[ CAS No. 85064-61-5 ] {[proInfo.proName]}

Name: 85064-61-5|Tetrahydropyranyl-4-acetic acid|97%
Brand: Ambeed
SKU: A191595
Price: 5.0 USD
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Limited Quantity	USD 15-60
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Quality Control of [ 85064-61-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 85064-61-5 ]

SDS Specification

Alternatived Products of [ 85064-61-5 ]

Product Details of [ 85064-61-5 ]

CAS No. :	85064-61-5	MDL No. :	MFCD01631204
Formula :	C₇H₁₂O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PBXYNWPYMVWJAH-UHFFFAOYSA-N
M.W :	144.17	Pubchem ID :	2773575
Synonyms :

Calculated chemistry of [ 85064-61-5 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.86
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	36.51
TPSA :	46.53 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) :	-6.95 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.38
Log Po/w (XLOGP3) :	0.32
Log Po/w (WLOGP) :	0.89
Log Po/w (MLOGP) :	0.35
Log Po/w (SILICOS-IT) :	1.07
Consensus Log Po/w :	0.8

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-0.8
Solubility :	22.7 mg/ml ; 0.157 mol/l
Class :	Very soluble
Log S (Ali) :	-0.86
Solubility :	19.9 mg/ml ; 0.138 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.53
Solubility :	42.3 mg/ml ; 0.293 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.74

Safety of [ 85064-61-5 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P280-P305+P351+P338-P310	UN#:	1759
Hazard Statements:	H314	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 85064-61-5 ]

* 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 [ 85064-61-5 ]
Downstream synthetic route of [ 85064-61-5 ]

[ 85064-61-5 ] Synthesis Path-Upstream 1~16

1
[ 85064-61-5 ]
[ 130290-79-8 ]

Reference： [1] Justus Liebigs Annalen der Chemie, 1938, vol. 535, p. 37,45

2
[ 85064-61-5 ]
[ 4677-18-3 ]

Yield	Reaction Conditions	Operation in experiment
90%	With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; Inert atmosphere	To a suspension of 0.55 g of LiAlH₄(13.9 mmol) in THF (10 mL) is added dropwise a solution of 2 g (13.9 mmol) of Compound 17 in THF (10 mL) under nitrogen atmosphere. Upon complete addition, the reaction is stirred at room temperature for 18 h. The reaction is cooled in an ice-bath and quenched with addition of 1M aqueous NH₄Cl solution (2 mL). The resulting precipitate is removed by filtration through Celite.(R). and is rinsed with ethyl acetate (3.x.100 mL). The filtrate is dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford 1.63 g of Compound 18 as a colorless oil. Yield: 90percent; ES-MS m/z 131 [M+H]; ¹H-NMR (500 MHz, CHLOROFORM-d) δ ppm 1.29 (2H, qd, J=12.08, 4.04 Hz), 1.50 (2H, qd, J=6.71, 1.37 Hz), 1.55-1.73 (3H, m), 1.95-2.07 (1H, m), 3.37 (2H, t, J=11.83 Hz), 3.66 (2H, t, J=6.03 Hz), 3.92 (2H, dd, J=11.44, 4.12 Hz).
90%	Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 18 h; Inert atmosphere Stage #2: With ammonium chloride In tetrahydrofuran; waterCooling with ice	S nthesis of Compound D6Step 1: Synthesis of Compound D2To a suspension of 0.55 g of LiAlH₄ (13.9 mmol) in THF (10 mL) is added dropwise a solution of 2 g (13.9 mmol) of compound Dl in THF (10 mL) under nitrogen atmosphere (CAUTION: highly exothermic reaction.). Upon complete addition, the reaction is stirred at room temperature for 18 h. The reaction is cooled in an ice-bath and quenched with addition of 1M aqueous NH₄C1 solution (2 mL). The resulting precipitate is removed by filtration through Celite.(R). and is rinsed with ethyl acetate (3 x 100 mL). The filtrate is dried over Na₂S0₄, filtered and concentrated under reduced pressure to afford 1.63 g of compound D2 as a colorless oil. Yield: 90percent; ES-MS m/z 131 [M+H]; 1H-NMR (500 MHz, CHLOROFORM-d) 5 ppm l.29 (2 H, qd, 7=12.08, 4.04 Hz), 1.50 (2 H, qd, 7=6.71, 1.37 Hz), 1.55 - 1.73 (3 H, m), 1.95 - 2.07 (1 H,m), 3.37 (2 H, t, 7=11.83 Hz), 3.66 (2 H, t, 7=6.03 Hz), 3.92 (2 H, dd, 7=11.44, 4.12 Hz)

Reference： [1] Journal of Medicinal Chemistry, 2018, vol. 61, # 18, p. 8321 - 8336
[2] Patent: US2011/71196, 2011, A1, . Location in patent: Page/Page column 17-18
[3] Patent: WO2011/109324, 2011, A1, . Location in patent: Page/Page column 28

3
[ 85064-61-5 ]
[ 850429-50-4 ]

Reference： [1] Patent: CN104557610, 2018, B,

4
[ 103260-44-2 ]
[ 85064-61-5 ]

Yield	Reaction Conditions	Operation in experiment
94%	With water; sodium hydroxide In methanol at 0 - 20℃; for 15 h;	A solution of sodium hydroxide (15.9 g, 44.06 mmol) in water (150 ml) was added dropwise to a solution of ethyl 2-(tetrahydro-2H-pyran-4-yl)acetate (15 g, 8.81 mmol) in methanol (150 ml) at a temperature of 0 °C or below, and the mixture was stirred at room temperature for 15 hr. The solvent of the reaction mixture was removed by distillation under reduced pressure, and the water layer was adjusted to pH 3 by the addition of 1 M hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give a corresponding acid as a colorless solid (12.0 g, 94percent). This compound was used in the next step without further purification. Benzyl bromide (14.3 g, 83.33 mmol) was added dropwise to a suspension of this compound (10.0 g, 69.44 mmol) and anhydrous potassium carbonate (28.8 g, 208.3 mmol) in acetonitrile (100 ml) at room temperature, and the mixture was refluxed for 48 hr. The solvent of the mixture was removed by distillation under reduced pressure, the residue was diluted with water and was extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was chromatographed on silica gel column (hexane:ethyl acetate = 9:1) to give the tile compound as an oil (12.0 g, yield 75percent). 1H-NMR (400 MHz, CDCl₃): δ (ppm) 7.39-7.34 (m, 5H), 5.12 (s, 2H), 3.95-3.92 (m, 2H), 3.42-3.36 (m, 2H), 2.30 (d, J = 7.2 Hz, 2H), 2.09-1.99 (m, 1H) 1.64-1.61 (m, 2H), 1.39-1.29 (m, 2H); MS (ESI): m/z 234 (M⁺).

Reference： [1] Patent: EP2737900, 2014, A1, . Location in patent: Paragraph 0114; 0117-0118
[2] Journal of Medicinal Chemistry, 1993, vol. 36, # 16, p. 2300 - 2310
[3] Patent: US5221671, 1993, A,
[4] Patent: EP1019398, 2004, B1, . Location in patent: Page 51

5
[ 156002-64-1 ]
[ 85064-61-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	With lithium hydroxide monohydrate In tetrahydrofuran; water at 60℃; for 1.5 h; Inert atmosphere	General procedure: Lithium hydroxide monohydrate (151.7 mmol), as a solution indistilled water (79.5 mL, 1.9 M), was added to a solution of the ester (7.59 mmol) in THF (79.5 mL, 0.1 M) at room temperature in air and stirred at 60 C for 90 min. The mixture was cooled to room temperature, acidified to pH 0 with 1M HCl and partitioned with EtOAc (20 mL). The aqueous layer was extracted with EtOAc (20 mL) and the organic layer was washed with brine (20 mL), dried (MgSO4), filtered, and concentrated under vacuum to give the desired compound, which was taken forward without purification.

Reference： [1] Australian Journal of Chemistry, 2015, vol. 68, # 4, p. 660 - 679
[2] Patent: WO2004/113298, 2004, A1, . Location in patent: Page 30
[3] Patent: WO2004/113312, 2004, A1, . Location in patent: Page 23

6
[ 29943-42-8 ]
[ 867-13-0 ]
[ 85064-61-5 ]

Reference： [1] Patent: EP434365, 1991, A2,

7
[ 29943-42-8 ]
[ 85064-61-5 ]

Reference： [1] Journal of Medicinal Chemistry, 1993, vol. 36, # 16, p. 2300 - 2310
[2] Patent: EP2737900, 2014, A1,
[3] Patent: WO2015/5901, 2015, A1,
[4] Patent: US2015/23913, 2015, A1,
[5] Australian Journal of Chemistry, 2015, vol. 68, # 4, p. 660 - 679

8
[ 130312-00-4 ]
[ 85064-61-5 ]

Reference： [1] Journal of Medicinal Chemistry, 1993, vol. 36, # 16, p. 2300 - 2310
[2] Patent: EP2737900, 2014, A1,
[3] Patent: WO2015/5901, 2015, A1,
[4] Patent: US2015/23913, 2015, A1,

9
[ 138302-49-5 ]
[ 85064-61-5 ]

Reference： [1] Australian Journal of Chemistry, 2015, vol. 68, # 4, p. 660 - 679

10
[ 850429-50-4 ]
[ 85064-61-5 ]

Reference： [1] Justus Liebigs Annalen der Chemie, 1937, vol. 532, p. 80[2] Chem.Abstr., 1940, p. 4396

11
[ 2081-44-9 ]
[ 85064-61-5 ]

Reference： [1] Justus Liebigs Annalen der Chemie, 1937, vol. 532, p. 80[2] Chem.Abstr., 1940, p. 4396

12
[ 14774-37-9 ]
[ 85064-61-5 ]

Reference： [1] Justus Liebigs Annalen der Chemie, 1937, vol. 532, p. 80[2] Chem.Abstr., 1940, p. 4396

13
[ 125552-89-8 ]
[ 85064-61-5 ]

Reference： [1] Justus Liebigs Annalen der Chemie, 1937, vol. 532, p. 80[2] Chem.Abstr., 1940, p. 4396

14
[ 854697-63-5 ]
[ 85064-61-5 ]

Reference： [1] Justus Liebigs Annalen der Chemie, 1937, vol. 532, p. 80[2] Chem.Abstr., 1940, p. 4396

15
[ 14390-06-8 ]
[ 85064-61-5 ]

Reference： [1] Justus Liebigs Annalen der Chemie, 1937, vol. 532, p. 80[2] Chem.Abstr., 1940, p. 4396

16
[ 67-56-1 ]
[ 85064-61-5 ]
[ 156002-64-1 ]

Reference： [1] Patent: WO2015/164480, 2015, A1, . Location in patent: Page/Page column 53

[ 85064-61-5 ] Synthesis Path-Downstream 1~88

1
[ 14390-06-8 ]
[ 85064-61-5 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1937,vol. 532,p. 80
Chem.Abstr.,1940,p. 4396

2
[ 85064-61-5 ]
[ 3282-30-2 ]
C₁₂H₂₀O₄ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 2300 - 2310

3
[ 85064-61-5 ]
[ 960216-62-0 ]
(3S,4R)-3-[cyclopropyl-(2-tetrahydro-pyran-4-yl-acetyl)-amino]-methyl}-4-{(S)-2-[4-methoxy-3-(3-methoxy-propoxy)-phenoxy]-3-methyl-butyl}-pyrrolidine-1-carboxylic acid tert-butyl ester [ No CAS ]
(3R,4S)-3-[cyclopropyl-(2-tetrahydro-pyran-4-yl-acetyl)-amino]-methyl}-4-{(S)-2-[4-methoxy-3-(3-methoxy-propoxy)-phenoxy]-3-methyl-butyl}-pyrrolidine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;	A mixture of (3f?,4S)-3-cyclopropylaminomethyl-4-{(S)-2-[4-methoxy-3-(3-methoxy-prop- oxy)-phenoxy]-3-methyl-butyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (250 mg, 0.48 mmol), tetrahydropyran-4-ylacetic acid (83 mg, 0.58 mmol), 1 -hydroxy -benzotriazol hydrate (78 mg, 0.58 mmol), N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (110 mg, 0.58 mmol) and triethylamine (80 muL, 0.58 mmol) in CH2CI2 (10 mL) is stirred at room temperature overnight . The reaction mixture is then diluted with CH2CI2, and the organic layer is subsequently washed with 1 M HCI (5 mL), saturated NaHCO3 and brine, dried over Na2SO4 and evaporated. The residue is purified by flash chromatography on silica gel (eluent gradient: hexane/EtOAc 3:1 to 1 :1) to give the title compound. RP-HPLC: tR = 6.10 min (Nucleosil C18-HD column, 5-100percent CH3CN/H2O/6 min, 100percent CH3CN/1.5 min, CH3CN and H2O containing 0.1percent TFA, flow: 1.0 ml_/min). MS: 647.4 [M+H]+.

Reference： [1]Patent: WO2007/144128,2007,A1 .Location in patent: Page/Page column 71

4
[ 85064-61-5 ]
[ 100-51-6 ]
[ 929556-48-9 ]

Yield	Reaction Conditions	Operation in experiment
32%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 12h;	Benzyl 2-(tetrahydropyran-4-yl)acetate To a solution of <strong>[85064-61-5]2-(tetrahydropyran-4-yl)acetic acid</strong> (325 mg, 2.26 mmol) in anhydrous dichloromethane (10 mL) were added benzyl alcohol (439 mg, 2.94 mmol), 1-ethyl-3-(3-dimethylammoniumpropyl)carbodiimide hydrochloride (564 mg, 2.94 mmol) and triethylamine (297 mg, 2.94 mmol) at room temperature, and the mixture was stirred for 12 h. The reaction mixture was diluted with water (1 mL) to separate the phases, and the organic layer was further washed with water (1 mL) and brine (1 mL). The organic layer was concentrated under reduced pressure, and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 7:1) to give 172 mg of the title compound as oil (yield: 32percent). 1H NMR (CDCl3) delta 1.34 (m, 2H), 1.63 (m, 2H), 2.02 (m, 1H), 2.30 (d, J=7.1 Hz, 2H), 3.39 (m, 2H), 3.93 (m, 2H), 5.12 (s, 2H), 7.31-7.40 (m, 5H).

Reference： [1]Patent: US2008/90825,2008,A1 .Location in patent: Page/Page column 25

5
[ 29943-42-8 ]
[ 85064-61-5 ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 2300 - 2310
[2]Patent: EP2737900,2014,A1
[3]Patent: WO2015/5901,2015,A1
[4]Australian Journal of Chemistry,2015,vol. 68,p. 660 - 679

6
[ 85064-61-5 ]
[ 150332-04-0 ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 2300 - 2310

7
[ 85064-61-5 ]
(S)-4-benzyl-3-(2-(tetrahydro-2H-pyran-4-yl)acetyl)oxazolidin-2-one [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 2300 - 2310

8
[ 85064-61-5 ]
(S)-3-[(S)-2-Azido-2-(tetrahydro-pyran-4-yl)-acetyl]-4-benzyl-oxazolidin-2-one [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 2300 - 2310

9
[ 85064-61-5 ]
(3S,4aS,8aS)-2-{(2R,3S)-3-[(S)-2-Amino-2-(tetrahydro-pyran-4-yl)-acetylamino]-2-hydroxy-4-phenyl-butyl}-decahydro-isoquinoline-3-carboxylic acid tert-butylamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 2300 - 2310

10
[ 85064-61-5 ]
(3S,4aS,8aS)-2-{(2R,3S)-3-[(S)-2-Azido-2-(tetrahydro-pyran-4-yl)-acetylamino]-2-hydroxy-4-phenyl-butyl}-decahydro-isoquinoline-3-carboxylic acid tert-butylamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 2300 - 2310

11
[ 85064-61-5 ]
N-tert-butyl-2-(2(S)-hydroxy-4-phenyl-3(S)-((N-(2-quinolylcarbonyl)-2(S)-(4-tetrahydropyranyl)glycinyl)amino)butyl)decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 2300 - 2310

12
[ 130312-00-4 ]
[ 85064-61-5 ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 2300 - 2310
[2]Patent: EP2737900,2014,A1
[3]Patent: WO2015/5901,2015,A1

13
[ 2081-44-9 ]
[ 85064-61-5 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1937,vol. 532,p. 80
Chem.Abstr.,1940,p. 4396

14
[ 14774-37-9 ]
[ 85064-61-5 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1937,vol. 532,p. 80
Chem.Abstr.,1940,p. 4396

15
[ 125552-89-8 ]
[ 85064-61-5 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1937,vol. 532,p. 80
Chem.Abstr.,1940,p. 4396

16
[ 854697-63-5 ]
[ 85064-61-5 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1937,vol. 532,p. 80
Chem.Abstr.,1940,p. 4396

17
[ 85064-61-5 ]
[ 854697-76-0 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1940,vol. 545,p. 229,244

18
[ 85064-61-5 ]
[ 86428-61-7 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1940,vol. 545,p. 229,244

19
[ 85064-61-5 ]
[ 855235-50-6 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1940,vol. 545,p. 229,244

20
[ 85064-61-5 ]
1-tetrahydropyran-4-yl-butan-2-one oxime [ No CAS ]

Reference： [1]Justus Liebigs Annalen der Chemie,1940,vol. 545,p. 229,244

21
[ 85064-61-5 ]
tetrahydropyran-4-yl-acetone-(2,4-dinitro-phenylhydrazone) [ No CAS ]

Reference： [1]Justus Liebigs Annalen der Chemie,1940,vol. 545,p. 229,244

22
[ 85064-61-5 ]
1-tetrahydropyran-4-yl-butan-2-one-(2,4-dinitro-phenylhydrazone) [ No CAS ]

Reference： [1]Justus Liebigs Annalen der Chemie,1940,vol. 545,p. 229,244

23
[ 85064-61-5 ]
[ 193276-49-2 ]
(+)-4-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine-11(R)-yl)-1-[(tetrahydro-4H-pyran-4-yl)acetyl]piperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; benzotriazol-1-ol; N,N'-diethylcarbodiimide; In DMF (N,N-dimethyl-formamide); at 20℃; for 18h;	Dissolve the (+) product of Preparative Example 6, Step B, (0.1 g, 0.212 mmol) in 5 mL of DMF, stir at room temperature and add 0.043 g (0.424 mmol) of 4-methylmorpholine, 0.053 g (0.0276 mmol) of DEC, 0.037 g (0.276 mmol) of HOBT and 0.0397 g (0.276 mmole) of the product of Preparative Example 32. Stir the mixture at room temperature for 18 hours, then concentrate in vacuo to a residue and partition between methylene chloride and water. Wash the organic phase with aqueous sodium bicarbonate solution then brine. Dry the organic phase over magnesium sulfate, filter and concentrate in vacuo to a residue. Chromatograph the residue on a silica gel plate, eluting with methylene chloride - methanol (96percent - 4percent) to yield the product (0.13g) as a white solid. M.p. = 83.2-88.7°C, Mass Spec.: MH+ = 597. [a]D23.2°C = +55.5°, c=0.2, methylene chloride.

Reference： [1]Patent: EP1019398,2004,B1 .Location in patent: Page 56-57

24
[ 85064-61-5 ]
[ 554411-25-5 ]
[ 798533-14-9 ]

Yield	Reaction Conditions	Operation in experiment
17%		EXAMPLE 33 N-[4-Methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-2-(tetrahydro-pyran-4-yl)-acetamide Using 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-ylamine and (tetrahydro-7pyran-4-yl)-acetic acid, the title compound was prepared as light yellow crystals (17percent yield). MS: m/e=391(M+H+), mp 218-220° C.

Reference： [1]Patent: US2004/235915,2004,A1 .Location in patent: Page 15

25
[ 85064-61-5 ]
7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine [ No CAS ]
[ 798532-93-1 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 12 N-(7-[1,4]Dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-2-(tetrahydro-pyran-4-yl)-acetamide Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine and tetrahydropyran-4-yl acetic acid, the tide compound was prepared as white powder. MS: m/e=407(M+H+).

Reference： [1]Patent: US2004/235915,2004,A1 .Location in patent: Page 14

26
[ 156002-64-1 ]
[ 85064-61-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	With lithium hydroxide monohydrate; In tetrahydrofuran; water; at 60℃; for 1.5h;Inert atmosphere;	General procedure: Lithium hydroxide monohydrate (151.7 mmol), as a solution indistilled water (79.5 mL, 1.9 M), was added to a solution of the ester (7.59 mmol) in THF (79.5 mL, 0.1 M) at room temperature in air and stirred at 60 C for 90 min. The mixture was cooled to room temperature, acidified to pH 0 with 1M HCl and partitioned with EtOAc (20 mL). The aqueous layer was extracted with EtOAc (20 mL) and the organic layer was washed with brine (20 mL), dried (MgSO4), filtered, and concentrated under vacuum to give the desired compound, which was taken forward without purification.
	With sodium hydroxide; In methanol; water; at 20℃;	Sodium hydroxide (16 g) in water (400 mi) was added to a solution of Intermediate 27 (13 g) in MeOH (60 ML). The mixture was stirred overnight at room temperature, then evaporated in vacuo. The solution was washed with Et2O (50 ml), acidified with concentrated hydrochloric acid to pH 2 and extracted with EtOAc (100 ML), the solvent washed with brine (50 ML), dried (MGS04) and evaporated to give the title compound as a colourless solid (10.2 g). MS 144 (M)
		Sodium hydroxide (16 g) in water (400 mi) was added to a solution of (TETRAHYDROPYRAN-4-YL) acetic acid methyl ester (13 g) in methanol. The mixture was stirred overnight at room temperature, then evaporated in vacuo. The solution was washed with diethyl ether, acidified with concentrated hydrochloric acid to pH 2 and extracted with ethyl acetate, the solvent washed with brine, dried and evaporated to give the title compound as a colourless solid (10. 2 G). MS 144 (M).

Reference： [1]Australian Journal of Chemistry,2015,vol. 68,p. 660 - 679
[2]Patent: WO2004/113298,2004,A1 .Location in patent: Page 30
[3]Patent: WO2004/113312,2004,A1 .Location in patent: Page 23

27
[ 85064-61-5 ]
N-[4-(4-[4-(butylamino)piperidin-1-yl]methyl}phenoxy)phenyl]methanesulfonamide dihydrochloride [ No CAS ]
N-butyl-N-[1-(4-[4-(methylsulfonyl)amino]phenoxy}benzyl)piperidin-4-yl]-2-(tetrahydro-2H-pyran-4-yl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide);	To a solution of the compound prepared in Example 3 (183 mg) in dimethylformamide (3 mL) were added <strong>[85064-61-5]4-tetrahydropyranylacetic acid</strong> (70 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (105 mg) and dimethylaminopyridine (155 mg) and the solution was stirred over night. After finishing the reaction, water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (methylene chloride: methanol=25:1). 4N hydrogen chloride/ethyl acetate solution was added to the reaction mixture, which was concentrated to give the compound of the present invention (79 mg) having the following physical data. TLC:Rf 0.49(chloroform:methanol=10:1); NMR (CD3OD): delta 0.98 (t, J=7.0 Hz, 3H), 1.24-1.69 (m, 8H), 1.87-2.40 (m, 7H), 2.95 (s, 3H), 3.02-3.48 (m, 6H), 3.49-3.61 (m, 2H), 3.87-3.95 (m, 2H), 4.12 (m, 1H), 4.27-4.30 (m, 2H), 7.03 (d, J=9.0 Hz, 2H), 7.06 (d, J=8.5 Hz, 2H), 7.29 (d, J=9.0 Hz, 2H), 7.49 (d, J=8.5 Hz, 2H).

Reference： [1]Patent: EP1604981,2005,A1 .Location in patent: Page/Page column 28-29

28
[ 85064-61-5 ]
[ 879274-76-7 ]
1-(4-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; HATU; In N,N-dimethyl-formamide;	2-(6-Fluoro-4-(piperazin-l-yl)quinazolin-2-yl)phenol (25 mg, 0.077 mmol), 2-(tetrahydro-2i7-pyran-4-yl)acetic acid (14.3 mg, 0.10 mmol), triethylamine (22uL, 0.154 mmol),and HATU (38 mg, 0.10 mmol) were stirred in DMF (1 mL) overnight. Purification via reversephase HPLC (10-99percent CH3CN (0.035percent TFA)/H20 (0.05percent TFA)) gave l-(4-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1 -yl)-2-(tetrahydro-2No.-pyran-4-yl)ethanone. LC/MS:m/z 451.5 (M+H)+ at 2.60 min (10percent-99percent CH3CN (0.035percent TFA)/H20 (0.05percent TFA)).

Reference： [1]Patent: WO2006/28904,2006,A1 .Location in patent: Page/Page column 148-149

29
[ 29943-42-8 ]
[ 867-13-0 ]
[ 85064-61-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide;palladium; In ethanol; water; benzene;	EXAMPLE 27 Preparation of 4-tetrahydropyranylacetic acid To a stirred, cooled suspension of 0.9 g of sodium hydride (60percent oil dispersion) in 5 mL of benzene was added 5.32 g of triethylphosphonoacetate in 3 mL of benzene, keeping the temperature below 30°C. After 1 hour at 25°C, a solution of 2 g of tetrahydro-4H-pyran-4-one in 3 mL of benezene was added slowly. After 1 hour at 25°C, 20 mL of water and 50 mL of ether were added. The organic layer was dried over MgSO4 and concentrated to dryness. Evaporative distillation at 5 mm, oven temperature 130°C, gave 1.8 g of product as a fragrant liquid. Hydrogenation in 20 mL of ethanol with 0.5 g of 10percent palladium on carbon under 1 atmosphere of hydrogen for 10 days gave 1.8 g of saturated product, after filtration and concentration. Saponification using 20 mL of ethanol, 10 mL of 10percent NaOH for 4 hours followed acidification (H2SO4) and ether extraction gave 1.5 g of product. Evaporative distillation at 0.1 mm, oven temperature 160-8°C gave 1.1 g of product as a crystalline solid, mp 61-2°C.

Reference： [1]Patent: EP434365,1991,A2

Yield	Reaction Conditions	Operation in experiment
		PREPARATIVE EXAMPLE 32 Tetrahydropyran-4-acetic acid The product of Preparative Example 11 (3.04 g, 17.7 mmol) was dissoloved in 90 mL of ethanol containing 3 g (53 mmol) of potassium hydroxide. This was stirred for 18 hours and then concentrated under vacuum. The residue was dissolved in 15 mL of water, adjusted to pH 2 with 12 N HCl, and extracted with three 50 mL portions of dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated under vacuum giving 2.04 g of the product as a white solid, mp=60-63° C. Using the hydrolysis procedure of Preparative Example 32, the esters of Preparative Examples 10-20 were hydrolyzed to the carboxylic acids identified as Preparative Examples 33 to 46 in Table 1. If one were to follow the hydrolysis procedure of Preparative Example 32, the esters of Preparative Examples 21 to 31 could be hydrolyzed to obtain the carboxylic acids identified as Preparative Examples 47-59 in Table 1.

31
[ 85064-61-5 ]
[ 40217-17-2 ]
[ 815618-35-0 ]

Yield	Reaction Conditions	Operation in experiment
66%		General procedure: Triethylamine (14.84 mmol) was added to a solution of the carboxylic acid (7.42 mmol) in THF (31.0 mL, 0.2 M) at room temperature, stirred for 10 min, and then cooled to 0 C before addition of pivaloyl chloride (8.90 mmol). After 30 min at 0 C, lithium chloride (0.5 M in THF, 8.90 mmol) was added, followed by (R)-(+)- or (S)-(-)-4-benzyloxazolidin-2-one (8.90 mmol) and the mixture was stirred at room temperature for 20 h. The mixture was partitioned with EtOAc (20 mL) and 1M HCl (320 mL) and the organic layer was washed with 1M K2CO3 (320mL). The acidic aqueous layer was extracted with EtOAc (20 mL) and the combined organic layer was washed with brine (10 mL), dried (MgSO4), filtered, and concentrated under vacuum. The crude material was purified as indicated.
		Oxalyl chloride (5 ml) and DMF (1 drop) were added to a solution of (TETRAHYDROPYRAN-4-YL) acetic acid (10 g) in DCM. The mixture was stirred for 3 h, then EVAPORATED IN VACUO and thoroughly azeotroped with toluene. The residue was dissolved in THF and added dropwise to a solution of (R)- BENZYLOXAZOLIDINONE (12.1 g) and nBuLi (2.5M in hexanes, 30 ml) in THF (200 ml) AT-78°C. The solution was stirred for 2 h, then quenched with saturated aqueous ammonium chloride and evaporated in vacuo. The mixture was extracted with ethyl acetate, solvent washed with water and brine, dried and evaporated to give the title compound as a colourless solid (14 g). MS 304 (M + H).

Reference： [1]Australian Journal of Chemistry,2015,vol. 68,p. 660 - 679
[2]Patent: WO2004/113312,2004,A1 .Location in patent: Page 23

32
[ 85064-61-5 ]
5-(trans-2-amino-cyclohex-1-ylmethyl)-3-isopropyl-1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one [ No CAS ]
N-{trans-2-[(3-isopropyl-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)methyl]cyclohexyl}-2-(tetrahydro-2H-pyran-4-yl)acetamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 2537 - 2541

33
[ 85064-61-5 ]
[ 959937-92-9 ]
[ 959937-91-8 ]

Yield	Reaction Conditions	Operation in experiment
		a) N-{2-r(2S,5R)-5-r4-(3-Methoxypropyl)-3,4-dihvdro-2H-benzopi ,41oxazin-6- ylmethoxyi-1 -(toluene-4-sulphonyl)piperidin-2-yl1-1 ,1 -dimethylethyl)-2-(tetrahvdro- pyran-4-yl)acetamide; A solution of 0.511 mmol of tetrahydropyranyl-4-acetic acid [85064-61-5] in 5 ml of dichloromethane is treated with 1.023 mmol of 1 -chloro-N,N-2-thmethylpropenyl- amine. The reaction mixture is stirred at room temperature for 1.5 hours. In a second flask, a solution of 0.341 mmol of 2-[(2S,5R)-5-[4-(3-methoxypropyl)-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-ylmethoxy]-1 -(toluene-4-sulphonyl)piperidin-2-yl]-1 ,1 -dimethyl- ethylamine in 10 ml of dichloromethane are treated with 1.023 mmol of thethylamine, and cooled to 00C. The solution of acid chloride is added dropwise to this second flask, and the reaction mixture is stirred at room temperature for 2 hours. Water is added, and the aqueous phase is extracted with dichloromethane (3X). The combined organic extracts are dried over sodium sulphate, concentrated and purified by flash chromatography (SiO2 60F) to afford the title compound as a dark yellow resin. Rf = 0.20 (dichloromethane-methanol-conc ammonia); Rt = 4.94 (gradient I).

Reference： [1]Patent: WO2009/106599,2009,A2 .Location in patent: Page/Page column 76-77

34
[ 85064-61-5 ]
[ 112275-50-0 ]
[ 1028854-13-8 ]

Yield	Reaction Conditions	Operation in experiment
56%		Example 5; Synthesis of 4-(2-Tetrahydro-pyran-4-yl-acetyl)-[1,4]diazepane-1-carboxylic acid (4-trifluoromethoxy-phenyl)-amide (Compound 27 in Table 1, Method E); To a solution of 4-tetrahydropyran acetic acid (669 mg; 4.64 mmol) and HOBt (531 mg; 5.52 mmol) in 10 mL DMF was added EDC (1.06 g; 5.52 mmol). After stirring 15 min at room temperature the diazapane amine was added (0.78 mL; 4.03 mmol), then a catalytic amount of DMAP was added, and the mixture was left stirring overnight.Water was added and the product was extracted with EtOAc. The combined extracts were washed sequentially with water, saturated aqueous sodium bicarbonate solution, saturated ammonium chloride aqueous solution, and brine. The extracts were then dried over anhydrous sodium sulfate, filtered, and the solvent was removed in vacuo. The product was purified by flash column chromatography on silica gel using 50percent EtOAc in hexanes as eluent mixture, followed by to 5percent methanol in DCM. An off-white solid was isolated, 738 mg (56percent yield). The Boc-protected diazapane amide from above (738 mg; 2.26 mmol) was dissolved in 10 mL methanol. HCl in dioxane was added (4M; 5.7 mL). The mixture was stirred at room temperature for 2 hours. Thin layer chromatography (TLC) showed complete conversion, whereupon solvent was removed in vacuo to afford 599 mg of the salt as a waxy solid. To a suspension of the above salt (50 mg; 0.19 mmol) and TEA (0.053 mL; 0.38 mmol) in 2 mL THF was added the isocyanate (0.029 mL; 0.19 mmol). The mixture was left stirring at room temperature for 3 hours, then the solvent was removed in vacuo, water was added, and the product was extracted with EtOAc twice. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated in vacuo. The resulting oil was purified by flash column chromatography on silica gel using 5percent methanol in DCM mixtures as eluent. The title compound was obtained as a colorless oil, 74 mg (88percent yield).

Reference： [1]Patent: US2010/9964,2010,A1 .Location in patent: Page/Page column 8

35
[ 85064-61-5 ]
[ 1247873-84-2 ]

Reference： [1]Patent: US2011/53912,2011,A1

36
[ 85064-61-5 ]
[ 79-37-8 ]
[ 40500-05-8 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 2h;	Example 13 To a mixture of <strong>[85064-61-5]tetrahydro-2H-pyran-4-ylacetic acid</strong> (89 mg), N,N-dimethyl formamide (1 muL), and dichloromethane (1 mL) was added oxalylchloride (54 muL), and the mixture was stirred at room temperature for 2 hours. The reaction liquid was concentrated under reduced pressure, and then toluene (1 mL) was added thereto, followed by further concentration under reduced pressure, to obtain crude tetrahydro-2H-pyran-4-yl acetyl chloride.
	With N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 4h;Cooling;	To an ice-cold solution of <strong>[85064-61-5]2-(tetrahydro-2H-pyran-4-yl)acetic acid</strong> (150 mg, 1.0 mmol) in 3 mL of CH2Cl2 was added oxalyl chloride (0.11 mL, 1.2 mmol) followed by addition of one drop of DMF. The reaction mixture was allowed to warm to a room temperature over 4 hours, then concentrated to dryness under reduced pressure and kept on a high vacuum line for an hour. The crude mixture was used in the next step without further purification.

Reference： [1]Patent: US2011/53912,2011,A1 .Location in patent: Page/Page column 21
[2]Patent: US2016/83365,2016,A1 .Location in patent: Paragraph 0758; 0759; 0760

37
[ 85064-61-5 ]
[ 959748-73-3 ]

Reference： [1]Patent: US2011/71196,2011,A1
[2]Patent: WO2011/109324,2011,A1

38
[ 85064-61-5 ]
[ 1277174-06-7 ]

Reference： [1]Patent: US2011/71196,2011,A1
[2]Patent: WO2011/109324,2011,A1

39
[ 85064-61-5 ]
[ 1277174-07-8 ]

Reference： [1]Patent: US2011/71196,2011,A1
[2]Patent: WO2011/109324,2011,A1

40
[ 85064-61-5 ]
[ 1277174-08-9 ]

Reference： [1]Patent: US2011/71196,2011,A1
[2]Patent: WO2011/109324,2011,A1

41
[ 85064-61-5 ]
[ 1198409-41-4 ]
[ 1309784-91-5 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of <strong>[85064-61-5]tetrahydro-2H-pyran-4-ylacetic acid</strong> (35 mg) (available from Anichem) in DMF (1 ml) was added HATU (92 mg) and the mixture stirred at RT for 10 min when 6- (1 H-indol-4-yl)-1 H-indazol-4-amine (50 mg) and DIPEA (0.070 ml) were added and the mixture allowed to stand for 18 h. The mixture was blown to dryness under a stream of nitrogen and purified by MDAP (method A) to afford the title compound as a white solid, 16 mg.LCMS (method A); Rt = 2.1 min, MH+ = 375.

Reference： [1]Patent: WO2011/67365,2011,A1 .Location in patent: Page/Page column 90

42
[ 85064-61-5 ]
[ 106-40-1 ]
[ 355372-81-5 ]

Yield	Reaction Conditions	Operation in experiment
		Lambda^Lambda^-dimethylformamide (0.27 mL, 3.47 mmol) was added to a solution of tetrahydropyranyl-4-acetic acid (5.0 g, 34.7 mmol) and thionyl chloride (2.53 mL, 34.7 mmol) in DCM (200 mL) at 0 °C. After stirring 1 h at RT the solution was cooled to 0 °C. 7V-Ethyl-A sopropylpropan-2 -amine (15.14 mL, 87 mmol) was added, followed by 4- bromoaniline (5.97 g, 34.7 mmol) in 20 mL DCM were added slowly and the solution was stirred at 0 °C. After 1 h the reaction was diluted with saturated ammonium chloride and the organics were removed. Ethyl acetate was added and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water, saturated sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material N-(4- bromophenyl)-2-(tetrahydro-2//-pyran-4-yl)acetamide as a tan solid.

Reference： [1]Patent: WO2011/90911,2011,A1 .Location in patent: Page/Page column 72

43
[ 85064-61-5 ]
[ 1319197-09-5 ]

Reference： [1]Patent: WO2011/90911,2011,A1

44
[ 85064-61-5 ]
[ 1319197-10-8 ]

Reference： [1]Patent: WO2011/90911,2011,A1

45
[ 85064-61-5 ]
[ 1332896-23-7 ]

Reference： [1]Patent: WO2011/109324,2011,A1

46
[ 85064-61-5 ]
[ 1337543-32-4 ]
[ 1359965-79-9 ]

Yield	Reaction Conditions	Operation in experiment
		Example 144a ethyl 4-amino-2-methyl-5-(2-methyl-2-(2-(tetrahydro-2H-pyran-4-yl)acetamido)propoxy)quinoline-3-carboxylate Prepared as in Example 24a from ethyl 4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate (Example 24b) and <strong>[85064-61-5]2-(tetrahydro-2H-pyran-4-yl)acetic acid</strong> as a yellow solid (37%). 1H NMR (400 MHz, DMSO-d6) delta 1.05-1.08 (m, 2H), 1.30-1.38 (m, 11H), 1.79 (m, 1H), 1.97 (d, J=4.0 Hz, 2H), 2.56 (s, 3H), 3.07 (t, J=8.0 Hz, 2H), 3.61 (d, J=8.0 Hz, 2H), 4.28-4.34 (m, 4H), 6.87 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.73 (s, 1H), 8.21 (s, 2H). MS 444 (MH+).

Reference： [1]Patent: US2012/41078,2012,A1

47
[ 85064-61-5 ]
[ 918145-09-2 ]
[ 1357009-16-5 ]

Reference： [1]ACS Medicinal Chemistry Letters,2012,vol. 3,p. 216 - 221

48
[ 85064-61-5 ]
[ 1420039-48-0 ]

Reference： [1]Patent: EP2737900,2014,A1

49
[ 85064-61-5 ]
[ 1420039-50-4 ]

Reference： [1]Patent: EP2737900,2014,A1

50
[ 85064-61-5 ]
[ 1420039-52-6 ]

Reference： [1]Patent: EP2737900,2014,A1
[2]Patent: EP2737900,2014,A1

51
[ 85064-61-5 ]
[ 1420039-54-8 ]

Reference： [1]Patent: EP2737900,2014,A1
[2]Patent: EP2737900,2014,A1

52
[ 85064-61-5 ]
[ 1420039-56-0 ]

Reference： [1]Patent: EP2737900,2014,A1
[2]Patent: EP2737900,2014,A1

53
[ 85064-61-5 ]
2,3-bis(tetrahydro-2H-pyran-4-yl)maleate disodium salt [ No CAS ]

Reference： [1]Patent: EP2737900,2014,A1
[2]Patent: EP2737900,2014,A1

54
[ 85064-61-5 ]
[ 100-39-0 ]
[ 929556-48-9 ]

Yield	Reaction Conditions	Operation in experiment
75%	With potassium carbonate; In acetonitrile; for 48h;Reflux;	A solution of sodium hydroxide (15.9 g, 44.06 mmol) in water (150 ml) was added dropwise to a solution of ethyl 2-(tetrahydro-2H-pyran-4-yl)acetate (15 g, 8.81 mmol) in methanol (150 ml) at a temperature of 0 °C or below, and the mixture was stirred at room temperature for 15 hr. The solvent of the reaction mixture was removed by distillation under reduced pressure, and the water layer was adjusted to pH 3 by the addition of 1 M hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give a corresponding acid as a colorless solid (12.0 g, 94percent). This compound was used in the next step without further purification. Benzyl bromide (14.3 g, 83.33 mmol) was added dropwise to a suspension of this compound (10.0 g, 69.44 mmol) and anhydrous potassium carbonate (28.8 g, 208.3 mmol) in acetonitrile (100 ml) at room temperature, and the mixture was refluxed for 48 hr. The solvent of the mixture was removed by distillation under reduced pressure, the residue was diluted with water and was extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was chromatographed on silica gel column (hexane:ethyl acetate = 9:1) to give the tile compound as an oil (12.0 g, yield 75percent). 1H-NMR (400 MHz, CDCl3): delta (ppm) 7.39-7.34 (m, 5H), 5.12 (s, 2H), 3.95-3.92 (m, 2H), 3.42-3.36 (m, 2H), 2.30 (d, J = 7.2 Hz, 2H), 2.09-1.99 (m, 1H) 1.64-1.61 (m, 2H), 1.39-1.29 (m, 2H); MS (ESI): m/z 234 (M+).

Reference： [1]Patent: EP2737900,2014,A1 .Location in patent: Paragraph 0114; 0117-0118

55
[ 85064-61-5 ]
(1S,1'S)-1,1'-(5,5'-([1,1'-biphenyl]-4,4^,-diyl)bis(1H-imidazole-5,2-diyl))bis(2,2-dimethylpropan-1-amine) hidrochloride [ No CAS ]
C₄₂H₅₆N₆O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 6h;	General procedure: To(1S,1?S)-1,1?-(5,5?-([1,1?-biphenyl]-4,4?-diyl)bis(1H-imidazole-5,2-diyl))bis(2,2-dimethylpropan-1-amine)tetrahydrochloride(75 mg, 0.124 mmol) was added3-hydroxy-2,2,3-trimethylbutanoic acid(38.2 mg, 0.261 mmol) inDMF(3 mL) followed byDIPEA(0.174 mL, 0.996 mmol) at 0° C. ThenHATU(97 mg, 0.255 mmol) was added and stirred from 0° C. to RT for 6 h. The crude was dissolved inEtOAc(50 mL), washed with saturated NH4Cl (25 mL), 10percent NaHCO3(25 mL), brine (25 mL), dried over Na2SO4and concentrated under reduced pressure. The crude material was purified by reverse phase HPLC (ACN/water/TFA) to getTFA saltof Example B-69 (30 mg) as awhitesolid. HPLC (Condition B-1 and B-2): >97percent homogeneity index. LC/MS (Condition B-12): Rt=2.13 min.1H NMR (MeOD, delta=3.34 ppm, 400 MHz): delta 7.92-7.85 (m, 10H), 4.94 (s, 2H), 1.28 (s, 18H), 1.16 (s, 12H), 1.15 (s, 12H). LC/MS:Anal. Calcd. for [M+H]+C42H61N6O4: 713.47; found 713.3. Example B-90-147 were prepared in a similar fashion starting from (1S,1?S)-1,1?-(5,5?-([1,1?-biphenyl]-4,4?-diyl)bis(1H-imidazole-5,2-diyl))bis(2,2-dimethylpropan-1-amine)tetrahydrochloride and appropriate acids according to the procedure described for Example B-69.

Reference： [1]Patent: US2015/23913,2015,A1 .Location in patent: Paragraph 1250-1251; 1280-1281

56
2-(dihydro-2H-pyran-4(3H)-ylidene)acetic acid [ No CAS ]
[ 85064-61-5 ]

Yield	Reaction Conditions	Operation in experiment
82 mg	With palladium on activated charcoal; hydrogen; In methanol; at 20℃; for 12h;Inert atmosphere;	To a solution of Cap B-5 (100 mg, 0.703 mmol) in MeOH (5 mL) was added Pd/C (374 mg, 0.352 mmol) and the reaction mixture was purged with nitrogen for 2 minutes. Then the reaction mixture was hydrogenated for 12 h at ambient temperature. The reaction mixture was filtered through celite and washed with MeOH (2×10 mL). The filtrate was concentrated under reduced pressure to obtain Cap B-7 (82 mg) as a color less liquid.1H NMR (CDCl3, delta=7.26 ppm, 400 MHz): delta 3.98-3.94 (m, 2H), 3.45-3.41 (m, 2H), 2.30 (d, J=6.8, 2H), 2.05-1.95 (m, 1H), 1.71-1.66 (m, 2H), 1.43-1.28 (m, 2H).
82 mg	With palladium on activated charcoal; hydrogen; In methanol; at 20℃; for 12h;Inert atmosphere;	To a solution of Cap B-5 (100 mg, 0.703 mmol) in MeOH (5 mL) was added Pd/C (374 mg, 0.352 mmol) and the reaction mixture was purged with nitrogen for 2 minutes. Then the reaction mixture was hydrogenated for 12 h at ambient temperature. The reaction mixture was filtered through celite and washed withMeOH (2x10 mL). The filtrate was concentrated under reduced pressure to obtain Cap B-7 (82 mg) as a color less liquid.XH NMR (CDC13, delta = 7.26 ppm, 400 MHz): delta 3.98-3.94 (m, 2 H), 3.45-3.41 (m, 2 H), 2.30 (d, J = 6.8, 2 H), 2.05-1.95 (m, 1 H), 1.71-1.66 (m, 2 H), 1.43-1.28 (m, 2 H).

Reference： [1]Patent: US2015/23913,2015,A1 .Location in patent: Paragraph 1910-1911
[2]Patent: WO2015/5901,2015,A1 .Location in patent: Page/Page column 626

57
[ 85064-61-5 ]
[ 77317-55-6 ]
methyl 5-iodo-2-(2-(tetrahydro-2H-pyran-4-yl)acetamido)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; trichlorophosphate; at -40℃; for 1h;Inert atmosphere;	A solution of methyl 2-amino-5-iodobenzoate (7.02 g, 25.3 mmol) and <strong>[85064-61-5]2-(tetrahydro-2H-pyran-4-yl)acetic acid</strong> (3.76 g, 26.1 mmol) in pyridine (25 mL) was stirred at ?-40° C. under argon while POCl3 (2.58 g, 27.8 mmol) was added dropwise over 3 minutes. The cold bath was immediately removed and the reaction was allowed to stir for 1 hour. The reaction was then diluted with water (75 mL) and extracted with DCM (75 mL). The combined orange organic layers were washed with 6 M aqueous HCl (50 mL), 1 M aqueous HCl (50 mL), and 2 M aqueous K3PO4 (50 mL), dried (Na2SO4), filtered, and concentrated to provide the title compound as an orange solid.

Reference： [1]Patent: US2015/111870,2015,A1 .Location in patent: Paragraph 0345; 0346

58
[ 85064-61-5 ]
2,4-dichloro-6-iodo-3-(tetrahydro-2H-pyran-4-yl)quinoline [ No CAS ]

Reference： [1]Patent: US2015/111870,2015,A1
[2]Patent: US2015/111870,2015,A1

59
[ 85064-61-5 ]
4-chloro-6-iodo-2-methoxy-3-(tetrahydro-2H-pyran-4-yl)quinoline [ No CAS ]

Reference： [1]Patent: US2015/111870,2015,A1
[2]Patent: US2015/111870,2015,A1

60
[ 85064-61-5 ]
4-hydroxy-6-iodo-3-(tetrahydro-2H-pyran-4-yl)quinolin-2(1H)-one [ No CAS ]

Reference： [1]Patent: US2015/111870,2015,A1
[2]Patent: US2015/111870,2015,A1

61
[ 85064-61-5 ]
[ 90719-32-7 ]
(S)-4-benzyl-3-(2-(tetrahydro-2H-pyran-4-yl)acetyl)oxazolidin-2-one [ No CAS ]