[ CAS No. 104641-60-3 ] {[proInfo.proName]}

Name: 104641-60-3|(R)-3-Hydroxy-1-methyl-pyrrolidine|98%
Brand: Ambeed
SKU: A273989
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Quality Control of [ 104641-60-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 104641-60-3 ]

Product Details of [ 104641-60-3 ]

CAS No. :	104641-60-3	MDL No. :	MFCD03788747
Formula :	C₅H₁₁NO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	101.15	Pubchem ID :	-
Synonyms :

Calculated chemistry of [ 104641-60-3 ]

Physicochemical Properties

Num. heavy atoms :	7
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	32.01
TPSA :	23.47 Å²

Pharmacokinetics

GI absorption :	Low
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) :	-7.07 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.56
Log Po/w (XLOGP3) :	-0.22
Log Po/w (WLOGP) :	-0.7
Log Po/w (MLOGP) :	-0.16
Log Po/w (SILICOS-IT) :	0.26
Consensus Log Po/w :	0.15

Druglikeness

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

Water Solubility

Log S (ESOL) :	-0.33
Solubility :	47.5 mg/ml ; 0.469 mol/l
Class :	Very soluble
Log S (Ali) :	0.18
Solubility :	155.0 mg/ml ; 1.53 mol/l
Class :	Highly soluble
Log S (SILICOS-IT) :	0.17
Solubility :	150.0 mg/ml ; 1.48 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.34

Safety of [ 104641-60-3 ]

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 [ 104641-60-3 ]

* 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 [ 104641-60-3 ]
Downstream synthetic route of [ 104641-60-3 ]

[ 104641-60-3 ] Synthesis Path-Upstream 1~3

1
[ 50-00-0 ]
[ 40499-83-0 ]
[ 104641-60-3 ]

Yield	Reaction Conditions	Operation in experiment
92%	With formic acid In tetrahydrofuran for 5 h; Heating / reflux	In a 100 ml flask, 2 g (R)-3-Hydroxy pyrrolidine, 25 ml THF, 0.49 g paraformaldehyde and 1.5 g formic acid (90percent) were added. The mixture was stirred under reflux for 5 hours (until all solid disappeared), then cooled at 0° C. and added with 10 ml of NaOH solution (10 N) to adjust the pH to about 10. The organic layer was separated and dried over MgSO₄. After filtering the dried solution and removing the solvent (THF), an oily product (1.5 g, 92percent) of (R)3 was obtained. ¹H NMR (CDCl₃, 300 MHz): 1.50-1.60 (m, 1H), 1.98-2.10 (m, 1H), 2.25 (s, 3H), 2.25-2.40 (m, 2H), 2.50-2.60 (m, 1H), 2.61-2.70(m, 1H), 3.80(brs, 1H), 4.20-4.30(m, 1H).
85.6%	Stage #1: With sodium tetrahydroborate In methanol; water at 10 - 20℃; for 2.33333 h; Stage #2: With hydrogenchloride In methanol; water for 0.333333 h;	15 g (0.172 mol) of (3R)-pyrrolidin-3-ol (commercially available) were dissolved in 240 ml of MeOH. This solution was cooled to 10-15°C, and formaldehyde (124.5 mi of a 36 percent solution in water, diluted with 125 ml of MeOH) and NaBH4 (16.27 g, 0.43 mol) were added in small portions, alternativately during 1h, maintaining the temperature at 10-15°C. After 20 min the mixture was warmed to room temperature and the reaction continued for 1 hour. The reaction mixture was acidified with HCI 2N, stirred during 20 minutes and neutralised with solid NaHCO3. MeOH and most of the water were evaporated and the residue was diluted with a small quantity of water, basified with solid K2C03 and exhaustively extracted with CHC13. The organic phases were combined and dried over Na2SO4. CHCl3 was evaporated to give an oil which was purified by Kugelrohr distillation at reduced pressure (0.2-0. 3 mbar, 50-60°C oven) to give 14.91 g (85.6 percent) of the title product. 'H-NMR (CDCI3) :. No. 1.60-1. 80 (m, 1H), 2.10-2. 40 (m, 5H), 2.40-2. 70 (m, 2H), 2.75-2. 95 (m, 1H), 4.20-4. 40 (m, 1H), 4.40-4. 50 (bs, 1H, OH).

Reference： [1] Patent: US2007/123557, 2007, A1, . Location in patent: Page/Page column 16
[2] Patent: WO2003/87094, 2003, A2, . Location in patent: Page/Page column 34

2
[ 50-00-0 ]
[ 104706-47-0 ]
[ 104641-60-3 ]

Yield	Reaction Conditions	Operation in experiment
92%	With sodium hydroxide; formic acid In tetrahydrofuran; water at 60℃; for 2.33333 h; Heating / reflux	In a 100 ml flask, 4 g (R)-3-Hydroxy pyrrolidine hydrochloride salt, 50 ml THF and 1.3 g NaOH were added and stirred for 20 min. Then, 1.1 g paraforaldehyde and 4.8 g formic acid (90percent) were added. The mixture was heated (60° C.) and stirred at reflux for 2 hr until all solid disappeared. The mixture was cooled to 0° C., combined with 6.5 ml of 10 N NaOH solution (pH about 10), and extracted twice by ethyl ether (50 ml). The combined organic layer was dried over Na₂SO₄. Evaporation of the dried organic layer gave a yellowish, oily product of (R)3 (3.0 g, 92percent). ¹H NMR (CDCl₃, 300 MHz): 1.65-1.75 (m, 1H), 2.15-2.36 (m, 2H), 2.33 (s, 3H), 2.55-2.59 (m, 2H), 2.76-2.85 (m, 1H), 4.30-4.40(m, 1H), 4.8-5.10 (brs, 1H). ¹³C NMR (CDCl₃, 300 MHz): 35.4, 41.9, 54.7, 64.9, 70.9.

Reference： [1] Patent: US2007/123557, 2007, A1, . Location in patent: Page/Page column 18; 22
[2] Pharmazie, 2008, vol. 63, # 3, p. 200 - 209

3
[ 131237-81-5 ]
[ 104641-60-3 ]

Reference： [1] Journal of Medicinal Chemistry, 1991, vol. 34, # 4, p. 1314 - 1328
[2] Patent: WO2018/26869, 2018, A1, . Location in patent: Paragraph 0161; 0168; 0169; 0170; 0171; 0197; 0204-0207

[ 104641-60-3 ] Synthesis Path-Downstream 1~65

1
[ 2942-59-8 ]
[ 104641-60-3 ]
[ 91832-76-7 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 1314 - 1328

2
[ 59782-85-3 ]
[ 104641-60-3 ]
Sodium; 5-chloro-2-((R)-1-methyl-pyrrolidin-3-yloxy)-nicotinate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 1314 - 1328

3
[ 131237-81-5 ]
[ 104641-60-3 ]

Yield	Reaction Conditions	Operation in experiment
	With N-methylsuccinimide; sodium aluminum tetrahydride; lithium chloride; In tetrahydrofuran; at 15 - 40℃; for 2.5h;Inert atmosphere;	[0171] R(-)-malic acid (also known as (S)-2-hydroxysuccinic acid) (compound ) was reacted with methyl amine (CH3NH2) to form (R)-3-hydroxy-1-methylpyrrolidine-2,5- dione (compound ). (R)-3-hydroxy-1-methylpyrrolidine-2,5-dione (6) was treated with a reducing agent to form (R)-1-methylpyrrolidin-3-ol (compound 2). In one instance, reduction of compound 6 was performed using NaA1H4/LiC1. To a cooled solution of lithium chloride (0.11 mol) in THF was added NaA1H4 (0.22 mol) in toluene/THF under argon. Nmethylsuccinimide (0.083 mol) in THF was added while holding the temperature below 15C. After the addition was complete, the reaction was allowed to warm to room temperature. After 30 minutes at room temperature, the reaction was heated to greater than 40C for 2 hr. The reaction was then cooled to less than 5C. and toluene (50 ml) was then added. Water (9 ml) was then added slowly holding the temperature below 15C. Additional H20 or aqueous NaOH was used as necessary. The insoluble inorganic salts are removed by filtration. These solids are washed with additional THF or toluene to obtain a solution which contained N-methyl pyrrole, as determined by GLC analysis.

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 1314 - 1328
[2]Patent: WO2018/26869,2018,A1 .Location in patent: Paragraph 0161; 0168; 0169; 0170; 0171; 0197; 0204-0207

4
[ 57-41-0 ]
[ 104641-60-3 ]
[ 895148-84-2 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 1693 - 1697

5
[ 104641-60-3 ]
[ 895149-14-1 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 1693 - 1697

6
[ 104641-60-3 ]
1-methyl-3-(S)-(2-oxo-4,4-diphenyl-imidazolidin-1-yl)-1-benzyl-pyrrolidinium iodide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 1693 - 1697

7
[ 104641-60-3 ]
1-methyl-3-(S)-(2-oxo-4,4-diphenyl-imidazolidin-1-yl)-1-(2-phenoxy-ethyl)-pyrrolidinium iodide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 1693 - 1697

8
[ 104641-60-3 ]
[ 104713-31-7 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 1314 - 1328

9
[ 104641-60-3 ]
[ 104641-65-8 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 1314 - 1328

10
[ 104641-60-3 ]
2-((R)-1-Methyl-pyrrolidin-3-yloxy)-nicotinoyl chloride [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 1314 - 1328

11
[ 104641-60-3 ]
[ 131346-29-7 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 1314 - 1328

12
[ 104641-60-3 ]
[ 131321-35-2 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 1314 - 1328

13
[ 104641-60-3 ]
5-Chloro-2-((R)-1-methyl-pyrrolidin-3-yloxy)-nicotinoyl chloride [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 1314 - 1328

14
[ 104641-60-3 ]
[ 104611-67-8 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 1314 - 1328

15
[ 104641-60-3 ]
[ 104641-57-8 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 1314 - 1328

16
[ 104641-60-3 ]
[ 131321-37-4 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 1314 - 1328

17
[ 787628-96-0 ]
[ 104641-60-3 ]
[ 896125-71-6 ]

Yield	Reaction Conditions	Operation in experiment
	In acetonitrile; at 20℃; for 3h;	A solution of 2-Bromo-N-pyrazin-2-yl-acetamide (Intermediate A)(3.0 g, 13.9 mmol) in acetonitrile (80 ml) is treated with(R)-hydroxy-methyl pyrrolidone (1.4 g, 13.9 mmol). The resulting suspension is stirred at room temperature for 3 hours and then filtered. The solid is washed with acetonitrile and dried in vacuo overnight to yield the titled compound as a brown solid.

Reference： [1]Patent: WO2006/66928,2006,A1 .Location in patent: Page/Page column 22

18
[ 896125-72-7 ]
[ 104641-60-3 ]
[ 1012325-95-9 ]

Yield	Reaction Conditions	Operation in experiment
	In acetonitrile; at 20℃; for 2h;	A stirred suspension of 2-bromo-N-pyridazin-3-yl-acetamide (0.5 g, 2.31 mmol) in acetonitrile (10 ml) is treated with (R)-3-hydroxy-l-methyl pyrrolidine (0.234 g, 2.31 mmol). The suspension is stirred at room temperature for 2 hours and then filtered and washed with acetonitrile to yield the titled compound.

Reference： [1]Patent: WO2006/66928,2006,A1 .Location in patent: Page/Page column 23

19
[ 87-69-4 ]
[ 104641-60-3 ]
[ 104712-67-6 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; diethyl ether;	A sample of 1 g of this material was treated with 1.5 g of (2R, 3R) -tartaric acid in MeOH/ether to obtain 2.3 g of the tartrate salt [a] p = +10. 6 (c=1, H20)'. ' [a] 22 D = +11. 1 (c=9.57, H20), Sleevi et al. J. Med. Chem. , (1991), Vol 34, n4, 1314- 1328).

Reference： [1]Patent: WO2003/87094,2003,A2 .Location in patent: Page/Page column 34

20
[ 50-00-0 ]
[ 40499-83-0 ]
[ 104641-60-3 ]

Yield	Reaction Conditions	Operation in experiment
92%	With formic acid; In tetrahydrofuran; for 5h;Heating / reflux;	In a 100 ml flask, 2 g (R)-3-Hydroxy pyrrolidine, 25 ml THF, 0.49 g paraformaldehyde and 1.5 g formic acid (90%) were added. The mixture was stirred under reflux for 5 hours (until all solid disappeared), then cooled at 0 C. and added with 10 ml of NaOH solution (10 N) to adjust the pH to about 10. The organic layer was separated and dried over MgSO4. After filtering the dried solution and removing the solvent (THF), an oily product (1.5 g, 92%) of (R)3 was obtained. 1H NMR (CDCl3, 300 MHz): 1.50-1.60 (m, 1H), 1.98-2.10 (m, 1H), 2.25 (s, 3H), 2.25-2.40 (m, 2H), 2.50-2.60 (m, 1H), 2.61-2.70(m, 1H), 3.80(brs, 1H), 4.20-4.30(m, 1H).
85.6%		15 g (0.172 mol) of (3R)-pyrrolidin-3-ol (commercially available) were dissolved in 240 ml of MeOH. This solution was cooled to 10-15C, and formaldehyde (124.5 mi of a 36 % solution in water, diluted with 125 ml of MeOH) and NaBH4 (16.27 g, 0.43 mol) were added in small portions, alternativately during 1h, maintaining the temperature at 10-15C. After 20 min the mixture was warmed to room temperature and the reaction continued for 1 hour. The reaction mixture was acidified with HCI 2N, stirred during 20 minutes and neutralised with solid NaHCO3. MeOH and most of the water were evaporated and the residue was diluted with a small quantity of water, basified with solid K2C03 and exhaustively extracted with CHC13. The organic phases were combined and dried over Na2SO4. CHCl3 was evaporated to give an oil which was purified by Kugelrohr distillation at reduced pressure (0.2-0. 3 mbar, 50-60C oven) to give 14.91 g (85.6 %) of the title product. 'H-NMR (CDCI3) :. No. 1.60-1. 80 (m, 1H), 2.10-2. 40 (m, 5H), 2.40-2. 70 (m, 2H), 2.75-2. 95 (m, 1H), 4.20-4. 40 (m, 1H), 4.40-4. 50 (bs, 1H, OH).

Reference： [1]Patent: US2007/123557,2007,A1 .Location in patent: Page/Page column 16
[2]Patent: WO2003/87094,2003,A2 .Location in patent: Page/Page column 34

21
[ 104641-60-3 ]
[ 26454-53-5 ]
[ 616866-15-0 ]

Yield	Reaction Conditions	Operation in experiment
93%	In chloroform; at 0 - 20℃;	2 g of 9H-Xanthene-9-carboxylic acid (0.0088 mol) were dissolved in 30 ml of CHCI3 (ethanol free). The solution was cooled at 0C and 1.08 ml (0.0123 mol) of oxalyl chloride and a drop of DMF was added. The mixture was stirred and allowed to warm to room temperature. After an hour at this temperature the solvents were evaporated and the residue was dissolved in CHCI3 and evaporated again. This procedure was repeated two times. The solid obtained (2.19 g) was dissolved in 20 ml of CHCI3 and added to a solution of 0.975 g (0.0097 mol) of (3R)-1-methylpyrrolidin-3-ol (Intermediate 1-19) in 15 ml of CHCI3 cooled at 0-5C. The reaction mixture was allowed-to warm to room temperature and stirred overnight. The solvent was evaporated and the residue was dissolved in toluene and extracted with HCI 2N. The aqueous layer was basified with K2CO3 and extracted with CHCI3. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness to yield 2.53 g (93%) of the title product as an oil. 1H-NMR (CDCl3): No. 1. 65-1.85 (m, 1 H), 2.05-2. 42 (m, 2H), 2.30 (s, 3H), 2.45-2. 60 (m, 1H), 2.60-2. 80 (m, 2H), 5.0 (s, 1 H), 5.05-5. 20 (m, 1 H), 7.0-7. 25 (m, 4H), 7.25-7. 40 (m, 4H). MS [M+1] + : 310

Reference： [1]Patent: WO2003/87094,2003,A2 .Location in patent: Page/Page column 28

22
[ 26447-85-8 ]
[ 104641-60-3 ]
(R)-1-methylpyrrolidin-3-yl 2-hydroxy-2,2-di(thiophen-2-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%	With sodium hydride; In toluene; at 120℃; for 2h;	Methyl 2,2-dithienylglycolate (1.0 g, 3.9 mmol) was dissolved in 25 mL of dry toluene.3R-3-hydroxy-1-methylpyrrolidine (465 mg, 4.6 mmol) was added,Warm up to 120C,Sodium hydrogen (85 mg, 2.1 mmol) was added in 3 batches and reacted for 2 h.The reaction was extracted 3 times with 2N hydrochloric acid,Combine the aqueous layers and wash with a small amount of ethyl acetate, use solid sodium carbonate to adjust the water layer to alkaline (to bubble free)The aqueous layer is extracted three times with ethyl acetate.Combining organic layersThe organic layer was washed with 1N sodium hydroxide solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give a yellow solid (450 mg, 35%).
	With sodium hydride; In toluene; at 20℃; for 3.5h;Heating / reflux;	1 g of 2-Hydroxy-2, 2-dithien-2-ylacetic acid methyl ester (0.0039 mol) was dissolved in 30 ml of toluene. To this solution were added 0.394 g (0.0039 mol) of (3R)-1-methylpyrrolidin- 3-ol (Intermediate 1-19), and 0.078 g (0.00195 mol) of HNa (60% dispersion in mineral oil). The mixture was stirred 30 min at room temperature, refluxed for 1 hour, and then refluxed with continuous removal of distillate with replacement with fresh toluene when necessary for 2 hours. The cooled mixture was extracted with 2N HCI, the aqueous layer was washed with a small volume of ethyl acetate, basified with solid K2CO3 and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The yield was 0.73 g (58%) of the title product (structure confirmed by'H-NMR). This product was purified by chromatography on silica gel eluting with chloroform/ethanol/NH40H (200: 8: 1). Appropiate fractions were combined and evaporated to give the title compound. m. p.: 84C. 'H-NMR (DMSO-d6) :. No. 1.62-1. 75 (m, 1H), 2.10-2. 32 (m, 2H), 2.21 (s, 3H), 2.45-2. 55 (m, 1H), 2.55-2. 70 (m, 2H), 5.18 (m, 1H), 6.95-7. 0 (m, 2H), 7.05-7. 15 (m, 2H), 7.32 (s, 1H, OH), 7.45-7. 50 (m, 2H). MS [M+1] + : 324

Reference： [1]ChemMedChem,2017,vol. 12,p. 1173 - 1182
[2]Patent: CN103965178,2018,B .Location in patent: Paragraph 0035-0037
[3]Patent: WO2003/87094,2003,A2 .Location in patent: Page/Page column 27

23
[ 440676-20-0 ]
[ 104641-60-3 ]
2-cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid (3R)-1-methylpyrrolidin-3-yl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%	With sodium hydride; In toluene; for 24h;Heating / reflux; Dean-Stark system;	5.0 g (0.021 mol) of 2-Cyclohexyl-2-fur-2-yl-2-hydroxyacetic acid methyl ester were dissolved in 150 ml of dry toluene. To this solution 2.12 g (0.021 mol) of (3R)-1- methylpyrrolidin-3-ol (Intermediate 1-19) and 500 mg (0.021 mol) of HNa were added and the mixture was refluxed using a Dean-Stark system for 24 hours. The reaction mixture was cooled, and extracted with HCI 2N. The aqueous layer was basified with K2CO3 and extracted with AcOEt (3 x 100 ml). The organic layers were combined, dried over Na2SO4 and evaporated to dryness to yield a residue which was purified by chromatography on silica gel eluting with chloroform plus isopropanol (0% 10%). Appropiate fractions were combined and evaporated to give 1.37 g (21 %) of the title product as an oil. 'H-NMR (CDCI3) : 6 7.38 (s, 1 H), 6.37-6. 30 (m, 2H), 5.30-5. 22 (m, 1 H), 2.87-2. 58 (m, 3H), 2.50-2. 10 (m, 3H), 2. 36 and 2.32 (s, 3H), 1.93-1. 62 (m, 4H), 1.38-1. 07 (m, 7H). MS [M+1] + : 308

Reference： [1]Patent: WO2003/87094,2003,A2 .Location in patent: Page/Page column 30

24
[ 1216-44-0 ]
[ 104641-60-3 ]
9-hydroxy-9H-fluorene-9-carboxylic acid (3R)-1-methylpyrrolidin-3-yl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31%	sodium; In toluene; for 24h;Heating / reflux; Dean-Stark system;	0.980 g (0.0041 mol) of 9-Hydroxy-9H-fluorene-9-carboxylic acid methyl ester were dissolved in 30 ml of toluene. To this solution 0.412 g (0.0041 mol) of (3R)-1- methylpyrrolidin-3-ol (Intermediate 1-19) and a catalitic amount of Na () were added and the mixture was refluxed using a Dean-Stark system for 24 hours. The reaction mixture was cooled, and extracted with HCI 2N. The aqueous layer was basified with K2CO3 and extracted with AcOEt (3 x 100 ml). The organic layers were combined, dried over Na2SO4 and evaporated to dryness to yield a residue which was purified by chromatography on silica gel eluting with chloroform plus isopropanol (0% 20%). Appropiate fractions were combined and evaporated to give 0.390 g (31%) of the title compound as an oil. 'H-NMR (CDCl3) : 8 7.65 (d, 2H), 7.51 (d, 2H), 7.43-7. 37 (m, 2H), 7.33-7. 27 (m, 2H), 5.11 (m, 1H), 2.65-2. 59 (m, 1H), 2.26-2. 17 (m, 3H), 2.07-1. 93 (m, 1H), 1.99 (s, 3H), 1.57-1. 45 (m, 1 H). MS [M+1] + : 310

Reference： [1]Patent: WO2003/87094,2003,A2 .Location in patent: Page/Page column 29

25
[ 2942-59-8 ]
methane sulfonic acid [ No CAS ]
[ 104641-60-3 ]
[ 104641-63-6 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; triphenylphosphine; In tetrahydrofuran; tetrachloromethane; dichloromethane; mineral oil;	(R)-2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]1,4-oxazepin-5-(4H)-one hydrochloride [1:1] A solution of 47.4 g (0.3 mole) of 2-chloronicotinic acid and 30 g (0.3 mole) of <strong>[104641-60-3](R)-1-methyl-3-pyrrolidinol</strong> in 400 ml of tetrahydrofuran was added over a period of 1 hr to a stirred suspension of 26.4 g (0.66 mole) of 60% sodium hydride/mineral oil in 500 ml of tetrahydrofuran at 55-60 C. The mixture was stirred at reflux for 2.5 hr and allowed to cool to 25 C. About 400 ml of methylene chloride was added to the slurry followed by a dropwise addition of 34.5 g (0.36 mole) of methane sulfonic acid in 100 ml of methylene chloride. The mixture was stirred for 10 min and 157 g (0.6 mole) of triphenylphosphine was added followed by 200 ml of carbon tetrachloride. The mixture was heated to reflux for 4 hr. To the cooled (25 C.) solution was added 100 ml of triethylamine at a rapid drop. The solution was concentrated on the rotary evaporator and the residue was partitioned between methylene chloride and dilute hydrochloric acid. The methylene chloride was extracted 6 times with dilute hydrochloric acid. The acid extracts were combined, made basic with sodium hydroxide and extracted with chloroform which was dried and concentrated. The residue was dissolved in isopropyl alcohol and treated with a solution of hydrogen chloride in isopropyl alcohol. The resulting hydrochloride weighed 25 g (30%). One gram was recrystallized from isopropyl alcohol, m.p. 152-154 C.; [alpha]D25 =+36.2 (water). Analysis: Calculated for C11 H14 N2 O2 Cl2: C, 47.67; H, 5.09; N, 10.11. Found: C, 47.65; H, 5.20; N, 9.03.
	With hydrogenchloride; triphenylphosphine; In tetrahydrofuran; tetrachloromethane; dichloromethane; mineral oil;	(R)-2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepin-5-(4H)-one hydrochloride [1:1] A solution of 47.4 g (0.3 mole) of 2-chloronicotinic acid and 30 g (0.3 mole) of <strong>[104641-60-3](R)-1-methyl-3-pyrrolidinol</strong> in 400 ml of tetrahydrofuran was added over a period of 1 hr to a stirred suspension of 26.4 g (0.66 mole) of 60% sodium hydride/mineral oil in 500 ml of tetrahydrofuran at 55-60 C. The mixture was stirred at reflux for 2.5 hr and allowed to cool to 25 C. About 400 ml of methylene chloride was added to the slurry followed by a dropwise addition of 34.5 g (0.36 mole) of methane sulfonic acid in 100 ml of methylene chloride. The mixture was stirred for 10 min and 157 g (0.6 mole) of triphenylphosphine was added followed by 200 ml of carbon tetrachloride. The mixture was heated to reflux for 4 hr. To the cooled (25 C.) solution was added 100 ml of triethylamine at a rapid drop. The solution was concentrated on the rotary evaporator and the residue was partitioned between methylene chloride and dilute hydrochloric acid. The methylene chloride was extracted 6 times with dilute hydrochloric acid. The acid extracts were combined, made basic with sodium hydroxide and extracted with chloroform which was dried and concentrated. The residue was dissolved in isopropyl alcohol and treated with a solution of hydrogen chloride in isopropyl alcohol. The resulting hydrochloride weighed 25 g (30%). One gram was recrystallized from isopropyl alcohol, m.p. 152-154 C.; [alpha]D25 =+36.2 (water). Analysis: Calculated for C11 H14 N2 O2 Cl2: C, 47.67; H, 5.09; N, 10.11. Found: C, 47.65; H, 5.20; N, 9.03.

Reference： [1]Patent: US4592866,1986,A
[2]Patent: US4705853,1987,A

26
(R)-1-methyl-3-pyrrolidinol-(2R,3R) tartrate [ No CAS ]
[ 104641-60-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide;	Preparation 47 (R)-1-Methyl-3-pyrrolidinol A 200 g sample of (R)-1-methyl-3-pyrrolidinol-(2R,3R) tartrate [1:1] was treated with 135 g of potassium hydroxide and the resulting solution continuously extracted with chloroform for 24 hr. The chloroform extract was dried over anhydrous sodium sulfate, concentrated and distilled. Yield of product was 73 g, b.p. 103-106/35 mm, [alpha]D25 =-0.852 (neat). Analysis: Calculated for C5 H11 NO: C, 59.37; H, 10.96; N, 13.85. Found: C, 57.71; H, 10.78; N, 13.49.

Reference： [1]Patent: US4592866,1986,A

27
(R)-1-Methyl-3-pyrrolidinol(2R,3R)-tartrate [ No CAS ]
[ 104641-60-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide;	PREPARATION 47 (R)-1-Methyl-3-pyrrolidinol A 200 g sample of (R)-1-methyl-3-pyrrolidinol-(2R,3R)tartrate [1:1] was treated with 135 g of potassium hydroxide and the resulting solution continuously extracted with chloroform for 24 hr. The chloroform extract was dried over anhydrous sodium sulfate, concentrated and distilled. Yield of product was 73 g, b.p. 103-106/35 mm, [alpha]D25 =-0.852 (neat). Analysis: Calculated for C5 H11 NO: C, 59.37; H, 10.96; N, 13.85. Found: C, 57.71; H, 10.78; N, 13.49.

Reference： [1]Patent: US4705853,1987,A

28
[ 19833-96-6 ]
[ 104641-60-3 ]
C₁₈H₂₅NO₃ [ No CAS ]

Reference： [1]Patent: WO2004/54971,2004,A1 .Location in patent: Page/Page column 11-12

29
C₁₄H₁₇ClO [ No CAS ]
[ 104641-60-3 ]
(3R)-1-methylpyrrolidin-3-yl (2R)-2-cyclopentyl-2-phenylpropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; at 40℃; for 20h;	A solution of (2i?)-2-Cyclopentyl-2-phenylpropanoic acid (Example Ie), 0.8 g) in toluene (20 mL) was treated with thionyl chloride (5 mL) and the resultant mixture heated at 100C for 2hours. The solvent was removed under reduced pressure and the residue azeotroped three times with toluene yielding 0.87 g of the acid chloride. A solution of the acid chloride (0.43 g) in dichloromethane (7 mL) was treated with (R)-l-methyl-3- hydroxypyrrolidine (556 mg) (obtained from Lancaster Synthesis Limited with a quoted e.e. of 99%) and the reaction mixture was heated at 4O0C for 20 hours. The reaction mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution, the organic layer was dried and evaporated under reduced pressure. The crude product was purified by flash chromatography on a silica column, eluting with EPO <DP n="40"/>1% triethylamine in ethyl acetate/iso-hexane (1/1) to yield the sub-titled compound (0.26 g)- m/e 302 (M+H+, 100%)

Reference： [1]Patent: WO2006/112778,2006,A1 .Location in patent: Page/Page column 38; 39

30
C₁₄H₁₇ClO [ No CAS ]
[ 104641-60-3 ]
(3R)-1-methylpyrrolidin-3-yl (2S)-2-cyclopentyl-2-phenylpropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; at 40℃; for 20h;	A solution of (25)-2-Cyclopentyl-2-phenylpropanoic acid (Example 3b), 0.85 g) in toluene (100 mL) was treated with thionyl chloride (15 mL) and the resultant mixture heated at 1000C for 2hours. The solvent was removed under reduced pressure and the residue azeotroped three times with toluene yielding 0.87 g of the acid chloride. A solution of the acid chloride (0.43 g) in dichloromethane (7 mL) was treated with (i?)-l-methyl-3- hydroxypyrrolidine (556 mg) (obtained from Lancaster Synthesis Limited with a quoted e.e. of 99%) and the reaction mixture was heated at 400C for 20 hours. The reaction mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate, the organic layer was separated and dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The crude product was purified by flash chromatography on a silica column, eluting with 1% triethylamine in ethyl acetate/iso- hexane (1/1) to yield the sub-titled compound (0.23 g). m/e 302 (M+H+, 100%)

Reference： [1]Patent: WO2006/112778,2006,A1 .Location in patent: Page/Page column 43

31
[ 50-00-0 ]
[ 104706-47-0 ]
[ 104641-60-3 ]

Yield	Reaction Conditions	Operation in experiment
92%	With sodium hydroxide; formic acid; In tetrahydrofuran; water; at 60℃; for 2.33333h;Heating / reflux;	In a 100 ml flask, 4 g (R)-3-Hydroxy pyrrolidine hydrochloride salt, 50 ml THF and 1.3 g NaOH were added and stirred for 20 min. Then, 1.1 g paraforaldehyde and 4.8 g formic acid (90%) were added. The mixture was heated (60 C.) and stirred at reflux for 2 hr until all solid disappeared. The mixture was cooled to 0 C., combined with 6.5 ml of 10 N NaOH solution (pH about 10), and extracted twice by ethyl ether (50 ml). The combined organic layer was dried over Na2SO4. Evaporation of the dried organic layer gave a yellowish, oily product of (R)3 (3.0 g, 92%). 1H NMR (CDCl3, 300 MHz): 1.65-1.75 (m, 1H), 2.15-2.36 (m, 2H), 2.33 (s, 3H), 2.55-2.59 (m, 2H), 2.76-2.85 (m, 1H), 4.30-4.40(m, 1H), 4.8-5.10 (brs, 1H). 13C NMR (CDCl3, 300 MHz): 35.4, 41.9, 54.7, 64.9, 70.9.

Reference： [1]Patent: US2007/123557,2007,A1 .Location in patent: Page/Page column 18; 22
[2]Pharmazie,2008,vol. 63,p. 200 - 209

32
[ 64471-47-2 ]
[ 104641-60-3 ]
[ 616866-21-8 ]

Yield	Reaction Conditions	Operation in experiment
44%	With sodium; In toluene; for 3h;	A solution of R(-)2 (0.7 g, 3 mmol) and (R)3 (0.7 g, 7 mmol) in 40 ml of toluene was heated until 20 ml of toluene had distilled. Approximately 0.003 g of sodium was added, and the solution was stirred and heated for 2 h as the distillation was continued. More toluene was added at such a rate as to keep the reaction volume constant. Additional sodium was added at the end of an hour. The solution was then cooled and extracted with 3N HCl. The acid extract was made alkaline with concentrated NaOH and extracted three times with ether. Removal of dried ether solution gave a crude oil. Flash chromatography of the crude product on silica gel with 8:1 of EtOAc and EtOH gave an oil product of 4 (0.4 g, 44%). 1H NMR (CDCl3, 300 MHz): 1.28-1.37, 1.51-1.70, 1.83-1.90[8H, m, (CH2)4], 2.27-2.40 (m, 3H), 2.52-2.55 (m, 1H), 2.64-2.72(m, 1H), 2.74-2.81(m, 1H), 2.33(3H, s, NCH3), 2.93[1H, p, CHC(OH)], 3.85(1H, bs, OH), 5.22(m, 1H), 7.24-7.27, 7.31-7.35, 7.64-7.66(5H, m, Ph)ppm.

Reference： [1]Pharmazie,2008,vol. 63,p. 200 - 209
[2]Patent: US2007/123557,2007,A1 .Location in patent: Page/Page column 16

33
[ 860644-54-8 ]
[ 104641-60-3 ]
(3R)-1-methylpyrrolidin-3-yl (2S)-2-cyclopentyl-2-hydroxy-2-phenylacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61.5%	With sodium; In n-heptane; at 25 - 110℃; for 4h;	In a 250 ml 3-neck flask equipped with Dean-Stark condenser, a mixture of methyl S(+)-cyclopentylmandelate, 13 (2 g, 8.8 mmol), <strong>[104641-60-3](R)-3-hydroxy-N-methylpyrrolidine</strong>, (R)-3 (2 g, 20 mmol), and 100 ml of heptane was stirred and heated (110 C.) until 20 ml of heptane had been distilled. The temperature was reduced to 25 C., and approximately 0.003 g of sodium was added. The mixture was stirred and heated to 110 C. again for 3 hr as the distillation was continued. An additional piece of sodium (0.002 g) was added at the 1 hr point. More heptane was added at such a rate as to keep the reaction volume constant. The mixture was cooled to 0 C., mixed with 5 ml of water, and the organic layer was separated. The organic layer was extracted with 3N HCl. The acid extract was made alkaline (pH 10) with 5N NaOH and extracted three times with ether. Removal of dried ether solution (over Na2SO4) gave a clear, oily product 14 (1.6 g, 61.5%). 1H NMR (CDCl3, 300 MHz): 1.28-1.80 mum, 9H], 2.15-2.25 (m, 1H), 2.30-2.40 (m, 1H), 2.37 (s, 3H), 2.65-2.80 (m, 3H), 2.90-3.00 (m, 1H), 3.85(1H, brs, OH), 5.22(m, 1H), 7.20-7.35 (m, 3H), 7.64-7.70(m, 2H). 13C NMR (CDCl3, 300 MHz):26.0, 26.4, 26.5, 26.7, 32.1, 42.0, 47.1, 54.8, 62.0, 76.5, 79.1, 125.8, 127.3, 128.0, 141.7, 175.3.

Reference： [1]Patent: US2007/123557,2007,A1 .Location in patent: Page/Page column 18; 22
[2]Pharmazie,2008,vol. 63,p. 200 - 209

34
[ 1061750-40-0 ]
[ 104641-60-3 ]
[ 1061749-60-7 ]

Yield	Reaction Conditions	Operation in experiment
20%		Compound 13-1 : N- {2-(3,5-Dimethyl-rhoyrazol-l -ylV6-r3-((R)-l -methyl-pyrrolidin-3- yloxymethyl Vphenyl] -pyrimidin-4-yl I -acetamide; To a solution of Intermediate 22 (0.72 mmol, 300 mg) in anhydrous DMF (2 mL) was added sodium iodide (0.72 mmol, 108 mg). The reaction mixture was stirred at room temperature for ten minutes. A solution of (R)-(-)-l-methyl-3- hydroxypyrrolidine (1.1 mmol, 110 mg) in anhydrous DMF (1.0 mL) and sodium hydride (0.72 mmol, 30 mg) was then added. The reaction mixture was stirred at 60 0C for 12 hr. Once cool, the reaction was diluted with methanol, filtered and purified by HPLC/MS using 15-75% acetonitrile in water (0.05%TFA) to yield the title compound (20%). LCMS (Method 1) m/z 421.2 [MH+], Tr = 5.57 min.

Reference： [1]Patent: WO2008/116185,2008,A2 .Location in patent: Page/Page column 57

35
[ 104641-60-3 ]
[ 124-63-0 ]
[ 952747-40-9 ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 4601 - 4608
[2]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 2742 - 2746

36
[ 1061750-32-0 ]
[ 104641-60-3 ]
[ 1061748-73-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 5402 - 5405

37
[ 1061750-36-4 ]
[ 104641-60-3 ]
[ 1061749-23-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 5402 - 5405

38
[ 1061750-39-7 ]
[ 104641-60-3 ]
[ 1061749-60-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 5402 - 5405

39
[ 1197848-21-7 ]
[ 104641-60-3 ]
[ 1197848-64-8 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of (R)-I -methylpyrrolidin-3-ol (66 mg, 0.65 mmol) in THF (3 ml) was added NaH (25 mg, 65% in mineral oil). The mixture was stirred for 30 min and 4-chloro-N- ((6-chloro-2-(4-fluorophenyl)imidazo[ 1 ,2-a]pyridin-3-yl)methyl)pyrimidin-2-amine (50 mg, 0.13 mmol) was added. The mixture was heated from 65 to 95 0C until the reaction was <n="132"/>completed. The mixture was diluted with ethyl acetate and the resulting mixture was washed with saturated NaHCO3 and brine, dried over Na2SO4 and concentrated by evaporation. The crude product was purified by silica gel chromatography (methanol/methylene chloride gradient) to obtain the desired product. 1H-NMR (CDCl3, 400 MHz, delta) 8.23 (s, IH), 7.69 (m, 2H), 7.52 (d, J = 9.5Hz, IH), 7.12 (m, 3H), 5.97 (s, IH), 5.36 (s, IH), 4.96 (d, J = 4.7Hz, 2H), 2.80 (m, 3H), 2.68 (m, IH), 2.34 (s, 3H), 2.25 (m, 2H), 1.96 (m, IH) ppm; m/e 453 (M+H)+.

Reference： [1]Patent: WO2009/143156,2009,A2 .Location in patent: Page/Page column 130-131

40
[ 104641-60-3 ]
[ 64471-45-0 ]
[ 616866-21-8 ]

Yield	Reaction Conditions	Operation in experiment
> 90%	With 1,1'-carbonyldiimidazole; In toluene;	[0174] R(-)-cyclopentylmandelic acid (4) was coupled to (R)-1-methylpyrrolidin-3-ol(2) to make the diasterically pure 2R3?R-glycopyrrolate base (compound ) using 1,1- carbonyldiimideazole (CDI) activated esterification. The R2R3?R-glycopyrrolate base (compound ) was obtained in greater than 90% yield.
60%		0.545 g (0.0025 mol) of (2R)-2-cyclopentyl-2-hydroxy-2-phenylacetic acid were dissolved in 8 ml of dry DMF. To this solution 0.481 g (0.003 mol) of 1,1'- carbonildiimidazol were added and the mixture was stirred at room temperature for 1 h. After this time, the mixture obtained was added to a suspension of (3R)-1- methylpyrrolidin-3-ol (Intermediate 1-19, 0.531 g, 0. 0046 mol) and HNa (0.065 g, 0.0027 mol) in 3 ml of dry DMF. After stirring 26 h at room temperature the reaction mixture was treated with water and extracted two times with Et2O. The organic layers were combined, washed with water and dried. The residue was purified by silica gel column chromatography (eluent : CHCl3 plus isopropanol 0%No.10%) to obtain 450 mg (60%) of the title product as an oil. 'H-NMR (CDCI3) :. 8 7.60-7. 56 (m, 2H), 7.29-7. 15 (m, 3H), 5.19-5. 11 (m, 1H), 3.77 (bs, OH, 1H), 2.92-2. 79 (m, 1H), 2.79-2. 16 (m, 5H), 2.26 (s, 3H), 1.85-1. 72 (m, 1 H), 1.61-1. 18 (m, 8H). MS [M+1] + : 304

Reference： [1]Patent: WO2018/26869,2018,A1 .Location in patent: Paragraph 0161; 0172; 0173; 0174
[2]Patent: WO2003/87094,2003,A2 .Location in patent: Page/Page column 31

41
[ 1218913-73-5 ]
[ 104641-60-3 ]
[ 1218913-68-8 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 24; (3R)- l-methylpyrrolidin-3-yl 4-isopropyl- 1 ,4,6,7- tetrahydro-5H-imidazo [4,5-c] - pyridine-5-carboxylate; NaH (0.19 g, 5.00 mmol, 60% dispersion in mineral oil) was suspended in THF (10 mL) at 0 0C and (i?)-l-methylpyrrolidin-3-ol (0.47 mL, 4.00 mmol) was added. The suspension was stirred at 0 0C for 30 min and added to a solution of Intermediate 2 (1.33 g, 4.00 mmol) in THF (10 mL) and the reaction mixture was stirred at room temperature. Two additional such portions of NaH and (i?)-l-methylpyrrolidin-3-ol in THF were added after18 and 26 h, respectively. After 44 h the reaction mixture was quenched with water (10 mL) and the solvents were removed in vacuo. The residue was dissolved in EtOAc (100 - -mL), washed with 1 M aq Na2CO3 solution (4 x 10OmL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, 20 g, Strata SI-I, silica gigatube, DCM (200 ml) followed by 2%, 4%, 5%, 10% and 20% MeOH in DCM (200 mL)) and reverse phase HPLC (Phenomenex Synergi, RP-5 Hydro 150 x 10 mm, 10 mum, 15 mL per min, gradient 0% to 30% (over 12 min) to 100% (over 3 min) MeOH in water [1% formic acid]). The residue was de-salted using K2CO3 in DCM to give (3i?)-l-methylpyrrolidin-3-yl 4-isopropyl- 1,4, 6, 7-tetrahydro-5H-imidazo- [4,5-c]pyridine-5-carboxylate (32.3mg, 2.7%) as a colourless gum. Analytical HPLC: purity 100% (System B, Rtau = 2.99 min); Analytical LCMS: purity 100%o (System B, Rtau = 3.36 min), ES+: 293.1 [MH]+; HRMS calculated for Ci5H24N4O2: 292.1899, found 292.1910.

Reference： [1]Patent: WO2010/31789,2010,A1 .Location in patent: Page/Page column 44-45

42
[ 104641-60-3 ]
[ 3684-12-6 ]
[ 1233326-74-3 ]

Yield	Reaction Conditions	Operation in experiment
33%	With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In tetrahydrofuran; at 20℃;Inert atmosphere;	A mixture of 2-phenyl-2-(phenylamino)acetic acid (II) (200 mg, 0.88 mmol), DCC (218 mg, 1.05 mmol), HOBt (142 mg, 1.05 mmol) and (R)- I- methylpyrrolidin-3-ol (289 uL, 2.64 mmol) in dry THF (10 mL) is stirred at room temperature overnight under nitrogen flowstream (LC-MS monitoring: complete conversion). The solvent is evaporated and the residue is taken up with aq. HCl (pH about 2) and washed with DCM. The aqueous phase is basified with NaHCO3 and extracted with DCM (three times). The organic layers are combined, dried over Na2SO4, filtered and evaporated to dryness. The resulting crude is first purified by flash chromatography (DCM to DCM/MeOH=95/5) and then by preparative LC-MS. The purified compound is partitioned between sat. NaHCO3 and DCM, the organic phase is dried over Na2SO4, filtered and evaporated under vacuum to give 90.8 mg of the title compound as brown oil (33% yield, mixture of diastereoisomers).1H NMR (300 MHz, CHLOROFORM-d) ppmDiastereoisomer 1 of C 14: 7.46 - 7.57 (m, 2 H), 7.29 - 7.45 (m, 3 H), 7.08 - 7.21 (m, 2 H), 6.67 - 6.81 (m, 1 H), 6.50 - 6.67 (m, 2 H), 5.20 - 5.37 (m, 1 H), 5.12 (d, 1 H), 4.84 - 5.05 (m, 1 H), 2.46 - 3.04 (m, 4 H), 2.44 (s, 3 H), 2.10 - 2.26 (m, 1 H), 1.63 - 1.82 (m, 1 H). Diastereoisomer 2 of C14: 7.46 - 7.57 (m, 2 H), 7.29 - 7.45 (m, 3 H), 7.08 - 7.21 (m, 2 H), 6.67 - 6.81 (m, 1 H), 6.50 - 6.67 (m, 2 H), 5.20 - 5.37 (m, 1 H), 5.12 (d, 1 H), 4.84 - 5.05 (m, 1 H), 2.46 - 3.04 (m, 4 H), 2.33 (s, 3 H), 2.26 - 2.40 (m, 1 H), 1.86 - 2.05 (m, 1 H);LC-MS (ESI POS): 31 1.3 (MH+).
33%	With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In tetrahydrofuran; at 20℃; for 40h;Inert atmosphere;	A mixture of 2-phenyl-2-(phenylamino)acetic acid (II) (200 mg, 0.88 mmol), DCC (218 mg, 1.05 mmol), HOBt (142 mg, 1.05 mmol) and (R)-l- methylpyrrolidin-3-ol (289 uL, 2.64 mmol) in dry THF (10 mL) was stirred at room temperature overnight under nitrogen flowstream (LC-MS monitoring: complete conversion). The solvent was evaporated and the residue was taken up with aq. HCl (pH about 2) and washed with DCM. The aqueous phase was basified with NaHCO3 and extracted with DCM (three times). The organic layers were combined, dried over Na2SO4, filtered and evaporated to dryness. The resulting crude was first purified by flash chromatography (DCM to DCM/MeOH=95/5) and then by preparative LC-MS. The purified compound was partitioned between sat. NaHCO and DCM, the organic phase was dried over Na2SO4, filtered and evaporated under vacuum to give 90.8 mg of the title compound (33% yield, mixture of diastereomers).1H NMR (300 MHz, CHLOROFORM-d) ppmDiastereomer 1 of 133: 7.46 - 7.57 (m, 2 H), 7.29 - 7.45 (m, 3 H), 7.08 - 7.21 (m, 2 H), 6.67 - 6.81 (m, 1 H), 6.50 - 6.67 (m, 2 H), 5.20 - 5.37 (m, 1 H), 5.12 (d, 1 H), 4.84 - 5.05 (m, 1 H), 2.46 - 3.04 (m, 4 H), 2.44 (s, 3 H), 2.10 - 2.26 (m, 1 H), 1.63 - 1.82 (m, 1 H).Diastereomer 2 of 133: 7.46 - 7.57 (m, 2 H), 7.29 - 7.45 (m, 3 H), 7.08 - 7.21 (m, 2 H), 6.67 - 6.81 (m, 1 H), 6.50 - 6.67 (m, 2 H), 5.20 - 5.37 (m, 1 H), 5.12 (d, 1 H), 4.84 - 5.05 (m, 1 H), 2.46 - 3.04 (m, 4 H), 2.33 (s, 3 H), 2.26 - 2.40 (m, 1 H), 1.86 - 2.05 (m, 1 H);LC-MS (ESI POS): 31 1.3 (MH+).

Reference： [1]Patent: WO2010/72338,2010,A1 .Location in patent: Page/Page column 59-60
[2]Patent: WO2011/160919,2011,A1 .Location in patent: Page/Page column 52-53

43
[ 42523-29-5 ]
[ 104641-60-3 ]
[ 1361108-42-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 1633 - 1638

44
[ 104641-60-3 ]
[ 2900-27-8 ]
[ 1379513-77-5 ]

Yield	Reaction Conditions	Operation in experiment
64%	With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In tetrahydrofuran; at 20℃; for 15h;	To a solution of 2-(tert-butoxycarbonylamino)-2-phenylacetic acid (13)(400 mg, 1.59 mmol) in THF (20 ml), (R)-l-methylpyrrolidin-3-ol (193 mg, 1.91 mmol), N,N'-methanediylidenedicyclohexanamine (394 mg, 1.91 mmol) and lH-benzo[d][ l,2,3]triazol-l-ol (258 mg, 1.91 mmol) were added. The reaction was stirred at RT for 15h then the solvent was evaporated. The residue was taken up with DCM, the insoluble was filtered off and the clear solution was washed twice with aq. Na2CO3 and brine, dried over Na2SO4 and evaporated to obtain (R)-l-methylpyrrolidin-3-yl2-(tert-butoxycarbonylamino)-2-phenylacetate (340 mg; 64% yield).
64%	With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In tetrahydrofuran; at 20℃; for 15h;	To a solution of 2-(tert-butoxycarbonylamino)-2-phenylacetic acid (I3) (400 mg, 1.59 mmol) in THF (20 ml), were added (R)-1-methylpyrrolidin-3-ol (193 mg, 1.91 mmol), N,N'-methanediylidenedicyclohexanamine (394 mg, 1.91 mmol), and 1H-benzo[d][1,2,3]triazol-1-ol (258 mg, 1.91 mmol). The reaction was stirred at RT for 15, hours, and then the solvent was evaporated. The residue was taken up with DCM, the insoluble was filtered off, and the clear solution was washed twice with aq. Na2CO3 and brine, dried over Na2SO4 and evaporated to obtain (R)-1-methylpyrrolidin-3-yl 2-(tert-butoxycarbonylamino)-2-phenylacetate (340 mg; 64% yield).

Reference： [1]Patent: WO2012/69275,2012,A1 .Location in patent: Page/Page column 71
[2]Patent: US2012/134934,2012,A1 .Location in patent: Page/Page column 33-34

45
[ 104641-60-3 ]
[ 34617-65-7 ]
[ 1404095-39-1 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 10229 - 10240

46
[ 104641-60-3 ]
[ 1404095-32-4 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 10229 - 10240

47
[ 104641-60-3 ]
[ 1404095-36-8 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 10229 - 10240

48
[ 1355682-76-6 ]
[ 104641-60-3 ]
[ 1355683-07-6 ]

Yield	Reaction Conditions	Operation in experiment
7.4 mg		Example 95 [0785] <strong>[104641-60-3](R)-(-)-1-methyl-3-hydroxypyrrolidine</strong> (0.14 mL) in N-methylpyrrolidone (NMP) (0.4 mL) was added sodium hydroxide (60%, 12 mg), and the solution mixture was stirred for 20 minutes at room temperature. Then, the compound of Example 81 (30 mg) was added thereto, and the mixture was stirred for 66 hours at room temperature. Acetic acid was added to the reaction mixture, which was further dilulted with methanol, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified with preparative reversed-phase HPLC and further demineralization by using PL-HCO3 MP SPE Device (a column filled with Polymer supported Hydrogen carbonate, Polymer Laboratories) to give the titled compound (7.4 mg) as a white solid. [0787] Analyzing method SB1, tR 3.02 min, obs MS [M+1] 564.4

Reference： [1]Patent: US2013/116227,2013,A1 .Location in patent: Paragraph 0785; 0786; 0787

49
[ 352-34-1 ]
[ 104641-60-3 ]
[ 1430472-20-0 ]

Yield	Reaction Conditions	Operation in experiment
7.6%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 85℃; for 18h;	The title compound was synthesized as per 4-(4-bromophenoxy)-l -(oxetan-3 - .- yl)piperidine by utilizing (R)-l-methylpyrrolidin-3-ol (500 mg, 4.94 mmol), 4- fluoro-l-iodobenznene (1.21 g, 5.44 mmol), NaH (55-60% in mineral oil, 247 mg, 6.17 mmol) and anh DMF (10 mL) at 85C for 18 h. After work up and purification the title compound was isolated as a white solid (115 mg, 7.6%). ? NMR (400 MHz, CDCl3) delta 7.47 - 7.56 (m, 2 H), 6.59 - 6.66 (m, 2 H), 4.74-4.78 (m, 1 H), 2.74 - 2.87 (m, 3 H), 2.41 - 2.47 (m, 1 H), 2.39 (s, 3 H), 2.30 (d, J=7.8 Hz, 1 H), 1.92 - 2.01 (m, 1 H); MS ESI 303.9 [M + Hf, calcd for[0, 1Eta14GammaNu04+Eta]+ 304

Reference： [1]Patent: WO2013/53051,2013,A1 .Location in patent: Page/Page column 86

50
[ 104641-60-3 ]
(S)-3-methoxy-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-amine [ No CAS ]

Reference： [1]Patent: US2015/141402,2015,A1
[2]Patent: WO2016/183094,2016,A1

51
[ 1810-71-5 ]
[ 104641-60-3 ]
(R)-6-bromo-2-((1-methylpyrrolidin-3-yl)oxy)quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With sodium hydride; In tetrahydrofuran; mineral oil; for 5h;Reflux;	Preparation of Compound 3, (R)-6-bromo-2-((1-methylpyrrolidin-3-yl)oxy)quinoline[0005] NaH (60% in mineral oil, 0.049 g, 1.24 mmol) was added to a solution of (R)-(-)-1- methyl-3-hydroxypyrrolidine (0.125 g, 1.24 mmol) in dry THF (3.5 mL) at 0 C. The reaction mixture was stirred at 0 C for 5 min, then allowed to warm to rt, and stirred for 35 min before 6-bromo-2-chloroquinoline (0.250 g, 1.03 mmol) was added. The reaction mixture was then heated at reflux for 5 h, cooled to rt, concentrated to remove most of the THF, diluted with water and saturated NaHC03(aq), extracted with DCM (3x). The combined organic phases were washed with water (1x), dried (MgS04), andconcentrated. The crude material was purified by silica gel column chromatography using a gradient of 2 to 5% MeOH in DCM to afford the title compound (206 mg, 65%) as a pale yellow oil. 1H NMR (500 MHz, CDCI3) delta 7.86 (d, J= 8.9 Hz, 1 H), 7.85-7.83 (m, 1 H), 7.68-7.64 (m? 2H), 6.92 (d, J = 8.8 Hz, 1 H), 5.68-5.63 (m, 1 H), 2.94 - 2.88 (m, 2H), 2.83 (dd, J= 10.8, 5.9 Hz, 1 H), 2.49 - 2.36 (m, 5H), 2.08-2.01 (m, 1 H). HRMS (ESI+): calcd for C14H1579BrN20 (M+H)+, 307.0440; found 307.0447.

Reference： [1]Patent: WO2015/49535,2015,A1 .Location in patent: Paragraph 0005

52
[ 400755-41-1 ]
[ 104641-60-3 ]
(S)-3-methoxy-1-(1-methylpyrrolidin-3-yl)-4-nitro-1H-pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 16h;	To a stirred solution of DIAD (25.42 g, 125.8 mmol) in THF (200 mL) was added PPh3 (33 g, 125.8 mmol) portionwise at 0 C, and the mixture was stirred at 0 C for 5 mins. To this mixture was added <strong>[400755-41-1]3-methoxy-4-nitro-1H-pyrazole</strong> (10 g, 69.93 mmol) in THF (300 mL) portionwise at 0 C followed by a solution of (R)-1-methylpyrrolidin-3-ol (7.78 g, 76.92 mmol) in THF (100 mL) at 0C. The mixture was stirred at RT for 16 h. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on Si02 (5-10% MeOH in CH2C12) to afford (S)-3-methoxy-1-(1-methylpyrrolidin-3-yl)-4-nitro-1H-pyrazole as a pale yellow solid (13 g, 82%). XH NMR (300 MHz, DMSO-J6) delta 8.72 (s, IH), 4.82-4.72 (m, IH), 3.94 (s, 3H), 2.89-2.70 (m, 3H), 2.45-2.25 (m, 5H), 2.18-2.05 (m, IH); MS (ESI) m/z 227.03 [M+H]+.
80%	With di-tert-butyl-diazodicarboxylate; In tetrahydrofuran; for 18h;	To a suspension of <strong>[400755-41-1]3-methoxy-4-nitro-1H-pyrazole</strong> (2.00 g, 14.0 mmol, 1.00 eq), (R)-1-methyl-pyrrolidin-3-ol (1.56 g, 15.4 mmol, 1.10 eq), and polystyrene bound triphenylphosphine (6.53 g, 19.6 mmol, 1.40 eq, 3 mmol/gram) in THF (140 mL) was added a solution of di-tert-butyl azodicarboxylate (4.51 g, 19.6 mmol, 1.40 eq) in THF (25 mL) in a drop-wise manner over 5 min. The reaction mixture was allowed to stir for 18 hr. The reaction mixture was then diluted with EtOAc (100 mL), filtered and the filtrate concentrated. The crude reaction mixture was purified via flash chromatography on silica gel eluting with a gradient of 50-100% EtOAc in heptane then to 10% 7 N methanolic ammonia/EtOAc to give the title compound (2.39 g, 80% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 8.69 (s, 1H), 4.84-4.72 (m, 1H), 3.94 (s, 3H), 2.86-2.75 (m, 2H), 2.72 (dd, J=7.0, 10.0 Hz, 1H), 2.40 (dt, J=6.2, 8.4 Hz, 1H), 2.36-2.29 (m, 1H), 2.28 (s, 3H), 2.16-2.06 (m, 1H). m/z (APCI+) for C9H15N4O3 227.2 (M+H)+

Reference： [1]Patent: WO2016/183094,2016,A1 .Location in patent: Paragraph 0158
[2]Patent: US2015/141402,2015,A1 .Location in patent: Paragraph 0783; 0784

53
[ 64-18-6 ]
[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]5-[(2-fluoroanilino)methyl]thiophene-2-carboxylate [ No CAS ]
[ 104641-60-3 ]
[ 503-38-8 ]
[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]5-[(2-fluoro-N-[(3R)-1-methylpyrrolidin-3-yl]oxycarbonyl-anilino)methyl]thiophene-2-carboxylate formate salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15%		Example 26 [(1S)-2-(3,5-Dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]5-[(2-fluoro-N-[(3R)-1-methylpyrrolidin-3-yl]oxycarbonyl-anilino)methyl]thiophene-2-carboxylate formate salt (E26) A solution of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]5-[(2-fluoroanilino)methyl]thiophene-2-carboxylate (177 mg, 0.306 mmol) in acetonitrile (6 mL) was added with diphosgene (75 muL, 0.61 mmol) and the reaction mixture was stirred at room temperature for 5 minutes. After which time, a solution of diisopropylethylamine (341 mul, 2.0 mmol) and (R)-1-methylpyrrolidin-3-ol (220 mul, 2.0 mmol) in acetonitrile (3 mL) was added over 10 minutes. The brown mixture was stirred at room temperature for 1 h and then the solvent was removed in vacuo. The crude product was dissolved in chloroform (70 mL) and the organic layer was washed with HCl 1M (50 mL). The organic layer was dried over sodium sulfate and evaporated under vacuum. The crude material was purified by flash chromatography (on a reverse phase C18 60 g column). The collected fractions were evaporated under vacuum and the product was further purified by means of preparative HPLC (Fraction Lynx). The collected fractions were evaporated in vacuo at 45 C. The residue was treated with acetone and diethyl ether to give the title compound as a formate salt as a foam (32 mg, 15%). 1H NMR (400 MHz, acetone) delta ppm 8.25 (s, 2H), 8.13 (s, 1H), 7.52-7.72 (m, 1H), 7.24-7.41 (m, 2H), 7.16-7.22 (m, 2H), 7.09-7.14 (m, 1H), 6.96 (m, 3H), 6.20-6.29 (m, 1H), 5.10-5.22 (m, 1H), 5.00 (s, 2H), 3.81 and 3.78 (2s, 6H, 3H each), 3.60-3.71 (m, 1H), 3.18-3.46 (m, 1H), 2.64-2.89 (m, 2H), 2.09-2.54 (m, 7H)
15%		A solution of [(1 S)-2-(3 ,5-dichloro- 1 -oxido-pyridin- 1 -ium-4-yl)- 1 -(3,4-dimethoxyphenyl)ethyl] 5- [(2-fluoroanilino)methyl]thiophene-2-carboxylate (177 mg,0.306 mmol) in acetonitrile (6 mL) was added with diphosgene (75 jiL, 0.61 mmol) andthe reaction mixture was stirred at room temperature for 5 minutes. After which time, asolution of diisopropylethylamine (341 tl, 2.0 mmol) and (R)-1-methylpyrrolidin-3-ol(220 tl, 2.0 mmol) in acetonitrile (3 mL) was added over 10 minutes. The brown mixture was stirred at room temperature for 1 h and then the solvent was removed in vacuo. The crude product was dissolved in chloroform (70 mL) and the organic layer was washed with HC1 1 M (50 mL). The organic layer was dried over sodium sulfate and evaporated under vacuum. The crude material was purified by flash chromatography (on a reversephase C18 60 g column). The collected fractions were evaporated under vacuum and the product was further purified by means of preparative HPLC (Fraction Lynx). The collected fractions were evaporated in vacuo at 45 C. The residue was treated with acetone and diethyl ether to give the title compound as a formate salt as a foam (32 mg, 15%).1H NMR (400 MHz, acetone) 5 ppm 8.25 (s, 2 H), 8.13 (s, 1 H), 7.52 - 7.72 (m, 1H), 7.24 - 7.41 (m, 2 H), 7.16 - 7.22 (m, 2 H), 7.09 - 7.14 (m, 1 H), 6.96 (m, 3 H), 6.20 -6.29 (m, 1 H), 5.10 - 5.22 (m, 1 H), 5.00 (s, 2 H), 3.81 and 3.78 (2s, 6 H, 3 H each), 3.60 -3.71 (m, 1 H), 3.18 - 3.46 (m, 1 H), 2.64-2.89 (m, 2 H), 2.09-2.54 (m, 7 H) [MH+] = 704.

Reference： [1]Patent: US2015/158858,2015,A1 .Location in patent: Paragraph 0481; 0482; 0483
[2]Patent: WO2015/82616,2015,A1 .Location in patent: Page/Page column 105; 106

54
[ 1207203-37-9 ]
[ 104641-60-3 ]
O₁-benzyl-O₃-[(3R)-1-methylpyrrolidin-3-yl]-3-phenylazetidine-1,3-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%		A stirred suspension of 1 -benzyloxycarbonyl-3 -phenyl-azetidine-3 -carboxylic acid (352 mg, 1.04 mmol) in CHC13 (20 mL) 2 drops of DMF were added. The mixture was cooled in an ice-bath and oxalyl chloride (0.14 mL, 1.67 mmol) was added with dropwise. After stirring in the cold bath for a further 10 minutes the mixture was stirred at roomtemperature for 2 hours. The solvent was removed in vacuo, co-evaporated further with CHC13 (20 mL). The residue was taken up with CHC13 (5 mL) and the resulting solution was added dropwise to a solution of (R)- 1 -methylpyrrolidin-3-ol (0.13 mL, 1.15 mmol) in CHC13 (5 mL) at 0 C under N2. The mixture was stirred at 0 C for 30 minutes and allowed to warm to room temperature overnight. The reaction mixture was washed withH20 (2 x 10 mL), the organic phase was separated and the solvent removed in vacuo. The residue was taken up in EtOAc (20 mL) and washed with saturated NaHCO3 solution (2 x 10 mL). The organic phase was separated, filtered through a phase separator and the solvent removed in vacuo to give the title compound as a brown gum (301 mg, 73%). LCMS (Method 1): [MH+] = 395 at 2.69 mm.

Reference： [1]Patent: WO2016/177849,2016,A1 .Location in patent: Page/Page column 78; 80; 81

55
[ 104641-60-3 ]
(S)-N-(3-methoxy-1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)-7-methyl-2-(methylthio)imidazo[2,1-f][1,2,4]triazin-4-amine [ No CAS ]

Reference： [1]Patent: WO2016/183094,2016,A1

56
[ 104641-60-3 ]
N-(3-methoxy-1-((S)-1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)-7-methyl-2-(methylsulfinyl)imidazo[2,1-f][1,2,4]triazin-4-amine [ No CAS ]

Reference： [1]Patent: WO2016/183094,2016,A1

57
[ 104641-60-3 ]
tert-butyl ((3R,4R)-4-fluoro-1-(4-((3-methoxy-1-((S)-1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-7-methylimidazo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-3-yl)carbamate [ No CAS ]

Reference： [1]Patent: WO2016/183094,2016,A1

58
[ 104641-60-3 ]
2-((3R,4R)-3-amino-4-fluoropyrrolidin-1-yl)-N-(3-methoxy-1-((S)-1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)-7-methylimidazo[2,1-f][1,2,4]triazin-4-amine [ No CAS ]

Reference： [1]Patent: WO2016/183094,2016,A1

59
[ 104641-60-3 ]
N-((3R,4R)-4-fluoro-1-(4-((3-methoxy-1-((R)-1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)-7-methylimidazo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-3-yl)acrylamide [ No CAS ]

Reference： [1]Patent: WO2016/183094,2016,A1

60
[ 104641-60-3 ]
[ 64471-45-0 ]
(3R)-3-((R)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1-(2-ethoxy-2-oxoethyl)-1-methylpyrrolidin-1-ium bromide [ No CAS ]

Reference： [1]Patent: WO2018/26869,2018,A1

61
[ 104641-60-3 ]
[ 64471-43-8 ]
(3R)-1-methylpyrrolidin-3-yl (2S)-2-cyclopentyl-2-hydroxy-2-phenylacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
> 90%	With 1,1'-carbonyldiimidazole; In toluene;	[0210] S(+)-cyclopentylmandelic acid () was coupled to (R)-1-methylpyrrolidin-3- ol () to make the diasterically pure 253?R-glycopyrrolate base (compound ) using 1,1-carbonyldiimideazole (CDI) activated esterification. The S2R3 ?R-glycopyrrolate base (compound ) was obtained in greater than 90% yield.

Reference： [1]Patent: WO2018/26869,2018,A1 .Location in patent: Paragraph 0197; 0208; 0209; 0210

62
[ 104641-60-3 ]
[ 64471-43-8 ]
(3R)-3-((3S)-2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1-(2-ethoxy-2-oxoethyl)-1-methylpyrrolidin-1-ium bromide [ No CAS ]

Reference： [1]Patent: WO2018/26869,2018,A1

63
[ 104641-60-3 ]
[ 106-48-9 ]
(R)-5-methyl-1-(4-((4'-((1-methylpyrrolidin-3-yl)oxy)-[1,1'-biphenyl]-4-yl)methyl)phenyl)-1H-1,2,4-triazole-3-carboxamide [ No CAS ]

Reference： [1]Patent: US2019/77773,2019,A1

64
[ 104641-60-3 ]
[ 106-48-9 ]
(R)-3-(4-chlorophenoxy)-1-methylpyrrolidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0℃;	Step 1: Preparation of (R)-3-(4-chlorophenoxy)-1-methylpyrrolidine (R)-(-)-1-Methyl-3-hydroxypyrrolidine (472 mg, 4.67 mmol) and triphenyl phosphine (1224 mg, 4.67 mmol) were dissolved in dry THF (10 mL) under nitrogen. The solution was cooled to 0 C. and 4-chlorophenol (500 mg, 3.89 mmol) was added, followed by DIAD (0.907 mL, 4.67 mmol). After 15 minutes the ice bath was removed and the reaction was stirred overnight. The reaction mixture was concentrated under reduced pressure and the residue was stirred with ether. The solid triphenyl phosphine oxide was filtered off and the solution was washed with sodium hydroxide (1M) and concentrated in vacuo. The resulting crude product was purified by FCC (gradient 2%-10% MeOH in DCM) to afford (R)-3-(4-chlorophenoxy)-1-methylpyrrolidine (600 mg, 72%): LCMS Rt=0.49 min (condition B), MS (M+1)=212.1.

Reference： [1]Patent: US2019/77773,2019,A1 .Location in patent: Paragraph 1377

65
N-(3-chloro-4-phenoxyphenyl)-7-fluoro-6-nitroquinazolin-4-amine [ No CAS ]
[ 104641-60-3 ]
(R)-N-(3-chloro-4-phenoxyphenyl)-7-((1-methylpyrrolidin-3-yl)oxy)-6-nitroquinazolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In dimethyl sulfoxide;	To a solution of N-(3-chloro-4-phenoxyphenyl)-7-fluoro-6-nitroquinazolin-4-amine (2.00 g, 4.87 mmol, 1.00 eq), (R)-l-methylpyrrolidin-3-ol (985 mg, 9.74 mmol, 1.07 mL, 2.00 eq) in dimethyl sulfoxide (25.0 mL) was added potassium tert-butoxide (1 .64 g, 14.6 mmol, 3.00 eq) The mixture was stirred at 20 C'C for 12 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 c 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give (R)-N-(3-chloro-4-phenoxyphenyl)-7-((l-methylpyrrolidin-3 -yl)oxy)-6-nitroquinazolin-4- amine (2.00 g, crude) as a yellow solid. MS (ESI) m/z 492.1 [ M i l ]

Reference： [1]Patent: WO2020/68867,2020,A1 .Location in patent: Page/Page column 478

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P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 104641-60-3 ] {[proInfo.proName]}

Quality Control of [ 104641-60-3 ]

Related Doc. of [ 104641-60-3 ]

Product Details of [ 104641-60-3 ]

Calculated chemistry of [ 104641-60-3 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 104641-60-3 ]

Application In Synthesis of [ 104641-60-3 ]

[ 104641-60-3 ] Synthesis Path-Upstream 1~3

[ 104641-60-3 ] Synthesis Path-Downstream 1~65

Related Functional Groups of [ 104641-60-3 ]

Alcohols

Related Parent Nucleus of [ 104641-60-3 ]

Aliphatic Heterocycles

Pyrrolidines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 104641-60-3 ]

Related Parent Nucleus of
[ 104641-60-3 ]