[ CAS No. 14891-10-2 ] {[proInfo.proName]}

Name: 14891-10-2|Ethyl 3-oxopyrrolidine-1-carboxylate|98%
Brand: Ambeed
SKU: A765834
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3d Animation Molecule Structure of 14891-10-2

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Quality Control of [ 14891-10-2 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 14891-10-2 ]

SDS Specification

Alternatived Products of [ 14891-10-2 ]

Product Details of [ 14891-10-2 ]

CAS No. :	14891-10-2	MDL No. :	MFCD02093840
Formula :	C₇H₁₁NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DQYGBMLEVQLDQC-UHFFFAOYSA-N
M.W :	157.17	Pubchem ID :	277754
Synonyms :

Calculated chemistry of [ 14891-10-2 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.71
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	42.33
TPSA :	46.61 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.22 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.81
Log Po/w (XLOGP3) :	0.05
Log Po/w (WLOGP) :	0.04
Log Po/w (MLOGP) :	-0.2
Log Po/w (SILICOS-IT) :	0.49
Consensus Log Po/w :	0.44

Druglikeness

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

Water Solubility

Log S (ESOL) :	-0.65
Solubility :	35.4 mg/ml ; 0.225 mol/l
Class :	Very soluble
Log S (Ali) :	-0.58
Solubility :	41.2 mg/ml ; 0.262 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.68
Solubility :	32.7 mg/ml ; 0.208 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.77

Safety of [ 14891-10-2 ]

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 [ 14891-10-2 ]

* 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 [ 14891-10-2 ]
Downstream synthetic route of [ 14891-10-2 ]

[ 14891-10-2 ] Synthesis Path-Upstream 1~7

1
[ 14891-10-2 ]
[ 13220-33-2 ]

Reference： [1] Angewandte Chemie, 1957, vol. 69, p. 60

2
[ 13756-47-3 ]
[ 292638-85-8 ]
[ 14891-10-2 ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: With sodium hydride In benzene for 0.5 h; Reflux Stage #2: at 20℃; for 24 h; Reflux Stage #3: With hydrogenchloride In benzene for 16 h; Reflux	Compound 12 (8.350 g, 29.59 mmol) was diluted with benzene (50 mL). Sodium hydride (1.420 g, 59.18 mmol) was added and the mixture was heated at reflux for 30 min. Methyl acrylate (3.057 g, 35.51 mmol) was added and the reaction mixture was heated at reflux for 8 h and then allowed to stir at room temperature for 16 h. 6 M HCl (30 mL) was added and the reaction mixture was heated at reflux for 16 h. The reaction mixture was allowed to cool to room temperature and the aqueous and organic phases were separated. The aqueous phase was extracted with EtOAc (3 x 30 mL) and the combined organic layer was washed with sat NaHCO₃ (3 x 30 mL) and sat NaCl (30 mL). The organic layer was dried over sodium sulfate and concentrated to provide a yellow oil (3.089 g, 73percent). ¹H NMR (300 MHz, CDCl₃) δ 4.39- 4.01 (m, 2 H), 3.82-3.78 (m, 4 H), 2.60 (t, J= 7.8 Hz, 2 H), 1.27 (q, J= 7.2 Hz, 3 H); CIMS m/z (rel intensity) 158 (MH⁺, 100).

Reference： [1] Journal of Medicinal Chemistry, 2008, vol. 51, # 15, p. 4609 - 4619
[2] Patent: WO2009/140467, 2009, A1, . Location in patent: Page/Page column 29

3
[ 3751-82-4 ]
[ 14891-10-2 ]

Reference： [1] Tetrahedron, 1999, vol. 55, # 17, p. 5449 - 5456
[2] Chemische Berichte, 1956, vol. 89, p. 1423,1436
[3] Journal of the Chemical Society, Chemical Communications, 1990, # 15, p. 1047 - 1048

4
[ 130482-76-7 ]
[ 14891-10-2 ]
[ 130482-83-6 ]

Reference： [1] Journal of the Chemical Society, Chemical Communications, 1990, # 15, p. 1047 - 1048

5
[ 93591-91-4 ]
[ 14891-10-2 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 12, p. 3219 - 3223
[2] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 4, p. 1716 - 1723

6
[ 14891-08-8 ]
[ 14891-10-2 ]

Reference： [1] Heterocycles, 1982, vol. 19, # 9, p. 1605 - 1607

7
[ 3783-61-7 ]
[ 541-41-3 ]
[ 14891-10-2 ]

Reference： [1] Journal of Organic Chemistry, 1983, vol. 48, # 21, p. 3644 - 3648

[ 14891-10-2 ] Synthesis Path-Downstream 1~88

1
[ 14891-10-2 ]
[ 105-56-6 ]
[ 76182-53-1 ]

Reference： [1]Tetrahedron,1980,vol. 36,p. 1757 - 1761
[2]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1959,vol. 79,p. 1133,1137
Chem.Abstr.,1960,p. 3376

2
[ 14891-10-2 ]
[ 96-42-4 ]

Reference： [1]Angewandte Chemie,1957,vol. 69,p. 60

3
[ 14891-10-2 ]
[ 13220-33-2 ]

Reference： [1]Angewandte Chemie,1957,vol. 69,p. 60

4
[ 14891-10-2 ]
[ 93591-91-4 ]

Reference： [1]Angewandte Chemie,1957,vol. 69,p. 60
[2]Process Biochemistry,2017,vol. 56,p. 90 - 97

5
[ 14891-10-2 ]
[ 23126-68-3 ]
[ 34086-69-6 ]

Reference： [1]Journal of the Chemical Society C: Organic,1971,p. 3551 - 3554

6
[ 123-75-1 ]
[ 14891-10-2 ]
[ 73602-47-8 ]

Yield	Reaction Conditions	Operation in experiment
41%	With toluene-4-sulfonic acid; In benzene;	EXAMPLE 1 Preparation of ethyl 3-(1'-pyrrolidinyl)-2,5-dihydro-1-pyrrole-carboxylate (AM=A with R1 =R2 =H) In 50 ml of anhydrous benzene 17.7 g (0.113 mol) of ethyl 3-oxo-1-pyrrolidine-carboxylate were dissolved and then 10 g (0.141 mol) of pyrrolidine followed by 0.1 g of p-toluenesulphonic acid were added. In a Dean-Stark apparatus the reaction mixture was heated to the reflux temperature of the medium for 12 hours under nitrogen atmosphere so that the water was eliminated by azeotropic distillation. The benzene was then evaporated off and the residue was distilled under nitrogen atmosphere. In this manner, 9.7 g of ethyl 3-(1'-pyrrolidinyl)-2,5-dihydro-1-pyrrole-carboxylate were obtained in the form of a liquid which was kept under nitrogen atmosphere in a refrigerator. Yield: 41%; B.P.: 138 C. under 0.5 mm Hg

Reference： [1]Organic Magnetic Resonance,1982,vol. 19,p. 108 - 111
[2]Patent: US4299768,1981,A

7
[ 110-91-8 ]
[ 14891-10-2 ]
[ 50603-71-9 ]
[ 106183-63-5 ]
[ 106183-64-6 ]

Reference： [1]Chemistry Letters,1986,p. 1021 - 1024

8
[ 110-91-8 ]
[ 14891-10-2 ]
[ 106183-59-9 ]
[ 106183-60-2 ]

Reference： [1]Chemistry Letters,1986,p. 1021 - 1024

9
[ 67-56-1 ]
[ 14891-10-2 ]
[ 24424-99-5 ]
[ 129242-67-7 ]

Reference： [1]Journal of the Chemical Society. Chemical communications,1990,p. 831 - 833

10
[ 67-56-1 ]
[ 14891-10-2 ]
[ 129242-68-8 ]

Reference： [1]Journal of the Chemical Society. Chemical communications,1990,p. 831 - 833

11
[ 14891-10-2 ]
[ 81028-03-7 ]
[ 83925-25-1 ]

Reference： [1]Journal of Organic Chemistry,1983,vol. 48,p. 3644 - 3648
[2]Heterocycles,1982,vol. 19,p. 2075 - 2077

12
[ 14891-10-2 ]
[ 823-85-8 ]
[ 58039-18-2 ]

Yield	Reaction Conditions	Operation in experiment
	With phosphoric acid; sodium acetate; In water;	A. 7-fluoro-2-carbethoxy-1,2,3,4-tetrahydropyrrolo[3,4-b]indole (II: X = F) To a stirring suspension of 5.67 g. (0.035 mole) of p-fluorophenyl hydrazine hydrochloride and 2.87 g. (0.035 mole) of sodium acetate in 200 ml. of water is added dropwise 5.5 g. (0.035 mole) of 1-carbethoxy-3-pyrrolidinone in 50 ml. of the same solvent. After stirring for 20 min., the precipitated hydrazone is filtered, washed with water and dried, 9.0 g. The analytical sample is recrystallized from methylene chloride-hexane, m.p. 157-160 C. To 3.9 g. (14.7 m moles) of the above hydrazone is added 25 ml. of 85% phosphoric acid, the mixture becoming mildly exothermic as the solid dissolves. Within 30 min. the mixture sets-up to a semisolid, which is treated with an additional 10 ml. of phosphoric acid and allowed to stir until a uniform brown suspension results. The reaction mixture is quenched with 200 ml. of cold water, and the resulting precipitate is filtered and dried, 2.19 g. Recrystallization from ethanol-water provided 1.4 g. of the desired product, m.p. 248-249 C. Anal. Calc'd for C13 H13 O2 N2 F: c, 62.9; H, 5.2; N, 11.3. Found: C, 62.9; H, 5.3; N, 11.5.

Reference： [1]Journal of Medicinal Chemistry,1980,vol. 23,p. 704 - 707
[2]Patent: US3968231,1976,A

13
[ 14891-10-2 ]
[ 124-63-0 ]
[ 93591-92-5 ]

Reference： [1]Chemical and pharmaceutical bulletin,1985,vol. 33,p. 1826 - 1835

14
[ 14891-10-2 ]
[ 107-18-6 ]
[ 83455-91-8 ]

Reference： [1]Journal of Organic Chemistry,1983,vol. 48,p. 3644 - 3648
[2]Heterocycles,1982,vol. 19,p. 1605 - 1607

15
[ 14891-08-8 ]
[ 14891-10-2 ]

Reference： [1]Heterocycles,1982,vol. 19,p. 1605 - 1607

16
[ 3783-61-7 ]
[ 541-41-3 ]
[ 14891-10-2 ]

Reference： [1]Journal of Organic Chemistry,1983,vol. 48,p. 3644 - 3648

17
[ 130482-76-7 ]
[ 14891-10-2 ]
[ 130482-83-6 ]

Reference： [1]Journal of the Chemical Society. Chemical communications,1990,p. 1047 - 1048

18
[ 857350-33-5 ]
[ 14891-10-2 ]
ethyl 1,3-dihydro-2,4,4b,9-tetraazacyclopenta[b]fluorene-2-carboxylate [ No CAS ]
ethyl 2,3-dihydro-1,4,4b,9-tetraazacyclopenta[b]fluorene-1-carboxylate [ No CAS ]

Reference： [1]Heterocycles,2005,vol. 65,p. 1121 - 1137

19
[ 93591-91-4 ]
[ 14891-10-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 3219 - 3223
[2]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 1716 - 1723

20
[ 14891-10-2 ]
[ 873-77-8 ]
[ 96431-51-5 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; for 24h;Heating / reflux;	Grignard reagent for this reaction was obtained from Mg (3.1 g, 0.129 g-atom), 1-bromo-4-chlorobenzene (23.0 g, 0.12 mol.) and anhydrous Et20 (200 mL) and the resulting mixture was refluxed for 5 h. A solution of ketone (13.3 g, 0.085 mol.) in dry THF (100 mL) was added rapidly and the resulting mixture was allowed to reflux with stirring for 24 h. The mixture was allowed to cool and 30% NH4Cl solution was added until all solids dissolved. The aqueous phase was separated and extracted with Et2O (3×100 mL). The combined organic phase was shaken with H2O (50 mL) and dried (Na2SO4). The solvent was removed under reduced pressure to afford an oil (13.7 g, 60%). Column chromatography on silica gel afforded the desired product; mp 83-86 C. IR (Neat, cm-1) 3400 (br., OH), 1680 (NCOOEt). 1H-NMR (CDCl3) delta 1.20-1.27 (t, 3H, CH3), 2.13-2.27 (m, 2H, C4-H), 3.52-3.76 (m, 4H, C2-H & C5-H), 4.04-4.12 (m, 2H, OCH2), 7.31-7.42 (dd, 4H)

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 3219 - 3223
[2]Patent: US2006/52363,2006,A1 .Location in patent: Page/Page column 5
[3]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 1716 - 1723

21
[ 14891-10-2 ]
[ 959976-52-4 ]
ethyl (R)-3-[4-[(3aR,7aR)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-1-yl]-1-piperidyl]pyrrolidine-1-carboxylate [ No CAS ]
ethyl (S)-3-[4-[(3aR,7aR)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-1-yl]-1-piperidyl]pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃;	Example 14 and Example 15 Ethyl (3R)-3-[4-[(3aR,7aR)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-1-yl]-1-piperidyl]pyrrolidine-1-carboxylate and ethyl (3S)-3-[4-[(3aR,7aR)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-1-yl]-1-piperidyl]pyrrolidine-1-carboxylate Step A The preparation of Ethyl 3-[4-[(3aR,7aR)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-1-yl]-1-piperidyl]pyrrolidine-1-carboxylate To a stirred solution of (3aR,7aR)-1-piperidin-4-yloctahydro-2H-benzimidazol-2-one TFA salt (400 mg, 1.24 mmol) in dichloromethane (10 mL) was added acetic acid (0.35 mL 6.12 mmol)-ethyl 3-oxopyrrolidine-1-carboxylate (0.35 mL 2.23 mmol). Sodium triacetoxyoborohydride (0.8 g, 3.77 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was quenched with ice water, then diluted with dichloromethane (200 mL) and was washed successively with 1N NaOH (10 mL), water (10 mL) and brine. The solvent was removed under reduced pressure and the residue was purified by high pH prep LCMS (acetonitrile/water) to provide the mixture of two diastereoisomers (260 mg 58%).

Reference： [1]Patent: US2007/287695,2007,A1 .Location in patent: Page/Page column 32

22
[ 14891-10-2 ]
[ 959976-91-1 ]
ethyl (3R)-3-{4-[(3aR,7aS)-2-oxooctahydro-1H-indol-1-yl]piperidin-1-yl}pyrrolidine-1-carboxylate [ No CAS ]
ethyl (3S)-3-{4-[(3aR,7aS)-2-oxooctahydro-1H-indol-1-yl]piperidin-1-yl}pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 90 and 91 Ethyl (3S)-3-{4-[(3aR,7aS)-2-oxooctahydro-1H-indol-1-yl]piperidin-1-yl}pyrrolidine-1-carboxylate and ethyl (3R)-3-{4-[(3aR,7aS)-2-oxooctahydro-1H-indol-1-yl]piperidin-1-yl}pyrrolidine-1-carboxylate Step A The preparation of mixture of two diastereomers (3aR,7aS)-1-(piperidin-4-yl)hexahydro-1H-indol-2(3H)-one (0.38 g, 1.44 mmol) was dissolved in MeOH (5 ml) and triethylamine (0.200 ml, 1.44 mmol) was added followed by 1-N-ethoxycarbonyl-3-pyrrolidinone (0.226 g, 1.44 mmol). After 15 minutes a solution of sodium cyanoborohydride (0.135 g, 2.15 mmol) and zinc chloride (0.098 g, 0.72 mmol) in methanol (1 ml) was added dropwise at room temperature. The mixture was stirred at room temperature over night. The solvent was then removed under reduced pressure and the residue was diluted in dichloromethane (60 mL) and washed with 1N NaOH (10 mL) followed by brine (5 mL) and concentrated under reduced pressure. The crude was then purified by using high pH prep LCMS to provide the mixture of two enantiomers (0.15 g). MS (M+1): 364.26

Reference： [1]Patent: US2007/287695,2007,A1 .Location in patent: Page/Page column 77

23
[ 14891-10-2 ]
[ 1000198-73-1 ]

Yield	Reaction Conditions	Operation in experiment
61%		364 mg magnesium was suspended in 2 ml ether, under nitrogen. 150 ul 4-bromobenzo-trifluoride was added and then a solution of 12.6 mmol 4-bromobenzotrifluoride in 1.5 ml ether was added dropwise over a period of 10 minutes at room temperature. The mixture came mildly exothermic and turned red-brown while the grignard reagent formed during 1.5 h of stirring. The mixture was cooled down to 0 C. A solution of 12.5 mmol 1-N-ethoxycarbonyl-3-pyrrolidone in 14 ml ether was added dropwise. The reaction mixture was allowed to come to room temperature and stirred for 2 h30. 20% NH4Cl was added dropwise, at 0 C., to quench the reaction. The mixture was allowed to warm to room temperature. The aqueous layer was extracted 3 times with ether. The combined organic phases were washed with water and brine, dried over Na2SO4 and evaporated. The residue was purified on silica gel (eluent: heptane-ethyl acetate 1/1) to yield the title compound (61%) as a yellow solid. MS (m/e): 362.2 ([M+59], 100%).

Reference： [1]Patent: US2007/299071,2007,A1 .Location in patent: Page/Page column 7-8

24
[ 14891-10-2 ]
C₁₄H₁₇N₃O [ No CAS ]
ethyl endo-3-[3-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step C. The preparation of ethyl 3-[3-(2-oxo-2,3-dihydro-1/tauf-benzimidazol-1-yl)-8- azabicyclo[3.2.1]oct-8-yl]pyrrolidine-1-carboxylate <n="68"/>ferf-Butyl 3-(2-oxo-2,3-dihydro-1f/-benzimidazol-1-yl)-8- azabicyclo[3.2.1]octane-8-carboxylate (176.6 mg, 0.515 mmol) and trifluoroacetic acid (1 ml) in CH2CI2 (5ml) was stirred at RT for 2hrs. The reaction mixture was evaporated to dryness and the crude was used without purification. This amine, ethyl 3-oxopyrrolidine-i-carboxylate (81 mg, 0.515 mmol) and sodium triacetoxyborohydride (327 mg, 1.545 mmol) in CH2CI2 (5 ml) and acetic acid (0.5 ml) were stirred at RT overnight. The reaction mixture was washed with 1 M NaOH., organic phase was collected and the aqueous phase was extracted with CH2CI2 (2x). The combined organic phases was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by high pH HPLC to afford the title compound. Ethyl 3-[3-(2-oxo-2,3-dihydro-1 /-/-benzimidazoi-1-yI)-8- azabicyclo[3.2.1]oct-8-yl]pyrrolidine-1-carboxylate was obtained as white solid (140.3 mg, 71 % yield). 1 H NMR (400 MHz, METHANOL-D4): delta ppm 1.16-1.31 (m, 3 H), 1.64-1.85 (m, 3 H), 1.93 (t, J = 12.21 Hz, 2 H), 2.00-2.22 (m, 3 H), 2.24-2.40 (m, 2 H), 2.84-2.99 (m, 1 H), 3.11 (q, J = 8.92 Hz, 1 H), 3.21-3.43 (m, 3 H), 3.47-3.69 (m, 3 H), 4.09 (q, J = 7.03 Hz, 2 H), 4.59-4.78 (m, 1 H), 6.91-7.19 (m, 4 H). MS (M+1): 385.3

Reference： [1]Patent: WO2007/142585,2007,A1 .Location in patent: Page/Page column 66-67

25
[ 14891-10-2 ]
[ 16223-25-9 ]
ethyl 3-[4-(2-oxo-2,3-dihydro-1H-indol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%		Example 1. ethyl 3-[4-(2-oxo-2,3-dihydro-1H-indol-1-yl)piperidin-1- yl]pyrrolidine-1 -carboxylate ;<n="46"/>1-Piperindin-4-yl-1 ,3-dihydro-2H-indoi-2-one (216.3 mg, 1 mmol), ethyl 3- oxopyrrolidine-1-carboxylate (157 mg, 1 mmol) and sodium triacetoxyborohydride (424 mg, 2 mmol) in CH2Ci2 (5 ml) and acetic acid (0.5 ml) were stirred at RT overnight. The reaction mixture was washed with 1 M NaOH solution. The organic phase was collected and the aqueous phase was extracted with CH2CI2 (2x). The combined organic phases was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography, eluting with a gradient of 1 :3 EtOAc/hexane to 1 :2 EtOAc/hexane to give white solid (237 mg, 66% yield). The solid was re-purified by reverse phase HPLC (gradient 10-30% CH3CN in H2O containing 0.1 % trifluoroacetic acid) to give white solid as TFA salt. 1 H NMR (400 MHz, METHANOL-D4): delta ppm 1.26 (t, J = 7.13 Hz, 3 H), 2.04 (d, J = 17.58 Hz, 2 H), 2.11-2.30 (m, 1 H), 2.41-2.57 (m, 1 H), 2.78-2.97 (m, 2 H), 3.18-3.35 (m, 3 H), 3.37- 3.50 (m, 1 H), 3.55 (s, 2 H), 3.63-3.82 (m, 3 H), 3.84-4.04 (m, 2 H), 4.14 (q, J = 7.10 Hz, 2 H), 4.44 (t, J = 12.01 Hz, 1 H), 7.05 (t, J = 7.52 Hz, 1 H), 7.14 (d, J = 7.81 Hz, 1 H), 7.27 (t, J = 8.30 Hz, 2 H).

Reference： [1]Patent: WO2007/142585,2007,A1 .Location in patent: Page/Page column 44-45

26
[ 109-04-6 ]
[ 14891-10-2 ]
[ 41338-36-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 1868 - 1877

27
[ 626-55-1 ]
[ 14891-10-2 ]
[ 929083-36-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 1868 - 1877

28
[ 14891-10-2 ]
[ 1120-87-2 ]
[ 929083-37-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 1868 - 1877

29
[ 14891-10-2 ]
[ 344-04-7 ]
[ 929083-47-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 1868 - 1877

30
[ 2005-43-8 ]
[ 14891-10-2 ]
[ 929083-48-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 1868 - 1877

31
[ 14891-10-2 ]
[ 929083-50-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 1868 - 1877

32
[ 14891-10-2 ]
[ 929083-51-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 1868 - 1877

33
[ 14891-10-2 ]
[ 58039-20-6 ]

Reference： [1]Journal of Medicinal Chemistry,1980,vol. 23,p. 704 - 707

34
[ 14891-10-2 ]
[ 58039-19-3 ]

Reference： [1]Journal of Medicinal Chemistry,1980,vol. 23,p. 704 - 707

35
[ 14891-10-2 ]
1-ethoxycarbonyl-3-(1-pyrrolidinyl)-4-(3-oxo-oct-1-ene)-2,5-dihydro-1H-pyrrole [ No CAS ]

Reference： [1]Organic Magnetic Resonance,1982,vol. 19,p. 108 - 111

36
[ 14891-10-2 ]
[ 83455-92-9 ]

Reference： [1]Heterocycles,1982,vol. 19,p. 1605 - 1607
[2]Journal of Organic Chemistry,1983,vol. 48,p. 3644 - 3648

37
[ 14891-10-2 ]
[ 83455-93-0 ]

Reference： [1]Heterocycles,1982,vol. 19,p. 1605 - 1607
[2]Journal of Organic Chemistry,1983,vol. 48,p. 3644 - 3648

38
[ 14891-10-2 ]
[ 93592-80-4 ]

Reference： [1]Chemical and pharmaceutical bulletin,1985,vol. 33,p. 1826 - 1835

39
[ 14891-10-2 ]
[ 93591-94-7 ]

Reference： [1]Chemical and pharmaceutical bulletin,1985,vol. 33,p. 1826 - 1835

40
[ 14891-10-2 ]
[ 93591-93-6 ]

Reference： [1]Chemical and pharmaceutical bulletin,1985,vol. 33,p. 1826 - 1835

41
[ 14891-10-2 ]
platinum [ No CAS ]
[ 106183-69-1 ]

Reference： [1]Chemistry Letters,1986,p. 1021 - 1024

42
[ 14891-10-2 ]
platinum [ No CAS ]
[ 106183-67-9 ]

Reference： [1]Chemistry Letters,1986,p. 1021 - 1024

43
[ 14891-10-2 ]
[ 76182-40-6 ]

Reference： [1]Tetrahedron,1980,vol. 36,p. 1757 - 1761

44
[ 14891-10-2 ]
[ 343228-49-9 ]

Reference： [1]Tetrahedron,1980,vol. 36,p. 1757 - 1761

45
[ 14891-10-2 ]
[ 76182-50-8 ]

Reference： [1]Tetrahedron,1980,vol. 36,p. 1757 - 1761

46
[ 14891-10-2 ]
[ 76182-43-9 ]

Reference： [1]Tetrahedron,1980,vol. 36,p. 1757 - 1761

47
[ 14891-10-2 ]
[ 107273-61-0 ]

Reference： [1]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1959,vol. 79,p. 1133,1137
Chem.Abstr.,1960,p. 3376

48
[ 14891-10-2 ]
[ 105789-39-7 ]

Reference： [1]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1959,vol. 79,p. 1133,1137
Chem.Abstr.,1960,p. 3376

49
[ 109-72-8 ]
[ 87310-65-4 ]
[ 14891-10-2 ]
ammonium chloride [ No CAS ]
1-ethoxycarbonyl-3-hydroxy-3-(2-methylthiothien-4-yl)pyrrolidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	In diethyl ether; hexane;	n-Butyl-lithium (1.5M in hexane, 6.7 ml) was added dropwise to a stirred mixture of 4-bromo-2-methylthiothiophene (2.09 g) in diethyl ether (30 ml) which had been cooled to -70 C. The mixture was stirred at -70 C. for 6 minutes. A solution of 1-ethoxycarbonylpyrrolidin-3-one (1.57 g) in diethyl ether (5 ml) was added. The mixture was stirred for 1 hour and allowed to warm to ambient temperature. A saturated aqueous ammonium chloride solution (100 ml) was added and the mixture was extracted with ethyl acetate. The organic extract was dried (Na2 SO4) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus obtained 1-ethoxycarbonyl-3-hydroxy-3-(2-methylthiothien-4-yl)pyrrolidine as a gum (1.7 g, 60%).

Reference： [1]Patent: US5420298,1995,A

50
[ 109-72-8 ]
[ 14891-10-2 ]
[ 156538-07-7 ]
[ 130722-33-7 ]
[ 156538-06-6 ]

Yield	Reaction Conditions	Operation in experiment
68%	With acetic acid; In tetrahydrofuran; hexane; water;	The 1-ethoxycarbonyl-3-methoxy-3-[3-(naphth-2-ylmethoxy)phenyl]pyrrolidine used as a starting material was obtained as follows: n-Butyl-lithium (1.6M in hexane, 4 ml) was added dropwise to a stirred mixture of 3-(naphth-2-ylmethoxy)bromobenzene (1.88 g) and THF (30 ml) which had been cooled to -70 C. The mixture was stirred at -70 C. for 30 minutes. A solution of 1-ethoxycarbonylpyrrolidin-3-one (J. Med. Pharm. Chem., 1962, 5, 755; 0.94 g) in THF (5 ml) was added, the mixture was allowed to warm to ambient temperature and stirred for 1 hour. Acetic acid (2 ml) and water (50 ml) were added in turn and the mixture was extracted with ethyl acetate. The organic phase was dried (Na2 SO4) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluent. There was thus obtained 1-ethoxycarbonyl-3-hydroxy-3-[3-(naphth-2-ylmethoxy)phenyl]pyrrolidine (1.6 g, 68%) as a gum. NMR Spectrum 1.26 (t, 3H), 2.1-2.4 (m, 2H), 3.6-3.9 (m, 4H), 4.15 (q, 2H), 5.23 (s, 2H), 6.96 (m, 1H), 7.04 (m, 1H), 7.18 (m, 1H), 7.30 (t, 1H), 7.46-7.56 (m, 3H), 7.81-7.89 (m, 4H).

Reference： [1]Patent: US5420298,1995,A

51
[ 14891-10-2 ]
[ 1774-47-6 ]
[ 125033-33-2 ]

Yield	Reaction Conditions	Operation in experiment
	In diethyl ether; dimethyl sulfoxide; paraffin oil;	a) Ethyl 5-aza-1- oxaspiro[2,4]heptane-5-carboxylate 23.5 g (107 mmol) of trimethylsulphoxonium iodide and 3.3 g of sodium hydride (80% strength in paraffin oil) are initially introduced and 80 ml of absolute dimethyl sulphoxide are added dropwise at 10 C. The mixture is stirred for an hour at room temperature and 15.7 g (100 mmol) of ethyl 3-oxopyrrolidine-1-carboxylate [J. Med. Pharm. Chem. 5, 752 (1962] in 20 ml of absolute dimethyl sulphoxide are then added dropwise in the course of 15 minutes. The mixture is stirred for one hour at room temperature, poured onto a mixture of ice and saturated sodium chloride solution and extracted using diethyl ether. The ether solutions are washed with sodium chloride solution, dried over Na2 SO4, concentrated and distilled. Yield: 6 g Boiling point: 80 C./0.15 mbar

Reference： [1]Patent: US5173484,1992,A

52
[ 14891-10-2 ]
[ 108-44-1 ]
ethyl 3-[(3-methylphenyl)amino]-1-pyrrolidinecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12.4 parts (100%)	palladium; In thiophene; methanol;	Example 8 A mixture of 7.9 parts of ethyl 3-oxo-1-pyrrolidinecarboxylate, 5.35 parts of 3-methylbenzenamine, 1 part of a solution of thiophene in methanol 4% and 200 parts of methanol was hydrogenated at normal pressure and at 50 C. with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 12.4 parts (100%) of ethyl 3-[(3-methylphenyl)amino]-1-pyrrolidinecarboxylate as a residue (intermediate 19).
12.4 parts (100%)	palladium; In thiophene; methanol;	Example 8 A mixture of 7.9 parts of ethyl 3-oxo-1-pyrrolidinecarboxylate, 5.35 parts of 3-methylbenzenamine 1 part of a solution of thiophene in methanol 4% and 200 parts of methanol was hydrogenated at normal pressure and at 50C with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 12.4 parts (100%) of ethyl 3-[(3-methylphenyl)amino]-1-pyrrolidinecarboxylate as a residue (intermediate 19).

Reference： [1]Patent: US5001125,1991,A
[2]Patent: EP156433,1991,B1

53
[ 14891-10-2 ]
[ 59-88-1 ]
[ 63277-60-1 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; hydrogenchloride; In water; acetonitrile;	EXAMPLE 12 2-Carboethoxy-1,2,3,4-tetrahydropyrrolo[ 3,4-b]indole Phenylhydrazine hydrochloride (10.0 g., 0.069 mole). N-carbethoxy-3-pyrrolidinone (11.0 g., 0.069 mole) and dry pyridine (11.0 g., 0.138 mole) are combined in a reaction vessel maintained under a nitrogen atmosphere. The resulting mixture is stirred vigorously for 15 minutes at room temperature then heated at 70-80 C. for 20 minutes. The heat is removed and the reaction mixture, which had turned a deep red color and then thickened during the heating period, is allowed to cool to room temperature. After stirring for an additional 15 minutes at room temperature, the precipitated solid is collected by filtration, washed with benzene and dried to afford 7.35g. of the title compound, M.P. 191-194 C. The mother liquor was washed with 100 ml. of water, three 20 ml. portions of 1N hydrochloric acid, once with 40 ml. of saturated sodium bicarbonate solution, and once with saturated sodium chloride solution and finally dried over anhydrous sodium sulfate. The dried solution was then carbon treated (1/4 teaspoon of Darco G-60), gravity filtered and the filtrate evaporated to afford a dark oil. Upon slurrying the oil with 10 ml. of cold acetonitrile and filtering an additional 1.30g. of product was obtained, M.P. 193-196 C.

Reference： [1]Patent: US4014890,1977,A

54
[ 14891-10-2 ]
2-aminobenzamidine hydrochloride [ No CAS ]
ethyl 4'-aminospiro[pyrrolidine-3,2'(1'H)-quinazoline]-1-carboxylate hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 188 Ethyl 4'-aminospiro[pyrrolidine-3,2'(1'H)-quinazoline]-1-carboxylate hydrochloride This was prepared by the method of Example 173 using 2-aminobenzamidine hydrochloride and ethyl 3-oxopyrrolidine-1-carboxylate to give the title compound, MS (+EI) 274 ([M+H]+), 1H NMR (d6 -DMSO) (rotamers) 10.48 (1H, s), 9.2-8.2 (2H, m), 7.94 (1H, s), 7.88 (1H, d), 7.49 (1H, t), 6.89 (1H, d), 6.85 (1H, t), 4.04 (2H, dt), 3.6-3.4 (4H, m) 2.86-2.7 (1H, m), 2.09-2.02 (1H, m), 1.18 (3H, dq).

Reference： [1]Patent: US5883102,1999,A

55
[ 14891-10-2 ]
[ 2687-43-6 ]
1-(ethoxycarbonyl)pyrrolidin-3-one O-benzyloxime [ No CAS ]
1-(ethoxycarbonyl)pyrrolidin-3-one O-benzyloxime [ No CAS ]

Reference： [1]Synthesis,2008,p. 2353 - 2362

56
[ 14891-10-2 ]
[ 72748-99-3 ]
(R)-N-[1-(ethoxycarbonyl)pyrrolidin-3-ylidene]-2-(methoxymethyl)pyrrolidin-1-amine [ No CAS ]
(R)-N-[1-(ethoxycarbonyl)pyrrolidin-3-ylidene]-2-(methoxymethyl)pyrrolidin-1-amine [ No CAS ]

Reference： [1]Synthesis,2008,p. 2353 - 2362

57
[ 14891-10-2 ]
[ 613-94-5 ]
ethyl (Z)-3-(2-benzoylhydrazono)pyrrolidine-1-carboxylate [ No CAS ]
ethyl (E)-3-(2-benzoylhydrazono)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Synthesis,2008,p. 2353 - 2362

58
[ 14891-10-2 ]
[ 1576-35-8 ]
ethyl (Z)-3-(tosylhydrazono)pyrrolidine-1-carboxylate [ No CAS ]
ethyl (E)-3-(tosylhydrazono)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Synthesis,2008,p. 2353 - 2362

59
[ 5382-16-1 ]
[ 14891-10-2 ]
[ 5804-85-3 ]
[ 1131451-62-1 ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred solution of 4-hydroxypiperidine (464 mg, 4.58 mmol) and ethyl 3-oxopyrrolidine-1-carboxylate (610 mg, 3.82 mmol) in 1,2-dichloroethane (25 mL) was added titanium isopropoxide (1.09 g, 3.82 mmol), and the mixture was stirred at room temperature overnight. Then a 1.0 M solution of diethylaluminum cyanide (1.02 g, 9.17 mmol) was added at room temperature and the mixture was stirred for 24 h. Diluted with dichloromethane (25 mL) and quenched with saturated ammonium chloride solution (10 mL) at 0 C. Then mixture was filtered through a small pad of celite, and the resulting filtrate was concentrated in vacuo to afford the title compound as a yellow gum (1.0 g). 1H NMR (CDCl3, 400 MHz): delta 4.22 (q, 2H), 4.21-4.1 (dd, 1H), 3.79-3.62 (m, 3H), 3.38 (dd, 1H), 2.9 (brs, 1H), 2.7 (brs, 1H), 2.54-2.35 (m, 3H), 2.18-1.85 (brm, 3H), 1.68-1.45 (m, 3H), 1.25 (t, 3H). MS (M+1): 268.14.
		Step A. The preparation of ethyl 3-cyano-3-(4-hydroxy-1-piperidyl)pyrrolidine-1-carboxylate A stirred solution of 4-hydroxypiperidine (464 mg, 4.58 mmol) and ethyl 3-oxopyrrolidine-1-carboxylate (610 mg, 3.82 mmol) in 1,2-dichloroethane (25 mL) was added with titanium isopropoxide (1.09 g, 3.82 mmol), and the mixture was stirred at room temperature overnight. Then a 1.0 M solution of diethylaluminum cyanide (1.02 g, 9.17 mmol) was added at room temperature and the mixture was stirred for 24 hours. The reaction mixture was diluted with dichloromethane (25 mL) and quenched with saturated ammonium chloride solution (10 mL) at 0 C. Then mixture was filtered through a small pad of celite, and the filtrate was concentrated in vacuo to afford the title compound as a yellow gum (1.0 g). 1H NMR (CDCl3, 400 MHz): delta 4.22 (q, 2H), 4.21-4.1 (dd, 1H), 3.79-3.62 (m, 3H), 3.38 (dd, 1H), 2.9 (brs, 1H), 2.7 (brs, 1H), 2.54-2.35 (m, 3H), 2.18-1.85 (brm, 3H), 1.68-1.45 (m, 3H), 1.25 (t, 3H). MS (M+1): 268.14.

Reference： [1]Patent: US2009/76078,2009,A1 .Location in patent: Page/Page column 10; 21
[2]Patent: US2009/221567,2009,A1 .Location in patent: Page/Page column 59

60
[ 14891-10-2 ]
[ 105-56-6 ]
[ 220415-20-3 ]

Yield	Reaction Conditions	Operation in experiment
15%	With sulfur; triethylamine; In ethanol; at 0 - 20℃;	Ethyl 3-oxopyrrolidine-l-carboxylate (14.0 g, 89.1 mmol), ethyl cyanoacetate (10.1 g, 89.1 mmol) and sulfur (2.86 g, 89.1 mmol) in ethanol (44 mL) were cooled to 0-50C, and triethylamine (9.01 g, 89.1 mmol) was added dropwise. Subsequently, the mixture was warmed to rt and stirred overnight. The solvent was removed in vacuo, and the product was isolated after column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 2:1) to yield 4.04 g (15%) of the title compound.1H-NMR (400 MHz, DMSOd6): delta = 1.18-1.26 (m, 6H), 4.05-4.13 (m, 2H), 4.12-4.19 (m, 2H), 4.35-4.43 (m, 4H), 7.34-7.38 (m, 2H).LC/MS (method 2): R, = 1.07 min; MS (ESIpos): m/z = 285 [M+H]+.

Reference： [1]Patent: WO2009/33581,2009,A1 .Location in patent: Page/Page column 69

61
[ 13756-47-3 ]
[ 292638-85-8 ]
[ 14891-10-2 ]

Yield	Reaction Conditions	Operation in experiment
73%		Compound 12 (8.350 g, 29.59 mmol) was diluted with benzene (50 mL). Sodium hydride (1.420 g, 59.18 mmol) was added and the mixture was heated at reflux for 30 min. Methyl acrylate (3.057 g, 35.51 mmol) was added and the reaction mixture was heated at reflux for 8 h and then allowed to stir at room temperature for 16 h. 6 M HCl (30 mL) was added and the reaction mixture was heated at reflux for 16 h. The reaction mixture was allowed to cool to room temperature and the aqueous and organic phases were separated. The aqueous phase was extracted with EtOAc (3 x 30 mL) and the combined organic layer was washed with sat NaHCO3 (3 x 30 mL) and sat NaCl (30 mL). The organic layer was dried over sodium sulfate and concentrated to provide a yellow oil (3.089 g, 73%). 1H NMR (300 MHz, CDCl3) delta 4.39- 4.01 (m, 2 H), 3.82-3.78 (m, 4 H), 2.60 (t, J= 7.8 Hz, 2 H), 1.27 (q, J= 7.2 Hz, 3 H); CIMS m/z (rel intensity) 158 (MH+, 100).

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 4609 - 4619
[2]Patent: WO2009/140467,2009,A1 .Location in patent: Page/Page column 29

62
[ 14891-10-2 ]
(4aR,8aS)-1-(4-piperidyl)-3,4,4a,5,6,7,8,8a-octahydroquinazolin-2-one hydrochloride [ No CAS ]
[ 1185732-69-7 ]

Yield	Reaction Conditions	Operation in experiment
27.4%		The residue was dissolved in CH2Cl2 (5 mL), and ethyl 3-oxopyrrolidine-1-carboxylate (0.076 g, 0.48 mmol) and acetic acid (5.50 muL, 0.10 mmol) were added. The reaction mixture was stirred at room temperature for 45 minutes and then sodium triacetoxyborohydride (0.143 g, 0.67 mmol) was added. The reaction mixture was stirred at room temperature for 136 hours. Saturated aqueous NaHCO3 (5 mL) was added, the mixture was loaded onto a Varian ChemElut extraction cartridge, and the product was eluted with CH2Cl2 (3*8 mL). The eluant was concentrated in vacuo. The crude product was purified by preparative LC/MS (high pH) to give the title compound (gradient 35-55% CH3CN in H2O) as a mixture of diastereomers (27.4%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-D) delta ppm. 0.93-1.41 (m, 7H), 1.52-2.51 (m, 14H), 2.64-3.40 (m, 7H), 3.45-3.83 (m, 3H), 4.11 (q, J=7.3 Hz, 2H), 4.71 (d, J=3.5 Hz, 1H).

Reference： [1]Patent: US2009/221567,2009,A1 .Location in patent: Page/Page column 38

63
[ 14891-10-2 ]
[ 1009837-00-6 ]