[ CAS No. 94994-25-9 ] {[proInfo.proName]}

Name: 94994-25-9|Methyl 4-formylbicyclo[2.2.2]octane-1-carboxylate|95%
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Quality Control of [ 94994-25-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 94994-25-9 ]

CAS No. :	94994-25-9	MDL No. :	MFCD19105426
Formula :	C₁₁H₁₆O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KNSYWHCOJRHWRP-UHFFFAOYSA-N
M.W :	196.24	Pubchem ID :	11074324
Synonyms :

Calculated chemistry of [ 94994-25-9 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.82
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	51.73
TPSA :	43.37 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) :	-6.87 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.05
Log Po/w (XLOGP3) :	0.89
Log Po/w (WLOGP) :	1.7
Log Po/w (MLOGP) :	1.49
Log Po/w (SILICOS-IT) :	2.47
Consensus Log Po/w :	1.72

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.42
Solubility :	7.47 mg/ml ; 0.0381 mol/l
Class :	Very soluble
Log S (Ali) :	-1.39
Solubility :	8.08 mg/ml ; 0.0412 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.1
Solubility :	1.54 mg/ml ; 0.00787 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.21

Safety of [ 94994-25-9 ]

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 [ 94994-25-9 ]

* 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 [ 94994-25-9 ]
Downstream synthetic route of [ 94994-25-9 ]

[ 94994-25-9 ] Synthesis Path-Upstream 1~7

1
[ 94994-15-7 ]
[ 94994-25-9 ]

Yield	Reaction Conditions	Operation in experiment
74.8%	With Dess-Martin periodane In dichloromethane at 20℃;	Intermediate A51L: Methyl 4-formylbicyclo[2.2.2]octane-1-carboxylate To a solution of Intermediate A511 (540 mg, 2.72 mmol) in CH₂Cl₂ (20 mL) was added Dess-Martin periodinane (1502 mg, 3.54 mmol). The reaction mixture was stirred at RT overnight. The reaction mixture was cooled to 0° C. and carefully quenched with a solution of NaHCO₃. The layers were separated. The aqueous layer was extracted with CH₂Cl₂. The combined organic layer was washed with brine, dried over Na₂SO₄, and filtered. The filtrate was concentrated. The residue was purified by silica gel chromatography (40 g REDISEP® column, eluting with 10-50percent EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate A51L (400 mg, 74.8percent). (ES): m/z=199 [M+H]⁺; ¹H NMR (400 MHz, chloroform-d) δ ppm 9.48 (s, 1H), 3.68 (s, 3H), 1.94-1.78 (m, 6H), 1.78-1.61 (m, 6H).

Reference： [1] Tetrahedron Letters, 1999, vol. 40, # 4, p. 781 - 784
[2] Patent: US9273058, 2016, B2, . Location in patent: Page/Page column 534
[3] Journal of Labelled Compounds and Radiopharmaceuticals, 2007, vol. 50, # 4, p. 219 - 223
[4] Journal of Organic Chemistry, 1985, vol. 50, # 7, p. 1079 - 1087

2
[ 110371-29-4 ]
[ 94994-25-9 ]

Reference： [1] Patent: WO2011/63268, 2011, A2, . Location in patent: Page/Page column 37-38

3
[ 18720-35-9 ]
[ 94994-25-9 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 8, p. 2568 - 2572
[2] Journal of Labelled Compounds and Radiopharmaceuticals, 2007, vol. 50, # 4, p. 219 - 223
[3] Tetrahedron Letters, 1999, vol. 40, # 4, p. 781 - 784
[4] Journal of Organic Chemistry, 1985, vol. 50, # 7, p. 1079 - 1087
[5] Patent: WO2011/63268, 2011, A2,
[6] Patent: US9273058, 2016, B2,

4
[ 1459-96-7 ]
[ 94994-25-9 ]

Reference： [1] Tetrahedron Letters, 1999, vol. 40, # 4, p. 781 - 784
[2] Patent: US9273058, 2016, B2,

5
[ 23062-52-4 ]
[ 94994-25-9 ]

Reference： [1] Journal of Organic Chemistry, 1985, vol. 50, # 7, p. 1079 - 1087

6
[ 953-69-5 ]
[ 94994-25-9 ]

Reference： [1] Journal of Organic Chemistry, 1985, vol. 50, # 7, p. 1079 - 1087

7
[ 94-60-0 ]
[ 94994-25-9 ]

Reference： [1] Tetrahedron Letters, 1999, vol. 40, # 4, p. 781 - 784

[ 94994-25-9 ] Synthesis Path-Downstream 1~82

1
[ 94993-99-4 ]
[ 94994-25-9 ]
[ 94993-89-2 ]

Reference： [1]Journal of Organic Chemistry,1985,vol. 50,p. 1079 - 1087

2
[ 94994-15-7 ]
[ 94994-25-9 ]

Yield	Reaction Conditions	Operation in experiment
74.8%	With Dess-Martin periodane; In dichloromethane; at 20℃;	Intermediate A51L: Methyl 4-formylbicyclo[2.2.2]octane-1-carboxylate To a solution of Intermediate A511 (540 mg, 2.72 mmol) in CH2Cl2 (20 mL) was added Dess-Martin periodinane (1502 mg, 3.54 mmol). The reaction mixture was stirred at RT overnight. The reaction mixture was cooled to 0 C. and carefully quenched with a solution of NaHCO3. The layers were separated. The aqueous layer was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated. The residue was purified by silica gel chromatography (40 g REDISEP column, eluting with 10-50% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate A51L (400 mg, 74.8%). (ES): m/z=199 [M+H]+; 1H NMR (400 MHz, chloroform-d) delta ppm 9.48 (s, 1H), 3.68 (s, 3H), 1.94-1.78 (m, 6H), 1.78-1.61 (m, 6H).
67%	With Dess-Martin periodane; In dichloromethane; at 20℃; for 3h;	To a solution of Intermediate 159A (0.10 g, 0.50 mmol) in DCM (5 mL) was added DMP (0.28 g, 0.66 mmol) and the reaction was stirred at rt. After 3 h, the reaction was cooled to 0 C. and carefully quenched with a solution of sat. NaHCO3 (aq.) (30 mL). The layers were separated, and the aqueous layer was extracted with CH2Cl2 (2*15 mL). The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography (12 g silica gel cartridge, A=PE, B=EtOAc; 15 min grad.; 20% to 100% B; flow rate=12 mL/min; TLC visualized with KMnO4). The pure fractions were combined, concentrated and dried in vacuo to afford the title compound (0.070 g, 0.34 mmol, 67% yield) as colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) delta 9.4 (s, 1H), 3.66 (s, 3H), 1.86-1.82 (m, 7H), 1.69-1.66 (m, 5H).

Reference： [1]Tetrahedron Letters,1999,vol. 40,p. 781 - 784
[2]Patent: US9273058,2016,B2 .Location in patent: Page/Page column 534
[3]Patent: US2019/127358,2019,A1 .Location in patent: Paragraph 0690-0691
[4]Journal of labelled compounds and radiopharmaceuticals,2007,vol. 50,p. 219 - 223
[5]Journal of Organic Chemistry,1985,vol. 50,p. 1079 - 1087

3
[ 67-66-3 ]
[ 94994-25-9 ]
[ 220934-69-0 ]

Reference： [1]Tetrahedron Letters,1999,vol. 40,p. 781 - 784

4
[ 94994-25-9 ]
[ 96102-85-1 ]

Reference： [1]Journal of labelled compounds and radiopharmaceuticals,2007,vol. 50,p. 219 - 223
[2]Patent: WO2011/63268,2011,A2

5
[ 18720-35-9 ]
[ 94994-25-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2568 - 2572
[2]Journal of labelled compounds and radiopharmaceuticals,2007,vol. 50,p. 219 - 223
[3]Tetrahedron Letters,1999,vol. 40,p. 781 - 784
[4]Journal of Organic Chemistry,1985,vol. 50,p. 1079 - 1087
[5]Patent: WO2011/63268,2011,A2
[6]Patent: US9273058,2016,B2
[7]Patent: US2019/127358,2019,A1

6
[ 94994-25-9 ]
4-(2-methoxycarbonyl-vinyl)-bicyclo[2.2.2]octane-1-carboxylic acid [ No CAS ]

Reference： [1]Journal of labelled compounds and radiopharmaceuticals,2007,vol. 50,p. 219 - 223

7
[ 94994-25-9 ]
[ 340023-15-6 ]

Reference： [1]Journal of labelled compounds and radiopharmaceuticals,2007,vol. 50,p. 219 - 223

8
[ 94994-25-9 ]
[ 959958-69-1 ]

Reference： [1]Journal of labelled compounds and radiopharmaceuticals,2007,vol. 50,p. 219 - 223

9
[ 94994-25-9 ]
3-(4-(2,6-dioxo-1-propyl-3-heptadeuteriopropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl)propionic acid [ No CAS ]

Reference： [1]Journal of labelled compounds and radiopharmaceuticals,2007,vol. 50,p. 219 - 223

10
[ 94-60-0 ]
[ 94994-25-9 ]

Reference： [1]Tetrahedron Letters,1999,vol. 40,p. 781 - 784

11
[ 1459-96-7 ]
[ 94994-25-9 ]

Reference： [1]Tetrahedron Letters,1999,vol. 40,p. 781 - 784
[2]Patent: US9273058,2016,B2

12
[ 94994-25-9 ]
4-(amino-carboxy-methyl)-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Tetrahedron Letters,1999,vol. 40,p. 781 - 784

13
[ 94994-25-9 ]
4-(amino-methoxycarbonyl-methyl)-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Tetrahedron Letters,1999,vol. 40,p. 781 - 784

14
[ 94994-25-9 ]
[ 220934-70-3 ]

Reference： [1]Tetrahedron Letters,1999,vol. 40,p. 781 - 784

15
[ 23062-52-4 ]
[ 94994-25-9 ]

Reference： [1]Journal of Organic Chemistry,1985,vol. 50,p. 1079 - 1087

16
[ 953-69-5 ]
[ 94994-25-9 ]

Reference： [1]Journal of Organic Chemistry,1985,vol. 50,p. 1079 - 1087

17
[ 94994-25-9 ]
[ 719274-44-9 ]

Yield	Reaction Conditions	Operation in experiment
		[2-(2-Methyl-1,3-dioxolan-2-yl)ethyl](triphenyl)phosphonium bromide (4-A, Synthesis: 532 (1986)) (5.99 g, 12.7 mmol) was stirred in dry THF (200 mL). Potassium bis(trimethylsilyl)amide (20.4 mL, 2M soln in toluene, 10.2 mmol) was added. The reaction was allowed to stir for 30 min. The reaction mixture was then cooled to -78 C. Methyl 4-formylbicyclo[2.2.2]octane-1-carboxylate was added at -78 C. by cannula. The reaction was allowed to warm to room temperature overnight. The volume was reduced by evaporation of THF in vacuo. 100 mL of water was added. The mixture was then layered with 100 mL of diethyl ether. The ether was extracted and dried (MgSO4). The product (methyl 4-[(1E)-3-(2-methyl-1,3-dioxolan-2-yl)prop-1-enyl]bicyclo[2.2.2]octane-1-carboxylate (4-B)) was purified by flash chromatography on silica gel with 10/90 ethyl acetate-hexane mixture.

Reference： [1]Patent: US2004/133011,2004,A1 .Location in patent: Page 23-24

18
[ 94994-25-9 ]
[ 719274-85-8 ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred solution of methyltriphenylphosphonium bromide (9.1 g, 12.8 mmol) in THF (50 ml) at 0 C. was added potassium hexamethyldisilazide (0.5M in toluene, 48.6 ml), dropwise over 5 min. The resulting mixture was allowed to warm up to room temperature over 1 h, then cooled again to 0 C. and treated with <strong>[94994-25-9]methyl 4-formylbicyclo[2.2.2]octane-1-carboxylate</strong> 15-A (Chapman, N. B. et al. J. Org. Chem., 1970, 35, 917) (2.5 g, 12.8 mmol). The reaction mixture was stirred at room temperature for 18 h then diluted with EtOAc (350 ml). The organic phase was washed with aqueous HCl (1 N), saturated aqueous sodium bicarbonate, and brine, then dried (Na2SO4) and concentrated in vacuo. The resulting solid was purified by flash silica gel chromatography, eluting with a gradient 0-4% EtOAc/hexanes. The resulting methyl 4-vinylbicyclo[2.2.2]octane-1-carboxylate 15-B was isolated as a clear, colorless oil.

Reference： [1]Patent: US2004/133011,2004,A1 .Location in patent: Page 37

19
[ 94994-25-9 ]
[ 719274-69-8 ]

Yield	Reaction Conditions	Operation in experiment
		(Benzyloxycarbonylmethyl)triphenylphosphonium bromide (4.6 g, 9.4 mmol) was azeotroped twice from toluene, and then suspended in 30 mL dry THF. Potassium hexamethyldisilazide (0.5 M in toluene, 16.8 mL, 8.4 mmol) was added dropwise at room temperature and the yellow solution was allowed to stir for 1 h, after which time it became milky white. A solution of <strong>[94994-25-9]4-carbomethoxybicyclo[2.2.2]octane-1-carboxaldehyde</strong> (11-1) (0.50 g, 2.55 mmol) (Adcock, W., Kok, G. B. J. Org. Chem. 50: 1079-1087 (1985)) and benzoic acid (0.015 g, 0.13 mmol) in 2 mL of dry THF was prepared and added dropwise by syringe at room temperature. The mixture was heated to 90 C. and allowed to stir at reflux temperature, after which time the mixture was diluted with 200 mL of ethyl acetate and washed consecutively with 50 mL portions of 1 N HCl (twice), saturated aq. sodium bicarbonate, and brine. The organic layer was dried using magnesium sulfate, and the solvent was removed under reduced pressure. The residue was chromatographed on silica, eluting with a gradient of 5% to 10% ethyl acetate in hexane to provide methyl 4-[(1E)-3-(benzyloxy)-3-oxoprop-1-en-1-yl]bicyclo[2.2.2]octane-1-carboxylate (11-2) as a colorless oil. 1H NMR (500 MHz, CDCl3): delta 7.4 (5H, m), 6.94 (1H, d, J=17 Hz), 5.77 (1H, d, J=17 Hz), 5.21 (2H, s), 3.69 (3H, s), 1.86 (6H, m), 1.63 (6H, m) ppm.

Reference： [1]Patent: US2004/133011,2004,A1 .Location in patent: Page 31-32

20
[ 40321-37-7 ]
[ 94994-25-9 ]
[ 876400-25-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate; In methanol; at 0℃; for 4h;Heating / reflux;	Diethyl(ethylsulfonomethane)phosphonate (1.12 g, 4.6 mmol) (Popoff, I. C. et al. J. Org. Chem. 34: 1128-30 (1969)) and <strong>[94994-25-9]4-carbomethoxybicyclo[2.2.2]octane-1-carboxaldehyde</strong> (10-1) (0.82 g, 4.2 mmol) (Adcock, W., Kok, G. B. J. Org. Chem. 50: 1079-1087 (1985)) were dissolved in 8 mL of absolute methanol. The mixture was placed under nitrogen atmosphere, cooled in an ice-bath, and treated with 0.5M solution of sodium methoxide in methanol (8.8 mL, 4.4 mmol). The reaction mixture was kept under reflux for 4 h, then cooled to room temperature, concentrated under diminished pressure, then treated with 2 mL of water and allowed to sit in the refrigerator overnight. The mixture was filtered and the solid washed with a small amount of cold 1:1 MeOH/water. The resulting white solid was collected and dried under vacuum to give the unsaturated sulfone 10-2. MS (ESI)+=287 (M+1).

Reference： [1]Patent: US2004/133011,2004,A1 .Location in patent: Page 30-31

21
1-benzo[1,3]dioxol-5-yl-2-(6-methyl-pyridin-2-yl)-ethane-1,2-dione 2-oxime [ No CAS ]
[ 94994-25-9 ]
[ 614749-69-8 ]

Yield	Reaction Conditions	Operation in experiment
65%		EXAMPLE 21 4-[4-Benzo[1,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-2-yl]-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester <strong>[94994-25-9]4-Formyl-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester</strong> (0.284 g, 1.0 mmol) was added to a solution of 1-benzo[1,3]dioxol-5-yl-2-(6-methyl-pyridin-2-yl)-ethane-1,2-dione 2-oxime (see Example 4; 0.215 g, 1.1 mmol) and ammonium acetate (1.54 g, 20 mmol) in acetic acid (5 mL). The mixture was refluxed for 2 hours. Solvent was removed under reduced pressure. The reaction mixture was then quenched with ammonia/ice mixture. The aqueous solution was extracted with ethyl acetate. Ethyl acetate extract was washed with brine, dried over sodium sulfate, filtered, and concentrated to give 0.300 g (65%) of the hydroxyimidazole as a yellow solid. MS (ESP+) m/z 462.3 (M+1).

Reference： [1]Patent: US2006/63809,2006,A1 .Location in patent: Page/Page column 20

22
[ 94994-25-9 ]
[ 19493-09-5 ]
[ 719274-85-8 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; toluene; at 0 - 20℃; for 18h;	Step A:To a stirred solution of methyltriphenylphosphonium bromide (9.1g, 12.8 mmol) in THF(50 ml) at 0C was added potassium hexamethyldisilazide (0.5M in tolue'ne, 48.6 ml), dropwise over 5min. The resulting mixture was allowed to warm up to room temperature over 1 h, then cooled again to0C and treated with methyl 4-formylbicyclo[2.2.2]octane-l-carboxylate (4-1) (Chapman, N. B. et al. J.Org. Chem., 1970, 35, 917) (2.5 g, 12.8 mmol). The reaction mixture was stirred at room temperature for18 h then diluted with EtOAc (350 ml). The organic phase was washed with aqueous HC1 (1 N),saturated aqueous sodium bicarbonate, and brine, then dried (Na2SO4) and concentrated in vacua. Theresulting solid was purified by flash silica gel chromatography, eluting with a gradient 0-4%EtOAc/hexanes. The resulting methyl 4-vinylbicyclo[2.2.2]octane-l-carboxylate (4-2) was isolated as aclear, colorless oil.

Reference： [1]Patent: WO2006/17542,2006,A1 .Location in patent: Page/Page column 48

23
[ 40321-37-7 ]
[ 94994-25-9 ]
[ 719274-63-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate; In methanol; for 4h;Heating / reflux;	Step A:Diethyl (ethylsulfonomethane)phosphonate (1.12 g, 4.6 mmol) (Popoff, I. C. et al. J. Org.Chem. 34: 1128-30 (1969)) and 4-carbomethoxybicyclo[2.2.2] octane-1-carboxaldehyde (1-1) (0.82 g,4.2 mmol) (Adcock, W., Kok, G. B. J. Ore. Chem. 50: 1079-1087 (1985)) were dissolved in 8 mL ofabsolute methanol. The mixture was placed under nitrogen atmosphere, cooled in an ice-bath, andtreated with 0.5M solution of sodium methoxide in methanol (8.8 mL, 4.4 mmol). The reaction mixturewas kept under reflux for 4 h, then cooled to room temperature, concentrated under diminished pressure,then treated with 2 mL of water and allowed to sit in the refrigerator overnight. The mixture was filteredand the solid washed with a small amount of cold 1:1 MeOH/water. The resulting white solid wascollected and dried under vacuum to give the unsaturated sulfone 1-2. MS (ESI"1") = 287 (M+l).

Reference： [1]Patent: WO2006/17542,2006,A1 .Location in patent: Page/Page column 40

24
[ 15097-38-8 ]
[ 94994-25-9 ]
[ 719274-69-8 ]

Yield	Reaction Conditions	Operation in experiment
	With benzoic acid; In tetrahydrofuran; at 20℃;Heating / reflux;	Step A:(Benzyloxycarbonylmethyl)triphenylphosphonium bromide (4.6 g, 9.4 mmol) wasazeotroped twice from toluene, and then suspended in 30 mL dry THF. Potassium hexamethyldisilazide(0.5 M in toluene, 16.8 mL, 8.4 mmol) was added dropwise at room temperature and the yellow solutionwas allowed to stir for 1 h, after which time it became milky white. A solution of 4-carbomethoxybicyclo[2.2.2] octane-1-carboxaldehyde (2-1) (0.50 g, 2.55 mmol) (Adcock, W., Kok, G. B.J. Ore. Chem. 50: 1079-1087 (1985)) and benzoic acid (0.015 g, 0.13 mmol) in 2 mL of dry THF wasprepared and added dropwise by syringe at room temperature. The mixture was heated to 90 C andallowed to stir at reflux temperature, after which time the mixture was diluted with 200 mL of ethylacetate and washed consecutively with 50 mL portions of 1 N HCI (twice), saturated aq. sodiumbicarbonate, and brine. The organic layer was dried using magnesium sulfate, and the solvent wasremoved under reduced pressure. The residue was chromatographed on silica, eluting with a gradient of5% to 10% ethyl acetate in hexane to provide methyl 4-[(lE)-3-(benzyloxy)-3-oxoprop-l-en-l-yl]bicyclo[2.2.2]octane-l-carboxylate (2-2) as a colorless oil. IH NMR (500 MHz, CDCls): 5 7.4 (5H,m), 6.94 (IH, d, J = 17 Hz), 5.77 (IH, d, J = 17 Hz), 5.21 (2H, s), 3.69 (3H, s), 1.86 (6H, m), 1.63 (6H,m) ppm.

Reference： [1]Patent: WO2006/17542,2006,A1 .Location in patent: Page/Page column 42-43

25
[ 878792-28-0 ]
[ 94994-25-9 ]
4-[1-hydroxy-4-(6-methyl-pyridin-2-yl)-5-(2-methylsulfanyl-pyrimidin-4-yl)-1H-imidazol-2-yl]-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With ammonium acetate; In acetic acid; for 2h;Heating / reflux;	4-Formyl-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester (0.72 g, 2.5 mmol) was added to a solution of l-(6-methyl-pyridin-2-yl)-2-(4-methylsulfanyl-pyrimidin-2-yl)-ethane- 1,2-dione 2-oxime (0.6 g, 2.1 mmol) and ammonium acetate (3.1 g, 40 mmol) in acetic acid (30 mL). The mixture was reflux for 2 hours. Solvent was removed under reduced pressure. Reaction mixture was then quenched with ammonia/ice mixture. The aqueous solution was extracted with ethyl acetate. Ethyl acetate was washed with brine, dried over sodium sulfate, filtered, and concentrated to 0.9 g (92%) of the title methyl ester as a yellow solid.

Reference： [1]Patent: WO2006/26306,2006,A1 .Location in patent: Page/Page column 32

26
[ 878792-26-8 ]
[ 94994-25-9 ]
4-[1-hydroxy-4-(2-methyl-pyrimidin-4-yl)-5-[1,2,4]triazolo[1,5-a]pyridin-6-yl-1H-imidazol-2-yl]-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With ammonium acetate; In acetic acid; for 3h;Heating / reflux;	4-Formyl-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester (0.170 g, 1.0 mmol) was added to a solution of l-(2-methyl-pyrimidin-4-yl)-2-[l,2,4]triazolo[l,5-a]pyridin-6-yl-ethane- 1,2-dione 2-oxime (0.282 g, 1 mmol) and ammonium acetate (1.54 g, 20 mmol) in acetic acid (5 mL). The mixture was refluxed for 3 hours. Solvent was removed under reduced pressure. The reaction mixture was then quenched with an ammonia/ice mixture. The aqueous solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give 0.40Og (87%) of the title compound as a yellow solid.

Reference： [1]Patent: WO2006/26306,2006,A1 .Location in patent: Page/Page column 29

27
[ 94994-25-9 ]
[ 1257397-59-3 ]

Yield	Reaction Conditions	Operation in experiment
70%		Step 1:4-(difluoromethyl)bicyclo [2.2.2] octane-1-carboxylic acidTo a solution of diethylaminosulfur trifluoride (2.69 mL, 0.0204 mol) in methylene chloride (187.8 mL, 2.929 mol) , cooled to -50 0C was added a solution of 4-formyl- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester (2.00 g, 0.0102 mol) in methylene chloride and reaction stirred overnight. The reaction is quenched with water and extracted with DCM. The organic is dried over MgSO4 and concentrated. The residue purified by flash chromatography (0-50% ethyl acetate/hexanes) to give methyl 4- (difluoromethyl)bicyclo[2.2.2]octane-l-carboxylate. LCMS m/z 219.2 [M+ 1]+ The ester was dissolved in isopropyl alcohol (20.00 mL) and 4 M of sodium hydroxide in water (6.00 mL, 0.0240 mol) was added to it. Solution stirred overnight. Quench with 1 M of hydrogen chloride in water (20.38 mL, 0.02038 mol). The precipitated solid is filtered to give the acid (1.45g, 70%). 1H NMR (400 MHz, DMSOd6) delta 11.92 - 12.21 (m, IH), 5.69 (m, IH), 1.63 - 1.74 (m, 6H), 1.41 - 1.54 (m, 6H); LCMS m/z 205.1 [M+ 1]+.

Reference： [1]Patent: WO2010/138901,2010,A1 .Location in patent: Page/Page column 119-120

28
[ 71864-02-3 ]
[ 94994-25-9 ]
C₁₇H₂₆O₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2568 - 2572

29
[ 2537-48-6 ]
[ 94994-25-9 ]
[ 1308728-83-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium t-butanolate; In tetrahydrofuran; for 2.16667h;Cooling with ice;	Method B. 1 (9.81 g, 0.0500 mol) was dissolved in THF (100 mL). Diethyl cyanomethyl- phosphonate (8.90 mL, 0.0550 mol) was added. The mixture was cooled with an ice bath. Sodium tert-butoxide (5.28 g, 0.0550 mol) was added slowly. After 10 min, the suspension became a clear solution. After 2 h, aq NaOH (1M, 50 mL) was added. The mixture was stirred at room temperature overnight. To the reaction mixture was added water (100 mL) and MTBE (100 mL). The aqueous layer was separated and washed with MTBE (100 mL) cooled with ice batch and acidified with HCI (2M, 50 mL). The precipitate was collected by filtration and dried in a vacuum oven at 50 C overnight to yield the product (3) as white solid (7.92 g) in 72.2% yield.

Reference： [1]Patent: WO2011/63268,2011,A2 .Location in patent: Page/Page column 34

30
[ 94994-25-9 ]
[ 75-05-8 ]
[ 1308728-83-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide;Reflux;	Example 1. Preparation of Intermediate 4Preparation of Nitrile 2 from Aldehyde 1:Method A. 1 (29.4 g, 0.150 mol) and KOH (19.8 g, 0.300 mol) were placed in a round-bottom flask followed by addition of Acetonitrile (300 mL). The mixture was heated at reflux overnight and formed a cloudy suspension. To the reaction mixture was added water (300 mL). A clear solution is formed. The solution was subsequently heated at 65 C for 3 h, and then stirred at rt overnight. The mixture was cooled with ice bath and added HCI (12N, 30 mL) to pH 2. White precipitates form in the mixture. The solid was collected by filtration and washed with water. The filtration cake was dried in a vacuum oven at 50 C overnight to yield the crude product 3 (21 g) in 68% yield.

Reference： [1]Patent: WO2011/63268,2011,A2 .Location in patent: Page/Page column 34

31
[ 110371-29-4 ]
[ 94994-25-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen;Pd-BaSO4; In 2-methyltetrahydrofuran; at 30℃;Industry scale;	Preparation of 13 from Acid Chloride 11: 9.4 Kg of 11 was dissolved in 9.4 liters of 2-MeTHF and subsequently added to a mixture of 0.94 kg of Pd/BaS04 and 5.18 Kg (1.05eq) of collidine in 49.4 liters of 2- MeTHF under nitrogen. The reaction was allowed to stir under hydrogen pressure at about 30C. The mixture was then cooled to 20C and filtered. The collidine was removed by washing the resulting mixture with acid, e.g., aqueous HC1. The organic layer was further washed with aqueous Na2C03 followed by addition of 98 Kg of 39%> aqueous NaHS03 (9 eq) at about 20C to convert 11 to crystalline 13. The heterogeneous mixture was filtered, washed with MTBE and dried in vacuo to give 9.77 Kg of 13 in 93% molar yield from 11.

Reference： [1]Patent: WO2011/63268,2011,A2 .Location in patent: Page/Page column 37-38

32
[ 94994-25-9 ]
[ 1308728-85-9 ]

Reference： [1]Patent: WO2011/63268,2011,A2
[2]Patent: WO2011/63268,2011,A2

33
[ 94994-25-9 ]
[ 1308728-87-1 ]

Reference： [1]Patent: WO2011/63268,2011,A2
[2]Patent: WO2011/63268,2011,A2

34
[ 94994-25-9 ]
[ 1308728-89-3 ]

Reference： [1]Patent: WO2011/63268,2011,A2
[2]Patent: WO2011/63268,2011,A2

35
[ 94994-25-9 ]
C₂₂H₃₃N₅O₃ [ No CAS ]

Reference： [1]Patent: WO2011/63268,2011,A2
[2]Patent: WO2011/63268,2011,A2

36
[ 94994-25-9 ]
C₂₂H₃₄N₄O₅ [ No CAS ]

Reference： [1]Patent: WO2011/63268,2011,A2
[2]Patent: WO2011/63268,2011,A2

37
[ 94994-25-9 ]
[ 340021-17-2 ]

Reference： [1]Patent: WO2011/63268,2011,A2
[2]Patent: WO2011/63268,2011,A2
[3]Patent: WO2011/63268,2011,A2
[4]Patent: WO2011/63268,2011,A2
[5]Patent: WO2011/63268,2011,A2

38
[ 94994-25-9 ]
[ 1308728-99-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogensulfite; In 2-methyltetrahydrofuran; at 20℃;Industry scale;	Preparation of 13 from Acid Chloride 11: 9.4 Kg of 11 was dissolved in 9.4 liters of 2-MeTHF and subsequently added to a mixture of 0.94 kg of Pd/BaS04 and 5.18 Kg (1.05eq) of collidine in 49.4 liters of 2- MeTHF under nitrogen. The reaction was allowed to stir under hydrogen pressure at about 30C. The mixture was then cooled to 20C and filtered. The collidine was removed by washing the resulting mixture with acid, e.g., aqueous HC1. The organic layer was further washed with aqueous Na2C03 followed by addition of 98 Kg of 39%> aqueous NaHS03 (9 eq) at about 20C to convert 11 to crystalline 13. The heterogeneous mixture was filtered, washed with MTBE and dried in vacuo to give 9.77 Kg of 13 in 93% molar yield from 11.

Reference： [1]Patent: WO2011/63268,2011,A2 .Location in patent: Page/Page column 37-38

39
[ 94994-25-9 ]
[ 1308729-02-3 ]

Reference： [1]Patent: WO2011/63268,2011,A2

40
[ 94994-25-9 ]
[ 1269294-06-5 ]

Reference： [1]Patent: WO2011/63268,2011,A2

41
[ 94994-25-9 ]
[ 1308729-05-6 ]

Reference： [1]Patent: WO2011/63268,2011,A2

42
[ 94994-25-9 ]
C₂₄H₃₈N₄O₅ [ No CAS ]

Reference： [1]Patent: WO2011/63268,2011,A2

Yield	Reaction Conditions	Operation in experiment
	With pyridinium chlorochromate; In dichloromethane; at 0 - 20℃; for 3h;	General procedure: [ 1270] Pyridinium chlorochromate (10.1 g) was added to a solution of methyl 4-(hydroxymethyl)bicyclo[2.2.1]heptane-l-carboxylate (4.30 g) in dichloromethane (80 mL) at 0C, and the resultant was stirred for 3 hours at room temperature. The reaction mixture was filtered using celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by a silica gel column chromatography (hexane ethyl acetate), thereby obtaining the title compound (2.60 g). 1H NMR (400 MHz, DMSO-d6)6 1.44-1.49 (1H, m), 1.55-1.70 (3H, m), 1.81 (2H, s), 1.91-2.01 (4H, m), 3.60 (3H, s), 9.75 (1H, s).

44
[ 94994-25-9 ]
methyl 4-(difluoromethyl)bicyclo[2.2.2]octane-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62.9%	With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 20℃;	Intermediate A51M: Methyl 4-(difluoromethyl)bicyclo[2.2.2]octane-1-carboxylate To a solution of Intermediate A51L (400 mg, 2.038 mmol) at 0 C. in CH2Cl2 (8 mL) was added DAST (0.673 mL, 5.10 mmol). The reaction mixture was stirred at RT overnight. The reaction mixture was cooled to 0 C. and carefully quenched with a solution of NaHCO3. The layers were separated. The aqueous layer was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated. The residue was purified by silica gel chromatography (40 g REDISEP column, eluting with 0-20% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate A51M (280 mg, 62.9%). MS(ES): m/z=199 [M+H]+; 1H NMR (400 MHz, chloroform-d) delta ppm 5.54-5.26 (m, 1H), 3.68 (s, 3H), 1.89-1.76 (m, 6H), 1.65-1.50 (m, 6H).

Reference： [1]Patent: US9273058,2016,B2 .Location in patent: Page/Page column 534; 535

45
[ 94994-25-9 ]
3-chloro-4-{5-[4-(4-hydroxypentyl)bicyclo[2.2.2]oct-1-yl]-1-methyl-1-H-1,2,4-triazol-3-yl}phenol [ No CAS ]