-5 ]
[ 93565-09-4 ]

Reference： [1]Journal of Medicinal Chemistry,1985,vol. 28,p. 1 - 2

17
[ 94994-39-5 ]
[ 99230-20-3 ]

Reference： [1]Journal of Medicinal Chemistry,1985,vol. 28,p. 1 - 2

18
[ 94994-39-5 ]
[ 93565-10-7 ]

Reference： [1]Journal of Medicinal Chemistry,1985,vol. 28,p. 1 - 2

19
[ 94994-39-5 ]
N-Buta-2,3-dienyl-N'-methyl-butane-1,4-diamine; hydrochloride [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1985,vol. 28,p. 1 - 2

20
[ 872-50-4 ]
4-methoxy-butyl magnesium bromide [ No CAS ]
[ 94994-39-5 ]

Reference： [1]Journal of Organic Chemistry,1985,vol. 50,p. 1302 - 1304

21
[ 94994-39-5 ]
4-Methylamino-thiobutyric acid S-dibenzofuran-4-yl ester; compound with trifluoro-acetic acid [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1985,vol. 50,p. 1302 - 1304

22
[ 94994-39-5 ]
[ 75-31-0 ]
4-[5-(N-t-butoxycarbonylam:ino)valeryl]morpholine [ No CAS ]
N-Isopropyl-4-(N-t-butoxycarbonyl-N-methylamino)butyramide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		(1) N-Isopropyl-4-(N-t-butoxycarbonyl-N-methylamino)butyramide (3.13 g) was obtained according to a similar manner to that of Preparation 17 from 4-(N-t-butoxycarbonyl-N-methylamino)butyric acid (3.26 g) and isopropylamine (0.91 g). Rf: 0.62 (chloroform:methanol, 10:1, V/V)

Reference： [1]Patent: US4921855,1990,A

23
[ 24424-99-5 ]
[ 6976-17-6 ]
[ 94994-39-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine; In dichloromethane; at 20℃; for 72h;	Example 12; Preparation of 4-(ter*-Butoxycarbonylmethylamino)butyric Acid To a stirred mixture of 4-(methylamino)butyric acid hydrochloride (1.00 g, 6.51 mmol) and triethylamine (2.72 mL, 19.5 mmol) in DCM (60 mL) at room temperature was added di-tert-butyldicarbonate (1.56 g, 7.16 mmol). The resulting mixture was stirred for about 72 h. LC-MS showed product was present (Rt 4.11 min; m/z 216.2 [M + H]+). DCM and water were added and the pH of the aqueous layer was adjusted to pH 4.5 to 6 with aqueous hydrochloric acid (1 M). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (1.5 g, 100 percent yield) as light yellow thick oil.1H NMR (CDCl3) delta 3.28 (br s); 2.85 (s); 2.35 (t); 1.84 (t); 1.46 (s).
96%	With triethylamine; In methanol; at 20℃; for 1.16667h;	Di-t-butyl dicarbonate (7 g, 32.1 mmol) was added dropwise over 10 minutes to a mixture of 4-(methylamino)butyric acid hydrochloride (5 g, 32.5 mmole) in MeOH (50 mL) and 3 eq. Et3N (5 mL). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was dissolved in EtOAc (150 mL), and washed with an ice-cold 0.1 N aqueous HCl solution (2.x.70 mL). The organic layer was then washed with water (2.x.100 mL) to neutral pH, and then washed with sat. NaCl (1.x.100 mL). The EtOAc layer was dried over Na2SO4 and concentrated to give the Boc-protected product (6.8 g, 96percent yield).
70%		[0335] To a stirred solution of 4-(methylamino)-butyric acid hydrochloride (303 mg, 1.97 mmol) and dioxane (2 mL) in saturated aqueous NaHCO3 (2 mL) was added added di-tert-butyl di-carbonate (523 mg, 2.40 mmol) and the mixture was stirred at 0° C. for 20 minutes followed by stirring at room temperature for 22 hours. The reaction was concentrated under reduced pressure and the residue was diluted with water (20 mL). The aqueous phase was extracted with ethyl acetate (2.x.15 mL). The aqueous phase was treated with 5percent w/v aqueous citric acid until a pH of 4 was obtained. The aqueous phase was then again extracted with ethyl acetate (4.x.15 mL). The combined organic phase was dried (MgSO4), filtered and concentrated under reduced pressure to give a colourless oil (300 mg, 70percent). [0336] To a stirred solution of the N-protected acid from above (143 mg, 0.659 mmol) in THF (5 mL) was added BH3.THF (1.0M in THF, 2.5 mmol) and the mixture was stirred at 50° C. for 64 hours. Dry CH3OH (5 mL) was added, and the mixture stirred at 70° C. for 1 hour. The reaction was concentrated under reduced pressure. The crude yellow oil (148 mg) was purified by column chromatography (2 cm OD, 20 g silica, 1:1 EtOAc: hexanes) to afford the N-protected alcohol (71 mg, 53percent). [0337] To a suspension of the N-protected alcohol from above (71 mg, 0.35 mmol), NMO (65 mg, 0.56 mmol) and 3 molecular sieves (186 mg) in CH2Cl2 (2.55 mL) was added TPAP (13 mg, 0.04 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was filtered through a silica gel plug with ethyl acetate. The filtrate was concentrated under reduced pressure to give a yellow oil (46 mg, 65percent). [0338] Using the General Procedure B: To a stirred solution of the N-protected aldehyde from above (46 mg, 0.229 mmol) and [1-(tert-butyloxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydroquinolin-8-yl)-amine (89 mg, 0.229 mmol) in CH2Cl2 (2.55 mL) was added NaBH(OAc)3 (100 mg, 0.47 mmol) and the mixture was stirred for 19 hours. Purification of the crude yellow oil (126 mg) by flash chromatography (12 g silica, 50:1:1 CH2Cl2: CH3OH: NH4OH) afforded the N-protected tertiary amine (80 mg, 62percent). [0339] Using the General Procedure D: The N-protected tertiary amine from above (76 mg, 0.135 mmol) was converted to COMPOUND 34 as a white solid (71 mg, 75percent). 1H NMR (D2O) delta 1.54 (br s, 4H), 1.74-1.90 (m, 1H), 1.95-2.09 (m, 1H), 2.13-2.23 (m, 1H), 2.32-2.42 (m, 1H), 2.50-2.64 (m, 4H) containing 2.61 (s, 3H), 2.77-2.94 (m, 3H), 2.97-3.04 (m, 2H), 4.39 (d, 1H, J=17.1 Hz), 4.47-4.60 (m, 2H) containing 4.53 (d, 1H, J=17.2 Hz), 7.60 (dd, 2H, J=6.1, 3.0 Hz), 7.80 (dd, 2H, J=6.1, 3.0 Hz), 7.86 (dd, 1H, J=7.9, 6.2 Hz), 8.34 (d, 1H, J=7.9 Hz), 8.62 (d, 1H, J=5.0 Hz). 13C NMR (D2O) delta 20.42 (2 carbons), 23.69, 25.40, 27.64, 33.05, 48.23, 49.00, 51.68, 60.66, 114.25 (2 carbons), 125.93, 126.93 (2 carbons), 130.97, 139.31, 140.61, 148.10, 151.25, 151.77. ES-MS m/z 364 (M+H). Anal Calc. for C21H25N5O.3.2HBr.1.9H2O: C, 38.41; H, 4.91; N, 10.67; Br, 38.94. Found: C, 38.53; H, 5.02; N, 10.42; Br, 38.79.

		a) 4-(N-tert-Butoxycarbonyl-N-methylamino)butyric acid Using 4-(N-methylamino)butyric acid hydrochloride (23 g, 150 mmol) and di-tert-butyl dicarbonate (32.7 g, 150 mmol), the title compound was obtained as an oil according to the method of Example 1(a) (31 g, yield: 95percent).
	With triethylamine; In tetrahydrofuran; at 25℃;	A solution of 4-(methylamino)butyric acid hydrochloride (2.0 g, 13.0 mmol) in 25 mL of THF at 25° C. was treated with Boc2O (4.3 g, 19.5 mmol) and Et3N (7.3 mL, 52.0 mmol), and the mixture was stirred overnight before being quenched with the addition of 40 mL of aqueous 1N NaOH. The mixture was washed with CH2Cl2 (2.x.100 mL), cooled to 0° C., acidified (pH 5-6) with the addition of aqueous 3.5 N HCl, and extracted with CH2Cl2 (2.x.75 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to give 4-[[(1,1-dimethylethyl)oxy]carbonyl}(methyl)amino]butanoic acid as a white solid.
	With potassium carbonate; In 1,4-dioxane; water; for 6h;	3 g of 4-(methylamino)butyric acid hydrochloride, 7 g of potassium carbonate in 40 mL of 1,4-dioxane and 20 mL of water are placed in a round-bottomed flask. Next, 4.86 g of di-tert-butyl dicarbonate are added. After stirring for 6 hours, the dioxane is evaporated off and 30 mL of water are then added. Aqueous 1 M potassium bisulfate solution is added until pH 2 is obtained. The resulting mixture is extracted twice with 10 mL of ethyl acetate, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. 4.37 g of 4-(tert-butoxycarbonylmethylamino)butyric acid are obtained.

Reference： [1]Patent: WO2010/123766,2010,A1 .Location in patent: Page/Page column 59
[2]Patent: US2009/48147,2009,A1 .Location in patent: Page/Page column 41
[3]Patent: US2003/220341,2003,A1 .Location in patent: Page/Page column 32-33
[4]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 1376 - 1392
[5]Patent: EP881220,1998,A1
[6]Patent: US2010/317697,2010,A1 .Location in patent: Page/Page column 54
[7]Patent: US2011/178053,2011,A1 .Location in patent: Page/Page column 28-29

24
[ 6976-17-6 ]
[ 94994-39-5 ]

Yield	Reaction Conditions	Operation in experiment
		a) 4-(N-tert-Butyloxycarbonyl-N-methylamino)butyric acid Using 4-methylaminobutyric acid hydrochloride (30 g, 200 mmol), a reaction was performed in the same manner as described in Example 1 (a) to obtain the title compound as an oil (44.08 g, quantitative). 1H-NMR (CDCl3): 3.28 (t, 2H), 2.85 (s, 3H) 2.36 (t, 2H), 1.85 (m, 2H), 1.45 (s, 9H)

Reference： [1]Patent: EP1043319,2000,A1

25
[ 6373-46-2 ]
[ 94994-39-5 ]
C₂₃H₃₀N₂O₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 4963 - 4983

26
[ 94994-39-5 ]
[ 3694-52-8 ]
[ 1075748-33-2 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 96h;	To a solution of 9 g of 4-(terf-butoxycarbonyl-methyl-amino)-butyric acid (prepared from 4- (methylamino)butyric acid and BOC anhydride) in 159 mL DCM were added 14.2 mL of DIPEA, 8 g of HOBt and 9.1 g of EDC. After stirring for 5 min 6.1 g of 3-nitro-benzene-1 ,2-diamine were added and the mixture was stirred for 4 days at rt. Saturated aq. NaHCO3 solution was added, the phases were separated and the organic phase washed with brine. The combined organic phases were dried over MgSO4, and concentrated in vacuo. Purification by CC using EtOAc/heptane 1/4 to 3/1 yielded 5.2 g of [3-(2-Amino-3-nitro-phenylcarbamoyl)-propyl]-methyl-carbamic acid tert-butyl ester as orange foam.LC-MS: tR = 0.94 min; [M+H]+: 352.48.

Reference： [1]Patent: WO2008/132679,2008,A1 .Location in patent: Page/Page column 91

27
[ 6290-05-7 ]
[ 94994-39-5 ]
[ 1044159-41-2 ]

Yield	Reaction Conditions	Operation in experiment
86.7%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 4 - 20℃; for 4h;	A mixture of the Boc-protected 4-(methylamino)butyric acid (6.8 g, 31.3 mmol) and di-ethyl iminodiacetate (5.92 g, 29.7 mmol) in anhydrous DCM (80 mL) was cooled to 4 C. in an ice-bath. EDCI (7.1 g, 37.3 mmol) was added in portions to the reaction mixture. The resulting mixture was then warmed to room temperature and stirred for 4 hours. After removal of solvent nder reduced pressure, the residue was partitioned between ethyl acetate (200 mL) and water (100 mL). The organic layer was subsequently washed with H2O (4×100 mL), ice-cold 0.1 N HCl (2×100 mL), H2O (2×100 mL), sat. NaHCO3 (1×100 mL), H2O (2×100 mL), and finally followed by sat. NaCl (1×100 mL). The organic layer was dried over Na2SO4 and then concentrated to give the desired product (10 g, 86.7% yield).

Reference： [1]Patent: US2009/48147,2009,A1 .Location in patent: Page/Page column 41

28
[ 100-02-7 ]
[ 94994-39-5 ]
4-[Boc(methyl)amino]butyric acid p-nitrophenyl ester [ No CAS ]

Reference： [1]Tetrahedron Letters,2009,vol. 50,p. 2976 - 2978

29
[ 1052648-19-7 ]
[ 94994-39-5 ]
[ 1052648-34-6 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 3-2: Production of 4-amino-18-methoxy-15,20-dimethyl-7-thia-3,5,10,15-tetraazatricyclo[15.3.1.12,6]docosa-1(20), 2(22),3,5,17(21),18-hexaene-11,16-dione (Compound 10) [Show Image] Step 1: Preparation of 5-(2-amino-6-{2-[4-(tert-butoxycarbonylmethylamino)butyrylamino]ethylsulfanyl}pyrimidin-4-yl)-2-methoxy-4-methylbenzoic acid methyl ester [Show Image] 5-[2-Amino-6-(2-tert-butoxycarbonylaminoethylsulfanyl)pyrimldin-4-yl]-2-methoxy-4-methylbenzoic acid methyl ester (88 mg, 0.20 mmol) obtained in Step 1 of Example 3-1 was dissolved with dichloromethane (2.5 ml) in a reaction vessel, and cooled to 0C. Trifluoroacetic acid (0.7 ml) was added to the solution, and stirred for 2.5 hours while gradually warming from 0C to room temperature. The reaction solution was concentrated under reduced pressure, and then benzene (1.5 ml) was added to the resulting residue. The solution was again concentrated under reduced pressure. This treatment was repeated three times, and the obtained pale yellow oily material was dissolved in N,N-dimethylformamide (3.0 ml). 4-tert-Butoxycarbonylmethylaminobutanoic acid (65 mg, 0.3 mmol) and N-hydroxybenzotriazole (54 mg, 0.4 mmol) were added to the solution. Diisopropylethylamine (0.5 ml, 2.8 mmol) was added to the solution, and then 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (115 mg, 0.6 mmol) was added. The resulting mixture was stirred at room temperature for 13 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and extracted with ethyl acetate (100 ml). The ethyl acetate solution was sequentially washed with 1N hydrochloric acid (50 ml), water (50 ml), a saturated aqueous sodium bicarbonate solution (50 ml), water (50 ml), and a saturated aqueous sodium chloride solution (50 ml). The washed ethyl acetate solution was dried over anhydrous sodium sulfate (10 g). After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: ethyl acetate to ethyl acetate:methanol = 25:1) to yield 5-(2-amino-6-{2-[4-(tert-butoxycarbonylmethylamino)butyrylamino]ethylsulfanyl}pyrimidin-4-yl)-2-methoxy-4-methylbenzoic acid methyl ester (99 mg) as a colorless syrup-like material. Physicochemical properties of 5-(2-amino-6-{2-[4-(tert-butoxycarbonylmethylamino)butyrylamino]ethylsulfanyl}pyrimidin-4-yl)-2-methoxy-4-methylbenzoic acid methyl ester: Molecular weight: 547.ESI (LC/MS positive mode): m/z = 548 (M+H+).Chemical shift value delta in 1H-NMR (400 MHz, in dimethylsulfoxide d-6): 1.37 (9H, s), 1.62-1.70 (2H, m), 2.03 (2H, t, J=8Hz), 2.44 (3H, s), 2.74 (3H, s), 3.12 (2H, t, J=8Hz), 3.18 (2H, t, J=6Hz), 3.34 (2H, t, J=6Hz), 3.77 (3H, s), 3.86 (3H, s), 6.65 (1H, s), 6.69 (2H, brs), 7.08 (1H, s), 7.76 (1H, s), 8.05 (1H, t, J=4Hz).

Reference： [1]Patent: EP2119718,2009,A1 .Location in patent: Page/Page column 89-90

30
[ 118-92-3 ]
[ 94994-39-5 ]
[ 156-43-4 ]
[ 876016-45-4 ]

Yield	Reaction Conditions	Operation in experiment
		3 mL triphenylphosphite (22 g, 70 mmol) was added to a solution of anthranilic acid (8.0 g, 58.6 mmol) and 4-(tert-butoxycarbonyl-methyl-amino)-butyric acid (12.7 g, 58.6 mmol) in 100 mL of anhydrous pryridine at room temperature. The resultant yellow solution was stirred at 100 C. for 4 hours. 4-Ethoxylaniline (8.8 g, 64 mmol) was then added and the reaction mixture was stirred for another 3 hours at 100 C. The mixture was then cooled down to room temperature and concentrated under vacuum to give a brown residue. The residue was sequentially washed with 1N HCl (2×10 mL) and saturated sodium bicarbonate (2×10 mL), and then extracted with CH2Cl2 (3×30 mL). The organic layer was separated, dried over magnesium sulfate, and concentrated under vacuum to give a brown residue. The residue thus obtained was purified by silica gel chromatography to afford 12.5 of Intermediate IX.

Reference： [1]Patent: US2006/36093,2006,A1 .Location in patent: Page/Page column 35

31
[ 1253582-07-8 ]
[ 94994-39-5 ]
[ 1253582-08-9 ]

Yield	Reaction Conditions	Operation in experiment
	With 2,6-dimethylpyridine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;	Example 13; Preparation of {3- [3-(2- {Benzyl- [(R)-2-(8-benzyloxy-2-oxo- 1 ,2-dihydroquinolin-5-yl)-2-(tert-butyldimethylsilanyloxy)ethyl]amino}ethyl)phenylcarbamoyl]- propyl}methylcarbamic Acid tert-Buty Ester To a stirred solution of 4-(tert-butoxycarbonylmethylamino)butyric acid (72.0 mg,0.331 mmol); 5-[(i?)-2-[2-(3-aminophenyl)ethyl]benzylamino}-l-(te/t-butyl- dimethylsilanyloxy)ethyl]-8-benzyloxy-lH-quinolin-2-one (210 mg, 0.331 mmol); 2,6- lutidine (46.5 muL, 0.398 mmol); and Lambda/-(3-dimethylaminopropyl)-Lambda/"-ethylcarbodiimide hydrochloride (69.8 mg, 0.364 mmol) in DMF (3 mL) at room temperature was added a solution of l-hydroxy-7-azabenzotriazole in DMF (0.5 M, 0.729 mL, 0.364 mmol). The resulting mixture was stirred at room temperature overnight. LC-MS (Method 2-90) showed product was present (Rt 4.56 min; m/z 833.6 [M + H]+). Water was added and this mixture was diluted with aqueous 10% lithium chloride solution and DCM. The layers were separated and the organic layer was washed with aqueous 10% lithium chloride solution (2 x), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was further concentrated under high vacuum to give the title compound (containing a minor amount of DMF), which was used in the next reaction without further purification.

Reference： [1]Patent: WO2010/123766,2010,A1 .Location in patent: Page/Page column 60

32
[ 1070871-78-1 ]
[ 94994-39-5 ]
[ 1176225-29-8 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of methyl [4-(3'-ethyl-6-fluoro-2-biphenylyl)-4-hydroxy-4-(3-piperidinyl)butyl]carbamate (0.04 g, 0.093 mmol) in 1 mL of MeCN at 25 C. was treated with 4-[[(1,1-dimethylethyl)oxy]carbonyl}(methyl)amino]butanoic acid (0.024 mg, 0.11 mmol), HBTU (0.042 g, 0.011 mmol) and diisopropylethylamine (0.05 mL, 0.28 mmol) and stirred for 3 h before being filtered and subjected to reverse phase HPLC. The resulting solid was dissolved in 1 mL of MeCN, treated with 1 mL of aqueous 2N HCl, and the mixture was stirred at 25 C. overnight before being concentrated under reduced pressure to provide methyl (4-(3'-ethyl-6-fluoro-2-biphenylyl)-4-hydroxy-4-{(3R)-1-[4-(methylamino)butanoyl]-3-piperidinyl}butyl)carbamate as a white solid.

Reference： [1]Patent: US2010/317697,2010,A1 .Location in patent: Page/Page column 58
[2]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 4838 - 4843

33
[ 1167415-61-3 ]
[ 94994-39-5 ]
C₃₂H₃₉N₅O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 3h;	4-[[(1 ,1-Dimethylethyl)oxy]carbonyl}(methyl)amino]butanoic acid (64mg, 0.29 mmol), 2-[(1-methylethyl)oxy]-5-[3-(2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)-1 ,2,4- oxadiazol-5-yl]benzonitrile hydrochloride (Preparation 43) (100mg, 0.24 mmol) and HATU (139mg, 0.37 mmol) were combined with DMF (5ml), and DIPEA (0.149ml, 0.85 mmol). The mixture was stirred at room temperature for 3h, partitioned between DCM (2x 5ml) and saturated sodium hydrogen carbonate solution (5ml). The organic phases were combined, dried (hydrophobic frit) and evaporated in vacuo. The residue was dissolved in DCM (4ml), and trifluoroacetic acid (1 ml, 13 mmol) was added. The mixture was stirred at room temperature for 2h, and filtered through an aminopropyl SPE (5g), washing the SPE with methanol in DCM (10%). The appropriate fractions were combined and evaporated in vacuo. The residue was dissolved in DMSO (2x 1 ml) and purified by MDAP (Method HpH). The solvent was evaporated under a stream of nitrogen to give 5-(3-{3-[4-(methylamino)butanoyl]- 2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl}-1 ,2,4-oxadiazol-5-yl)-2-[(1 - methylethyl)oxy]benzonitrile as a yellow gum (82mg). LCMS (Method HpH): Retention time 1.16min, MH+ = 474

Reference： [1]Patent: WO2010/146105,2010,A1 .Location in patent: Page/Page column 267-268

34
[ 57294-38-9 ]
[ 94994-39-5 ]

Reference： [1]Organic and Biomolecular Chemistry,2011,vol. 9,p. 1846 - 1854

35
[ 94994-39-5 ]
[ 872-50-4 ]

Reference： [1]Organic and Biomolecular Chemistry,2011,vol. 9,p. 1846 - 1854

36
[ 94994-39-5 ]
[ 108-95-2 ]
[ 1290070-54-0 ]

Reference： [1]Organic and Biomolecular Chemistry,2011,vol. 9,p. 1846 - 1854

37
[ 94994-39-5 ]
[ 108-95-2 ]
[ 1290070-21-1 ]

Reference： [1]Organic and Biomolecular Chemistry,2011,vol. 9,p. 1846 - 1854

38
[ 133171-74-1 ]
[ 94994-39-5 ]

Reference： [1]Organic and Biomolecular Chemistry,2011,vol. 9,p. 1846 - 1854

39
[ 123-75-1 ]
[ 94994-39-5 ]
[ 1201786-96-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	1 g of 4-(tert-butoxycarbonylmethylamino)butyric acid in 10 mL of dimethylformamide, 1.925 g of [dimethylamino-(1,2,3-triazolo[4,5-b]pyrid-3-yloxy)methylene]dimethylammonium hexafluorophosphate, 713 mg of N,N-diisopropylethylamine and 360 mg of pyrrolidine are introduced into a 100 mL round-bottomed flask. The solution is stirred overnight at room temperature. The reaction mixture is poured into 50 mL of water and extracted three times with 200 mL of ethyl acetate. The product is taken up in dichloromethane and filtered through 2 cm of silica. The filtrate is evaporated to dryness under vacuum. 806 mg of tert-butyl methyl(4-oxo-4-pyrrolidin-1-ylbutyl)carbamate are thus obtained.

Reference： [1]Patent: US2011/178053,2011,A1 .Location in patent: Page/Page column 29

40
[ 94994-39-5 ]
[ 1178650-54-8 ]

Reference： [1]Patent: US2011/178053,2011,A1

41
[ 1318256-69-7 ]
[ 94994-39-5 ]
C₃₆H₅₆N₂O₆Si [ No CAS ]

Reference： [1]Proceedings of the National Academy of Sciences of the United States of America,2011,vol. 108,p. 6751 - 6756

42
[ 1318257-07-6 ]
[ 94994-39-5 ]
C₃₆H₅₆N₂O₆Si [ No CAS ]

Reference： [1]Proceedings of the National Academy of Sciences of the United States of America,2011,vol. 108,p. 6751 - 6756

43
[ 1256380-50-3 ]
[ 94994-39-5 ]
11,14,14-trimethyl-7,12-dioxo-1,1,1-triphenyl-13-oxa-6,11-diaza-1-phosphoniapentadecane bromide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		<strong>[94994-39-5]4-[(tert-butoxycarbonyl)(methyl)amino]butanoic acid</strong> (J. Organic Chemistry, 1985, 50, 1302-1304, 349 mg, 1.61 mol) was dissolved in N.N-dimethylformamide (3.5 mL) and treated with N,N-carbonyldiimidazole (273 mg, 1.69 mmol). The mixture was stirred at room temperature for 30 minutes. (4-Aminobutyl)(triphenyl) phosphonium bromide (929 mg, 1.40 mmol) was added, and the reaction was stirred overnight at room temperature. The reaction mixture was diluted with methylene chloride and washed with 5% aqueous lithium chloride (3 times), IN aqueous hydrogen chloride, and saturated sodium bicarbonate. The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (0.91 g, 92%, 83% pure) as a white foam. Sample was used crude in next step. Gamma002291 1H NMR delta 7.81 (m, 16 H), 3.55 (m, 2 H), 3.07 (m, 4 H), 2.72 (s, 3 H), 1.94 (m, 2 H), 1.57 (m, 6 H), 1.37 (s, 9 H). MS (ESI+) for C32H42N2O3P m/z 534.4 (M)+.

Reference： [1]Patent: WO2013/43580,2013,A2 .Location in patent: Paragraph 00227; 00228; 00229

44
[ 94994-39-5 ]
(4-[4-(methylamino)butanoyl]amino}butyl)(triphenyl)phosphonium bromide [ No CAS ]

Reference： [1]Patent: WO2013/43580,2013,A2

45
[ 94994-39-5 ]
{4-[(4-[amino(imino)methyl] (methyl)amino}butanoyl)amino] butyl}(triphenyl)phosphonium bromide [ No CAS ]

Reference： [1]Patent: WO2013/43580,2013,A2

46
[ 94994-39-5 ]
{4-[(4-[amino(imino)methyl](methyl)amino}butanoyl)amino]butyl}(triphenyl)phosphonium trifluoroacetate - trifluoroacetic acid [ No CAS ]

Reference： [1]Patent: WO2013/43580,2013,A2

47
[ 94994-39-5 ]
[ 1538609-66-3 ]

Reference： [1]Patent: US2014/18345,2014,A1

48
[ 94994-39-5 ]
[ 543-27-1 ]
[ 1538609-67-4 ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; In tetrahydrofuran; at -22 - -15℃; for 0.333333h;Inert atmosphere;	10816] A solution of 4-(tert-butoxycarbonyl-methyl- amino)-butyric acid (109mg, 0.50 mmol) in THF (5 mE) was treated with 4-methyl-morpholine (101 mg, 1.0 mmol) followed by isobutyl chloroformate (68 mg, 0.5 mmol) and cooled to -22 C. under argon. The reaction mixture was stirred for 20 mins while warming to -15 C. Afier re-cooling to -24 C., 4-{5-[2-amino-7-methyl-8-(3-trifluoromethyl- phenyl)-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-6-yl] -pyrazol- 1 -yl}benzonitrile (Ex. 1, 230 mg, 0.50 mmol) was added and the resulting suspension was slowly warmed to RT and stirred for 16 irs. The reaction mixture was treated with a fresh batch of1 -G [(4-{ [(tert-butoxy)carbonyl] (methyl)-amino}butanoyl) oxy]carbonyl}oxy)-2-methylpropane prepared from a solution of 4-(tert-butoxycarbonyl-methyl-amino)-butyric acid (218 mg, 1.0 mmol) in THF (5 mE), 4-methyl-morpholine(101 mg, 1.0 mmol) and isobutyl chloroformate (137mg, 1.0 mmol) at RT. The reaction mixture was stirred at RT for 24 irs and then heated at 60 C. for 7 irs. After standing at RT for 18 hrs, the volatiles were removed in vacuo and the resulting residue was purified by flash chromatography eluting withgradient of 0-100% EtOAc in DCM. The product containing fractions were concentrated in vacuo and the resulting residue (456 mg, 0.5 mmol) in THF (5 mE) was treated with a freshbatch of 1 -({ [(4-{ [(tert-butoxy)carbonyl] (methyl)amino}butanoyl)oxy]carbonyl}oxy)-2-methylpropane prepared from a solution of 4-(tert-butoxycarbonyl-methyl- amino)-butyric acid (1.09 g, 5.0 mmol) in THF (20 mE), 4-methyl-morpholine (760 mg, 7.55 mmol) and isobutyl chioroformate (680 mg, 5.01 mmol) at RT. The resulting mixture was heated at 50 C. for 65 irs and then purified by flash chromatography eluting with a gradient of 0-100% EtOAc in DCM followed by 10% MeOH in DCM affording the title compound (241 mg).10817] EC-MS (Method 1): Rt=4.06 mi mlz=659.3 [M+H]

Reference： [1]Patent: US2014/18345,2014,A1 .Location in patent: Paragraph 0815; 0816; 0817

49
(2R,4R)-2-amino-5-(5'-chloro-2'-fluorobiphenyl-4-yl)-4-[(1H-[1,2,3]triazole-4-carbonyl)amino]pentanoic acid ethyl ester [ No CAS ]
[ 94994-39-5 ]
C₃₂H₄₀ClFN₆O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		[0717] 4-(t-Butoxycarbonylmethylamino )butyric acid (7 .8mg, 36 flillOI) and HATU (13.6 mg, 36 f.tmol) were dissolvedin DMF (2 mL) and stirred at room temperature for 15 minutes.(2R,4R)-2-Amino-5-(5'-chloro-2'-fluorobiphenyl-4-yl)-4-[ (I H -[I ,2,3]triazole-4-carbonyl)amino ]pentanoic acidethyl ester (15 mg, 33 flillOI) and DIPEA (17 f.LL, 98 flillOI)were then added, and the mixture was stirred at room temperaturefor 15 minutes (LC/MS showed reaction completion)then concentrated in vacuo. The residue was dissolved inMeCN (2 mL) and a solution of 4N HCI in dioxane (122 f.LL,489 f.tmol) was added. The mixture was stirred at room temperaturefor 20 minutes (LC/MS showed the mass of thedesired product) then concentrated in vacuo and the residuewas dissolved in EtOH (2 mL). A solution of IN LiOH inwater (261 f.LL, 261 f.tmol) was added and the mixture wasstirred at room temperature for 30 minutes (LC/MS showedreaction completion) then concentrated in vacuo and the residuewas purified by preparative HPLC to yield the title compound(20.5 mg; purity 100%) as a TFA salt. MSm/z [M+Htcalc'd for C25H28CIFN60 4 , 531.18. found 531.2.
		4-(?-Butoxycarbonylmethylamino)butyric acid (7.8 mg, 36 muiotaetaomicron) and HATU (13.6 mg, 36 muiotaetaomicron) were dissolved in DMF (2 mL) and stirred at room temperature for 15 minutes . (2R, 4R) -2-Amino-5-(5 '-chloro-2'-fluorobiphenyl-4-yl)-4- [( 1 H- [ 1 ,2,3 ]triazole-4- carbonyl)amino]pentanoic acid ethyl ester (15 mg, 33 muiotaetaomicron) and DIPEA (17 mu^, 98 muiotaetaomicron) were then added, and the mixture was stirred at room temperature for 15 minutes (LC/MS showed reaction completion) then concentrated in vacuo. The residue was dissolved in MeCN (2 mL) and a solution of 4N HC1 in dioxane (122 muEpsilon, 489 muiotaetaomicron) was added. The mixture was stirred at room temperature for 20 minutes (LC/MS showed the mass of the desired product) then concentrated in vacuo and the residue was dissolved in EtOH (2 mL). A solution of IN LiOH in water (261 mu^, 261 muiotaetaomicron) was added and the mixture was stirred at room temperature for 30 minutes (LC/MS showed reaction completion) then concentrated in vacuo and the residue was purified by preparative HPLC to yield the title compound (20.5 mg; purity 100%) as a TFA salt. MS m/z [M+H] calc'd for (1167) C25H28C1FN604, 531.18; found 531.2.

Reference： [1]Patent: US2015/210690,2015,A1 .Location in patent: Paragraph 0231; 0716; 0717
[2]Patent: WO2015/116786,2015,A1 .Location in patent: Page/Page column 183; 184

50
(2R,4R)-2-amino-5-(5'-chloro-2'-fluorobiphenyl-4-yl)-4-[(1H-[1,2,3]triazole-4-carbonyl)amino]pentanoic acid ethyl ester [ No CAS ]
[ 94994-39-5 ]
(2R,4R)-5-(5'-chloro-2'-fluorobiphenyl-4-yl)-2-(4-methylaminobutyrylamino)-4-[(1H-[1,2,3]triazole-4-carbonyl)amino]pentanoic acid trifluoroacetate [ No CAS ]

Reference： [1]Patent: US2015/210690,2015,A1

51
[ 94994-39-5 ]
C₂₇H₃₂ClFN₆O₄ [ No CAS ]

Reference： [1]Patent: WO2015/116786,2015,A1

52
[ 94994-39-5 ]
(2R,4R)-5-(5'-chloro-2'-fluorobiphenyl-4-yl)-2-(4-methylaminobutyrylamino)-4-[(1H-[1,2,3]triazole-4-carbonyl)amino]pentanoic acid trifluoroacetate [ No CAS ]

Reference： [1]Patent: WO2015/116786,2015,A1

53
[ 118-92-3 ]
[ 94994-39-5 ]
C₁₇H₂₂N₂O₄ [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2016,vol. 14,p. 3950 - 3955

54
[ 94994-39-5 ]
[ 616-79-5 ]
phenyl 2-(4-((tertbutoxycarbonyl)(methyl)amino)butanamido)-5-nitrobenzoate [ No CAS ]
tert-butyl methyl(3-(6-nitro-4-oxo-4H-benzo[d][1,3]oxazin-2-yl)propyl)carbamate [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2016,vol. 14,p. 3950 - 3955

55
[ 94994-39-5 ]
C₂₃H₂₇N₃O₃ [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2016,vol. 14,p. 3950 - 3955

56
[ 94994-39-5 ]
C₁₈H₁₉N₃O [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2016,vol. 14,p. 3950 - 3955

57
[ 94994-39-5 ]
(E)-2-((1-methylpyrrolidin-2-ylidene)amino)-5-nitro-N-phenylbenzamide [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2016,vol. 14,p. 3950 - 3955

58
[ 94994-39-5 ]
(E)-2-((1-methylpyrrolidin-2-ylidene)amino)-N-phenylbenzamide [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2016,vol. 14,p. 3950 - 3955

59
[ 94994-39-5 ]
C₁₈H₁₈N₄O₃ [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2016,vol. 14,p. 3950 - 3955

60
[ 94994-39-5 ]
C₂₃H₂₆N₄O₅ [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2016,vol. 14,p. 3950 - 3955

61
[ 1070871-78-1 ]
[ 94994-39-5 ]
C₃₅H₅₀FN₃O₆ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 4838 - 4843

62
[ 1070871-21-4 ]
[ 94994-39-5 ]
C₃₀H₄₂ClN₃O₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 4838 - 4843

63
[ 1070871-21-4 ]
[ 94994-39-5 ]
C₃₅H₅₀ClN₃O₆ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 4838 - 4843

64
[ 94994-39-5 ]
[ 1253582-09-0 ]

Reference： [1]Patent: WO2010/123766,2010,A1

65
[ 94994-39-5 ]
[ 1253580-03-8 ]

Reference： [1]Patent: WO2010/123766,2010,A1

66
[ 94994-39-5 ]
[ 1253582-11-4 ]

Reference： [1]Patent: WO2010/123766,2010,A1

67
[ 94994-39-5 ]
[ 1253582-10-3 ]

Reference： [1]Patent: WO2010/123766,2010,A1

68
C₇H₈O*ClH [ No CAS ]
[ 94994-39-5 ]
(N)-methyl 2-(4-((tert-butoxycarbonyl)(methyl)amino)butanamido)-3-phenylpropionate [ No CAS ]