199174-24-8|(S)-1-Boc-(3-Hydroxymethyl)pyrrolidine| Ambeed

Structure of 199174-24-8

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Quality Control of [ 199174-24-8 ] Purity: 98% SDS Specification

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Product Details of [ 199174-24-8 ]

CAS No. :	199174-24-8
Formula :	C₁₀H₁₉NO₃
M.W :	201.26
SMILES Code :	CC(C)(C)OC(=O)N1CC[C@H](CO)C1
MDL No. :	MFCD03094726
InChI Key :	HKIGXXRMJFUUKV-QMMMGPOBSA-N
Pubchem ID :	1514341

Safety of [ 199174-24-8 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 199174-24-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	14
Num. arom. heavy atoms	0
Fraction Csp3	0.9
Num. rotatable bonds	4
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	57.75
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	49.77 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.45
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	0.82
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.85
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.86
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	0.65
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.13

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.34
Solubility	9.19 mg/ml ; 0.0457 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.45
Solubility	7.19 mg/ml ; 0.0357 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-0.83
Solubility	29.8 mg/ml ; 0.148 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.95 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.65

Application In Synthesis of [ 199174-24-8 ]

* 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.

Downstream synthetic route of [ 199174-24-8 ]

[ 199174-24-8 ] Synthesis Path-Downstream 1~35

1
[ 24424-99-5 ]
[ 109960-55-6 ]
[ 199174-24-8 ]

References: [1]Organic and Biomolecular Chemistry,2016,vol. 14,p. 5992 - 6009.
[2]Journal of Medicinal Chemistry,1997,vol. 40,p. 3497 - 3500.
[3]Journal of Medicinal Chemistry,1999,vol. 42,p. 677 - 690.
[4]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 2829 - 2834.

2
[ 124-63-0 ]
[ 199174-24-8 ]
[ 274692-06-7 ]

Yield	Reaction Conditions	Operation in experiment
90%	With triethylamine; In dichloromethane; at 0 - 20℃; for 4h;	To a solution of <strong>[199174-24-8]tert-butyl (S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate</strong> (2.0 g, 9.9 mmol) and triethylamine (2.8 mL, 19.8 mmol) in methylene chloride (50.0 mL) at 0C was dropwise added methanesulfonyl chloride (0.85 mL, 10.9 mmol). The reaction mixture was stirred at ambient temperature for 4 hours and then washed sequentially with 0.1 N hydrogen chloride and brine. The organic layer was dried over Na2S04 filtered, and concentrated in vacuo to yield 2.5 g (90 %) of the title product as an oil.
90%	With triethylamine; In dichloromethane; at 0 - 20℃; for 4h;	[0563] To a solution of <strong>[199174-24-8]tert-butyl (S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate</strong> (2.0 g, 9.9 mmol) and triethylamine (2.8 mL, 19.8 mmol) in methylene chloride (50.0 mL) at 0C was dropwise added methanesulfonyl chloride (0.85 mL, 10.9 mmol). The reaction mixture was stirred at ambient temperature for 4 hours and then washed sequentially with 0.1 N hydrogen chloride and brine. The organic layer was dried over Na2SO4 filtered, and concentrated in vacuo to yield 2.5 g (90 %) of the title product as an oil. [M+1]+ 280.
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 2h;Product distribution / selectivity;	a) 1,1-dimethylethyl 3-[(methylsulfonyl)oxy]methyl}-l-pyrrolidinecarboxylateA solution of 1,1-dimethylethyl 3-(hydroxymethyl)-l-pyrrolidinecarboxylate (3.051 mmol) and DIPEA (4.576 mmol) in CH2C12 (10 mL) was cooled to 0 C, treated with MsCl (3.051 mmol), and stirred at 0 C for 2 h. The reaction mixture was then diluted with water and CH2C12 (50 mL). After separating the layers, the aqueous layer was further extracted with CH2C12 (2 x 20 mL). The combined organic layers were dried over Na2S04 and concentrated in vacuo to provide the crude title compound (0.838 g) as an amber oil. LCMS (ES+) m/z 280 [M+H]+.

References: [1]Patent: KR2019/15535,2019,A .Location in patent: Paragraph 0852-0854; 1524-1526.
[2]Patent: WO2019/104418,2019,A1 .Location in patent: Paragraph 0562-0563; 0723-0724.
[3]Journal of Medicinal Chemistry,1997,vol. 40,p. 3497 - 3500.
[4]Journal of Medicinal Chemistry,1999,vol. 42,p. 677 - 690.
[5]Patent: WO2012/37298,2012,A1 .Location in patent: Page/Page column 61.
[6]Journal of Medicinal Chemistry,2019.

3
[ 199174-24-8 ]
[ 882868-71-5 ]

References: [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 677 - 690.

4
[ 199174-24-8 ]
(R)-3-(Benzylamino-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 677 - 690.
[2]Journal of Medicinal Chemistry,1997,vol. 40,p. 3497 - 3500.

5
[ 199174-24-8 ]
(3R)-3-(N-benzyl)aminomethyl-1-[2-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)ethyl]pyrrolidine [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 677 - 690.

6
[ 114214-69-6 ]
[ 138108-72-2 ]
[ 199174-24-8 ]

Yield	Reaction Conditions	Operation in experiment
73%	Resolution of racemate;	Racemic l-t-butoxycarbonylpyrrolidine-3-methanol (15 g,74.53 mmol) was chromatographed on a chiral column[ChiralPak AD 8 X 25 cm; 2.5% of (6% MeOH/94% EtOH); 400mL/min; UV: 210 nm] to give l-t-butoxycarbonylpyrrolidine-3-methanol:Isomer I (Rt: 8.81 min, ChiralPak AD 4.6 X 250 mm; 1.0mL/min; UV: 210 nm) (6.35 g, 42%, 94% ee) andIsomer II (Rt: 9.68 min)' (6.43 g, 43%, 90% ee) .Isomer I: FIA-MS, m/e: 202.2 (rrH-1) .Isomer II: FIA-MS, m/e: 202.2 (m+1).

References: [1]Patent: WO2004/108677,2004,A1 .Location in patent: Page 138.

7
[ 199174-24-8 ]
[ 110013-19-9 ]

Yield	Reaction Conditions	Operation in experiment
> 99%		(5) Cphi-t°rtf-Butyl 3-(hydroxymethyl)pyrrolidine-l-carboxylate (2.96 g, 14.7 mmol) in a round bottom flask was mixed with 4N hydrogen chloride in ethyl acetate (30 ml) at room temperature. The mixture was stirred for 2 hours and concentrated in vacuo. The residue was diluted with ethanol (10 ml) and solid potassium carbonate was added. To the resulting slurry was added small amount of water until bubbles were generated. After 2 hours, filtration was performed to remove solid materials and the filtrate was concentrated to yield GS)-pyrrolidin-3-yl-methanol (1.49 g, 14.7 mmol, >99 %) as an orange oil.
	With trifluoroacetic acid; In dichloromethane; at 20℃; for 16h;	a) tert-Butyl (3S)-3- (HYDROXYMETHYL) PYRROLIDINE-1-CARBOXYLATE (0.9 g, 4.48 mmol), was dissolved in dichloromethane (10 ml) and trifluoroacetic acid (2 ml) was added. The reaction mixture was stirred for 16 hours at ambient temperature. The reaction mixture was concentrated under reduced pressure and then co-evaporated with toluene. The residue was dissolved in methanol (20 ml) and then macroporous carbonate (3 g) was added and the heterogeneous mixture was stirred for 16 hours at ambient temperature to give a pH 9 mixture. The mixture was filtered and the filtrate was concentrated under reduced pressure to give (3S)-pyrrolidin-3-ylmethanol as an oil which was used without further purification: H-NMR (DMSO D6) : 3.25 (m, 2H), 3.10 (m, 3H), 2.85 (m, 1H), 2.30 (m, 1H), 1.90 (m, 1H), 1.60 (m, 1H) ; MS (+ve ESI) : 101 (M+H) +.
1.24 g	With acetyl chloride; In methanol; at 20℃;Inert atmosphere;	Intermediate 84: (S)-Pyrrolidin-3-ylmethanol Acetyl chloride (9mL) was added dropwise at 0C to methanol (4OmL) under an atmosphere of nitrogen. The mixture was stirred for 0.5 hours at 0C then tert-butyl (S)-3 - hydroxymethylpyrrolidine-1-carboxylate (2.5g) was added. The resulting solution was stirred at room temperature overnight then concentrated in vacuo. The residue was dissolved inisopropanol (4OmL) and potassium carbonate (lOg) was added. The mixture was stirred at room temperature overnight then filtered. The filtrate was concentrated in vacuo to give (S)pyrrolidin-3-ylmethanol (1.24g) as a yellow oil.

References: [1]Patent: WO2011/19090,2011,A1 .Location in patent: Page/Page column 46.
[2]Patent: WO2004/94410,2004,A1 .Location in patent: Page 191.
[3]Patent: WO2014/71369,2014,A1 .Location in patent: Paragraph 00588-00590.

Yield	Reaction Conditions	Operation in experiment
64%		39a. 1-(BOC)-3-(S)-pyrrolidinemethanol This compound was prepared by analogy to the procedures in Examples 34a and b, starting with (3S)-1-[(R)-1-phenethyl]-3-(hydroxymethyl)pyrrolidine (prepared as described in J. Med. Chem., 1990, 33, 71-77), to afford the title compound in 64% yield. MS (DCI-NH3) m/z 202 (M+H)+; 1H NMR (300 MHz, CDCl3) delta1.56 (s, 9H), 1.6-1.7 (m, 1 H),1.9-2.05 (m, 1H), 2.35-2.45 (m, 1 H), 3.05-3.15 (m, 1 H), 3.25-3.75 (m, 5H).

9
[ 173724-95-3 ]
[ 24424-99-5 ]
[ 199174-24-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen;palladium hydroxide on carbon; In methanol; at 50℃; under 2585.81 Torr;	To a solution of ((S)-l-((S)-l-phenylethyl)pyrrolidin-3-yl)methanol (M5) (42.2 g, 0.194 mol) and (BoC)2O (69.4 g, 0.292 mol) in methanol (300 mL) was added Pd(OH)2/C (5 g). The resultant mixture was heated to 50 0C at 50 psi under H2 and stirred overnight then cooled to room temperature. Pd(OH)2/C was filtered and the filtrate was evaporated under reduced pressure to give a residue which was purified by column chromatography (P.E./EtOAc 5:1) to give (S)-tert-butyl 3-(hydroxymethyl)pyrrolidine-l-carboxylate (M6). 1H NMR (300 MHz, CDCl3) delta 3.60-3.63 (m, 2 H), 3.29-3.52 (m, 3 H), 3.07-3.13 (m, 1 H), 2.37-2.42 (m, 1 H), 1.94- 1.98 (m, 1 H), 1.62-1.70 (m, 1 H), 1.45 (s, 9 H).

References: [1]Organic and Biomolecular Chemistry,2017,vol. 15,p. 2397 - 2402.
[2]Patent: WO2007/100670,2007,A1 .Location in patent: Page/Page column 51.

10
[ 199174-24-8 ]
(S)-3-formylpyrrolidine-1-carboxylic acid t-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; potassium bromide; In dichloromethane; water; at 0℃;	Preparation 4 (S)-3-Formylpyrrolidine-1-carboxylic Acid t-Butyl Ester To a solution of <strong>[199174-24-8](S)-3-hydroxymethylpyrrolidine-1-carboxylic acid t-butyl ester</strong> (7.4 g, 37 mmol) in DCM (74 mL, 1.2 mol) was added TEMPO (100 mg, 0.7 mmol) and potassium bromide (200 mg, 2 mmol). This mixture was cooled to 0 C. and vigorously stirred as a pre-chilled (at 0 C.) 1:1 mixture of 0.7 M of NaOCl in water (78 mL, 55 mmol) and a saturated, aqueous NaHCO3 solution (75 mL) was added dropwise over a period of 10 minutes. The resultant mixture was extracted with DCM (3100 mL). The combined organic layers were washed with water (2100 mL), then saturated aqueous NaCl (1*100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield the title compound, which was used without further purification (5.8 g).
	With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; potassium bromide; In dichloromethane; water; at 0℃;	To a solution of <strong>[199174-24-8](S)-3-hydroxymethylpyrrolidine-1-carboxylic acid t-butyl ester</strong> (7.4 g, 37 mmol) in DCM (74 mL, 1.2 mol) was added TEMPO (100 mg, 0.7 mmol) and potassium bromide (200 mg, 2 mmol). This mixture was cooled to 0 C. and vigorously stirred as a pre-chilled (at 0 C.) 1:1 mixture of 0.7 M of NaOCl in water (78 mL, 55 mmol) and a saturated, aqueous NaHCO3 solution (75 mL) was added dropwise over a period of 10 minutes. The resultant mixture was extracted with DCM (3×100 mL). The combined organic layers were washed with water (2×100 mL), then saturated aqueous NaCl (1×100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield (S)-3-formylpyrrolidine-1-carboxylic acid t-butyl ester, which was used without further purification (5.8 g).
	With sodium hypochlorite; sodium hydrogencarbonate; potassium bromide;2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; In dichloromethane; water; at -4℃; for 0.0833333h;	To a solution of <strong>[199174-24-8](S)-3-hydroxymethyl-pyrrolidine-1-carboxylic acid t-butyl ester</strong> (4.0 g, 19.9 mmol, 1.0 eq.) in DCM was added TEMPO (62 mg, 0.4 mmol, 0.02 eq.) and potassium bromide (120 mg, 1.0 mmol, 0.05 eq.). The resulting mixture was cooled over ice (and a small amount of salt, -4 C.). A 1:1 mixture of 0.7M sodium hypochlorite in water and saturated NaHCO3 (56 mL total) was added dropwise. The resulting mixture was allowed to stand in the ice bath until layers separated (-5 minutes). The layers were separated and extracted with DCM (3×30 mL). The organic layer was washed with water (30 mL) and saturated aqueous NaCl (30 mL), then dried over anhydrous Na2SO4, filtered and concentrated to yield (S)-3-formylpyrrolidine-1-carboxylic acid t-butyl ester (3.0 g), which was used without further purification.

		A solution of <strong>[199174-24-8](S)-3-hydroxymethylpyrrolidine-1-carboxylic acid t-butyl ester</strong> (25.0 g, 124 mmol) in DCM (200 mL) was cooled with stirring to 0 C. A solution of potassium bromide (1.5 g, 12.4 mmol) and sodium bicarbonate (1.5 g, 17.4 mmol) dissolved in water (100 mL) was added. After 15 minutes of stirring at 0 C. 2,2,6,6,-tetramethylpiperidin-1-oxyl (195.3 mg, 1.2 mmol) was added, followed by the slow addition of sodium hypochlorite (77.3 mL, 136.6 mmol) dropwise keeping the internal temperature in the 6-8 C. range. The mixture was placed in an ice bath until the layers separated and the layers were back extracted with DCM (200 mL). The combined organic layers were washed with 1M NaCl in water (200 mL), dried over Na2SO4, filtered and concentrated to yield crude (S)-3-formylpyrrolidine-1-carboxylic acid t-butyl ester (21.5 g).
	With 4-methyl-morpholine; oxalyl dichloride; dimethyl sulfoxide; In dichloromethane; at -78 - 0℃; for 1.33333h;	Step 2: tert-butyl (3S)-3-formylpyrrolidine-1-carboxylateOxalyl chloride (1.4 mL, 16 mmol) was dissolved in DCM (28 mL) and this solution was cooled to -78 C., then DMSO (1.8 mL, 26 mmol) was added. To this was then added a solution of <strong>[199174-24-8]tert-butyl (3S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate</strong> (2.15 g, 10.7 mmol) in DCM (28 mL), followed in 20 min by addition of 4-methylmorpholine (5.9 mL, 53 mmol). The reaction was held at -78 C. for 20 min, then warmed to 0 C. for 1 h, at which time tlc analysis showed complete oxidation to aldehyde. The reaction was quenched by addition of water and CHCl3, the phases were separated and the aqueous phase was extracted with additional CHCl3. The combined organic phase was washed with water, then 1N HCl, then sat'd NaHCO3, sat'd NaCl, dried over MgSO4 and reduced in vacuo to leave the crude product which was used without further purification, 2.1 g. 1H NMR (300 MHz, CDCl3): delta 9.68 (s, 1H), 3.68 (m, 1H), 3.50 (m, 1H), 3.37 (m, 2H), 3.0 (m, 1H), 2.13 (m, 2H), 1.42 (s, 9H). MS (EI): 144.1 (M-tBu+2H), 126.0 (M-OtBu).
	With sodium hypochlorite; sodium hydrogencarbonate; potassium bromide;2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; In dichloromethane; at 0 - 8℃;Product distribution / selectivity;	Preparation 1(R)-3-vinylpyrrolidine-1-carboxylic Acid t-Butyl Ester ; A solution of <strong>[199174-24-8](S)-3-hydroxymethyl-pyrrolidine-1-carboxylic acid t-butyl ester</strong> (25.0 g, 124 mmol, 1.0 eq.) in DCM (200 mL) was cooled with stirring to 0 C. A solution of potassium bromide (1.5 g, 12.4 mmol, 0.1 eq.) and sodium bicarbonate (1.5 g, 17.4 mmol, 0.14 eq.) dissolved in water (100 mL) was added. After 15 minutes of stirring at 0 C., TEMPO (195.3 mg, 1.2 mmol, 0.01 eq.) was added, followed by the slow addition of sodium hypochlorite (77.3 mL, 1.1 eq.) dropwise keeping the internal temperature in the 6-8 C. range. The mixture was placed in an ice bath until the layers separated. The organic layer was separated and the aqueous layer was extracted with DCM (200 mL). The combined organic layers were washed with saturated aqueous NaCl (200 mL), dried over Na2SO4, filtered, and concentrated to yield crude (S)-3-formylpyrrolidine-1-carboxylic acid t-butyl ester (21.5 g).
	With sodium hypochlorite; sodium hydrogencarbonate;2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; potassium bromide; In dichloromethane; water; at 6 - 8℃;Cooling with ice;	Preparation 1^ -3-vinylpyrrolidine-l-carboxylic Acid f-Butyl Ester; A solution of (S)-3-hydroxymethyl-pyrrolidine-l-carboxylic acid ?-butyl ester (25.0 g, 124 mmol, 1.0 eq.) in DCM (200 mL) was cooled with stirring to 0C. A solution of potassium bromide (1.5 g, 12.4 mmol, 0.1 eq.) and sodium bicarbonate (1.5 g,17.4 mmol, 0.14 eq.) dissolved in water (100 mL) was added. After 15 minutes of stirring at 0C, TEMPO (195.3 mg, 1.2 mmol, 0.01 eq.) was added, followed by the slow addition of sodium hypochlorite (77.3 mL, 136.6 mmol, 1.1 eq.) dropwise keeping the internal temperature in the 6-8C range. The mixture was placed in an ice bath until the layers separated. The organic layer was separated and the aqueous layer was extracted with DCM (200 mL). The combined organic layers were washed with saturated aqueous NaCl (200 mL), dried over Na2S04, filtered, and concentrated to yield crude compound la (21.5 g).
	With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; potassium bromide; In dichloromethane; water; at 0℃; for 0.166667h;	To a solution of <strong>[199174-24-8](S)-3-hydroxymethylpyrrolidine-1-carboxylic acid t-butyl ester</strong> 9 (7.4 g, 37 mmol) in DCM (74 mL, 1.2 mol) was added TEMPO (100 mg, 0.7 mmol) and potassium bromide (200 mg, 2 mmol). This mixture was cooled to 0C and vigorously stirred as a pre-chilled (at 0C) 1:1 mixture of 0.7 M of NaOCl in water (78 mL, 55 mmol) and a saturated, aqueous NaHCO3 solution (75 mL) was added dropwise over a period of 10 minutes. The resultant mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with water (2 x 100 mL), then saturated aqueous NaCl (1 x 100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield compound 10, which was used without further purification (5.8 g, 80% yield). 1H NMR (400 MHz, CDCl3) delta (ppm) = 9.62 (d, J = 1.6 Hz, 1H), 3.74-3.54 (m, 1H), 3.54-3.38 (m, 1H), 3.38-3.17 (m, 2H), 3.06 - 2.84 (m, 1H), 2.23 - 1.88 (m, 2H), 1.39 (s, 9H).
		A solution of <strong>[199174-24-8](S)-3-hydroxymethyl-pyrrolidine-1-carboxylic acid t-butyl ester</strong> (25.0 g, 124 mmol, 1.0 eq.) in DCM (200 mL) was cooled with stirring to 0C. A solution of potassium bromide (1.5 g, 12.4 mmol, 0.1 eq.) and sodium bicarbonate (1.5 g,17.4 mmol, 0.14 eq.) dissolved in water (100 mL) was added. After 15 minutes of stirring at 0C, TEMPO (195.3 mg, 1.2 mmol, 0.01 eq.) was added, followed by the slow addition of sodium hypochlorite (77.3 mL, 136.6 mmol, 1.1 eq.) dropwise keeping the internal temperature in the 6-8C range. The mixture was placed in an ice bath until the layers separated. The organic layer was separated and the aqueous layer was extracted with DCM(200 mL). The combined organic layers were washed with saturated aqueous NaC1 (200 mL), dried over Na2504, filtered, and concentrated to yield crude (S)-3- formylpyrrolidine-1-carboxylic acid t-butyl ester (21.5 g).
		To a solution of oxalyl chloride (22.17 g, 0.176 mol) in CH2Cl2 (200 mL) was added dropwise a solution of DMSO ( 20.59 g, 0.264 mol) in CH2Cl2 (50 mL) at -78 C. The mixture was stirred for 0.5 hrs at this temperature. A solution of (S)-tert-butyl 3- (hydroxymethyl)pyrrolidine-l-carboxylate (M6) (11.8 g, 58.7 mmol) in CH2Cl2 (50 mL) was added dropwise to the reaction mixture at -78 0C. The mixture continued to stir for 1 hr at that temperature. Et3N (29.7 g, 0.294 mol) was added at -78 0C. The resultant mixture was warmed to room temperature and stirred for 3 hrs. The mixture was poured into saturated aqueous NaHCO3 and shaken'. The organic layer was separated, washed twice with water, dried and evaporated to give a residue, which was purified by column chromatography (P.E./EtOAc 5:1) to give (S)-tert-butyl 3-formylpyrrolidine-l-carboxylate (M7). 1H NMR (CDCl3, 300 MHz): delta 9.68 (d, J = 1.8 Hz, 1 H), 3.67-3.68 (m, 1 H), 3.51-3.55 (m, 1 H), 3.35-3.40 (m, 2 H), 2.99-3.04 (m, 1 H), 2.04-2.18 (m, 2 H), 1.46 (s, 9 H).

References: [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 2829 - 2834.
[2]Patent: US2010/22616,2010,A1 .Location in patent: Page/Page column 35.
[3]Patent: US2010/267743,2010,A1 .Location in patent: Page/Page column 25.
[4]Patent: US2011/9465,2011,A1 .Location in patent: Page/Page column 19.
[5]Patent: US2011/21597,2011,A1 .Location in patent: Page/Page column 19.
[6]Patent: US2010/298334,2010,A1 .Location in patent: Page/Page column 68.
[7]Patent: US2012/88799,2012,A1 .Location in patent: Page/Page column 22.
[8]Patent: WO2012/75239,2012,A1 .Location in patent: Page/Page column 48.
[9]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1456 - 1461.
[10]Patent: WO2013/49617,2013,A1 .Location in patent: Page/Page column 35.
[11]Patent: WO2007/100670,2007,A1 .Location in patent: Page/Page column 51.

11
[ 199174-24-8 ]
[ 1018966-17-0 ]

Yield	Reaction Conditions	Operation in experiment
		Example 9 Production of 3-[(4-[(3S)-1-methylpyrrolidin-3-yl]methoxy}phenyl)thio-N-(3-methyl-1,2,4-thiadiazol-5-yl)-6-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]pyridine-2-carboxamide Starting from <strong>[199174-24-8]tert-butyl (3S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate</strong>, the entitled compound was obtained as a pale yellow solid in the same method as in Example 2. 1H-NMR (CDCl3) delta: 1.59-1.70 (1.0H, m), 2.05-2.18 (1.0H, m), 2.41 (3.0H, s), 2.53-2.59 (2.0H, m), 2.62 (3.0H, s), 2.64-2.78 (3.0H, m), 3.73 (3.0H, s), 3.92-3.95 (2.0H, m), 6.98 (2.0H, d, J=8.2 Hz), 7.05 (1.0H, dd, J=8.8, 0.6 Hz), 7.12 (1.0H, dd, J=8.8, 0.6 Hz), 7.44 (2.0H, d, J=8.2 Hz), 8.40 (1.0H, s). ESI-MS (m/e): 555[M+H]+.

References: [1]Patent: US2008/90799,2008,A1 .Location in patent: Page/Page column 20-21.

12
[ 199174-24-8 ]
[ 1067230-64-1 ]

Yield	Reaction Conditions	Operation in experiment
66%	With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 0℃; for 5h;Inert atmosphere;	STEP A: Tetrabromomethane (0.906 g, 2.73 mmol) and triphenylphosphine (0.717 g, 2.73 mmol) are added under nitrogen to the solution (S)-N-Boc-3-(bromomethyl)pyrrolidine (0.5 g, 2.484 mmol) in anhydrous DCM (10 mL) at 0C. The reaction is stirred at 0C for 5 h. During this period of time additional tetrabromomethane (0.906 g, 2.73 mmol) is added. The organic solvent is removed under reduced pressure and the crude is purified by flash column chromatography (eluent DCM 100%) to give the expected compound (0.433 g, 1.64 mmol, Yield: 66%). 1H-NMR (CDCl3) delta (ppm): 3.59 (dd, J=10.86, 7.34 Hz, 1 H); 3.49 (ddd, J=l 1.15, 8.22, 4.11 Hz, 1 H); 3.40 (d, J=6.75 Hz, 2 H); 3.28-3.37 (m, 1 H); 3.11 (dd, J=11.00, 7.48 Hz, 1 H); 2.45-2.73 (m, 1 H); 1.98-2.14 (m, 1 H); 1.64-1.79 (m, 1 H); 1.47 (s, 9 H)
		(S)-1-tert-Butoxycarbonylpyrrolidine-3-methanol [CASRN 199174-24-8] and (R)-1-tert-butoxycarbonylpyrrolidine-3-methanol [CASRN 138108-72-2] can be converted to the corresponding bromide by the procedure of M. O. Polla et al. Bioorg. Med. Chem. Lett. 2004 12:1151-1175.

References: [1]Patent: WO2013/64919,2013,A1 .Location in patent: Page/Page column 64.
[2]Patent: US2008/249087,2008,A1 .Location in patent: Page/Page column 32.

13
[ 1123786-71-9 ]
[ 138108-72-2 ]
[ 199174-24-8 ]

References: [1]Journal of the American Chemical Society,2009,vol. 131,p. 2786 - 2787.

14
[ 140148-70-5 ]
[ 199174-24-8 ]

Yield	Reaction Conditions	Operation in experiment
		Step 1. tert-butyl (3S)-3-(hydroxymethyl)pyrrolidine-1-carboxylateA solution of (3S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (Chem-Impex; 2.5 g, 12 mmol) in THF (54 mL) was cooled to 0 C. and 1.0 M of BH3 in THF (14 mL, 14 mmol) was slowly added. The reaction was allowed to warm to ambient temperature and was stirred for 4 h, at which time LCMS analysis showed complete reduction to alcohol. The solution was cooled to 0 C. and quenched by careful addition of 1N HCl. EtOAc was added and the phases were separated, the aqueous phase was extracted with additional EtOAc. The combined organic phase was washed with sat'd NaHCO3, then sat'd NaCl, dried over MgSO4 and reduced in vacuo to leave the crude product as a colorless oil, 2.15 g. 1H NMR (300 MHz, CDCl3): delta 3.7-3.2 (m, 5H), 3.1 (m, 1H), 2.4 (m, 1H), 1.95 (m, 1H), 1.7 (s, 2H), 1.45 (s, 9H). MS (EI): 146.0 (M-tBu+2H), 128.1 (M-OtBu).
		(3S) -1- ( Ter -butoxycarbonyl) pyrrolidine-3- carboxylic acid (10 g) was dissolved in tetrahydrofuran (100 ml) . To the solution was added dropwise dimethyl sulfide-borane tetrahydrofuran solution (54 ml) at 0C with stirring, and then the mixture was warmed to room temperature and stirred for 3 hours. To the reaction solution was added dropwise methanol (100 ml) at 0C with stirring, and then the reaction solution was concentrated under reduced pressure. The residue was purified by silica-gel chromatography (developing solvent: hexane / ethyl acetate = 1:9) to give tert-butyl (3S) -3 - (hydroxymethyl) pyrrolidine- 1-carboxylate (7.8 g) as a colorless oil.LC-MS, m/z; 202 [M+H] + .

References: [1]Patent: US2010/298334,2010,A1 .Location in patent: Page/Page column 68.
[2]Patent: WO2012/169649,2012,A1 .Location in patent: Page/Page column 164; 165.

15
[ 199174-24-8 ]
[ 1257070-34-0 ]

References: [1]Patent: US2010/298334,2010,A1 .

16
[ 199174-24-8 ]
[ 1257070-37-3 ]

References: [1]Patent: US2010/298334,2010,A1 .

17
[ 24424-99-5 ]
[ 1264942-79-1 ]
[ 199174-24-8 ]

Yield	Reaction Conditions	Operation in experiment
53%		(4) To a solution of (3^-3-([fer^butyl(dimethyl)silyl]oxy}methyl)"l-[(liS-l'phenylethyl]pyrrolidine (8.81 g, 27.6 mmol) in 1,2-dichloroethane (75 ml) was added 1-chloroethyl chloroformate (8.1 ml, 75 mmol) at room temperature. The resulting mixture was refluxed for 5 hours and cooled to room temperature. To the brown solution was added diisopropylethylamine (2.3 ml, 13 mmol). The mixture was refluxed for additional 3 hours and concentrated. The residue was diluted with ethyl acetate and washed with IN aqueous hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was dissolved in methanol (75 ml) and refluxed for one hour. After concentration under reduced pressure, IN aqueous hydrochloric acid was added. The aqueous solution was washed with ethyl acetate and basified by solid potassium carbonate. The basic solution was cooled to 0 T) and a solution of v terfrbutyl dicarbonate (6.3 g, 29 mmol) in tetrahydrofuran (75 ml) was added. The resulting mixture was stirred for 3 hours. The organic materials were extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent;hexane/ethyl acetate = 3/1 to 1/2) to afford C-°-ferf-butyl 3-(hydroxymethyl)pyrrolidine- 1-carboxylate (2.96 g, 14.7 mmol, 53%) as a colorless oil.

References: [1]Patent: WO2011/19090,2011,A1 .Location in patent: Page/Page column 45-46.

18
[ 617-52-7 ]
[ 199174-24-8 ]

References: [1]Patent: WO2011/19090,2011,A1 .

19
[ 109960-55-6 ]
[ 199174-24-8 ]

References: [1]Patent: WO2011/19090,2011,A1 .

20
[ 199174-24-8 ]
[ 1264942-17-7 ]

References: [1]Patent: WO2011/19090,2011,A1 .

21
[ 199174-24-8 ]
[ 1264942-86-0 ]

References: [1]Patent: WO2011/19090,2011,A1 .

22
[ 99735-46-3 ]
[ 199174-24-8 ]

References: [1]Patent: WO2011/19090,2011,A1 .
[2]Organic and Biomolecular Chemistry,2016,vol. 14,p. 5992 - 6009.

23
[ 1207840-79-6 ]
[ 199174-24-8 ]
C₂₇H₃₄N₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 4 5-(pyrrolidin-3-yl-methoxy)-7-(4-dimethylamino-3-methylphenyl)-[1,6]naphthyridine 118 mg (0.59 mmol) tert.butyl(S)-3-hydroxymethylpyrrolidinecarboxylate and 23.5 mg (0.59 mmol) sodium hydride (60%) were placed in 0.5 ml dimethylacetamide and stirred for 15 min at ambient temperature. Then 70 mg (0.24 mmol) of 6.1 was added and the mixture was stirred for 2 h at 70 C. 1 mL of trifluoroacetic acid was added and the mixture was stirred for 2 days at 25 C. The reaction mixture was purified by chromatography (RP-HPLC-MS). The corresponding fractions were freeze-dried. Yield: 110 mg (0.23 mmol=98% of theory) Analysis: HPLC-MS (method D): Rt: 1.05 min, (M+H)+: 363

References: [1]Patent: US2011/263549,2011,A1 .Location in patent: Page/Page column 13.

24
[ 199174-24-8 ]
5-[4-(1-[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-1H-imidazol-2-yl)phenyl]-1H-indole [ No CAS ]

References: [1]Patent: WO2012/37298,2012,A1 .

25
[ 199174-24-8 ]
1,1-dimethylethyl (3S)-3-[2-(4-bromophenyl)-1H-imidazol-1-yl]methyl}-1-pyrrolidinecarboxylate [ No CAS ]

References: [1]Patent: WO2012/37298,2012,A1 .

26
[ 199174-24-8 ]
2-(4-bromophenyl)-1-{ [(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-1H-imidazole [ No CAS ]

References: [1]Patent: WO2012/37298,2012,A1 .

27
[ 199174-24-8 ]
[ 1372149-84-2 ]
[ 1372149-85-3 ]

References: [1]Patent: US2012/88799,2012,A1 .

28
[ 1094044-92-4 ]
[ 199174-24-8 ]
C₃₄H₄₂N₆O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triphenylphosphine; diethylazodicarboxylate; In dichloromethane; at 20℃; for 18h;	Preparation of compound 2ePreparation of 2-((4-?.2-dimethyl-l-(4-(2-r('35f)-pyrrolidin-3-ylmethyll-2//- tetrazol-5-yl}phenyl)propyllphenoxy)methyl)pyrimidine (2e)Diethyl azodicarboxylate (80 muL, 0.51 mmol) was added dropwise to a solution of i-18Bg (50 mg, 0.11 mmol), triphenylphosphine (130 mg, 0.50 mmol) and (5)-Boc-prolinol (73 mg, 0.36 mmol) in DCM (1.0 mL). The resulting mixture was stirred at rt for 18 h, and then passed through a short column of silica gel (gradient elution; 0%-70% (EtOAc/hexanes as eluent), from which the major regioisomer was isolated to afford an intermediate that was converted to the title compound 2e using the procedures described in step B. mlz (ES) 484 (MH)+.

References: [1]Patent: WO2008/156721,2008,A1 .Location in patent: Page/Page column 69.

29
[ 199174-24-8 ]
[ 1204671-62-4 ]