[ CAS No. 17288-15-2 ] {[proInfo.proName]}

Name: 17288-15-2|H-Aib-OEt.HCl|95%
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2D 3D

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Quality Control of [ 17288-15-2 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 17288-15-2 ]

SDS Specification

Alternatived Products of [ 17288-15-2 ]

Product Details of [ 17288-15-2 ]

CAS No. :	17288-15-2	MDL No. :	MFCD06809830
Formula :	C₆H₁₄ClNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YREPHXXOTHNLEV-UHFFFAOYSA-N
M.W :	167.63	Pubchem ID :	22343822
Synonyms :

Calculated chemistry of [ 17288-15-2 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.83
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	41.95
TPSA :	52.32 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) :	-6.64 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	0.96
Log Po/w (WLOGP) :	1.09
Log Po/w (MLOGP) :	0.75
Log Po/w (SILICOS-IT) :	0.01
Consensus Log Po/w :	0.56

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.29
Solubility :	8.67 mg/ml ; 0.0517 mol/l
Class :	Very soluble
Log S (Ali) :	-1.65
Solubility :	3.79 mg/ml ; 0.0226 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.79
Solubility :	27.2 mg/ml ; 0.163 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.23

Safety of [ 17288-15-2 ]

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 [ 17288-15-2 ]

* 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 [ 17288-15-2 ]
Downstream synthetic route of [ 17288-15-2 ]

[ 17288-15-2 ] Synthesis Path-Upstream 1~4

1
[ 62-57-7 ]
[ 17288-15-2 ]

Yield	Reaction Conditions	Operation in experiment
70%	Stage #1: at 0 - 20℃; for 1 h; Stage #2: Heating / reflux	(B) General Procedure for Preparing amino acid ester hydrochloric Salts Thionyl chloride (2.0 mol. equivalents) was added dropwise to a stirred solution of the appropriate anhydrous alcohol (10.0 mol equivalents) under argon atmosphere and cooled to 0° C. The mixture was stirred at 0° C. for 1 h and then slowly allowed to warm to RT. The appropriate amino acid (1.0 mol. equivalents) was added and the mixture was heated at reflux overnight. The solvent was removed under reduced pressure (last traces of solvent were removed by co-evaporation with increasingly more volatile solvents). The crude product was then triturated with Et₂O to afford the pure amino acid ester hydrochloric salt. EXAMPLE 14 2-[(2R,3S,4R,5R)-5-(4-Amino-2-oxo-2H-pyrimidin- 1-yl)-2-azido-3,4-dihydroxy-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-2-methyl-propionic acid ethyl ester (I-10) and 2-[(2R,3S,5R)-5-(4-Amino-2-oxo-2H-pyrimidin-1-yl)-2-azido-3,4-dihydroxy-tetrahydro-furan-2-ylmethoxy]-hydroxy-phosphorylamino}-2-methyl-propionic acid; compound with ammonia (I-69) step 1-Ethyl 2-amino-2-methylpropanoate hydrochloride salt The title compound was prepared according to Example 1 (A) utilizing 2-amino-isobutyric acid (8.0 g, 77.6 mmol), thionyl chloride (11.3 mL, 155.2 mmol) and anhydrous EtOH (45.5 mL, 776.0 mmol). The product 14n was isolated as a white solid (9.12 g, yield 70percent). ¹H-NMR (CDCl₃; 300 MHz): δ 8.93 (3H, bs, NH₃Cl), 4.25 (2H, q, J=7.1 Hz, OCH₂CH₃), 1.72 (6H, s, [CH₃]₂C), 1.30 (3H, t, J=7.1 Hz, OCH₂CH₃); ¹³C-NMR (CDCl₃; 75 MHz): δ 14.4 (OCH₂CH₃), 24.3 ([CH₃]₂C), 57.8 (C[CH₃]₂), 63.0 (OCH₂CH₃), 171.5 (CO).

Reference： [1] Patent: US2007/42988, 2007, A1, . Location in patent: Page/Page column 18; 22
[2] Patent: US6028032, 2000, A,

2
[ 64-17-5 ]
[ 62-57-7 ]
[ 17288-15-2 ]

Reference： [1] Australian Journal of Chemistry, 1999, vol. 52, # 5, p. 379 - 385
[2] Tetrahedron Letters, 2007, vol. 48, # 34, p. 5973 - 5975
[3] ChemBioChem, 2017, vol. 18, # 3, p. 300 - 315
[4] Canadian Journal of Chemistry, 1992, vol. 70, # 5, p. 1328 - 1337
[5] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 19, p. 2699 - 2711
[6] Journal of the American Chemical Society, 1924, vol. 46, p. 412
[7] Patent: WO2012/52781, 2012, A1, . Location in patent: Page/Page column 23-24; 30-31
[8] Patent: US2013/211083, 2013, A1, . Location in patent: Paragraph 0094; 0095

3
[ 84758-56-5 ]
[ 17288-15-2 ]

Reference： [1] Patent: WO2016/69826, 2016, A1, . Location in patent: Paragraph 0236
[2] Patent: US2017/71964, 2017, A1, . Location in patent: Paragraph 0638-0639

4
[ 64-17-5 ]
[ 15028-41-8 ]
[ 17288-15-2 ]

Reference： [1] Tetrahedron, 1982, vol. 38, # 14, p. 2165 - 2182

[ 17288-15-2 ] Synthesis Path-Downstream 1~87

1
[ 75-44-5 ]
[ 17288-15-2 ]
[ 128326-91-0 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1952,vol. 575,p. 217,230

2
[ 16002-63-4 ]
[ 17288-15-2 ]
[ 51328-61-1 ]

Reference： [1]Journal of the American Chemical Society,1953,vol. 75,p. 2959,2962

3
[ 17288-15-2 ]
[ 97-63-2 ]

Reference： [1]Journal of the American Chemical Society,1924,vol. 46,p. 412

4
[ 17288-15-2 ]
[ 80-55-7 ]

Reference： [1]Journal of the American Chemical Society,1924,vol. 46,p. 412

5
[ 64-17-5 ]
[ 62-57-7 ]
[ 17288-15-2 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; at 20℃; for 6h;Reflux; Industry scale;	2A. 2-aminoisobutyric acid ethyl ester hydrochloride Stage 2aEthanol (395L) was added to 2-aminoisobutyric acid (79Kg) and the mixture stirred at 20C. Thionyl chloride (91.2Kg) was added, maintaining the temperature at <40C. The mixture was heated to reflux and stirred for 6 hours. The contents were distilled under atmospheric pressure to a residual volume of approximately 200L over a period of 14 hours. The mixture was cooled to 45-50C and methyl fert-butyl ether (395L) was added. The mixture was cooled to 0-5C and stirred for 1 hour. Material was isolated by filtration and washed with methyl fert-butyl ether (160L) pre-cooled to 0-5C, then dried in vacuo at 30-40C to give ethyl 2-aminoisobutyrate hydrochloride (105.5Kg) with 86.2% purity in 71 % yield (based on active).= The amine has 3 protons rather than 2 because it is protonated in the HCI in the solution.
	With thionyl chloride; at 20℃; for 6h;Reflux; Large scale;	2A. 2-aminoisobutyric acid ethyl ester hydrochloride Ethanol (395 L) was added to 2-aminoisobutyric acid (79 Kg) and the mixture stirred at 20 C. Thionyl chloride (91.2 Kg) was added, maintaining the temperature at 540 C. The mixture was heated to reflux and stirred for 6 hours. The contents were distilled under atmospheric pressure to a residual volume of approximately 200 L over a period of 14 hours. The mixture was cooled to 45-50 C. and methyl tert-butyl ether (395 L) was added. The mixture was cooled to 0-5 C. and stirred for 1 hour. Material was isolated by filtration and washed with methyl tert-butyl ether (160 L) pre-cooled to 0-5 C., then dried in vacuo at 30-40 C. to give ethyl-2-aminoisobutyrate hydrochloride (105.5 Kg) with 86.2% purity in 71% yield (based on active).
	With thionyl chloride; In ethanol; at 0 - 90℃; for 16h;	General procedure: Thionyl Chloride (3.87 mL, 53.3 mmol) was added dropwise to a stirred solution of 2-amino-2-methylpropanoic acid (5 g, 48.5 mmol) in cyclopentanol (26.4 ml, 291 mmol) at 0C. The mixture was stirred at 80 C for 16 hours. The reaction mixture was cooled, diluted with water (60 mL) and washed with DCM (2x80 mL). The aqueous layer was concentrated under reduced pressure to afford the title compound: 1 H NMR (400MHz, dMSO-<=) delta 8.61 (brs, 3H), 5.19-5.15 (m, 1H), 1.87- 1.81 (m, 2H), 1.72-1.55 (m, 6H), 1.45 (s, 6H).

Reference： [1]Australian Journal of Chemistry,1999,vol. 52,p. 379 - 385
[2]Tetrahedron Letters,2007,vol. 48,p. 5973 - 5975
[3]ChemBioChem,2017,vol. 18,p. 300 - 315
[4]Canadian Journal of Chemistry,1992,vol. 70,p. 1328 - 1337
[5]Journal of the Chemical Society. Perkin transactions I,1999,p. 2699 - 2711
[6]Journal of the American Chemical Society,1924,vol. 46,p. 412
[7]Patent: WO2012/52781,2012,A1 .Location in patent: Page/Page column 23-24; 30-31
[8]Patent: US2013/211083,2013,A1 .Location in patent: Paragraph 0094; 0095
[9]Patent: WO2018/39157,2018,A1 .Location in patent: Page/Page column 29; 30; 33

6
[ 121342-36-7 ]
[ 17288-15-2 ]
[ 17288-23-2 ]

Reference： [1]Journal of Organic Chemistry,1968,vol. 33,p. 3980 - 3983

7
[ 79-37-8 ]
[ 17288-15-2 ]
[ 17288-16-3 ]

Reference： [1]Journal of Organic Chemistry,1968,vol. 33,p. 3980 - 3983

8
[ 17288-15-2 ]
[ 4755-77-5 ]
[ 17288-20-9 ]

Reference： [1]Journal of Organic Chemistry,1968,vol. 33,p. 3980 - 3983

9
[ 17288-15-2 ]
[ 1138-80-3 ]
[ 2420-10-2 ]

Reference： [1]Journal of Medicinal Chemistry,1964,vol. 7,p. 820 - 821

10
[ 2899-60-7 ]
[ 17288-15-2 ]
[ 2420-10-2 ]

Reference： [1]Canadian Journal of Chemistry,1992,vol. 70,p. 1328 - 1337

11
[ 64-17-5 ]
[ 15028-41-8 ]
[ 17288-15-2 ]

Reference： [1]Tetrahedron,1982,vol. 38,p. 2165 - 2182

12
[ 54915-42-3 ]
[ 17288-15-2 ]
2-Methyl-2-(2-methyl-6-nitro-benzylamino)-propionic acid ethyl ester [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,1982,vol. 17,p. 547 - 556

13
[ 609-65-4 ]
[ 17288-15-2 ]
2-(2-Chloro-benzoylamino)-2-methyl-propionic acid ethyl ester [ No CAS ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1980,vol. 28,p. 2045 - 2051

14
[ 612-23-7 ]
[ 17288-15-2 ]
[ 85062-84-6 ]

Reference： [1]European Journal of Medicinal Chemistry,1982,vol. 17,p. 547 - 556

15
[ 17288-15-2 ]
[ 100-52-7 ]
[ 130146-17-7 ]

Reference： [1]Journal of the American Chemical Society,1990,vol. 112,p. 8982 - 8983

16
[ 17288-15-2 ]
[ 122-01-0 ]
[ 40963-08-4 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1980,vol. 28,p. 2045 - 2051

17
[ 17288-15-2 ]
[ 98-88-4 ]
[ 77919-05-2 ]

Reference： [1]Australian Journal of Chemistry,1999,vol. 52,p. 379 - 385

18
[ 1189-71-5 ]
[ 17288-15-2 ]
[ 75-65-0 ]
[ 252961-00-5 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1999,p. 2699 - 2711

19
[ 17288-15-2 ]
sodium compound of α.γ-dicarboxy-glutaconic acid tetraethyl ester [ No CAS ]
[(1-ethoxycarbonyl-1-methyl-ethylamino)-methylene]-malonic acid diethyl ester [ No CAS ]

Reference： [1]Journal of the Chemical Society,1914,vol. 105,p. 29

21
[ 7647-01-0 ]
[ 17288-15-2 ]
sodium nitrite [ No CAS ]
[ 79-41-4 ]
[ 97-63-2 ]
[ 80-55-7 ]

Reference： [1]Journal of the American Chemical Society,1924,vol. 46,p. 412

22
[ 17288-15-2 ]
[ 770-12-7 ]
[ 840506-41-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2005,vol. 13,p. 3219 - 3227

23
[ 100-39-0 ]
[ 17288-15-2 ]
[ 107411-95-0 ]

Reference： [1]Tetrahedron Letters,2007,vol. 48,p. 5973 - 5975

24
[ 17288-15-2 ]
[ 501-53-1 ]
[ 150391-25-6 ]

Reference： [1]Tetrahedron Letters,2007,vol. 48,p. 5973 - 5975

25
[ 17288-15-2 ]
C₃₄H₄₀N₂O₅ [ No CAS ]

Reference： [1]Tetrahedron Letters,2007,vol. 48,p. 5973 - 5975

26
[ 17288-15-2 ]
C₃₃H₃₈N₂O₅ [ No CAS ]

Reference： [1]Tetrahedron Letters,2007,vol. 48,p. 5973 - 5975

27
[ 17288-15-2 ]
C₃₃H₃₆N₂O₅ [ No CAS ]

Reference： [1]Tetrahedron Letters,2007,vol. 48,p. 5973 - 5975

28
[ 17288-15-2 ]
[ 950206-88-9 ]

Reference： [1]Tetrahedron Letters,2007,vol. 48,p. 5973 - 5975

29
[ 17288-15-2 ]
C₇H₁₅NO₂*HBr [ No CAS ]

Reference： [1]Tetrahedron Letters,2007,vol. 48,p. 5973 - 5975

30
[ 17288-15-2 ]
C₃₁H₃₄N₂O₅ [ No CAS ]

Reference： [1]Tetrahedron Letters,2007,vol. 48,p. 5973 - 5975

31
[ 17288-15-2 ]
C₃₇H₃₈N₂O₅ [ No CAS ]

Reference： [1]Tetrahedron Letters,2007,vol. 48,p. 5973 - 5975
[2]Tetrahedron Letters,2007,vol. 48,p. 5973 - 5975

32
[ 17288-15-2 ]
C₂₉H₃₄N₂O₅S [ No CAS ]

Reference： [1]Tetrahedron Letters,2007,vol. 48,p. 5973 - 5975

33
[ 17288-15-2 ]
(E)-5-(2-bromovinyl)-2'-deoxyuridine-5'-[phenyl-(ethoxy-α,α-dimethylglycinyl)]-phosphate [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2005,vol. 13,p. 3219 - 3227

34
[ 17288-15-2 ]
[ 252961-02-7 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1999,p. 2699 - 2711

35
[ 17288-15-2 ]
[ 252961-01-6 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1999,p. 2699 - 2711

36
[ 17288-15-2 ]
ethyl 2-[chloro(phenyl)methylidene]amino}-2-methylpropanoate [ No CAS ]

Reference： [1]Australian Journal of Chemistry,1999,vol. 52,p. 379 - 385

37
[ 17288-15-2 ]
2-(2-Amino-benzylamino)-2-methyl-propionic acid ethyl ester [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,1982,vol. 17,p. 547 - 556

38
[ 17288-15-2 ]
2-(2-Amino-6-methyl-benzylamino)-2-methyl-propionic acid ethyl ester [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,1982,vol. 17,p. 547 - 556

39
[ 17288-15-2 ]
C₆H₁₂ClNO₄S [ No CAS ]

Reference： [1]Patent: US6337398,2002,B1 .Location in patent: Page column 35

41
[ 853598-35-3 ]
[ 17288-15-2 ]
C₃₃H₄₃NO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12.17h;	A solution of 2- {1- [4- (3, 3-dimethyl-2-oxo-butoxy) -3-methyl-phenyl]- ethylpropyl}-benzofuran-5-carboxylic acid (110 mg, 0.252 mmol) in CH2Cl2 (5.0 mL) is treated with DMAP (92 mg, 0.756 mmol) and EDC (73 mg, 0.378 mmol). The mixture is stirred for 10 min at RT before the addition of ethyl, 2-amino-2- methylpropionate, hydrochloride (58 mg, 0.378 mmol). The reaction is stirred for 12 h and is loaded on silica gel column and purified with 20-50% EtOAc/Hex to afford the intermediate amide ester. The intermediate is dissolved in methanol (2.0 mL) and THF (2. 0 mL) and is treated with NaOH (2. 0 M, 4.0 mL). The resulting mixture is stirred at RT for 18 h. The mixture is concentrated and neutralized with HCl (1 N) till pH-3, and extracted with EtOAc (3 x 10 mL). The organic layer is dried over NagS04, concentrated to afford the title compound (95 mg, 72%). MS (ES) mle : 520.3 (M-1), 522.2 (M+1)

Reference： [1]Patent: WO2005/51938,2005,A1 .Location in patent: Page/Page column 123-124

42
[ 902169-75-9 ]
[ 17288-15-2 ]
[3-chloro-1-(4-isopropoxyphenyl)-5-(4-trifluoromethylphenoxy)indole-2-carbonyl]amino}-2-methylpropionic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In acetonitrile; at 20℃; for 63h;	HCl (1 M in MeOH, 1 mL, 1 mmol) and H2O n(3 drops) were added to [3-cliloro-l-(4-isopropoxyphenyl)-5-(4-trifluoromethylphenoxy)rndole-2-carbon- yl] amino} acetic acid ethyl ester (70 mg, 0.12 mmol, see step (d) above) in CH2Cl2(1 mL). The mixture was stirred at rt for 2 h and acidified with HCl (aq, cone).CH2Cl2 and H2O were added and the organic layer was washed twice with H2O , dried (Na2SO4), and concentrated. The residue was treated with hexane which gave the title compound (59 mg, 88%) as a white solid with. Mp.94-96 0C.

Reference： [1]Patent: WO2006/77365,2006,A1 .Location in patent: Page/Page column 98

43
[ 221535-99-5 ]
hydrochloride of 2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-1,2,3,4-tetrahydroquinazoline-3-acetic acid [ No CAS ]
[ 2942-58-7 ]
[ 17288-15-2 ]
[ 221536-44-3 ]

Yield	Reaction Conditions	Operation in experiment
60%	With triethylamine; In N,N-dimethyl-formamide;	EXAMPLE 70 N-(1-Ethoxycarbonyl-1-methyl)ethyl-2-[2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-1,2,3,4-tetrahydroquinazolin-3-yl]acetamide The hydrochloride of 2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-1,2,3,4-tetrahydroquinazoline-3-acetic acid obtained in Example 50 (0.87 g, 1.50 mmol) was dissolved in N,N-dimethylformamide (3 ml), and diethyl cyanophosphonate (0.27 ml, 1.58 mmol) was added dropwise with stirring and cooling on ice. After stirring at the same temperature for 1 hour, <strong>[17288-15-2]ethyl 2-aminoisobutyrate hydrochloride</strong> (0.30 g, 1.80 mmol) and triethylamine (0.71 ml, 5.10 mmol) were added. After stirring at room temperature overnight, the mixture was diluted with an iced water and extracted with ethyl ether. After the extract was washed with water and dried (MgSO4), the solvent was distilled off under reduced pressure. The residue was subjected to a column chromatography on a silica gel eluding with chloroform-methanol (20:1, v/v) to give the title compound (0.59 g, 60%). IR (KBr): 3296, 2945, 2931, 2869, 2810, 2767, 1739, 1706, 1658, 1610, 1540 cm-1. 1H-NMR (CDCl3) delta: 1.26 (3H, t, J=7.2 Hz), 1.59 (6H, s), 1.55-1.98 (8H, m), 2.05-2.18 (2H, m), 2.37 (2H, t, J=7.2 Hz), 2.70-2.81 (2H, m), 3.40-3.51 (1H, m), 4.10-4.18 (2H, m), 4.19 (2H, q, J=7.2 Hz), 4.73 (2H, s), 5.53 (1H, s), 6.51 (1H, s), 7.20-7.34 (12H, m), 7.62-7.71 (1H, m), 8.22 (1H, dd, J=1.6 Hz, 8.0 Hz).

Reference： [1]Patent: US6407116,2002,B1

44
[ 17288-15-2 ]
[ 215530-62-4 ]
N-(6-chloro[1,2,4]triazolo[1,5-b]pyridazine-2-carbonyl)-2,2-dimethylglycine ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole; In water; N,N-dimethyl-formamide;	REFERENCE EXAMPLE 37A Production of N-(6-Chloro[1,2,4]triazolo[1,5-b]pyridazine-2-carbonyl)-2,2-dimethylglycine Ethyl ester 1.52 g of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine-2-carboxylic acid and 1.45 ml of N-ethyldiisopropylamine were suspended in 15 ml of N,N-dimethylformamide; 1.37 g of N,N'-carbonyldiimidazole was added, followed by stirring at room temperature for 3 hours. To the reaction mixture, 1.41 g of <strong>[17288-15-2]2-aminoisobutyric acid ethyl ester hydrochloride</strong> was added, followed by stirring at room temperature for 4 hour. Water was added, followed by extraction with ethyl acetate-tetrahydrofuran (1:1); the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure; the crystal precipitated was washed with ethyl ether, collected by filtration and dried to yield 1.48 g of the title compound. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate. The desired fraction was collected and concentrated under reduced pressure to yield 450 mg of the title compound. 1H-NMR (CDCl3) delta ppm: 1.29 (3H, t, J=7.1 Hz), 1.73 (6H, s), 4.26 (2H, q, J=7.2 Hz), 7.52 (1H, d, J=9.4 Hz), 7.94 (1H, brs), 8.16 (1H, d, J=9.4 Hz).
	With N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole; In water; N,N-dimethyl-formamide;	Reference Example 37 Production of N-(6-chloro[1,2,4]triazolo[1,5-b]pyridazine-2-carbonyl)-2,2-dimethylglycine ethyl ester 1.52 g of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine-2-carboxylic acid and 1.45 ml of N-ethyldiisopropylamine were suspended in 15 ml of N,N-dimethylformamide; 1.37 g of N,N'-carbonyldiimidazole was added, followed by stirring at room temperature for 3 hours. To the reaction mixture, 1.41 g of <strong>[17288-15-2]2-aminoisobutyric acid ethyl ester hydrochloride</strong> was added, followed by stirring at room temperature for 4 hour. Water was added, followed by extraction with ethyl acetate-tetrahydrofuran (1:1); the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the crystal precipitated was washed with ethyl ether, collected by filtration and dried to yield 1.48 g of the title compound. The filtrate was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate. The desired fraction was collected and concentrated under reduced pressure to yield 450 mg of the title compound. 1H-NMR (CDCl3) delta ppm: 1.29 (3H, t, J=7.1 Hz), 1.73 (6H, s), 4.26 (2H, q, J=7.2 Hz), 7.52 (1H, d, J=9.4 Hz), 7.94 (1H, brs), 8.16 (1H, d, J=9.4 Hz).
	With N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole; In water; N,N-dimethyl-formamide;	Reference Example A37 Production of N-(6-chloro[1,2,4]triazolo[1,5-b]pyridazine-2-carbonyl)-2,2-dimethylglycine ethyl ester 6-Chloro[1,2,4]triazolo[1,5-b]pyridazine-2-carboxylic acid (1.52 g) and N-ethyldiisopropylamine (1.45 ml) were suspended in N,N-dimethylformamide (15 ml); N,N'-carbonyldiimidazole (1.37 g) was added thereto, followed bystirring at room temperature for 3 hours. To the reaction mixture, <strong>[17288-15-2]2-aminoisobutyric acid ethyl ester hydrochloride</strong> (1.41 g) was added, followed by stirring at room temperature for 4 hour. Water was added thereto, followed by extraction with ethyl acetate:tetrahydrofuran (1:1); the extract was washed with brine and dried over magnesium sulfate. The extract was concentrated under reduced pressure; the crystals precipitated were washed with ethyl ether, collected by filtration and dried to give the title compound (1.48 g). The filtrate was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate. The desired fractions were collected and concentrated under reduced pressure to give the title compound (450 mg). 1H-NMR(CDCl3)delta ppm: 1.29 (3H,t,J=7.lHz), 1.73(6H,s), 4.26(2H,q,J=7.2Hz), 7.52(1H,d,J=9.4Hz), 7.94(1H.brs), 8.16(1H,d,J=9.4Hz).

Reference： [1]Patent: US6627630,2003,B1
[2]Patent: US6248740,2001,B1
[3]Patent: EP1243271,2002,A1

45
[ 17288-15-2 ]
[ 14714-24-0 ]
N-(6-chloroimidazo[1,2-b]pyridazine-2-carbonyl]-2,2-dimethylglycine ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; 1,1'-carbonyldiimidazole; In water; N,N-dimethyl-formamide;	REFERENCE EXAMPLE 21A Production of N-(6-Chloroimidazo[1,2-b]pyridazine-2-carbonyl)-2,2-dimethylglycine Ethyl Ester 1.28 g of 6-chloroimidazo[1,2-b]pyridazine-2-carboxylic acid was suspended in 12 ml of N,N-dimethylformamide; 1.16 g of N,N'-carbonyldiimidazole was added, followed by stirring at room temperature for 30 minutes. To the reaction mixture, 1.20 g of <strong>[17288-15-2]2-aminoisobutyric acid ethyl ester hydrochloride</strong> and 1.00 ml of triethylamine were added, followed by stirring at room temperature for 16 hours. Water was added, the crystal precipitated was collected by filtration; the filtrate was extracted with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was combined with the above crystal collected by filtration and subjected to silica gel column chromatography and eluted with hexane:ethyl acetate (2:1). The desired fraction was collected and concentrated under reduced pressure to yield 1.20 g of the title compound. 1H-NMR (CDCl3) delta ppm: 1.28 (3H, t, J=7.2 Hz), 1.70 (6H, s), 4.25 (2H, q, J=7.0 Hz), 7.13 (1H, d, J=9.4 Hz), 7.87 (1H, brs), 7.89 (1H, d, J=9.6 Hz), 8.41 (1H, s).
	With triethylamine; 1,1'-carbonyldiimidazole; In water; N,N-dimethyl-formamide;	Reference Example 21 Production of N-(6-chloroimidazo[1,2-b]pyridazine-2-carbonyl)-2,2-dimethylglycine ethyl ester 1.28 g of 6-chloroimidazo[1,2-b]pyridazine-2-carboxylic acid was suspended in 12 ml of N,N-dimethylformamide; 1.16 g of N,N'-carbonyldiimidazole was added, followed by stirring at room temperature for 30 minutes. To the reaction mixture, 1.20 g of <strong>[17288-15-2]2-aminoisobutyric acid ethyl ester hydrochloride</strong> and 1.00 ml of triethylamine were added, followed by stirring at room temperature for 16 hours. Water was added, the crystal precipitated was collected by filtration; the filtrate was extracted with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was combined with the above crystal collected by filtration and subjected to silica gel column chromatography and eluted with hexane:ethyl acetate (2:1). The desired fraction was collected and concentrated under reduced pressure to yield 1.20 g of the title compound. 1H-NMR (CDCl3) delta ppm: 1.28 (3H, t, J=7.2 Hz), 1.70 (6H, s), 4.25 (2H, q, J=7.0 Hz), 7.13 (1H, d, J=9.4 Hz), 7.87 (1H, brs), 7.89 (1H, d, J=9.6 Hz), 8.41 (1H, s).
	With triethylamine; 1,1'-carbonyldiimidazole; In water; N,N-dimethyl-formamide;	Reference Example A21 Production of N-(6-chloroimidazo[1,2-b]pyridazine-2-carbonyl)-2,2-dimethylglycine ethyl ester 6-Chloroimidazo[1,2-b]pyridazine-2-carboxylic acid (1.28 g) was suspended in N,N-dimethylformamide (12 ml); N,N'-carbonyldiimidazole (1.16 g) was added thereto, followed by stirring at room temperature for 30 minutes. To the reaction mixture, <strong>[17288-15-2]2-aminoisobutyric acid ethyl ester hydrochloride</strong> (1.20 g) and triethylamine (1.00 ml) were added, followed by stirring at room temperature for 16 hours. Water was added, the crystals precipitated were collected by filtration; the filtrate was extracted with ethyl acetate; the extract was washed with brine and dried over magnesium sulfate. The extract was concentrated under reduced pressure; the residue was combined with the above crystals collected by filtration and subjected to silica gel column chromatography and eluted with hexane:ethyl acetate (2:1). The desired fractions were collected and concentrated under reduced pressure to give the title compound (1.20 g). 1H-NMR(CDCl3)delta ppm: 1.28(3H,t,J=7.2Hz), 1.70(6H,s), 4.25(2H,q,J=7.0Hz), 7.13(1H,d,J=9.4Hz), 7.87(1H,brs), 7.89(1H,d,J=9.6Hz), 8.41(1H,s).

Reference： [1]Patent: US6627630,2003,B1
[2]Patent: US6248740,2001,B1
[3]Patent: EP1243271,2002,A1

46
[ 215530-43-1 ]
[ 117204-61-2 ]
[ 17288-15-2 ]
[ 110-17-8 ]
N-[6-[3-[4-(diphenylmethoxy)piperidino]-propoxy][1,2,4]triazolo[1,5-b]pyridazine-2-carbonyl]-2,2-dimethylglycine ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; ethanol; N,N-dimethyl-formamide;	EXAMPLE 126A Production of N-[6-[3-[4-(Diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[1,5-b]pyridazine-2-carbonyl]-2,2-dimethylglycine Ethyl Ester 1.5 Fumarate 986 mg of [6-[3-[4-(diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[1,5-b]pyridazin-2-yl]carboxylic acid and 0.38 ml of N-ethyldiisopropylamine were suspended in 10 ml of N,N-dimethylformamide; 361 mg of N,N'-carbonyldiimidazole was added, followed by stirring at room temperature for 3 hours. After 372 mg of <strong>[17288-15-2]2-aminoisobutyric acid ethyl ester hydrochloride</strong> was added, the mixture was stirred at room temperature for 43 hours, then at 60 C. for 5 hours. Ice water was added, followed by extraction with ethyl acetate-tetrahydrofuran (1:1); the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:1:1). The desired fraction was collected and concentrated under reduced pressure, after which it was dissolved in 5 ml of ethanol; 139 mg of fumaric acid was added, followed by concentration. Ethanol-ethyl acetate (1:3) was added to cause crystallization; the crystal precipitated was washed with ethyl ether, collected by filtration and dried to yield 581 mg of the title compound. Melting point: 127-130 C.; Elemental analysis (for C39H46N6O11): Calculated (%): C, 60.45; H, 5.98; N, 10.85; Found (%): C, 60.06; H, 5.91; N, 10.80.
	With N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; ethanol; N,N-dimethyl-formamide;	EXAMPLE 126 Production of N-[6-[3-[4-(diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[1,5-b]pyridazine-2-carbonyl]-2,2-dimethylglycine ethyl ester 1.5 fumarate 986 mg of [6-[3-[4-(diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[1,5-b]pyridazin-2-yl]carboxylic acid and 0.38 ml of N-ethyldiisopropylamine were suspended in 10 ml of N,N-dimethylformamide; 361 mg of N,N'-carbonyldiimidazole was added, followed by stirring at room temperature for 3 hours. After 372 mg of <strong>[17288-15-2]2-aminoisobutyric acid ethyl ester hydrochloride</strong> was added, the mixture was stirred at room temperature for 43 hours, then at 60 C. for 5 hours. Ice water was added, followed by extraction with ethyl acetate-tetrahydrofuran (1:1); the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:1:1). The desired fraction was collected and concentrated under reduced pressure, after which it was dissolved in 5 ml of ethanol; 139 mg of fumaric acid was added, followed by concentration. Ethanol-ethyl acetate (1:3) was added to cause crystallization; the crystal precipitated was washed with ethyl ether, collected by filtration and dried to yield 581 mg of the title compound. Melting point: 127-130 C. Elemental analysis (for C39H46N6O11):

Reference： [1]Patent: US6627630,2003,B1
[2]Patent: US6248740,2001,B1

47
[ 62-57-7 ]
[ 17288-15-2 ]

Yield	Reaction Conditions	Operation in experiment
70%		(B) General Procedure for Preparing amino acid ester hydrochloric Salts Thionyl chloride (2.0 mol. equivalents) was added dropwise to a stirred solution of the appropriate anhydrous alcohol (10.0 mol equivalents) under argon atmosphere and cooled to 0 C. The mixture was stirred at 0 C. for 1 h and then slowly allowed to warm to RT. The appropriate amino acid (1.0 mol. equivalents) was added and the mixture was heated at reflux overnight. The solvent was removed under reduced pressure (last traces of solvent were removed by co-evaporation with increasingly more volatile solvents). The crude product was then triturated with Et2O to afford the pure amino acid ester hydrochloric salt. EXAMPLE 14 2-[(2R,3S,4R,5R)-5-(4-Amino-2-oxo-2H-pyrimidin- 1-yl)-2-azido-3,4-dihydroxy-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-2-methyl-propionic acid ethyl ester (I-10) and 2-[(2R,3S,5R)-5-(4-Amino-2-oxo-2H-pyrimidin-1-yl)-2-azido-3,4-dihydroxy-tetrahydro-furan-2-ylmethoxy]-hydroxy-phosphorylamino}-2-methyl-propionic acid; compound with ammonia (I-69) step 1-Ethyl 2-amino-2-methylpropanoate hydrochloride salt The title compound was prepared according to Example 1 (A) utilizing 2-amino-isobutyric acid (8.0 g, 77.6 mmol), thionyl chloride (11.3 mL, 155.2 mmol) and anhydrous EtOH (45.5 mL, 776.0 mmol). The product 14n was isolated as a white solid (9.12 g, yield 70%). 1H-NMR (CDCl3; 300 MHz): delta 8.93 (3H, bs, NH3Cl), 4.25 (2H, q, J=7.1 Hz, OCH2CH3), 1.72 (6H, s, [CH3]2C), 1.30 (3H, t, J=7.1 Hz, OCH2CH3); 13C-NMR (CDCl3; 75 MHz): delta 14.4 (OCH2CH3), 24.3 ([CH3]2C), 57.8 (C[CH3]2), 63.0 (OCH2CH3), 171.5 (CO).
	In ethanol;	REFERENCE EXAMPLE 4 A stirred suspension of 2-amino-2-methylpropanoic acid (165 g) in ethanol at 0 C. was saturated with hydrogen chloride gas. The mixture was heated at reflux for 4 hours and the solvent was evaporated under reduced pressure to give ethyl 2-amino-2-methylpropanoate hydrochloride as a white solid.

Reference： [1]Patent: US2007/42988,2007,A1 .Location in patent: Page/Page column 18; 22
[2]Patent: US6028032,2000,A

48
5-Ethoxy-1,3-dihydro-1-(2-methoxy-4-carboxybenzenesulfonyl)-3-cyclohexyl-2H-benzimidazol-2-one [ No CAS ]
[ 96042-30-7 ]
[ 17288-15-2 ]
5-Ethoxy-1,3-dihydro-1-[2-methoxy-4-(N-(1-ethoxycarbonyl-1-methylethyl)carbamoyl)benzenesulfonyl]-3-cyclohexyl-2H-benzimidazol-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In ethyl acetate;	EXAMPLE 15 5-Ethoxy-1,3-dihydro-1-[2-methoxy-4-(N-(1-ethoxycarbonyl-1-methylethyl)carbamoyl)benzenesulfonyl]-3-cyclohexyl-2H-benzimidazol-2-one 500 mg of the compound obtained in Example 13, 300 mg of <strong>[17288-15-2]1-ethoxycarbonyl-1-methylethylamine hydrochloride</strong> and 550 mg of BOP were mixed with 2 ml of DIPEA and 50 ml of DCM and the reaction medium was stirred for 30 minutes at room temperature. It was then concentrated under vacuum and the residue was taken up with water and then extracted with AcOEt, washed successively with 1N HCl, with 1N NaOH and then with water, dried over sodium sulfate and concentrated under vacuum. The residue was purified by chromatography on a silica column using a DCM/AcOEt mixture (97/3; v/v) as the eluent. 170 mg of the expected product were obtained in the form of a white solid by crystallization from an AcOEt/iso ether mixture (10/90; v/v). M.p.=202 C.

Reference： [1]Patent: US5585394,1996,A

49
[ 6940-76-7 ]
[ 17288-15-2 ]
[ 172150-91-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In water; N,N-dimethyl-formamide;	(1) A solution of ethyl aminoisobutyrate hydrochloride (10 g) in DMF (50 mL) was cooled to 0 C. To the solution were added potassium carbonate (18 g) and 1-chloro-3-iodopropane (12 g), and the mixture was stirred overnight at 0 C. to room temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 12.5 g of crude ethyl 2-(3-chloropropylamino)isobutyrate.

Reference： [1]Patent: US5834401,1998,A

50
[ 39161-85-8 ]
[ 17288-15-2 ]
[ 172150-79-7 ]

Yield	Reaction Conditions	Operation in experiment
	With formaldehyd; triethylamine;toluene-4-sulfonic acid; In ethyl acetate; toluene;	EXAMPLE 11 Preparation of ethyl 2-(5-phenylthiazolidin-4-on-3-yl)isobutyrate (Compound No. D-2) STR31 Triethylamine (3 g) was added to a suspension of <strong>[17288-15-2]ethyl 2-aminoisobutyrate hydrochloride</strong> (5 g) in toluene (60 mL) at room temperature. 2-Mercaptophenylacetic acid (6.44 g) was added to the mixture, which was then stirred at room temperature. After 10 minutes, a 35% formaldehyde aqueous solution (2.61 g) was added dropwise to the mixture. After the addition was completed, a catalytic amount of p-toluenesulfonic acid was added, and the mixture was allowed to react under heating at reflux for 4 hours, while water generated was excluded by azeotropic distillation from the reaction system. The reaction mixture was cooled to room temperature, to which ethyl acetate was added, and was then washed with a saturated sodium hydrogencarbonate aqueous solution and a saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled under reduced pressure to give 5.49 g of the title compound as viscous oil.

Reference： [1]Patent: US5834401,1998,A

51
[ 215530-43-1 ]
[ 17288-15-2 ]
[ 110-17-8 ]
N-[6-[3-[4-(diphenylmethoxy)piperidino]-propoxy][1,2,4]triazolo[1,5-b]pyridazine-2-carbonyl]-2,2-dimethylglycine ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; ethanol; ethyl acetate; N,N-dimethyl-formamide;	Reference Example B126 Production of N-[6-[3-[4-(diphenylmethoxy)piperidino]-propoxy][1,2,4]triazolo[1,5-b]pyridazine-2-carbonyl]-2,2-dimethylglycine ethyl ester 1.5 fumarate [6-[3-[4-(Diphenylmethoxy)piperidino]-propoxy][1,2,4]triazolo[1,5-b]pyridazin-2-yl]carboxylic acid (986 mg) and N-ethyldiisopropylamine (0.38 ml) were suspended in N,N-dimethylformamide (10 ml); N,N'-carbonyldiimidazole (361 mg) was added thereto, followed by stirring at room temperature for 3 hours. After <strong>[17288-15-2]ethyl 2-aminoisobutyrate hydrochloride</strong> (372 mg) was added thereto, the mixture was stirred at room temperature for 43 hours, then at 60C for 5 hours. Ice water was added thereto, followed by extraction with ethyl acetate:tetrahydrofuran (1:1); the extract was washed with brine and dried over magnesium sulfate. The extract was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:1:1). Thedesired fractions were collected and concentrated under reduced pressure, after which it was dissolved in ethanol (5 ml); fumaric acid (139 mg) was added thereto, followed by concentration. Ethanol:ethyl acetate (1:3) was added to cause crystallization; the crystals precipitated were washed with ethyl ether, collected by filtration and dried to give the title compound (581 mg). melting point: 127-130C elemental analysis for C39H46N6O11 Calculated (%): C,60.45; H,5.98; N,10.85 Found (%): C,60.06; H,5.91; N,10.80

Reference： [1]Patent: EP1243271,2002,A1

52
para-(ferrocenyl)benzoic acid [ No CAS ]
[ 17288-15-2 ]
[ 847186-07-6 ]

Reference： [1]Journal of Organometallic Chemistry,2005,vol. 690,p. 383 - 393

53
[ 17288-15-2 ]
[ 24032-84-6 ]
[ 89020-94-0 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In toluene; for 15h;Heating / reflux;	Stage a): 5,5-dimethyl-3-{4-[(trifluoromethyl)thio]phenyl}-imidazolidine-2,4-dione To a solution of 8.5 mL of trichloromethyl chloroformate (diphosgene) in 250 mL of toluene are added 1.8 g of 3S charcoal. To this suspension cooled to -20 C. are added 10 g of 4-trifluoromethylthioaniline dissolved in 160 mL of toluene. The reaction mixture is gradually warmed to room temperature and then refluxed for 4 hours. After cooling to room temperature, a suspension of 9.4 g of dimethylglycine ethyl ester hydrochloride in 90 mL of toluene is added, followed by 38 mL of triethylamine and the reaction mixture is refluxed for 15 hours. After filtering through Celite, the filtrate is concentrated under reduced pressure and the residue is taken up in 200 mL of dichloromethane, washed with three times 100 mL of water, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is then triturated in diethyl ether and the solid formed is filtered off and dried to give 12 g of 5,5-dimethyl-3-{4-[(trifluoromethyl)thio]phenyl}imidazolidine-2,4-dione, the characteristics of which are as follows: 1H NMR spectrum at 400 MHz: 1.40 (s, 6H); 7.60 (d, J=8.5 Hz, 2H); 7.82 (d, J=8.5 Hz, 2H); 8.65 (broad s, 1H). Mass Spectrum (EI): m/z=304 [M]+; m/z=219 [M]+-CONHCH(CH3)2; m/z=150 [219]+-CF3

Reference： [1]Patent: US2009/82379,2009,A1 .Location in patent: Page/Page column 29

54
C₈H₃F₃N₂O₄ [ No CAS ]
[ 17288-15-2 ]
[ 945103-91-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In toluene; for 15h;Heating / reflux;	Stage a): 5,5-dimethyl-3-[3-nitro-4-(trifluoromethoxy)phenyl]imidazolidine-2,4-dione To a solution of 15 mL of trichloromethyl chloroformate (diphosgene) in 500 mL of toluene are added 3 g of 3S charcoal. To this suspension cooled to -20 C. are added 20 g of 3-nitro-4-trifluoromethoxyaniline dissolved in 400 mL of toluene. The reaction mixture is gradually warmed to room temperature and then refluxed for 4 hours. After cooling to room temperature, a suspension of 18 g of dimethylglycine ethyl ester hydrochloride in 150 mL of toluene is added, followed by 66 mL of triethylamine, and the reaction mixture is refluxed for 15 hours. After filtering through Celite, the filtrate is concentrated under reduced pressure and the residue is taken up in 500 mL of dichloromethane, washed with three times 100 mL of water, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is then triturated in diethyl ether and the solid formed is filtered off and dried to give 7.8 g of 5,5-dimethyl-3-[3-nitro-4-(trifluoromethoxy)phenyl]imidazolidine-2,4-dione, the characteristics of which are as follows: 1H NMR spectrum at 300 MHz: 1.42 (s, 6H); 7.90 (qd, J=1.0 and 9.0 Hz, 1H); 8.00 (dd, J=3.0 and 9.0 Hz, 1H); 8.37 (d, J=3.0 Hz, 1H); 8.75 (broad s, 1H).

Reference： [1]Patent: US2009/82379,2009,A1 .Location in patent: Page/Page column 26

55
[ 31651-76-0 ]
[ 17288-15-2 ]
[ 1092106-41-6 ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 7593 - 7601

56
[ 363186-29-2 ]
[ 17288-15-2 ]
ethyl 2-(3-[1-dimethylaminomethylidene]sulfamoyl}propylamino)-2-methylpropionate [ No CAS ]

Reference： [1]Patent: WO2006/13887,2006,A1 .Location in patent: Page/Page column 53-54
[2]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 3159 - 3168

57
[ 811794-06-6 ]
[ 17288-15-2 ]
[ 811794-08-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 3159 - 3168
[2]Patent: WO2006/13887,2006,A1 .Location in patent: Page/Page column 47

58
[ 875056-31-8 ]
[ 17288-15-2 ]
C₁₃H₂₇N₃O₄S [ No CAS ]

Reference： [1]Patent: WO2006/13887,2006,A1 .Location in patent: Page/Page column 61-62

59
[ 882755-95-5 ]
[ 17288-15-2 ]
[ 68-12-2 ]
[ 100-51-6 ]
2-(dimethylaminomethyleneamino)-5-(2,2-dimethylpropionyl)-4-{2-[5-(N-(2-ethoxycarbonylprop-2-yl)-O-benzyl)monophosphonamido]furanyl}thiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step A. A solution of {5-[2-amino-5-(2,2-dimethyl-propionyl)-thiazol-4-yl]furan-2-yl}phosphonic acid (1.1) (1 mmole), DMF (1.1 mmole) and oxalyl chloride (3.2 mmole) in dichloromethane was heated at 50 C. for 2 h. The reaction solution was evaporated to dryness and the residue was redissolved in dichloromethane and cooled to 0 C. In another flask, a suspension of 2-methylalanine ethyl ester hydrogen chloride salt (1 mmole) in dichloromethane was treated with N,N-diethylisopropylamine (6 mmole). After 15 min, this solution was added to the initial dichloridate solution cooled at 0 C., and stirred at 25 C. for 2 h. Benzyl alcohol (2 mmole) was added and the reaction solution was stirred at 25 C. for 12 h. The reaction was subjected to extraction and chromatography to give 2-(dimethylamino-methyleneamino)-5-(2,2-dimethyl-propionyl)-4-{2-[5-(N-(2-ethoxycarbonyl-prop-2-yl)-O-benzyl)monophosphonamido]furanyl}thiazole.

Reference： [1]Patent: US2007/225259,2007,A1 .Location in patent: Page/Page column 36

60
[ 882755-95-5 ]
[ 64-17-5 ]
[ 17288-15-2 ]
[ 68-12-2 ]
2-(dimethylaminomethyleneamino)-5-(2,2-dimethylpropionyl)-4-{2-[5-(N-(2-ethoxycarbonylprop-2-yl)-O-ethyl)monophosphonamido]furanyl}thiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step A. A solution of {5-[2-amino-5-(2,2-dimethyl-propionyl)-thiazol-4-yl]furan-2-yl}phosphonic acid (1.1) (1 mmole), DMF (1.1 mmole) and oxalyl chloride (3.2 mmole) in dichloromethane was heated at 50 C. for 2 h. The reaction solution was evaporated to dryness and the residue was redissolved in dichloromethane and cooled to 0 C. In another flask, a suspension of 2-methylalanine ethyl ester hydrogen chloride salt (1 mmole) in dichloromethane was treated with N,N-diethylisopropylamine (6 mmole). After 15 min, this solution was added to the initial dichloridate solution cooled at 0 C., and stirred at 25 C. for 2 h. Ethanol (10 mmole) was added and the reaction solution was stirred at 25 C. for 12 h. The reaction was subjected to extraction and chromatography to give 2-(dimethylamino-methyleneamino)-5-(2,2-dimethyl-propionyl)-4-{2-[5-(N-(2-ethoxycarbonylprop-2-yl)-O-ethyl)monophosphonamido]furanyl}thiazole.

Reference： [1]Patent: US2007/225259,2007,A1 .Location in patent: Page/Page column 36

61
[ 21724-83-4 ]
[ 17288-15-2 ]
[ 875056-38-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 8150 - 8157

62
[ 17288-15-2 ]
[ 1372860-85-9 ]

Reference： [1]Patent: WO2012/52781,2012,A1
[2]Patent: US2013/211083,2013,A1

63
[ 17288-15-2 ]
ethyl 2-[(6-amino-2,3-dichlorobenzyl)amino]isobutyrate hydrochloride [ No CAS ]

Reference： [1]Patent: WO2012/52781,2012,A1
[2]Patent: US2013/211083,2013,A1

64
[ 75618-41-6 ]
[ 17288-15-2 ]
ethyl 2-[(2,3-dichloro-6-nitrophenyl)methylidene]amino}-2-methylpropanoate hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In toluene; at 17 - 110℃; for 8.91667h;Industry scale;	Part BToluene (250L) was added to 2,3-dichloro-6-nitrobenzaldehyde (46.4Kg) and the mixture stirred at 20-23 minutes until a solution forms (1 hour). The solution was added to the 2- aminoisobutyrate hydrochloride solution from part A, followed by a line rinse of toluene (50L) Triethylamine (31.9Kg) was added to the solution over a period of 25 minutes maintaining the temperature between 17 and 20C, followed by toluene (10L). The mixture was heated to 1 10C and stirred under azeotropic reflux for 185 minutes at which point the in-process check indicated <2% 2,3-dichloro-6-nitrobenzaldehyde remaining. The mixture was cooled to 20-25C and washed with water (2x 225L) then heated to reflux and stirred under azeotropic reflux for 325 minutes at which point the in-process check indicated a water content of <0.5%w/w.
	With triethylamine; In toluene; at 17 - 110℃; for 3.08333h;Reflux; Large scale;	Toluene (250 L) was added to 2,3-dichloro-6-nitrobenzaldehyde (46.4 Kg) and the mixture stirred at 20-23 minutes until a solution forms (1 hour). The solution was added to the 2-aminoisobutyrate hydrochloride solution from part A, followed by a line rinse of toluene (50 L) Triethylamine (31.9 Kg) was added to the solution over a period of 25 minutes maintaining the temperature between 17 and 20 C., followed by toluene (10 L). The mixture was heated to 110 C. and stirred under azeotropic reflux for 185 minutes at which point the in-process check indicated <2% 2,3-dichloro-6-nitrobenzaldehyde remaining. The mixture was cooled to 20-25 C. and washed with water (2×225 L) then heated to reflux and stirred under azeotropic reflux for 325 minutes at which point the in-process check indicated a water content of <0.5% w/w,

Reference： [1]Patent: WO2012/52781,2012,A1 .Location in patent: Page/Page column 25-26; 31-32
[2]Patent: US2013/211083,2013,A1 .Location in patent: Paragraph 0098

65
[ 17288-15-2 ]
C₁₄H₂₈N₂O₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 4486 - 4489

66
[ 17288-15-2 ]
(5S,8S)-ethyl 8-((R)-1-(tert-butoxy)ethyl)-5-((S)-sec-butyl)-1-(9H-fluoren-9-yl)-11,11-dimethyl-3,6,9-trioxo-2-oxa-4,7,10-triazadodecan-12-oate [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 4486 - 4489

67
[ 17288-15-2 ]
C₂₀H₃₉N₃O₅ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 4486 - 4489

68
[ 17288-15-2 ]
ethyl 2-((2S,3R)-2-((2S,3S)-2-acetamido-3-methylpentanamido)-3-(tert-butoxy)butanamido)-2-methylpropanoate [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 4486 - 4489

69
[ 17288-15-2 ]
[ 71989-35-0 ]
methyl 2-((2S,3R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(tert-butoxy)butanamido)-2-methylpropanoate [ No CAS ]