[ CAS No. 63126-47-6 ] {[proInfo.proName]}

Name: 63126-47-6|(S)-2-(Methoxymethyl)pyrrolidine|97%
Brand: Ambeed
SKU: A742383
Rating: 97 (27 reviews)

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Cat. No.: {[proInfo.prAm]}

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Quality Control of [ 63126-47-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 63126-47-6 ]

CAS No. :	63126-47-6	MDL No. :	MFCD00010408
Formula :	C₆H₁₃NO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	CHPRFKYDQRKRRK-LURJTMIESA-N
M.W :	115.17	Pubchem ID :	671217
Synonyms :

Calculated chemistry of [ 63126-47-6 ] Expand+

Physicochemical Properties

Num. heavy atoms :	8
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	36.64
TPSA :	21.26 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) :	-6.86 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.98
Log Po/w (XLOGP3) :	0.2
Log Po/w (WLOGP) :	0.0
Log Po/w (MLOGP) :	0.21
Log Po/w (SILICOS-IT) :	1.1
Consensus Log Po/w :	0.7

Druglikeness

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

Water Solubility

Log S (ESOL) :	-0.55
Solubility :	32.6 mg/ml ; 0.283 mol/l
Class :	Very soluble
Log S (Ali) :	-0.21
Solubility :	71.8 mg/ml ; 0.623 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.29
Solubility :	5.95 mg/ml ; 0.0516 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.69

Safety of [ 63126-47-6 ]

Signal Word:	Danger	Class:	3
Precautionary Statements:	P261-P305+P351+P338	UN#:	1993
Hazard Statements:	H225-H315-H319-H335	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 63126-47-6 ]

* 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 [ 63126-47-6 ]

[ 63126-47-6 ] Synthesis Path-Downstream 1~91

1
[ 67-56-1 ]
[ 132635-95-1 ]
[ 63126-47-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; trifluoroacetic acid 1.) reflux, 48 h, 2.) 90 deg C, 1 h; Yield given. Multistep reaction;

Reference： [1]Alker; Doyle; Harwood; McGregor [Tetrahedron Asymmetry, 1990, vol. 1, # 12, p. 877 - 880]

2
[ 101419-83-4 ]
[ 63126-47-6 ]
[ 102631-64-1 ]

Reference： [1]Journal of the American Chemical Society,1989,vol. 111,p. 7921 - 7925
[2]Journal of the American Chemical Society,1986,vol. 108,p. 3855 - 3856

3
[ 33558-75-7 ]
[ 63126-47-6 ]
[ 118722-59-1 ]

Yield	Reaction Conditions	Operation in experiment
74%	at 80℃; for 24h;

Reference： [1]Horvath, Raymond F.; Chan, Tak Hang [Journal of Organic Chemistry, 1989, vol. 54, # 2, p. 317 - 327]

4
[ 2566-22-5 ]
[ 63126-47-6 ]
N-benzoyl-(S)-phenylalanine (S)-prolinol methyl ether amide [ No CAS ]

Reference： [1]Journal of Chemical Research, Miniprint,1984,p. 1518 - 1530

5
[ 17816-85-2 ]
[ 63126-47-6 ]
[ 105335-57-7 ]

Reference： [1]Journal of Organic Chemistry,1986,vol. 51,p. 4920 - 4924

6
[ 63126-47-6 ]
[ 71887-28-0 ]
[ 139760-48-8 ]

Reference： [1]Journal of the American Chemical Society,1992,vol. 114,p. 3937 - 3943

7
[ 63126-47-6 ]
[ 124004-75-7 ]
[ 124097-61-6 ]

Yield	Reaction Conditions	Operation in experiment
53%	With potassium carbonate In N,N-dimethyl-formamide at 60 - 65℃; for 72h;

Reference： [1]Nijhuis, W. H. N.; Verboom, W.; Harkema, S.; Reinhoudt, D. N. [Recueil des Travaux Chimiques des Pays-Bas, 1989, vol. 108, # 4, p. 147 - 160]

8
[ 63126-47-6 ]
[ 108-94-1 ]
[ 83976-41-4 ]

Reference： [1]Helvetica Chimica Acta,1982,vol. 65,p. 1637 - 1654
[2]Liebigs Annalen der Chemie,1992,p. 233 - 238
[3]Tetrahedron Letters,1989,vol. 30,p. 5347 - 5348
[4]Synlett,1999,p. 234 - 236
[5]Journal of Organometallic Chemistry,1990,vol. 382,p. 295 - 301

9
[ 89999-52-0 ]
[ 17596-79-1 ]
[ 582-22-9 ]
[ 63126-47-6 ]

Reference： [1]Angewandte Chemie,1984,vol. 96,p. 368 - 369

10
[ 63126-47-6 ]
[ 103-80-0 ]
[ 102061-01-8 ]

Reference： [1]Organic letters,2002,vol. 4,p. 1963 - 1966
[2]Tetrahedron Letters,1985,vol. 26,p. 3539 - 3542

11
[ 63126-47-6 ]
[ 106-96-7 ]
[ 198149-15-4 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In acetone;	EXAMPLE 81 (2S)-2-Methoxymethyl-1-prop-2-ynylpyrrolidine A mixture of 4.82 g (41.9 mmol) of S-2-(methoxymethyl)pyrrolidine, 13.7 g (41.9 mmol) of cesium carbonate and 5.00 g (41.9 mmol) of propargyl bromide in 80 mL of acetone was stirred at 25° C. overnight. The reaction was filtered and solvent was removed from the filtrate. The residue was diluted with a small amount of water and satd NaHCO3 and extracted with ether. The extract was treated with Darco, dried and evaporated to give 5.93 g of (2S)-2-methoxymethyl-1-prop-2-ynylpyrrolidine as a yellow orange oil: mass spectrum (electrospray, m/e): 153.8.
	With caesium carbonate; In acetone;	EXAMPLE 30 (2S)-2-Methoxymethyl-1-prop-2-ynylpyrrolidine A mixture of 4.82 g (41.9 mmol) of S-2-(methoxymethyl)pyrrolidine, 13.7 g (41.9 mmol) of cesium carbonate and 5.00 g (41.9 mmol) of propargyl bromide in 80 mL of acetone was stirred at 25° C. overnight. The reaction was filtered and solvent was removed from the filtrate. The residue was diluted with a small amount of water and satd NaHCO3 and extracted with ether. The extract was treated with Darco, dried and evaporated to give 5.93 g of (2S)-2-methoxymethyl-1-prop-2-ynylpyrrolidine as a yellow orange oil: mass spectrum (electrospray, m/e): 153.8.
	With caesium carbonate; In acetone; at 25℃;	A mixture of 4.82 g (41.9 mmol) of S-2-(methoxymethyl)pyrrolidine, 13.7 g (41.9 mmol) of cesium carbonate and 5.00 g (41.9 mmol) of propargyl bromide in 80 mL of acetone was stirred at 25°C overnight. The reaction was filtered and solvent was removed from the filtrate. The residue was diluted with a small amount of water and satd NaHCO3 and extracted with ether. The extract was treated with Darco, dried and evaporated to give 5.93 g of (2S)-2-methoxymethyl-1-prop-2-ynylpyrrolidine as a yellow orange oil: mass spectrum (electrospray, m/e): 153.8.

	With caesium carbonate; In acetone; at 25℃;	A mixture of 4.82 g (41.9 mmol) of S-2-(methoxymethyl)pyrrolidine, 13.7 g (41.9 mmol) of cesium carbonate and 5.00 g (41.9 mmol) of propargyl bromide in 80 ML of acetone was stirred at 25° C. overnight.. The reaction was filtered and solvent was removed from the filtrate.. The residue was diluted with a small amount of water and saturated NaHCO3 and extracted with ether.. The extract was treated with activated charcoal, dried and evaporated to give 5.93 g of (2S)-2-methoxymethyl-1-prop-2-ynylpyrrolidine as a yellow orange oil: mass spectrum (electrospray, m/e): M+H 153.8.
	With caesium carbonate; In acetone; at 25℃;	A mixture of 4.82 g (41.9 mmol) of S-2-(methoxymethyl)pyrrolidine, 13.7 g (41.9 mmol) of cesium carbonate and 5.00 g (41.9 mmol) of propargyl bromide in 80 mL of acetone was stirred at 25C overnight. The reaction was filtered and solvent was removed from the filtrate. The residue was diluted with a small amount of water and saturated NaHCO3 and extracted with ether. The extract was treated with activated charcoal, dried and evaporated to give 5.93 g of (2S)-2-methoxymethyl-1-prop-2-ynylpyrrolidine as a yellow orange oil: mass spectrum (electrospray, m/e): M+H 153.8.

Reference： [1]Journal of Organometallic Chemistry,1997,vol. 541,p. 321 - 332
[2]Journal of Medicinal Chemistry,2001,vol. 44,p. 2719 - 2734
[3]Patent: US6297258,2001,B1
[4]Patent: US6288082,2001,B1
[5]Patent: EP1950201,2008,A1 .Location in patent: Page/Page column 61
[6]Patent: US6355636,2002,B1 .Location in patent: Page column 55
[7]Patent: EP1171440,2004,B1 .Location in patent: Page 46

12
[ 51731-17-0 ]
[ 63126-47-6 ]
[ 250696-14-1 ]

Reference： [1]Journal of the American Chemical Society,1999,vol. 121,p. 9562 - 9573

13
[ 63126-47-6 ]
(1R,3S,4S)-2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester [ No CAS ]
(1R,3S,4S)-N-tert-butoxycarbonyl-3-[N-((2S)-2-methoxymethyl)pyrrolidinyl]carbonyl-2-azabicyclo[2.2.1]heptane [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2000,vol. 122,p. 6610 - 6618

14
[ 63126-47-6 ]
[ 291775-53-6 ]
[ 291775-65-0 ]

Reference： [1]Journal of the American Chemical Society,2000,vol. 122,p. 6610 - 6618

15
[ 63126-47-6 ]
[ 132898-96-5 ]
[ 220509-74-0 ]

Yield	Reaction Conditions	Operation in experiment
93%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; chloroform; at 0℃; for 1.5h;	Step 2: 5-[(2S)-2-(Methoxymethyl)pyrrolidin-1-yl]sulfonyl}-1H-indole-2,3-dione To a cold suspension of <strong>[132898-96-5]2,3-dioxo-2,3-dihydro-1H-indole-5-sulfonylchloride</strong> (5.28 g, 21.5 mmol) in a 1:1 mixture of THF:CHCl3 (254 mL) was added drop-wise via syringe pump a solution of (S)-(+)-2-(methoxymethyl)-pyrrolidine (3.45 mL, 28.0 mmol, 1.3 eq) (Aldrich) and N,N-diisopropylethylamine (7.49 mL, 43 mmol, 2 eq) in CHCl3 (42 mL) over a period of 70 minutes under a dry N2 atmosphere with cooling in an ice bath. After stirring an additional 20 minutes the mixture was concentrated. The residue was flash chromatographed (Biotage KP silica gel, 98/2 CH2Cl2/CH3OH) to give the title compound as a dark greenish-yellow foam (6.48 g. 93% yield). NMR (400 MHz, DMSO-d6): consistent MS: (API-ES-) m/z 323[M-H].

Reference： [1]Patent: US2005/250798,2005,A1 .Location in patent: Page/Page column 21
[2]Journal of Medicinal Chemistry,2001,vol. 44,p. 2015 - 2026
[3]Journal of Medicinal Chemistry,2006,vol. 49,p. 6704 - 6715
[4]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 7755 - 7768

16
[ 63126-47-6 ]
[ 132898-96-5 ]
[ 220509-85-3 ]

Yield	Reaction Conditions	Operation in experiment
63.8%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; chloroform; at 0℃; for 2.5h;	Step 1: 5-[(2R)-2-(Methoxymethyl)pyrrolidin-1-yl]sulfonyl}-1H-indole-2,3-dione To a stirred cold suspension of 2,3-dioxo-2,3-dihydro-1H-indol-5-sulfonyl chloride (5.00 g, 20.4 mmol) in a 1:1 mixture of THF: CHCl3 (140 mL) was added dropwise, via syringe pump, a solution of N,N-diisopropylethylamine (7.11 mL, 40.8 mmol, 2 eq) and (R)-2-(Methoxymethyl)pyrrolidine (3.27 mL, 26.5 mmol, 1.3 eq) in CHCl3 (60 mL) over a period of 1.5 hours with cooling in an ice bath. After stirring an additional 1 h, the reaction was concentrated. The crude product was purified on Biotage KP silica gel eluding with 95/5 CH2Cl2/CH3OH followed by a second chromatography on silica gel eluding with EtOAc to give 4.21 g (63.8%) of the title compound. NMR (400 MHz, DMSO-d6): consistent.

Reference： [1]Patent: US2005/250798,2005,A1 .Location in patent: Page/Page column 28
[2]Journal of Medicinal Chemistry,2001,vol. 44,p. 2015 - 2026

17
[ 13195-50-1 ]
[ 63126-47-6 ]
[ 536-74-3 ]
(E)-1-[2-(5-nitrothien-2-yl)-1-phenylvinyl]-(2R)-methoxymethylpyrrolidine [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2003,vol. 68,p. 1503 - 1511

18
[ 63126-47-6 ]
[ 133283-74-6 ]
[ 579494-58-9 ]

Reference： [1]Chemical Communications,2003,p. 1072 - 1073

19
[ 63126-47-6 ]
[ 77086-38-5 ]
[ 100-52-7 ]
methyl 3-((S)-2-methoxymethylpyrrolidino)-3-phenylpropanoate [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2004,vol. 126,p. 13196 - 13197

20
[ 63126-47-6 ]
[ 4347-31-3 ]
C₁₁H₁₈BNO₃S [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2005,vol. 127,p. 4260 - 4269

21
[ 63126-47-6 ]
[ 115869-43-7 ]
[ 627-41-8 ]
1-[(1R)-1-(tert-butyldiphenylsilanyloxymethyl)-4-methoxy-2-butynyl]-(2S)-2-(methoxymethyl)pyrrolidine [ No CAS ]

Reference： [1]Organic Letters,2005,vol. 7,p. 2821 - 2824

22
[ 290-87-9 ]
[ 63126-47-6 ]
[ 542-92-7 ]
6-[(S)-2-(methoxymethyl)pyrrolidino]fulvalene [ No CAS ]

Reference： [1]European Journal of Inorganic Chemistry,2005,p. 4924 - 4935

23
[ 916049-16-6 ]
[ 63126-47-6 ]

Yield	Reaction Conditions	Operation in experiment
	With trifluoroacetic acid; In dichloromethane; at 0 - 20℃; for 2h;	To a solution of tert-butyl (S)-2-(methoxymethyl)pyrrolidine-1-carboxylate (663 mg, 3.08mmol) in DCM (10 mL) was added trifluoroacetic acid (1.76 g, 15.40 mmol) within 5 min at0°C. The mixture was warmed up to room temperature within 2 h and carefully poured into a10percent NaOH solution (60 mL). After extraction with DCM (2 × 50 mL) the combined organicphases were dried over MgSO4, and evaporated. The residue was dissolved in DCM (5 mL)and N,N-diisopropylethylamine (521 mg, 4.03 mmol) was added at room temperature. Thissolution containing the deprotected pyrrolidine was then stirred until it was needed.

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 6704 - 6715
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 9383 - 9395
[3]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 5734 - 5739

24
[ 953434-83-8 ]
[ 63126-47-6 ]
[ 953434-84-9 ]

Yield	Reaction Conditions	Operation in experiment
91%	With potassium carbonate;sodium iodide; In dichloromethane; acetone; for 3h;Heating / reflux;	Step 2: (S)-ferf-Butyl 2-(4-((2-(methoxymethyl)pyrrolidin-l-yl)methyl)benzamido)-4-(thiophen- 2-yl)phenylcarbamate (75); [0708] To a solution of chloride 74 (0.30 g, 0.68 mmol) in DCM (7 mL) was added (S)-2- (methoxymethyl)pyrrolidine (86 mg, 0.75 mmol), K2CO3 (0.31 g, 2.24 mmol) and NaI (12 mg, 0.075 mmol). Acetone (3 mL) was added and the reaction mixture was heated to reflux for 3 <n="96"/>days then concentrated. The residue was taken up in AcOEt, washed with H2O, brine, dried overMgSO4, filtered and concentrated to give title compound 75 (0.323 g, 91percent yield).[0709] 1H NMR (DMSO-de) delta (ppm): 9.87 (s, IH), 8.72 (s, IH), 7.91 (d, J= 8.4 Hz, 2H),7.80 (d, J= 2.2 Hz, IH), 7.59 (d, J= 8.6 Hz, IH), 7.51 (dd, J= 4.9, 1.0 Hz, IH), 7.49 (dd, J= 8.4,2.3 Hz, IH), 7.45 (d, J= 8.6 Hz, 2H), 7.44 (dd, J= 3.7, 1.0 Hz, IH), 7.11 (dd, J= 12.5 Hz, IH),3.39 (q, J= 5.7 Hz, IH), 2.79 to 2.75 (m, IH), 2.73 to 2.67 (m, IH), 2.15 (q, J= 7.6 Hz, IH), 1.86(dq, J= 11.9, 7.8 Hz, IH), 1.66 to 1.58 (m, IH), 1.54 to 1.46 (m, IH), 1.44 (s, 9H).

Reference： [1]Patent: WO2007/118137,2007,A1 .Location in patent: Page/Page column 94-95

25
[ 63126-47-6 ]
[ 100-52-7 ]
[ 536-74-3 ]
C₂₁H₂₃NO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With cycloaurated phosphinothioicamide gold(III) complex immobilized in a silica-supported ionic liquid; In neat (no solvent); at 60℃; for 8h;Green chemistry;	General procedure: A mixture of aldehyde (1.97 mmol), amine (1.97 mmol), acetylene (2.95 mmol), and thecorresponding supported Au catalyst (1percent wt, 60 mg, 0.002 mmol) was heated at 60 °C for 8 h,after which time the solution was cooled and the catalyst was removed by filtration. The filtrate wasevaporated under reduced pressure to afford propargylamine 5. Yields were determined by integration of the 1H-NMR spectra of the crude reaction mixtures. After separation and washing with n-pentane,the catalyst was reused intact for the next reaction without any further pre-treatment.

Reference： [1]Chemistry - A European Journal,2006,vol. 12,p. 4380 - 4392
[2]Molecules,2018,vol. 23
[3]Organometallics,2017,vol. 36,p. 1962 - 1973

26
7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid lithium salt [ No CAS ]
[ 63126-47-6 ]
[ 380237-33-2 ]

Yield	Reaction Conditions	Operation in experiment
74%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 16h;	To a mixture of lithium 7-chlorothieno [3,2-b] pyridine-2-carboxylate (6.59 g, 30 [MMOLE)] in DMF (100 [ML)] were added diisopropylethylamine, (6 [ML,] 4.45 g, 34.4 mmole), benzotriazol- 1-yloxytris (pyrrolidino) phosphonium [HEXAFLUOROPHOSPHATE] (16.16 g, 31 mmole) and [S- (+)-2-] (methoxymethyl) pyrrolidine (3.73 g, 32.4 [MMOLE).] The resultant reaction mixture was stirred at ambient temperaure for 16 hours. The crude reaction mixture was poured into water (600 [ML)] and extracted with EtOAc (3 x 200 ml). The combined organic extracts were washed with water (4 x 200 ml), dried over [NA2SO4] and concentrated, in vacuo, to give 8.8 g of an amber oil, which was purified by silica gel chromatography. Elution with Et2O : EtOAc (67: 33) and evaporation of the appropriate fractions gave 6.89 [G] (74percent) of an orange [SYRUP.APOS;H] NMR (DMSO-d6): 8 8.62 (1 H, d, J = 5.0 Hz), 7.88 (1 H, s), 7.35 (1 H, d, J = 5.0 Hz), 4.54-4. 47 [(1 H,] m), 3.93-3. 75 (2H, m), 3.71-3. 55 (2H, m), 3.37 (3H, s), 2.15-1. 92 (4H, [M). ANAL. CALCD.] for [C14H1SN202SCI] : [C,] 54.10 ; H, 4.87 ; N, 9.01 ; S, 10.32 ; Cl, 11.41. Found: C, 53.96

Reference： [1]Patent: WO2003/106462,2003,A1 .Location in patent: Page 36; 37

27
6-chloro-N-(1-ethyl-pyrrolidin-2-ylmethyl)-N'-(3-fluoro-4-methoxy-phenyl)-[1,3,5]triazine-2,4-diamine [ No CAS ]
[ 63126-47-6 ]
[ 502766-82-7 ]

Yield	Reaction Conditions	Operation in experiment
27.6%	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; acetonitrile; at 50℃;	Cyanuric chloride (11.07 g, 60 mmol) was dissolved in 40 mL CH3CN and was cooled to about -20° C. To this was added DIEA (11.5 mL, 60 mmol) followed by 3-fluoro-4-methoxyaninline (8.47 g, 60 mmol) in 20 mL CH3CN (reaction froze). The reaction was allowed to warm to room temperature after about 1 hour at -20° C. TLC (2percent CH3OH/CH2Cl2) and mass spectroscopy indicated the presence of the compound 124. The reaction mixture was cooled to about 0° C. before adding DIEA (11.5 mL, 66 mmol). 2-Aminomethyl-1-ethylpyrrolidine (7.77 g, 60 mmol) in CH3CN (10 mL) was added. The reaction was allowed to warm to rt and stirred overnight. Then DIEA (11.5 mL, 66 mmol) and S-(+)-2-methoxyethylpyrrolidine (6.91 g, 60 mmol) in 20 mL 1,4-dioxane were added. The reaction was heated at about 50° C. overnight. The solvent was removed in vacuo, and the resulting residue was purified by flash chromatography on silica gel packed in ethyl acetate. The front running impurities were removed and subsequently the eluent was increased in polarity to 10percent CH3OH:ethyl acetate. The material collected from the column was then dissolved in water and extracted in CH2Cl2 (4 times), dried over MgSO4, and concentrated to dryness to give a brown solid 145 (9.7 g, 27.6percent yield), 71-72° C.; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4 (0.01M, pH 3.2):CH3OH:CH3CN], 264 nm, Rt 5.37 min, 90.3percent purity; 1H NMR (600 MHz, CDCl3, 55° C.) delta 7.69 (s, 1H), 7.08 (d, J=7.8 Hz, 1H), 6.86 (t, J=9 Hz, 1H), 4.29 (s, 1H), 3.90-3.96 (m, 1H), 3.84 (s, 3H), 3.63-3.81 (m, 6H), 3.35 (s, 3H), 3.23-3.25 (m, 1H), 2.85 (broad s, 1H), 2.78 (broad s 1H), 2.14 (broad s, 2H), 1.89-2.04 (m, 6H), 1.37 (apparent t, J=7.2 Hz, 3H); 13C NMR (150.8 MHz, CDCl3, 55° C.) delta 165.8, 163.8 (2C), 152.3 (d, Jc-f=243.5 Hz), 143.0 (142.9, rotamer or diastereumer), 133.7 (133.67, rotamer or diastereomer), 115.0, 114.4, 109.1 (108.9, rotamer or diastereomer), 72.8, 66.6, 59.0, 57.0, 56.6, 53.7, 51.0, 46.8, 42.2, 28.4 (28.2, rotamer or diastereomer), 23.1 (23.0, rotamer or diastereomer), 10.9; MS (ESI) m/z 460.2 (M+H, 44.7), 251.1 (47.7), 235.1 (27.5), 231.1 (37.4), 230.6 (100), 214.6 (36.5).
27.6%	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; acetonitrile; at 50℃;	Cyanuric chloride (11.07 g, 60 mmol) was dissolved in 40 mL CH3CN and was cooled to about -20° C. To this was added DIEA (11.5 mL, 60 mmol) followed by 3-fluoro-4-methoxyaninline (8.47 g, 60 mmol) in 20 mL CH3CN (reaction froze). The reaction was allowed to warm to room temperature after about 1 hour at -20° C. TLC (2percent CH3OH/CH2Cl2) and mass spectroscopy indicated the presence of the compound 124. The reaction mixture was cooled to about 0° C. before adding DIEA (11.5 mL, 66 mmol). 2-Aminomethyl-1-ethylpyrrolidine (7.77 g, 60 mmol) in CH3CN (10 mL) was added. The reaction was allowed to warm to rt and stirred overnight. Then DIEA (11.5 mL, 66 mmol) and S-(+)-2-methoxyethylpyrrolidine (6.91 g, 60 mmol) in 20 mL 1,4-dioxane were added. The reaction was heated at about 50° C. overnight. The solvent was removed in vacuo, and the resulting residue was purified by flash chromatography on silica gel packed in ethyl acetate. The front running impurities were removed and subsequently the eluent was increased in polarity to 10percent CH3OH:ethyl acetate. The material collected from the column was then dissolved in water and extracted in CH2Cl2 (4 times), dried over MgSO4, and concentrated to dryness to give a brown solid 145 (9.7 g, 27.6percent yield), 71-72° C.; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4 (0.01M, pH 3.2):CH3OH:CH3CN], 264 nm, Rt 5.37 min, 90.3percent purity; 1H NMR (600 MHz, CDC3, 55° C.) delta 7.69 (s, 1H), 7.08 (d, J=7.8 Hz, 1H), 6.86 (t, J=9 Hz, 1H), 4.29 (s, 1H), 3.90-3.96 (m, 1H), 3.84 (s, 3H), 3.63-3.81 (m, 6H), 3.35 (s, 3H), 3.23-3.25 (m, 1H), 2.85 (broad s, 1H), 2.78 (broad s 1H), 2.14 (broad s, 2H), 1.89-2.04 (m, 6H), 1.37 (apparent t, J=7.2 Hz, 3H); 13C NMR (150.8 MHz, CDCl3, 55° C.) delta 165.8, 163.8 (2C), 152.3 (d, Jc-f=243.5 Hz), 143.0 (142.9, rotamer or diastereumer), 133.7 (133.67, rotamer or diastereomer), 115.0, 114.4, 109.1 (108.9, rotamer or diastereomer), 72.8, 66.6, 59.0, 57.0, 56.6, 53.7, 51.0, 46.8, 42.2, 28.4 (28.2, rotamer or diastereomer), 23.1 (23.0, rotamer or diastereomer), 10.9; MS (ESI) mn/z 460.2 (M+H, 44.7), 251.1 (47.7), 235.1 (27.5), 231.1 (37.4), 230.6 (100), 214.6 (36.5).

Reference： [1]Patent: US2004/209881,2004,A1 .Location in patent: Page/Page column 98-100
[2]Patent: US2004/209882,2004,A1 .Location in patent: Page/Page column 97

28
[ 63126-47-6 ]
[ 566905-89-3 ]
[ 828258-27-1 ]

Yield	Reaction Conditions	Operation in experiment
67%	With triethylamine; In acetonitrile; at 20℃;	(S)- (+)-2- (METHOXYMETHYL) PYRROLIDINE (320 P1L, 2.59 mmol) was added to a stirred solution OF 4- (2-BROMO-ETHYL)-PIPERIDINE-1-CARBOXYLIC ACID BENZYL ester from Step 2 (797 mg, 2.44 mmol) and TEA (360 RL, 2.58 mmol) in acetonitrile (12 mL). The yellow solution was stirred overnight at rt and concentrated under reduced pressure. The crude residue was diluted with EtOAc, washed with saturated sodium bicarbonate solution and brine, and dried with magnesium sulfate. The solvent was removed to give 591 mg (67percent) of (S)-4- [2- (2-methoxymethyl-pyrrolidin-l-yl)-ethyl]-piperidine-l-carboxylicacid benzyl ester as a yellow oil. MS (ES+) M/Z 361 (M+H).

Reference： [1]Patent: WO2005/5397,2005,A1 .Location in patent: Page/Page column 62

29
2-chloro-6-(2-chloropyridin-4-yl)-3-methyl-5-m-tolyl-3h-pyrimidin-4-one [ No CAS ]
[ 63126-47-6 ]
6-(2-chloro-pyridin-4-yl)-2-(2-methoxymethyl-pyrrolidin-1-yl)-3-methyl-5-m-tolyl-3H-pyrimidin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 12h;	To a 100 mL RBF, was [ADD ][~)-^-INETHOXYMETHYL-PYNOLIDINE] (0.172 g, 1.5 mmol), and 50 mL [DICHLOROME ; HANE] at [0 oC] under nitrogen. 0.35 mL diisopropylethylamine (2.0 mmol) was added drop wise, and stirred for 10 min. 2- [CHLORO-6- (2-CHLOROPYRIDIN-4-YL)-3-METHYL-5-M-TOLYL-3H-PYRIMIDIN-4-ONE] (0.345 g, 1.0 mmol) was added in one portion, and stirred at [0 oC] to rt for 12 h. The mixture was diluted with 100 mL dichloromethane, washed with sat. [NAHC03] and brine. After purified by flash chromatography, the title compound was obtained in 0.40 g as pale yellow solid. MS (ES+): 425 [(M+H) +.]

Reference： [1]Patent: WO2003/99808,2003,A1 .Location in patent: Page 43-44

30
[ 866838-42-8 ]
[ 63126-47-6 ]
N-[1-tert-butyl-3-(2-methoxymethyl-pyrrolidine-1-carbonyl)-1H-pyrazolo[3,4-d]thiazol-5-yl]-4-methyl-benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%		1-Tert-Butyl-5- (4-methyl-benzoylamino)-1 H-pyrazolo [3,4-d] thiazole-3- carboxylic acid (50 mg, 0.14 mmoles) was dissolved in 10 ml of anhydrous tetrahydrofuran. Then, 1-hydroxybenzotriazole (23 mg, 0. 168 mmoles) was added followed by addition of N- cyclohexylcarbodiimide N'-methyl polystyrene (155 mg, 0.28 mmoles, loading: 1.8 mmoles/g) and S-2-methoxymethyl pyrrolidine (22 mg, 0.14 mmoles). The mixture was heated at 50°C for overnight. Polymer supported triamine (100 mg, 0.417 mmoles, loading: 4.17 mmoles/g) was added and shaken for 4 hours at 50°C. The resin was filtered off and washed with tetrahydrofuran (2 x 5ml). The filtrate was evaporated in vacuo to give crude product, which was purified by preparative HPLC using MeOH/H2O/TFA solvent system. The combined pure fractions were evaporated in vacuo and further dried on lyophilizer (yield: 36percent, LC: Method A, RT = 4.020 min, MS: M+1 = 456).

Reference： [1]Patent: WO2005/95420,2005,A1 .Location in patent: Page/Page column 75-76

31
[ 63126-47-6 ]
[ 96-32-2 ]
[ 865712-40-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; sodium iodide; In acetonitrile; at 160℃; for 0.0833333h;Irradiation;	Method B Methyl bromoacetate (199 pI, 2.10 mmol) was added to a mixture of (S)-2- methoxymethyl pyrrolidine (268 pI, 2.17 mmol), potassium carbonate (319 mg, 2.31 mmol) and sodium iodide (315 mg, 2.10 mmol) in acetonitrile (3 ml). The mixture was subjected to microwave irradiation for 5 min at 160°C, then partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography eluting with 0-10percent (v/v) methanol in dichloromethane afforded (S)- (2-methoxymethyl-pyrrolidin-1- yl) acetic acid methyl ester (133 mg, 0.71 mmol).

Reference： [1]Patent: WO2005/89754,2005,A1 .Location in patent: Page/Page column 16-17

32
[ 869224-01-1 ]
[ 63126-47-6 ]
7-chloro-8-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonyl}-3,4-dihydropyrimido[1,2-a]indol-10(2H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52.3%	In dichloromethane; at 0 - 20℃; for 1.5h;	Step 8: 7-Chloro-8-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl-]sulfonyl}-3,4-dihydropyrimido[1,2-a]indol-10(2H)-one To a solution of 7-chloro-10-oxo-2,3,4,10-tetrahydropyrimido[1,2-a]indole-8-sulfonyl chloride (0.140 g, 0.439 mmol) in CH2Cl2 (10 mL) was added (S)-(+)-2-(methoxymethyl)pyrrolidine (0.119 g, 0.965 mmol, 2.2 eq) drop-wise with cooling in an ice bath under a dry N2 atmosphere. After stirring at room temperature for 1.5 hr, the mixture was quenched with H2O (10 mL) and extracted with EtOAc (3*). The combined organic extracts were dried over MgSO4, filtered, and concentrated to give a film on glass. The film was combined with the product of an earlier run and purified on Biotage KP silica gel eluding with a step gradient of 20/80 petroleum ether/EtOAc, followed by 100percent EtOAc to give the title compound as a bright yellow solid (0.104 g, 52.3percent yield). Anal. Calc'd. for C17H20ClN3O4S. 0.2H2O: C, 50.86; H, 5.12; N, 10.47; Found, C, 50.82; H, 5.00; N, 10.31; NMR (400 MHz, DMSO-d6): consistent. MS: (ES-) m/z 396/398 [M-H] 1 chlorine pattern observed. m.p.: 127-130° C. HRMS: consistent ESI Adduct [M+H]Exact 398.09358, Expt'l 398.09411, mmu 0.53, ppm 1.34, RIpercent 100.

Reference： [1]Patent: US2005/250798,2005,A1 .Location in patent: Page/Page column 28

33
[ 873015-38-4 ]
[ 63126-47-6 ]
[ 873015-03-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetonitrile; at 70℃; for 24h;	EXAMPLE 10 ; 8-12-[2-(2-(S)-Methoxymethyl-pyrrolidin-1-yl)-ethyl]-benzofuran-5-yl)-6,7-dihydro-5H-1,4,8a-triaza-s-indacene: Methanesulfonic acid 2-[5-(6,7-dihydro-5H-1,4,8a-triaza-s-indacen-8-yl)-benzo-furan-2-yl]-ethyl ester (0.085 mmol) described above was dissolved in acetonitrile (2 ml) followed by addition of 2-(S)-methoxymethylpyrrolidine (0.85 mmol) and potassium carbonate (0.425 mmol) and heated to 70° C. for 24 hours. The reaction was cooled, filtered and concentrated. The residue was purified via preparative HPLC to give the title compound. [M+1]+ calc'd for C25H29N4O2, 417; found, 417.

Reference： [1]Patent: US2006/9451,2006,A1 .Location in patent: Page/Page column 16

34
1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-aza-bicyclo[3.2.1]oct-3-yl}amide monotrifluoroacetate [ No CAS ]
[ 96-21-9 ]
[ 63126-47-6 ]
1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-hydroxy-3-((S)-2-methoxymethylpyrrolidin-1-yl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}amide bis-trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In methanol at 65℃; for 16h;	1.g (S)-2-Methoxymethylpyrrolidine (0.15 mmol) was added to a a stirred solution of 1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-aza-bicyclo[3.2.1]oct-3-yl}amide monotrifluoroacetic acid salt (64 mg, 0.15 mmol) and diisopropylethylamine (0.078 mL, 0.45 mmol) in methanol (1.5 mL). 1,3-Dibromopropanol (0.015 mL, 0.15 mmol) was subsequently added and the reaction mixture heated to 65° C. for 16 h. The reaction mixture was concentrated in vacuo, diluted with acetic acid/water 1:1 (1 mL) and purified by preparative HPLC, affording the bistrifluoroaceticacid salt of the title compound. (m/z): [M+H]+ calcd for C27H41N5O3, 484.33; found 484.3. Retention time (anal. HPLC)=2.04 min.

Reference： [1]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2006/135764, 2006, A1 Location in patent: Page/Page column 24

35
[ 237381-57-6 ]
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) HATU [ No CAS ]
[ 63126-47-6 ]
[ 288396-72-5 ]

Yield	Reaction Conditions	Operation in experiment
35%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;	EXAMPLE 76 Synthesis of 4-[4-(3-{2-[(3 R)-3-(methoxymethyl)pyrrolidinyl]-2-oxoethoxy}phenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine tifluoroacetate 100 mg (0.093 mmol) of resin-bound 2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic acid (0.93 mmol/g), as prepared in a manner similar to Example 60, was reacted with (S)-(+)-2-methoxymethyl pyrrolidine (0.5 M, 58 mg) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) HATU (0.5 M, 190 mg), 1-hydroxy-7-azabenzotriazole (HOAt) (0.5 M; 68 mg) and diisopropylethylamine (0.233 mmol, 40 muL) in 1 mL of anhydrous DMF in a manner similar to Example 63 to afford 16 mg (35percent yield) of 4-[4-(3-{2-[(3 R)-3-(methoxymethyl)pyrrolidinyl]-2-oxoethoxy}phenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine trifluoroacetate. Mass Spectrum (ESI, m/z) Calcd. for C23H26N4O3S3: 503.2 (M+H), found 503.3.

Reference： [1]Patent: US2002/37915,2002,A1

36
[ 63126-47-6 ]
[ 854669-12-8 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; phosphorus trichloride; In tetrahydrofuran; at 0 - 20℃; for 14h;Cooling with ice;	In a 500 ml round-bottomed flask provided with an argon inlet, PCl3 (7.38 g, 53.75 mmol) is dissolved in dry tetrahydrofuran (THF, 150 ml) under argon and the solution is cooled to 0° C. in an ice bath. Triethylamine (11.97 g, 118.25 mmol, 2.20 equivalents) is added dropwise and (S)-methoxymethylpyrrolidine (12.69 g, 110.19 mmol, 2.05 equivalents) is subsequently slowly added dropwise. During the addition, the formation of a white precipitate is observed. The ice bath is removed and the suspension obtained is stirred overnight (14 h) at room temperature (RT). The white precipitate formed is filtered under argon by means of an invertible frit filter and washed with dry THF (2.x.25 ml). A 31P-NMR spectrum (C6D6) of the yellowish filtrate obtained is recorded. The solution obtained in this way is reacted without further purification. 31P-NMR (C6D6, 121 MHz): 154.3 (s).
	With triethylamine; phosphorus trichloride; In tetrahydrofuran; at 0 - 20℃; for 14h;	In a 500 ml round-bottomed flask provided with an argon inlet, PCl3 (7.38 g, 53.75 mmol) is dissolved in dry tetrahydrofuran (THF, 150 ml) under argon and the solution is cooled to 0°C in an ice bath. Triethylamine (11.97 g, 118.25 mmol, 2.20 equivalents) is added dropwise and (S)-methoxymethylpyrrolidine (12.69 g, 110.19 mmol, 2.05 equivalents) is subsequently slowly added dropwise. During the addition, the formation of a white precipitate is observed. The ice bath is removed and the suspension obtained is stirred overnight (14 h) at room temperature (RT). The white precipitate formed is filtered under argon by means of an invertible frit filter and washed with dry THF (2 x 25 ml). A 31P-NMR spectrum (C6D6) of the yellowish filtrate obtained is recorded. The solution obtained in this way is reacted without further purification. 31P-NMR (C6D6, 121 MHz) : 154.3 (s).
	With triethylamine; phosphorus trichloride; In tetrahydrofuran; at 0 - 20℃;Cooling with ice; Inert atmosphere;	In a 500 ml round-bottom flask with argon inlet, PCl3 (7.38 g, 53.75 mmol) is dissolved in dry tetrahydrofuran (THF, 150 ml) under argon and the solution is cooled to 0° C. in an ice bath. Triethylamine (11.97 g, 118.25 mmol, 2.20 equivalents) is added dropwise and (S)-methoxymethylpyrrolidine (12.69 g, 110.19 mmol, 2.05 equivalents) is subsequently slowly added dropwise. During the addition, formation of a white precipitate is observed. The ice bath is removed and the suspension obtained is stirred at room temperature (RT) overnight (14 h). The white precipitate formed is filtered off under argon by means of a double-ended frit filter and washed with dry THF (2.x.25 ml). A 31P-NMR(C6D6) spectrum of the title compound is recorded on the yellowish filtrate obtained. The solution obtained in this way is used without further purification. 31P-NMR(C6D6, 121 MHz): 154.3 (s).

With triethylamine; phosphorus trichloride; In tetrahydrofuran; at 0 - 20℃; for 14h;Cooling with ice bath;

In a 500 ml round-bottom flask with argon inlet, PCI3 (7.38 g, 53.75 mmol) is dissolved in dry tetrahydrofuran (THF, 150 ml) under argon and the solution is cooled to 0°C in an ice bath. Triethylamine (11.97 g, 118.25 mmol, 2.20 equivalents) is added dropwise and (S)- methoxymethylpyrrolidine (12.69 g, 110.19 mmol, 2.05 equivalents) is subsequently slowly added dropwise. During the addition, formation of a white precipitate is observed. The ice bath is removed and the suspension obtained is stirred at room temperature (RT) overnight (14 h). The white precipitate formed is filtered off under argon by means of a double-ended frit filter and washed with dry THF (2 x 25 ml). A 31P-NMR (C6D6) spectrum of the title compound is recorded on the yellowish filtrate obtained. The solution obtained in this way is used without further purification. 31P-NMR (C6D6, 121 MHz): 154.3 (s).

Reference： [1]Patent: US2008/287698,2008,A1 .Location in patent: Page/Page column 11
[2]Patent: WO2005/56568,2005,A1 .Location in patent: Page/Page column 30
[3]Patent: WO2005/108409,2005,A2 .Location in patent: Page/Page column 24
[4]Patent: US2009/270622,2009,A1 .Location in patent: Page/Page column 11-12
[5]Tetrahedron Asymmetry,2010,vol. 21,p. 1199 - 1202
[6]Patent: WO2006/111535,2006,A2 .Location in patent: Page/Page column 26-27

37
[ 237381-57-6 ]
[ 63126-47-6 ]
[ 288396-72-5 ]

Yield	Reaction Conditions	Operation in experiment
35%	With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;	EXAMPLE 76 4-[4-(3-{2-[(3R)-3-(Methoxymethyl)pyrrolidinyl]-2-oxoethoxy}phenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine trifluoroacetate 100 mg (0.093 mmol) of resin-bound 2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic acid (0.93 mmol/g), as prepared in a manner similar to Example 60, was reacted with (S)-(+)-2-methoxymethyl pyrrolidine (0.5 M, 58 mg) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HATU, 0.5 M, 190 mg), 1-hydroxy-7-azabenzotriazole (HOAt) (0.5M; 68 mg) and diisopropylethylamine (0.233 mmol, 40 muL) in 1 mL of anhydrous DMF in a manner similar to Example 63 to afford 16 mg (35percent yield) of 4-[4-(3-{2-[(3R)-3-(methoxymethyl)pyrrolidinyl]-2-oxoethoxy}phenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine trifluoroacetate. Mass Spectrum (ESI, m/z) Calcd. for C23H26N4O3S3: 503.2 (M+H), found 503.3.

Reference： [1]Patent: US6291514,2001,B1

38
7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid lithium salt [ No CAS ]
[ 128625-52-5 ]
[ 63126-47-6 ]
[ 380237-33-2 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;	Example 2(a) 7-chloro-2-[(S)-2-(methoxymethyl)pyrrolidine-1-carbonyl]thieno[3,2-b]pyridine To a mixture of lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate (6.59 g, 30 mmole) in DMF (100 ml) were added diisopropylethylamine, (6 ml, 4.45 g, 34.4 mmole), benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (16.16 g, 31 mmole) and S-(+)-2-(methoxymethyl)pyrrolidine (3.73 g, 32.4 mmole). The resultant reaction mixture was stirred at ambient temperature for 16 hours. The crude reaction mixture was poured into water (600 ml) and extracted with EtOAc (3200 ml). The combined organic extracts were washed with water (4200 ml), dried over Na2SO4 and concentrated, in vacuo, to give 8.8 g of an amber oil, which was purified by silica gel chromatography. Elution with Et2O:EtOAc (67:33) and evaporation of the appropriate fractions gave 6.89 g (74%) of an orange syrup. 1H NMR (DMSO-d6): delta8.62 (1H, d, J=5.0 Hz), 7.88 (1H, s), 7.35 (1H, d, J=5.0 Hz), 4.54-4.47 (1H, m), 3.93-3.75 (2H, m), 3.71-3.55 (2H, m), 3.37 (3H, s), 2.15-1.92 (4H, m). Anal. Calcd. for C14H15N2O2SCl: C, 54.10; H, 4.87; N, 9.01; S, 10.32; Cl, 11.41. Found: C, 53.96;

Reference： [1]Patent: US2004/9965,2004,A1

39
1-{4-[4-amino-7-(3-bromopropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea [ No CAS ]
[ 63126-47-6 ]
N-[4-(4-amino-7-{3-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]propyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With triethylamine; potassium iodide; In N,N-dimethyl-formamide; at 55℃; for 2h;	l-{4-[4-amino-7-(3-bromopropyl)pyrrolo[2,l-f][l,2,4]triazin-5-yl]-2-fluoiOphenyl}-3-[2- fluoro-5-(trifluoromethyl)phenyl]urea (Example 193 step 1) (50 mg, 0.088 mmol) and (2S)- 2-(methoxymethyl)pyrrolidine (36uL, 0.263 mmol) were added to a vial. DMF was added (ImL) followed by triethylamine (15uL, 0.109mmol) and KI (spatula tip). The vial was <n="327"/>capped and the reaction heated at 55 0C for two hours. Upon cooloing the product precipitated out of solution. The solids were collected by filtration and rinsed with ether to yield 35mg (65percent) of clean product. 1H-NMR (DMSO-^6) delta 9.41 (s, IH), 9.25 (s,lH), 8.65 (d, /= 7.2Hz, IH), 8.26 (t, J= 8.4 Hz, IH), 7.89 (s, IH), 7.55 to 7.21 (m, 4H), 6.57 (s, IH), 3.32 (s, 3H), 3.18 to 2.83 (m, 7H), 2.37 to 1.45 (m, 5H); MS [M+H]+ = 604.2; LCMS RT = 2.59

Reference： [1]Patent: WO2007/64931,2007,A2 .Location in patent: Page/Page column 325-326

40
[ 57812-91-6 ]
[ 63126-47-6 ]
(CO)3Mn(C₆H₅(NC₄H₇)CH₂OCH₃)⁽¹⁺⁾*PF₆^(1-) = (CO)3Mn(C₆H₅(NC₄H₇)CH₂OCH₃)PF₆ [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1993,vol. 115,p. 10376 - 10377

41
[ 516-09-6 ]
[ 63126-47-6 ]
[ 1035419-85-2 ]

Yield	Reaction Conditions	Operation in experiment
81%	With toluene-4-sulfonic acid; In toluene; at 130℃;Heating / reflux;	Example 14: Synthesis of 4-(2(S)-Methoxymethyl-pyrrolidin-1-yl)-3-methyl-5H-furan-2-one.; [Show Image] p-Toluenesulphonic acid monohydrate (15.00 mg, 0.08 mmol) and then (S)-2-methoxymethyl)pyrrolidine (100.00 mg, 0.87 mmol) were added into a mixture of 4-hydroxy-3-methyl-5H-furan-2-one (90.00 mg, 0.80 mmol) in dry toluene (5 ml). The reaction mixture was stirred wildly at reflux temperature (130°C) and it became a brown transparent solution. Stirring was kept at 130°C overnight. The solvent was evaporated in vacuo and the residue was purified by radial chromatography using AcOEt/MeOH (from 100/0 to 100/10 in a 2percent polarity increment) to yield 136.70 mg (81percent) of 4-(2(S)-Methoxymethyl-pyrrolidin-1-yl)-3-methyl-5H-furan-2-one as a yellow oil. 1H-RMN (400 MHz, CDCl3): 4.89 (d, 1 H, J=15 Hz, 5-CH2 furanone); 4.53 (d, 1 H, J=15 Hz, 5-CH2 furanone); 3.97 (m, 1 H, 2-CH pyrrolidinyl); 3.57 (m, 1 H, 5-CH2 pyrrolodinyl); 3.42 (m, 1 H, 5-CH2 pyrrolodinyl); 3.32 (m and s, 4H, 2-CH2-OMe pyrrolidinyl and O-CH3 pyrrolodinyl); 3.25 (m, 1 H, 2-CH2-OMe pyrrolidinyl); 2.01-1.93 (m, 4H, 3-CH2 pyrrolodinyl, 4-CH2 pyrrolodinyl) 1.92 (s, 3H, CH3 furanone). 13C-RMN (100 MHz, CDCl3): 177.17 (2-CO furanone); 160.31 (4-C=N furanone); 88.70 (3-C(Me)= furanone); 74.47 (2-CH2-Ome, pyrrolidinyl); 66.64 (5-CH2 furanone); 59.29 (O-CH3 pyrrolidinyl); 58.77 (2-CH pyirrolidinyl); 48.66 (5-CH2 pyrrolidinyl); 28.01 (3-CH2 pyrrolidinyl); 22.92 (4-CH2, pyrrolidinyl); 8.98 (3-CH3 furanone).

Reference： [1]Patent: EP1939192,2008,A1 .Location in patent: Page/Page column 29-30

42
[ 1271-48-3 ]
[ 63126-47-6 ]
Fe(C₅H₄CH₂NC₄H₇CH₂OCH₃)2 [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2008,vol. 130,p. 14030 - 14031
[2]European Journal of Organic Chemistry,2014,vol. 2014,p. 7823 - 7829

43
[ 124-13-0 ]
[ 63126-47-6 ]
[ 536-74-3 ]
2-methoxymethyl-1-(1-phenylethynyl-octyl)-pyrrolidine [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2008,vol. 47,p. 4358 - 4361

44
[ 46331-50-4 ]
[ 63126-47-6 ]
[ 1042903-73-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 3236 - 3241

45
[ 1186426-97-0 ]
[ 63126-47-6 ]
[ 1186427-01-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;	(1) Preparation of 2-tert-butoxycarbonylamino-5-((S)-2-methoxymethyl-pyrrolidin-1-yl)-5-oxo-pentanoic acid methyl ester To a mixture of 4-(tert-butoxycarbonylamino)-5-methoxy-5-oxopentanoic acid (1.05 g, 4 mmol), (S)-2-(methoxymethyl)-pyrrolidine (0.46 g, 4 mmol), and 1-hydroxybenzotriazole hydrate (HOBt hydrate, 0.54 g, 4 mmol) in CH2Cl2 (10 mL) was added EDC (0.77 g, 4 mmol). The reaction mixture was stirred at ambient temperature for 12 h, diluted with CH2Cl2 (40 mL), washed sequentially with saturated aqueous sodium bicarbonate (20 mL), 0.5 N aqueous citric acid (20 mL) and brine (20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a crude viscous oil. The crude oil was purified by flash chromatography (silica gel, 50percent ethyl acetate/hexanes) to give the title compound (1.36 g, 95percent) as a colorless oil.

Reference： [1]Patent: US2009/227569,2009,A1 .Location in patent: Page/Page column 9

46
[ 1190735-24-0 ]
[ 63126-47-6 ]
[ 1190735-25-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine; In tetrahydrofuran; at 20 - 50℃; for 40h;	To a solution of Compound 2 ( 5.00 g, 18.2 mmol ) in THF ( 18.2 mL ) were added (S)-(+)-2-(methoxymethyl)pyrrolidine ( 3.37 ml, 27.3 mmol ) and triethylamine ( 3.81 ml, 27.3 mmol ), and the mixture was stirred at room temperature for 18 hours and further stirred at 50 °C for 22 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( hexane : ethyl acetate = 7 : 1 ) to give Compound 3 ( 6.72 mg, quant. ) as a viscous oil. MS: 354 [M+H]+, APCI.

Reference： [1]Patent: WO2009/125870,2009,A1 .Location in patent: Page/Page column 42

47
[ 1190735-28-4 ]
[ 63126-47-6 ]
[ 1190735-29-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine; In tetrahydrofuran; at 0 - 20℃;	To a solution of Compound 2 ( 150 mg, 564 mmol ) in THF ( 2.82 mL ) were added (S)-(+)-2-(methoxymethyl)pyrrolidine ( 73.1 mul, 592 mumol ) and triethylamine ( 118 mul, 677 mumol ) at 0 °C, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was filtered through Chem Elut.(R). ( Varian Inc. ) and Bond Elut.(R). ( Varian Inc. ), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( hexane -> hexane : ethyl acetate = 4 : 1 ) to give Compound 3 ( 218 mg, quant. ) as a solid. MS: 345/347 [M+H]+, APCI.

Reference： [1]Patent: WO2009/125870,2009,A1 .Location in patent: Page/Page column 43

48
[ 1190735-36-4 ]
[ 63126-47-6 ]
[ 1190735-37-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine; In tetrahydrofuran; at 20℃;	To a solution of Compound 3 ( 70 mg, 175 mumol ) in THF ( 1.75 mL ) were added (S)-(+)-2-(methoxymethyl)pyrrolidine ( 65 mul, 524 mumol ) and triethylamine ( 37 mul, 262 mumol ), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( hexane -> hexane : ethyl acetate = 4 : 1 ) to give Compound 4 ( 77 mg, quant. ) as powders. MS: 436/438 [M+H]+, APCI.

Reference： [1]Patent: WO2009/125870,2009,A1 .Location in patent: Page/Page column 47

49
[ 26116-12-1 ]
[ 108-77-0 ]
[ 366-99-4 ]
[ 63126-47-6 ]
[ 502766-82-7 ]

Yield	Reaction Conditions	Operation in experiment
27.6%		Example 47 Synthesis of N2-[(1-ethyl-2-pyrrolidinyl]-N4-(3-fluoro-4-methoxyphenyl)-6-[(S)-2-(methoxymethyl)-1-pyrrolidinyl]-1,3,5-triazine-2,4-diamine (145) Cyanuric chloride (11.07 g, 60 mmol) was dissolved in 40 mL CH3CN and was cooled to about -20° C. To this was added DIEA (11.5 mL, 60 mmol) followed by 3-fluoro-4-methoxyaninline (8.47 g, 60 mmol) in 20 mL CH3CN (reaction froze). The reaction was allowed to warm to room temperature after about 1 hour at -20° C. TLC (2percent CH3OH/CH2Cl2) and mass spectroscopy indicated the presence of the compound 124. The reaction mixture was cooled to about 0° C. before adding DIEA (11.5 mL, 66 mmol). 2-Aminomethyl-1-ethylpyrrolidine (7.77 g, 60 mmol) in CH3CN (10 mL) was added. The reaction was allowed to warm to rt and stirred overnight. Then DIEA (11.5 mL, 66 mmol) and S-(+)-2-methoxyethylpyrrolidine (6.91 g, 60 mmol) in 20 mL 1,4-dioxane were added. The reaction was heated at about 50° C. overnight. The solvent was removed in vacuo, and the resulting residue was purified by flash chromatography on silica gel packed in ethyl acetate. The front running impurities were removed and subsequently the eluent was increased in polarity to 10percent CH3OH: ethyl acetate. The material collected from the column was then dissolved in water and extracted in CH2Cl2 (4 times), dried over MgSO4, and concentrated to dryness to give a brown solid 145 (9.7 g, 27.6percent yield), 71-72° C.; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4 (0.01M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt 5.37 min, 90.3 percent purity; 1H NMR (600 MHz, CDCl3, 55° C.) delta 7.69 (s, 11H), 7.08 (d, J=7.8 Hz, 1H), 6.86 (t, J=9 Hz, 1H), 4.29 (s, 1H), 3.90 -3.96 (m, 1H), 3.84 (s, 3H), 3.63-3.81 (m, 6H), 3.35 (s, 3H), 3.23-3.25 (m, 1H), 2.85 (broad s, 1H), 2.78 (broad s 1H), 2.14 (broad s, 2H), 1.89-2.04 (m, 6H), 1.37 (apparent t, J=7.2 Hz, 3H); 13C NMR (150.8 MHz, CDCl3, 55° C.) delta 165.8, 163.8 (2C), 152.3 (d, Jc-f=243.5 Hz), 143.0 (142.9, rotamer or diastereumer), 133.7 (133.67, rotamer or diastereomer), 115.0, 114.4, 109.1 (108.9, rotamer or diastereomer), 72.8, 66.6, 59.0, 57.0, 56.6, 53.7, 51.0, 46.8, 42.2, 28.4 (28.2, rotamer or diastereomer), 23.1 (23.0, rotamer or diastereomer), 10.9; MS (ESI) m/z 460.2 (M+H, 44.7), 251.1 (47.7), 235.1 (27.5), 231.1 (37.4), 230.6 (100), 214.6 (36.5).

Reference： [1]Patent: US2004/209880,2004,A1 .Location in patent: Page/Page column 83-84

50
3-anilino-5-{2-[(tetrahydro-2H-pyran-4-ylcarbonyl)amino]pyridin-4-yl}benzoic acid [ No CAS ]
[ 63126-47-6 ]
(S)-N-[4-(3-anilino-5-[2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}phenyl)pyridin-2-yl]tetrahydro-2H-pyran-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%		3-anilino-5- {2-[(tetrahydro-2H-pyran-4-ylcarbonyl)amino]pyridin-4-yl}benzoic acid (42 mg, 0.10 mmol) AND N-[(DIMETHYLAMINO) (3H-[1, 2,3] triazolo [4, 5-b] pyridin-3- yloxy) METHYLENE]-N-METHYLMETHANAMINIUM hexafluorophosphate (58 mg, 0.15 mmol) were dissolved in 3 mL of DMF. Diisopropylethylamine (35 PLL, 0.20 mmol) was added dropwise and the solution stirred for lh at room temperature under nitrogen atmosphere. Then a solution of (S)-2- (methoxymethyl) pyrrolidine (11 mg, 0.10 mmol) in DMF (0.5 mL) was slowly added and the mixture stirred at 20°C for 15h. The solution was poured on a saturated aqueous solution OF NAHC03 (15 mL) and extracted with ethyl acetate. After concentration of the solvent under vacuum, the crude material was purified by HPLC. Yield: 39percent (20 mg). 1H NMR (400 MHz, CDC13) : 8 9.20 (s, 1 H), 8. 52 (s, 1 H), 8.19 (d, J=5. 6 Hz, 1 H), 7.29 (M, 3 H), 7.21-7. 25 (M, 3 H), 7.11 (d, J=7. 6 Hz, 2 H), 6.99 (t, J=7. 3 HZ, 1 H), 6.01 (s, 1 H), 4.41 (d, J=2. 0 Hz, 1 H), 4.11 (d, J=7. 6 Hz, 1 H), 4.05 (ddd, J=8. 7/4. 5/4. 4 Hz, 2 H), 3.70-3. 64 (M, 1 H), 3.59 (M, 1 H), 3.51-3. 46 (M, 4 H), 3. 38 (s, 3 H), 3.13 (s, 1 H), 2.63- 2.57 (M, 1 H), 2.11 (s, 2 H), 2.04 (s, 2 H), 1.95 (dd, J=12. 9/4.3 Hz, 3 H), 1.90-1. 76 (M, 6 H). MS (ES) m/z (M+1) : 515.

Reference： [1]Patent: WO2005/3123,2005,A1 .Location in patent: Page 31

51
[ 23356-96-9 ]
[ 74-88-4 ]
[ 63126-47-6 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of L-proline in methanol:THF (0.10 M; 1:2), at 0° C., is added a solution boran dimethyl sulfide (5 equivalents; 1.0 M) and allowed to stir for overnight. The solvent is then removed and the mixture is resuspended in methylene chloride (0.10 M) and 1.2 equivalents of NaH (30percent) is added at 0° C. and allowed to stir for 1 hour. Next, 1.1 equivlanents of methyliodide is added and allowed to stir at 0° C. for an additional hour. The reaction mixture is then quenched with water, extracted with 100percent ethylacetate, washed over bicarbonate, brine and dried over magnesium sulfate. The crude compound is purifed by flash chromatography to give compound 24.

Reference： [1]Patent: US6900238,2005,B1 .Location in patent: Page/Page column 35

52
[ 102-54-5 ]
[ 63126-47-6 ]
C₂₂H₃₃FeN₂O₂P [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		In a 1l round-bottomed flask provided with an argon inlet, ferrocene (10.00 g, 53.75 mmol) and potassium t-butoxide (754 mg, 6.72 mmol, 0.125 equivalents) are dissolved in dry THF (100 ml) under argon. The solution is cooled to -78°C, and t-butyllithium (1.5 M in hexane; 71.67 ml, 107.50 mmol, 2.00 equivalents) is then added dropwise over a period of 45 minutes. The solution is stirred at -78°C for 1.5 hours and admixed with heptane (75 ml). After the precipitate formed has settled, the supernatant solution is removed at -78°C under argon by means of a transfer needle. The precipitate is washed with heptane (60 ml) at -78°C and the washings are removed again by means of a transfer needle. This procedure is repeated three times. The precipitate obtained is dissolved in dry THF (50 ml) and a solution of the halophosphine prepared as described in a) (53.75 mmol, 1.00 equivalent) in THF (200 ml) is added at-78°C over a period of 1.5 hours. The solution is stirred overnight (14 h) while warming to RT. Borane-dimethylsulphide complex (5.10 ml, 53.75 mmol, 1.00 equivalent) is subsequently added dropwise and the mixture is stirred overnight at RT. The reaction mixture is hydrolysed by means of saturated NH4CI solution (50 ml) and extracted with tert-butyl methyl ether (TBME, 3 x 100 ml). The combined organic phases are dried over Na2S04 and the solvent is distilled off on a rotary evaporator. The crude product (24.18 g) is purified by column chromatography (200 g of silica gel, n-heptane/TBME 5:1). The title compound is obtained as an orange solid (17.23 g, 37.60 mmol, 70percent). 'H-NMR (C6D6): 4.22 (s, 5 H Cp), 3.11 (s, 3 H, OMe), 3.04 (s, 3 H, OMe) ; 31P-NMR (C6D6, 121 MHz) : 81.7-80.4 (m, br).

Reference： [1]Patent: WO2005/108409,2005,A2 .Location in patent: Page/Page column 25

53
[ 1239503-44-6 ]
[ 63126-47-6 ]
[ 1239500-08-3 ]

Yield	Reaction Conditions	Operation in experiment
62%		[00653] Example 5-B: Production of 3-[(2S)-2-(methoxymethyl)pyrrolidin-l-yl]-N-{4-[4-phenyl- 5-(4H-l,2,4-triazol-3-yl)-ltau3-thiazol-2-yl]pyridin-2-yl}propanamide[00654] To a solution of N-(4-{4-phenyl-5-[l-(tetrahydro-2H-pyran-2-yl)-lH-l,2,4-triazol-3-yl]-l,3- thiazol-2-yl }pyridin-2-yl)prop-2-enamide (92 mg, 0.2 mmol) prepared in Example 4-B (iii) in tetrahydrofuran (2.0 mL) was added (2S)-2-(methoxymethyl)pyrrolidine (120 mg, 1.0 mmol), and the mixture was heated under reflux for 14 hr. The reaction solution was cooled to room temperature, and diluted with ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL). The aqueous layer was separated, extracted with ethyl acetate (40 mL), and the combined organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated. The obtained residue was dissolved in trifluoroacetic acid (4.0 mL), and the mixture was stirred at room temperature for 3 hr. Trifluoroacetic acid was evaporated under reduced pressure, and the residue was diluted with ethyl acetate (30 mL), and washed with saturated aqueous sodium bicarbonate solution (30 mL). The aqueous layer was separated and extracted with ethyl acetate (30 mL), and the combined organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by basic MPI09-013Pl RNWOM PCT FILING silica gel column chromatography (methanol/ethyl acetate=0/100- >;50/50) to give the title compound (60 mg, 62percent) as a pale-yellow solid.[00655] 1H-NMR (DMSOd6, 300 MHz) delta 1.43 - 1.55 (IH, m), 1.61 - 1.72(2H, m), 1.79 - 1.90 (IH, m), 2.14 - 2.30 ( IH, m), 2.53 - 2.76 (4H, m), 3.13 - 3.25 (6H, m), 3.40 - 3.44 (IH, m), 7.32 - 7.56 (3H, m), 7.67 (IH, dd, J = 1.5, 5.1 Hz), 7.77 - 8.02 (2H, m), 8.31 - 8.55 (IH, m), 8.60 - 8.70 (IH, m), 8.74 (IH, d, J = 0.8 Hz), 10.95 (IH, s), 14.36 (IH, br s).

Reference： [1]Patent: WO2010/90716,2010,A1 .Location in patent: Page/Page column 257-258

54
[ 1240186-30-4 ]
[ 63126-47-6 ]
[ 1242181-14-1 ]

Yield	Reaction Conditions	Operation in experiment
81%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 140℃; for 20h;	INTERMEDIATE 99(S)-I- { 8-Chloro-2-[fiSV2-fmethoxymethyl)pyrrolidin- 1 -yl] quinolin-3 -yl) ethanamine A solution of Intermediate 11 (150 mg, 0.44 mmol), (<;S)-2-(methoxymethyl)- pyrrolidine (0.082 mL, 0.66 mmol) and DIPEA (0.39 mL, 2.2 mmol) in NMP (2 mL) was heated at 14O0C for 20 h. After cooling, the mixture was dissolved in a 1 : 1 mixture of EtOAc and Et2O (200 mL) and washed with saturated brine (3 x 30 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 5-10percent EtOAc in isohexane) gave an off-white solid (150 mg, 81percent). LCMS (ES+) 420, 422 (M+H)+. To the off-white solid (150 mg, 0.358 mmol) dissolved in DCM (5 mL) was added TFA (2 mL). The reaction mixture was stirred at r.t. for 2 h, concentrated in vacuo and azeotroped with toluene. Ion exchange chromatography (SCX cartridge eluting with 0.35M NH3 in MeOH) gave the title compound (107 mg, 94percent) as a yellow solid. deltaH (CDCl3) 8.18 (IH, s), 7.63 (IH, dd, J 7.60, 1.20 Hz), 7.58 (IH, dd, J7.60, 1.20 Hz), 7.15 (IH, t, J7.76 Hz), 4.96-4.88 (IH, m), 4.56 (IH, q, J6.47 Hz), 3.83-3.72 (2H, m), 3.53-3.41 (2H, m), 3.38 (3H, s), 2.29-2.16 (IH, m), 2.06-1.99 (IH, m), 1.96-1.82 (2H, m), 1.70-1.54 (2H, m), 1.31 (3H, d, J6.40 Hz).

Reference： [1]Patent: WO2010/100405,2010,A1 .Location in patent: Page/Page column 68

55
[ 919346-88-6 ]
[ 63126-47-6 ]
[ 76-05-1 ]
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({(2R)-2-[(methyloxy)methyl]-1-pyrrolidinyl}methyl)-3-thienyl]-1H-indole-7-carboxamide trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
13%		Example 124: 3-ri-(ethylsulfonvn-4-piperidinvn-5-r5-(((2ffl-2-r(methyloxy)methvn-1- Pyrrolidinyllmethvpi-S-thienvn-I H-indole-T-carboxamide trifluoroacetate; To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1 H-indole-7- carboxamide (50 mg, 0.112 mmol) in dichloromethane (3.0 mL) and methanol (1.5 mL), was added acetic acid (5 drops), (2R)-2-[(methyloxy)methyl]pyrrolidine (129 mg, 1.123 mmol) and stirred at room temperature for 6 h. Sodium borohydride (43 mg, 1.123 mmol) was then added and the reaction was stirred at room temperature overnight. The mixture EPO <DP n="159"/>was purified by reverse phase Gilson Preparatory HPLC to give 5.0 mg of the title compound (13percent).LCMS: 545.2 (M+H), Rt 1.62 min and 1.66 min.

Reference： [1]Patent: WO2007/5534,2007,A2 .Location in patent: Page/Page column 157-158

56
[ 63126-47-6 ]
[ 157864-32-9 ]
[ 1095659-84-9 ]

Yield	Reaction Conditions	Operation in experiment
48%	In acetonitrile; at 180℃; for 0.166667h;Microwave irradiation;	N-Benzyl-2-chloroquinazolin-4-amine (81 mg, 0.30 mmol) and (S)-(+)-2-(methoxymethyl)pyrrolidine (37 muL, 1 eq.) were dissolved in MeCN (2 mL) and the mixture was heated to 180° C. for 10 min under microwave irradiation. After cooling, the precipitate was isolated by filtration, and washed with MeCN. The solid was then partitioned between EtOAc and aqueous NaHCO3 solution. The organic layer was separated, dried (MgSO4) and filtered. The crude solution was then filtered through a pad of silica, eluting with EtOAc. Concentration of the eluent gave the product as a white solid (50 mg, 48percent).LCMS RT=1.57 min, MH+ 349.2; 1H NMR (DMSO-d6): 8.93 (1H, br s), 8.11 (1H, d, J 8.0), 7.57 (1H, t, J 7.4), 7.45-7.08 (7H, br m), 4.90-4.74 (1H, br m), 4.72-4.61 (1H, br m), 4.24 (1H, br s), 3.58-3.04 (7H, br m-obscured by water signal) and 2.01-1.81 (4H, br m).

Reference： [1]Patent: US2010/317607,2010,A1 .Location in patent: Page/Page column 22

57
[ 93783-15-4 ]
[ 63126-47-6 ]
[ 220428-23-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; chloroform; at 0 - 20℃;Inert atmosphere;	To the solution of 601 mg compound 4 (2.0 mmol) in 6 mL 1:1(v/v) chloroform-THF at 0 °C under argon, a solution of 272 mL <strong>[63126-47-6](S)-2-(methoxymethyl)pyrrolidine</strong> (2.2 mmol) and 523 mL diisopropylethylamine (3.0 mmol) in 1 mL chloroform was added dropwise. The reaction mixture was stirred at room temperature for 1 h. After removal of solvents, the brown oil obtained was used in the next step without purification.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 1626 - 1629

58
[ 1295602-22-0 ]
[ 63126-47-6 ]
[ 1295601-30-7 ]

Yield	Reaction Conditions	Operation in experiment
70%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃; for 3h;	Example 10 To a solution of Compound A (0.25 g, 0.60 mmol) in acetonitrile (6 mL) at room temperature were added diisopropylethylamine (0.42 mL, 2.4 mmol) and <strong>[63126-47-6](S)-2-(methoxymethyl)pyrrolidine</strong> (0.105 g, 0.91 mmol) and the reaction mixture was heated to 80° C. On heating, the reaction mixture became clear and after 15 min commencement of precipitation of solid was observed. Heating was continued for 3 hr and then the reaction mixture was cooled. The solid obtained was collected by filtration, washed with acetonitrile and dried under vacuum. LC/MS: (M+H)+: 490. An NMR spectrum is provided in FIG. 10.Yield: 0.21 g (70percent).

Reference： [1]Patent: US2011/105497,2011,A1 .Location in patent: Page/Page column 42

59
[ 1295602-29-7 ]
[ 63126-47-6 ]
[ 1295601-68-1 ]

Yield	Reaction Conditions	Operation in experiment
79%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃; for 3h;	Example 32 To a solution of Compound B (0.25 g, 0.67 mmol) in acetonitrile (5 mL) at room temperature were added diisopropylethylamine (0.5 mL, 2.9 mmol) and <strong>[63126-47-6](S)-2-(methoxymethyl)pyrrolidine</strong> (0.116 g, 1.0 mmol) and the reaction mixture was heated to 80° C. On heating, the reaction mixture became clear and after 15 min commencement of precipitation of solid was observed. Heating was continued for 3 hr and then the reaction mixture was cooled. The solid obtained was collected by filtration, washed with acetonitrile and dried under vacuum. LC/MS: (M+H)+: 450. An NMR spectrum is provided in FIG. 32.Yield: 0.24 g (79percent).

Reference： [1]Patent: US2011/105497,2011,A1 .Location in patent: Page/Page column 47

60
[ 1259439-39-8 ]
[ 63126-47-6 ]
[ 1354289-04-5 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In acetonitrile; at 140℃; for 1.5h;	2, 4-Dichloro-5,7-difluoro-3-methylquinoline (700 mg, 2.80 mmol), (S)-(-)-2- (methoxymethyl)pyrrolidine (390 mg, 3.40 mmol) and triethylamine (0.47 mL, 3.40 mmol) were combined in acetonitrile (10 mL). The mixture was then heated in a microwave reactor at 140 °C for 90 min. The reaction mixture was then concentrated then was diluted with water (~50 mL) and acetic acid (4 mL) to acidify the solution. This mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (50 mL) and dried over magnesium sulfate. The filtrate was concentrated and the residue was purified by medium pressure chromatography (silica, 0 to 25percent EtOAc : hexanes) to obtain (5)-4-chloro-5,7-difluoro-2-(2-(methoxymethyl)pyrrolidin-l-yl)-3-methyl- quinoline. Mass Spectrum (ESI) m/e = 327.1 (M + 1).

Reference： [1]Patent: WO2012/3283,2012,A1 .Location in patent: Page/Page column 205

61
[ 1432510-07-0 ]
[ 63126-47-6 ]
[ 1432510-14-9 ]

Yield	Reaction Conditions	Operation in experiment
34%		Step 1. Synthesis of (S)-methyl ^-4-((8-fluoro-2-(2-(2-(methoxymethyl)pyrrolidin-l-yl)ethyl)- 1 -oxo- 1 ,2,3 ,4-tetrahydropyrido[4,3-b]indol-5-yl)methyl)benzoate [formula 9-6](S)-methyl-4-((8-fluoro-2-(2-hydroxyethyl)-l-oxo-l,2,3,4-tetrahydropyrido[4,3-b]indol- 5-yl)methyl)benzoate [formula 9-5] (0.05 g, 0.13 mmol) was dissolved in ACN (1 mL). Thereto, DIPEA (0.11 mL, 0.63 mmol) and methanesulfonyl chloride (0.02 mL, 0.25 mmol) were added in order and stirred at room temperature for 5 minutes. And then, (S)-2- (methoxymethyl)pyrrolidin (0.044 mL, 0.38 mmol) was added and stirred at 50°C for 30 minutes. After the completion of the reaction, the reaction mixture was purified by column chromatography (Si02; dichloromethane/methanol, 20/1) to yield the title compound as yellow liquid (0.021 g, 34 percent).
34%		(S)-methyl-4-((8-fluoro-2-(2-hydroxyethyl)-1-oxo-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)methyl)benzoate [formula 9-5] (0.05 g, 0.13 mmol) was dissolved in ACN (1 mL). Thereto, DIPEA (0.11 mL, 0.63 mmol) and methanesulfonyl chloride (0.02 mL, 0.25 mmol) were added in order and stirred at room temperature for 5 minutes. And then, (S)-2-(methoxymethyl)pyrrolidin (0.044 mL, 0.38 mmol) was added and stirred at 50° C. for 30 minutes. After the completion of the reaction, the reaction mixture was purified by column chromatography (SiO2; dichloromethane/methanol, 20/1) to yield the title compound as yellow liquid (0.021 g, 34percent).

Reference： [1]Patent: WO2013/62344,2013,A1 .Location in patent: Page/Page column 141; 142
[2]Patent: US2014/315889,2014,A1 .Location in patent: Paragraph 0664-0666

62
[ 39684-80-5 ]
[ 63126-47-6 ]
[ 1426531-87-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; triethylamine; In acetonitrile; at 85℃;	Step 1 : (S)-tert-Butyl 2-(2-(methoxymethyl)pyrrolidin-1 -yl)ethylcarbamateA suspension comprising <strong>[63126-47-6](S)-2-(methoxymethyl)pyrrolidine</strong> (1 g, 8.68 mmol), tert- butyl 2-bromoethylcarbamate (1.946 g, 8.68 mmol), triethylamine (1.210 ml, 8.68 mmol) and potassium carbonate (1.200 g, 8.68 mmol) in MeCN (10 ml) was heated at 85°C overnight. The resulting mixture was filtered and washed with MeCN.Purification of the crude product by chromatography on silica eluting with 0-5percent MeOH in DCM afforded the title compound as a colourless oil;1 H NMR (400MHz), DMSO-d6) delta 3.3 (1 H, s), 3.25 (3H, s), 3.15 (1 H, m), 3.0 (2H, m), 2.9 (1 H, m), 2.8 (1 H, m), 2.55 (1 H, m), 2.3 (1 H, m), 2.15 (1 H, q), 1.8 (1 H, m), 1.65 (2H, m), 1 .45 (1 H, m), 1.4 (9H, s).

Reference： [1]Patent: WO2013/30802,2013,A1 .Location in patent: Page/Page column 136; 137

63
[ 1363293-51-9 ]
[ 63126-47-6 ]
[ 1363288-35-0 ]

Yield	Reaction Conditions	Operation in experiment
53 mg	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃;	Example 277 Preparation of (S)-7-(4-fluorophenyl)-5-(2-(methoxymethyl)pyrrolidin-1-yl)-2-methyl-3-(4-methylphenyl)pyrazolo[1,5-a]pyrimidine (Chemical Formula 111) 5-Chloro-3-(4-methylphenyl)-7-(3-fluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine (50 mg), <strong>[63126-47-6](S)-2-methoxymethylpyrrolidine</strong> (0.02 mL) and DIPEA (0.2 mL) are added to acetonitrile (10 mL) and stirred overnight at 80° C. After cooling to room temperature, the solvent and volatile substance are removed by distillation under reduced pressure. The remainder is extracted 3 times with ethyl acetate (20 mL) and water. The collected organic layer is washed with brine. The organic layer is dehydrated with anhydrous MgSO4 and the solvent is removed by distillation under reduced pressure. The remainder is purified by column chromatography to yield 53 mg of the target compound.

Reference： [1]Patent: US2013/158025,2013,A1 .Location in patent: Paragraph 0483; 0484

64
[ 936691-31-5 ]
[ 63126-47-6 ]
(S)-4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(2-(methoxymethyl)pyrrolidin-yl)thiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31%	With triethylamine; In 1,4-dioxane; at 100℃; for 18h;	A solution of 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole (Example 37B, 0.500 g, 1.622 mmol) and (5)-2-(methoxymethyl)pyrrolidine (0.224 g, 1.946 mmol) in 1,4-dioxane (5 mL) was treated with triethylamine (0.678 mL, 4.87 mmol) and the resulting mixture was heated at 100 °C for 18 h. The cooled reaction mixture was concentrated in vacuo and the residue was chromatographed on silica gel (ISCO, elution gradient of ethyl acetate in dichloromethane) to give 0.175 g (31percent) of the title material. LC (Method B): 2.685 min. LCMS (APCI): calcd for C16H31N2O2SSi [M+H]+ m/z 343.19; found 343.2. 1H NMR (400 MHz, CDCl3) delta ppm: 6.35 (s, 1H), 4.68 (s, 2H), 4.02 (dt, J= 6.65, 3.33 Hz, 1H), 3.61 (dd, J= 9.39, 3.4 Hz, 1H), 3.40-3.56 (m, 2H), 3.28-3.39 (m, 4H), 1.91-2.16 (m, 4H), 0.95 (s, 9H), 0.12 (s, 6H).

Reference： [1]Patent: WO2013/163279,2013,A1 .Location in patent: Paragraph 00304

65
[ 18052-76-1 ]
[ 63126-47-6 ]
dimethoxy[(S)-2-(methoxymethyl)-1-pyrrolidinyl](1-naphthyl)silane [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2014,vol. 53,p. 720 - 724
Angew. Chem.,2014,vol. 126,p. 738 - 742,5

66
[ 1443925-99-2 ]
[ 63126-47-6 ]
C₁₉H₃₁NO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 12h;Inert atmosphere;	General procedure: To a stirred solution of acid 12 (1.0 eq., 0.24 mmol, 50 mg) in dichloromethane(1 mL) at room temperature was added sequentially EDCI (1.4 eq., 0.34 mmol, 65mg), HOAt (1.4 eq., 0.34 mmol, 46 mg), R1R2NH (2.0 eq.,0.48 mmol) and Et3N (3.0 eq., 0.72 mmol, 0.1 mL) and stirred at thesame temperature. After 12 hours, the reaction mixture was extracted with etherand washed with water, brine, dried over Na2SO4 andconcentrated under reduce pressure followed by flash chromatography (SiO2, cyclohexaneto cyclohexane/EtOAc 2/1) to afford amides 21a-f.

Reference： [1]Tetrahedron Letters,2014,vol. 55,p. 6577 - 6581

67
[ 17865-54-2 ]
[ 63126-47-6 ]
cyclohexyldimethoxy[(2S)-2-(methoxymethyl)-1-pyrrolidinyl]silane [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2015,vol. 137,p. 4304 - 4307

68
methyl 4-((2-methyl-1-(2-(methylsulfonyloxy)ethyl)-1H-indol-3-yl)methyl)benzoate [ No CAS ]
[ 63126-47-6 ]
(S)-methyl 4-((1-(2-(2-(methoxymethyl)pyrrolidin-1-yl)ethyl)-2-methyl-1H-indol-3-yl)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 120℃; for 3h;Microwave irradiation;	Methyl 4-((2-methyl-1-(2-(methylsulfonyloxy)ethyl)-1H-indol-3-yl)methyl)benzoate (0.150 g, 0.37 mmol) was dissolved in acetonitrile (3 mL), and <strong>[63126-47-6](S)-2-(methoxymethyl)pyrrolidine</strong> (0.129 g, 1.12 mmol) and diisopropylethylamine (0.326 mL, 1.87 mmol) were added thereto. The mixture was allowed to react in a microwave reactor at 120 for 3 hours. Then, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2; methylene chloride / methanol = 20 / 1) to afford the title compound (0.097 g, 62%) as a light yellow liquid.

Reference： [1]Patent: WO2015/102426,2015,A1 .Location in patent: Paragraph 315-317

69
[ 63126-47-6 ]
[ 183208-22-2 ]
(S)-5-((2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%		To a solution of tert-butyl (S)-2-(methoxymethyl)pyrrolidine-1-carboxylate (663 mg, 3.08mmol) in DCM (10 mL) was added trifluoroacetic acid (1.76 g, 15.40 mmol) within 5 min at0C. The mixture was warmed up to room temperature within 2 h and carefully poured into a10% NaOH solution (60 mL). After extraction with DCM (2 × 50 mL) the combined organicphases were dried over MgSO4, and evaporated. The residue was dissolved in DCM (5 mL)and N,N-diisopropylethylamine (521 mg, 4.03 mmol) was added at room temperature. Thissolution containing the deprotected pyrrolidine was then stirred until it was needed.A two-neck flask was charged with <strong>[183208-22-2]5-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine</strong> (3)(500 mg, 2.37 mmol) and dry THF (30 mL) under argon. The solution was cooled to -80 C inan ethanol/nitrogen cooling bath and t-BuLi (1.4 M in pentane, 1.69 mL, 2.37 mmol) wasS 6added dropwise. The reaction mixture was warmed up to -75 C within 10 min and transferredto a solution of DABCO-bis(sulfur dioxide) (569 mg, 2.37 mmol) in dry THF (15 mL) at -75C. The cooling bath was removed after 30 min and the reaction mixture warmed up to roomtemperature. The THF solvent was removed under reduced pressure and dry DCM (20 mL)was added. N-Chlorosuccinimide (379 mg, 2.84 mmol) was slowly added as a solution in dryDCM (5 mL) followed by dropwise addition of the deprotected pyrrolidine. After the additionof water (35 mL) the mixture was extracted with DCM (2 × 20 mL). The combined organicphases were dried over MgSO4, and evaporated. Column chromatographic purification (SiO2,CH/EtOAc, 2:1) yielded a colorless, crystalline solid [291 mg, 40% yield].MP: 66 - 67 C (CH/EtOAc).1H-NMR (300 MHz, CDCl3): delta = 1.50-1.60 (m, 2H, 13-CHa, 14-CHa), 1.79-1.89 (m, 2H,13-CHb, 14-CHb), 3.08-3.18 (m, 1H, 15-CHa), 3.34-3.42 (m, 1H, 16-CHa), 3.38 (s, 3H,18-CH3), 3.44-3.52 (m, 1H, 15-CHb), 3.68 (dd, 2JH,H = 9.2 Hz, 3JH,H = 3.8 Hz, 1H, 16-CHb),3.71-3.81 (m, 1H, 12-CH), 3.95 (s, 3H, C-19), 6.60 (d, 3JH,H = 3.5 Hz, 1H, 3-CH), 7.33 (d,3JH,H = 3.5 Hz, 1H, 2-CH), 8.39 (d, 4JH,H = 2.1 Hz, 1H, 4-CH), 8.80 (d, 4JH,H = 2.1 Hz, 1H,6-CH) ppm.13C-NMR (75 MHz, CDCl3): delta = 24.1 (t, C-14), 28.9 (t, C-13), 31.7 (q, C-19), 49.5 (t, C-15),59.1 (q, C-18), 59.3 (d, C-12), 75.3 (t, C-16), 101.2 (d, C-3), 119.7 (s, C-9), 125.7 (s, C-5),129.0 (d, C-2), 131.7 (d, C-4), 142.0 (d, C-6), 149.0 (s, C-8) ppm.ESI(+)-MS: calcd. for C14H19N3O3S + H+, 310.1220; found 310.1220.

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 5734 - 5739

70
[ 63126-47-6 ]
[ 183208-22-2 ]
(S)-5-((2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine-2,3-dione [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 5734 - 5739

71
[ 1440956-68-2 ]
[ 63126-47-6 ]
(S)-5-((2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)-1-propyl-1H-pyrrolo[2,3-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%		To a solution of tert-butyl <strong>[63126-47-6](S)-2-(methoxymethyl)pyrrolidine</strong>-1-carboxylate (585 mg, 2.72 mmol) in DCM (10 mL) was added trifluoroacetic acid (1.55 g, 13.59 mmol) within 5 min at 0°C. The mixture was warmed up to room temperature within 2 h and carefully poured into a 10percent NaOH solution (60 mL). After extraction with DCM (2 × 50 mL) the combined organic phases were dried over MgSO4, and evaporated. The residue was dissolved in DCM (5 mL) and N,N-diisopropylethylamine (459 mg, 3.55 mmol) was added at room temperature. This solution containing the deprotected pyrrolidine was then stirred until it was needed.A two-neck flask was charged with 5-Bromo-1-propyl-1H-pyrrolo[2,3-b]pyridine (4) (500 mg, 2.09 mmol) and dry THF (30 mL) under argon. The solution was cooled to -80 °C in an ethanol/nitrogen cooling bath and t-BuLi (1.4 M in pentane, 1.49 mL, 2.09 mmol) was added dropwise. The reaction mixture was warmed up to -75 °C within 10 min and transferred to a solution of DABCO-bis(sulfur dioxide) (502 mg, 2.09 mmol) in dry THF (15 mL) at -75 °C. The cooling bath was removed after 30 min and the reaction mixture warmed up to room temperature. The THF solvent was removed under reduced pressure and dry DCM (20 mL) was added. N-Chlorosuccinimide (335 mg, 2.51 mmol) was slowly added as a solution in dry DCM (5 mL) followed by dropwise addition of the deprotected pyrrolidine. After the addition of water (35 mL) the mixture was extracted with DCM (3 × 30 mL). The combined organic phases were dried over MgSO4, and evaporated. Column chromatographic purification (SiO2, CH/EtOAc, 6:1) yielded a colorless oil [264 mg, 37percent yield].S 81H-NMR (300 MHz, CDCl3): delta = 0.94 (t, 3JH,H = 7.4 Hz, 3H, 21-CH3), 1.46-1.63 (m, 2H,13-CHa, 14-CHa), 1.78-1.88 (m, 2H, 13-CHb, 14-CHb), 1.85-1.97 (m, 2H, 20 CH2), 3.06-3.19(m, 1H, 15-CHa), 3.34-3.41 (m, 1H, 16-CHa), 3.37 (s, 3H, 18-CH3), 3.42-3.52 (m, 1H,15-CHb), 3.68 (dd, 2JH,H = 9.2 Hz, 3JH,H = 3.8 Hz, 1H, 16-CHb), 3.72-3.83 (m, 1H, 12-CH),4.23-4.34 (m, 2H, 19-CH2), 6.58 (d, 3JH,H = 3.5 Hz, 1H, 3-CH), 7.36 (d, 3JH,H = 3.5 Hz, 1H,2-CH), 8.37 (d, 4JH,H = 2.1 Hz, 1H, 4-CH), 8.76 (d, 4JH,H = 2.1 Hz, 1H, 6-CH) ppm.13C-NMR (75 MHz, CDCl3): delta = 11.5 (q, C-21), 23.7 (t, C-20), 24.1 (t, C-14), 28.8 (t, C-13),46.7 (t, C-19), 49.5 (t, C-15), 59.0 (q, C-18), 59.2 (d, C-12), 75.3 (t, C-16), 101.1 (d, C-3),119.7 (s, C-9), 125.7 (s, C-5), 128.9 (d, C-2), 130.7 (d, C-4), 141.8 (d, C-6), 148.7 (s,C-8) ppm.ESI(+)-MS: calcd. for C16H23N3O3SH + H+, 338.1533; found 338.1533.

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 5734 - 5739

72
[ 858116-66-2 ]
[ 63126-47-6 ]
(S)-5-((2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)-1-(triisopropylsilyl)-1H-pyrrolo-[2,3-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%		To a solution of tert-butyl <strong>[63126-47-6](S)-2-(methoxymethyl)pyrrolidine</strong>-1-carboxylate (861 mg,4.0 mmol) in DCM (20 mL) was added trifluoroacetic acid (1.54 ml, 20.0 mmol) within 5 minat 0°C. The mixture was warmed up to room temperature within 2 h and carefully poured intoS 12a 10percent NaOH solution (60 mL). After extraction with DCM (2 × 50 mL) the combinedorganic phases were dried over MgSO4, and evaporated. The residue was dissolved in DCM(16 mL) and N,N-diisopropylethylamine (517 mg, 4.0 mmol) was added at room temperature.This solution containing the deprotected pyrrolidine was then stirred until it was needed.A Schlenk tube was charged with 5-Bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine(10) (1.41 g, 4.0 mmol) and dry THF (40 mL) under argon. The solution was cooled to -80 °Cin an ethanol/nitrogen cooling bath and t-BuLi (1.20 M in pentane, 3.33 mL, 4.0 mmol) wasadded dropwise. After 10 min the reaction mixture was warmed up to -75 °C and DABCObis(sulfur dioxide) (961 mg, 4.0 mmol) was added at once. The cooling bath was removedafter 30 min and the reaction mixture warmed up to room temperature. The THF solvent wasremoved under reduced pressure and dry DCM (60 mL) was added. NCS (641 mg,4.80 mmol) was slowly added as a solution in dry DCM (16 mL) followed by dropwiseaddition of the deprotected pyrrolidine. After the addition of water (160 mL) the mixture wasextracted with DCM (2 × 80 mL). The combined organic phases were dried over MgSO4, andevaporated. Column chromatographic purification (SiO2, CH/EtOAc, 9:1) yielded a colorless,crystalline solid [1.15 g, 64percent yield].MP: 44 ? 45 °C (CH/EtOAc).1H-NMR (400 MHz, CDCl3): delta = 1.13 (d, 3JH,H = 7.6 Hz, 18H, 21-CH3), 1.87 (sep, 3JH,H = 7.6Hz, 3H, 20-CH), 1.53-1.62 (m, 2H, 13-CHa, 14-CHa), 1.79-1.91 (m, 5H, 13-CHb, 14-CHb,20-CH), 3.13-3.22 (m, 1H, 15-CHa), 3.34-3.40 (m, 1H, 16-CHa), 3.37 (s, 3H, 18-CH3),S 133.44-3.51 (m, 1H, 15-CHb), 3.67 (dd, 2JH,H = 9.3 Hz, 3JH,H = 3.8 Hz, 1H, 16-CHb), 3.76-3.84(m, 1H, 12-CH), 6.67 (d, 3JH,H = 3.5 Hz, 1H, 3-CH), 7.43 (d, 3JH,H = 3.5 Hz, 1H, 2-CH), 8.34(d, 4JH,H = 2.2 Hz, 1H, 4-CH), 8.72 (d, 4JH,H = 2.2 Hz, 1H, 6-CH) ppm.13C-NMR (101 MHz, CDCl3): delta = 12.3 (d, C-20), 18.2 (q, C-21), 24.1 (t, C-14), 28.9(t, C-13), 49.5 (t, C-15), 59.0 (q, C-18), 59.3 (d, C-12), 75.3 (t, C-16), 104.3 (d, C-3), 121.6(s, C-9), 126.1 (s, C-5), 128.0 (d, C-2), 133.8 (d, C-4), 141.3 (d, C-6), 155.3 (s, C-8) ppm.ESI(+)-MS: calcd. for C22H37N3O3SSi + Na+, 474.2217; found 474.2205.

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 5734 - 5739

73
C₂₈H₂₉ClN₂O₄ [ No CAS ]
[ 63126-47-6 ]
[ 1422160-60-8 ]

Yield	Reaction Conditions	Operation in experiment
98%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 140℃; for 24h;Sealed tube;	Procedure: A solution of chloride Q1 1 (100 mg,0.203 mmol), <strong>[63126-47-6](S)-2-(methoxymethyl)pyrrolidine</strong> (47 mg,0.408 mmol), and N,N-diisopropylethylamine (130 mg, 1.01mmol) in N-methyl-2-pyrrolidone (0.9 10 mE) was heated at140° C. in a sealed tube with stirring for 24 hours. Thereaction contents were directly purified by column chromatography using 96:3:1 chloroform/acetone/triethylamine toprovide 113 mg (98percent yield) of the desired amine Q3 as ayellow oil.10279] ?H NMR (d5-DMSO, 500 MHz, 80° C.): oe 7.56 (d,J9.1 Hz, 1H), 7.37 (d, J=2.9 Hz, 1H), 7.36-7.29 (m, 5H),7.24 (dd, J=9.1, 2.9 Hz, 1H), 7.17 (s, 1H), 5.80 (ddd, J=17.3,10.5, 8.6 Hz, 1H), 5.15 (ddd, J=17.3, 2.1, 1.1 Hz, 1H), 5.13-5.02 (m, 3H), 4.40 (ddddd, J=9.2, 3.2, 3.2, 2.4, 2.4 Hz, 1H),4.02-3.94 (m, 1H), 3.91 (ddd, J=13.0, 3.6, 1.7 Hz, 1H), 3.80(s, 3H), 3.68-3.57 (m, 2H), 3.51 (ddd, J=10.2, 8.8, 6.6 Hz,1H), 3.42 (dd, J=9.6, 6.9 Hz, 1H), 3.32 (s, 3H), 3.14-3.02 (m,2H), 2.98-2.89 (m, 1H), 2.41 (dddd, J=7.7, 3.7, 3.7, 3.7 Hz,1H), 2.12-1.93 (m, 5H), 1.73 (dddd, J=11.1, 7.4,3.8,3.8Hz,1H), 1.67-1.57(m,2H), 1.57-1.50(m, 1H), 1.38 (dddd, J=13.5, 11.3, 11.3, 4.4 Hz, 1H). ?3C NMR (CDC13, 125 MHz): oe204.7, 155.7, 155.6, 154.1, 145.3, 143.6, 137.1, 135.5, 128.6,128.1, 128.0, 121.8, 118.8, 117.9, 117.6, 109.7, 104.0, 74.0,67.2, 59.4, 57.5, 55.7, 49.3, 48.0,44.1,42.8,39.6,38.5,28.9,28.0, 27.6, 23.9. HRMS(ESI): mlz calc. for C34H42N305[M+H]: 572.3124. found: 572.3117.

Reference： [1]Patent: US2015/274638,2015,A1 .Location in patent: Paragraph 0278; 0279

74
1-(5-(2-fluorophenyl)pyrimidin-2-yl)-3-(methylsulfinyl)-1H-indole-6-carboxylic acid [ No CAS ]
[ 63126-47-6 ]
(1-(5-(2-fluorophenyl)pyrimidin-2-yl)-3-(methylsulfinyl)-1H-indol-6-yl)((S)-2-(methoxymethyl)pyrrolidin-1-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 0.5h;	[0443] HATU (144 mg, 0.379 mmol, 1.5 eq) and diisopropylethylamine(0.13 mL, 0.759 mmol, 3.0 eq) were added atroom temperature to a stirred solution of compound 51 e) (1 00mg, 0.253 mmol, 1.0 eq) and <strong>[63126-47-6](S)-2-(methoxymethyl)pyrrolidine</strong>(0.02mL, 0.303 mmol, 1.2 eq) in dry DMF (lOmL). Thereaction mixture was stirred for 30 min and then diluted withice water (20 mL ). The precipitating solid was filtered off anddried. White solid. Yield: 110 mg (88percent of theory). Meltingrange: 143-146° C. HPLC (method 1): R,=10.03 min[0444] 1H NMR (400 MHz, DMSO-d6, o ppm): 9.36 (s,2H), 9.24 (s, lH), 9.21 (s, lH), 8.07 (d, 1=8.3 Hz, lH),7.80-7.70 (m, lH), 7.58-7.39 (m, 4H), 4.35-4.30 (m, lH),3.65-3.29 (m, 7H) 3.09 (s, 4H), 2.05-2.00 (m, lH), 1.88-1.84(m, lH), 1.72-1.1.66 (m, lH).

Reference： [1]Patent: US2016/24053,2016,A1 .Location in patent: Paragraph 0443-0444

75
(2S,3R)-methyl 3-cyclopropyl-3-((S)-2-(4-(5-fluoro-2-methoxypyridin-4-yl)-3-formylphenyl)chroman-7-yl)-2-methylpropanoate [ No CAS ]
[ 63126-47-6 ]
(2S,3R)-methyl 3-cyclopropyl-3-((S)-2-(4-(5-fluoro-2-methoxypyridin-4-yl)-3-(((S)-2-(methoxymethyl)pyrrolidin-1-yl)methyl)phenyl)chroman-7-yl)-2-methylpropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 7: (2S, 3R)-methyl 3 -cyclopropyl-3 -((S)-2-(4-(5 -fluoro-2-methoxypyridin-4-yl)-3 -(((S)-2-(methoxymethyl)pyrrolidin- 1 -yl)methyl)phenyl)chroman-7-yl)-2-methylpropanoate To a solutionof (2S, 3R)-methyl 3 -cyclopropyl-3 -((S)-2-(4-(5 -fluoro-2-methoxypyridin-4-yl)-3 - formylphenyl)chroman-7-yl)-2-methylpropanoate (150 mg, 0.298 mmol) and (S)-2- (methoxymethyl)pyrrolidine (68.6 mg, 0.596 mmol) in MeOH (3.0 mL) was added titanium (iv) isopropoxide (169 mg, 0.596 mmol). The reaction mixture was stirred at 80 °C for lh, then cooledto 0 °C. Sodium borohydride (135 mg, 3.57 mmol) was added to the mixture in one portion, and the reaction was stirred at 25 °C for 30 mm. The reaction was then quenched by the slow addition of iN HC1 (2 mL). The resulting mixture was extrated with EtOAc (3 x 10 mL). The combined organic layers were washed with sodium bicarbonate (5 percent, 2x 5 mL), dried (Na2504), filtered and the filtrate was evaporated under reduced pressure to give the title compound, which was used to nextstep without further purification.

Reference： [1]Patent: WO2016/22742,2016,A1 .Location in patent: Page/Page column 157

76
(1R,3S,4S,11S)-16-(benzyloxy)-17-bromo-11-[(tertbutyldimethylsilyl)oxy]-4-(dimethylamino)-19-fluoro-8,12-dihydroxy-10,14-dioxo-6-oxa-7-azapentacyclo-[11.8.0.0^3,11.0^5,9.0^15,20]henicosa-5⁽⁹⁾,7,12,15,17,19-hexaene-18-carbaldehyde [ No CAS ]
[ 63126-47-6 ]
C₄₁H₅₁BrFN₃O₈Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Compound S1-11 (crude, 0.057 mmol,1.0 equiv) was dissolved in 1,2-dichloroethane (2 mL). HOAc (20 muL) and (S)-(+)-2-(methyoxymethyl)pyrrolidine (49 mg, 0.34 mmol, 6.0 equiv) were added. The mixture was stirred at rt for 1 h. Na(OAc)3BH (73 mg, 0.34 mmol, 6.0 equiv) was added and the resulting mixture was stirred for another hour. The mixture was washed with H2O (10 mL) and concentrated to give crude S1-12-3, which was used for the next step without further purification: MS (ESI) m/z 842.3 (M+H).

Reference： [1]Patent: US9315451,2016,B2 .Location in patent: Page/Page column 45; 46; 53

77
[ 63126-47-6 ]
[ 148550-51-0 ]
ethyl 2-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]pyrimidine-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With potassium carbonate; In acetonitrile; at 20℃; for 18h;	Example 18A Ethyl 2-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]pyrimidine-5-carboxylate (0370) (0371) 450 mg (3.91 mmol) of (R)-(+)-2-(methoxymethyl)pyrrolidine were added to a suspension of 818 mg (3.52 mmol) of ethyl 2-(methylsulphonyl)pyrimidine-5-carboxylate and 1.47 g (10.7 mmol) of potassium carbonate in 9.0 ml of acetonitrile. The mixture was stirred at RT for 18 h. The reaction mixture was then diluted with ethyl acetate and filtered off, the residue was washed with ethyl acetate/dichloromethane and the filtrate was concentrated. The crude product was purified on silica gel (elution: cyclohexane/ ethyl acetate 8:1-5:1), which gave 558 mg (59percent of theory) of the title compound. (0372) LC-MS [Method 8]: Rt=2.75 min; MS (ESIpos): m/z=266 (M+H)+ (0373) 1H-NMR (400 MHz, DMSO-d6): delta [ppm]=1.29 (t, 3H), 1.86-2.09 (m, 4H), 3.26 (s, 3H), 3.36 (dd, 1H), 3.46-3.63 (m, 3H), 4.22-4.35 (m, 3H), 8.79 (s, 2H).

Reference： [1]Patent: US2016/304492,2016,A1 .Location in patent: Paragraph 0370; 0371; 0372; 0373

78
(1S,5S,6S)-3-amino-5-(5-((Z)-2-(5-chloropyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylic acid [ No CAS ]
[ 63126-47-6 ]
((1S,5S,6S)-3-amino-5-(5-((Z)-2-(5-chloropyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)((S)-2-(methoxymethyl)pyrrolidin-1-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62 mg	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; at 20 - 50℃; for 0.833333h;	Preparation of ((l^S^^-S-amino-S-iS-i^-l-iS-chloropyridin-l-y^-l-fluorovinyl)-- fluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-l-yl)(2-methylazetidin-l- yl)methanone (Example 116). The acid 15 (150 mg, 0.268 mmol) was used without further purification and was suspended in DCM (3 mL) followed by the addition of 2-methylazetidine hydrochloride (100 mg, 0.930 mmol), 1-propanephosphonic acid cyclic anhydride (600 mu, 0.943 mmol), and TEA (180 mu, 1.30 mmol) slowly. After 30 minutes, more 1-propanephosphonic acid cyclic anhydride (200 mu, 0.310 mmol) and TEA (90 mu^, 0.65 mmol) were added at room temperature. The mixture was heated to 50 °C for 20 minutes. The mixture was quenched with MeOH (1 mL) and was purified by reverse-phase preparative HPLC (Gilson GX281) using a Phenomenex Gemini column, 5 micron, C 18, 1 10 A , 150 x 30 mm, 0.1percent TFA in CH3CN/H2O, gradient 30percent to 85percent over 12 minutes. The product fractions were concentrated to half the volume and saturated with Na2CC>3. The slurry was filtered followed by rinsing with water. The residue was dried under a stream of air to give the (( \S,5S,6S)-3- amino-5-(5-((Z)-2-(5-chloropyridin-2-yl)-2-fluorovinyl)-2-fluorophenyl)-5-methyl-2-thia-4- azabicyclo[4.1.0]hept-3-en-l-yl)(2-methylazetidin- l-yl)methanone (Example 116) (59 mg, 45percent yield) as a white powder. MS m/z = 489 [M+H]+. lH NMR (400 MHz, CDC13) delta 8.54 (s, IH), 7.72 (dd, J=2.35, 8.41 Hz, 2H), 7.64 (dd, J=2.54, 5.48 Hz, IH), 7.55 (d, J=7.83 Hz, IH), 7.03-7.12 (m, IH), 6.98 (d, J=39.52 Hz, IH), 4.54 (br. s., IH), 4.13-4.45 (m, 2H), 2.08- 2.53 (m, 2H), 1.86-1.94 (m, IH), 1.85 (s, 3H), 1.75-1.40 (m, IH), 1.46 (2d, J=6.65 Hz, 3H), 0.72-0.90 (m, IH). 19F NMR (376 MHz, CDC13) delta - 109.53, -109.82 (2s, IF), -124.14, 124.20 (2s, IF).

Reference： [1]Patent: WO2017/24180,2017,A1 .Location in patent: Page/Page column 138-139

79
[ 63126-47-6 ]
[ 5027-65-6 ]
C₁₄H₁₈N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 0 - 20℃; for 16.0h;Inert atmosphere;	A 50 mL round bottom flask was charged with 5-(methoxycarbonyl)pyridine-3- carboxylic acid (Enamine, 0.300 g, 1.656mmo1, 1 eq), (R)-(-)-2- (Methoxymethyl)pyrrolidine (Combi-Blocks, 0.200 g, 1.738 mmol, 1.05 eq) and a stir bar.The flask was evacuated and back-filled with Ar (x3). Anhydrous dichloromethane (20 mL) was added, and the resulting stirred suspension was cooled to 0 C. 2-(7-Aza-1H- benzotriazole- l-yl)-l,l ,3 , 3 -tetramethyluronium hexafluorophosphate (HATU) (0.818 g, 2.15 mmol, 1.3 eq) was added followed by addition of N,N-Diisopropylethylamine (0.642g,4.97 mmol, 3.0 eq) and stirred for 16h at ambient temperature. The reaction mixture was diluted with ethylacetate (100 mL) and washed with water (x2), brine (xl), and dried over Na2SO4. The solids were filtered off, and the volatiles were removed via rotary evaporation. Purification via flash chromatography on silica gel eluting with 0-50% EtOAc in hexanes yielded 0.460 g (1.65 mmol, 99% yield) of 217.

Reference： [1]Patent: WO2017/66742,2017,A1 .Location in patent: Paragraph 0245; 0246

80
[ 63126-47-6 ]
[ 100-52-7 ]
[ 1066-54-2 ]
(S)-2-(methoxymethyl)-1-(1-phenyl-3-(trimethylsilyl)prop-2-yn-1-yl)pyrrolidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With cycloaurated phosphinothioicamide gold(III) complex immobilized in a silica-supported ionic liquid; In neat (no solvent); at 60℃; for 8h;Green chemistry;	General procedure: A mixture of aldehyde (1.97 mmol), amine (1.97 mmol), acetylene (2.95 mmol), and thecorresponding supported Au catalyst (1percent wt, 60 mg, 0.002 mmol) was heated at 60 °C for 8 h,after which time the solution was cooled and the catalyst was removed by filtration. The filtrate wasevaporated under reduced pressure to afford propargylamine 5. Yields were determined by integration of the 1H-NMR spectra of the crude reaction mixtures. After separation and washing with n-pentane,the catalyst was reused intact for the next reaction without any further pre-treatment.

Reference： [1]Molecules,2018,vol. 23
[2]Organometallics,2017,vol. 36,p. 1962 - 1973

81
[ 110-52-1 ]
[ 63126-47-6 ]
C₁₀H₂₀NO⁽¹⁺⁾*Br^(1-) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In water; at 80℃;	(S) -2-methoxymethylpyrrolidine in an equimolar amount of 1,4-dibromobutane was dissolved in an equimolar amount of sodium hydroxide in water at 80 ° C.With stirring for several hours.The crude product obtained by vacuum degassing the solution after the reaction is refluxed and dissolved in isopropanol or acetone and filtered at room temperature,Diisopropyl ether was added to the filtrate to obtain a pale brown gel-like solid. Since it is easily deliquesced by the moisture in the atmosphere, recrystallization or alumina column purification was performed in a low humidity environment as an ionic liquid material. By mixing the equimolar amount ofLiTFSAwith the obtained bromide material in water,Water-insoluble (S) -MOMAS 44 [TFSA] precipitated.Although it is possible to separate by a separatory funnel as it is, in order to obtain an ionic liquid with a higher purity, it is extracted with dichloromethane, repeatedly washed several times with milli-Q water and dichloromethane extraction, and finally High purity ionic liquid was obtained by distilling off dichloromethane with a rotary evaporator.

Reference： [1]Patent: JP5780484,2015,B2 .Location in patent: Paragraph 0024

82
[ 813423-28-8 ]
[ 63126-47-6 ]
[ 813424-51-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h;	General procedure: Compound 11 (13.6g, 42.6mmol) was dissolved in DMF (50mL), and a mixture of piperidine (5.3g, 63mmol), potassium carbonate (9.2g, 67mmol), and DMF (50mL) was added, and the solution was stirred for 3h at room temperature. Water was added to the reaction solution and the mixture was extracted with EtOAc. The resulting organic layer was dried over MgSO4, and the solvent was removed by evaporation. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH/28percent aqueous NH3) to yield 12a as a pale yellow oil (12.6g, 91percent yield).

Reference： [1]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 3716 - 3726

83
C₁₂H₁₃F₃O [ No CAS ]
[ 63126-47-6 ]
C₁₈H₂₆F₃NO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%		j0347J To a solution of compound S7-9 (5.46 g, 23.7 mmol, 1.0 eq) in MeOH (100 mL) was added compound S7-14 (3.0 g, 26 mmol, 1.1 eq) and 2 drops of AcOH. The reaction mixture was stirred at rt for 2 h. NaBH4 (3.58 g, 94.63 mmol, 4.0 eq) was added and then the reaction mixture was stirred at rt for 2 h. The reaction was quenched with H20 (30 mL), filtered, extracted with EA (30 mL x 3) and concentrated to get a residue, which was purified by column chromatography (PE:EA=1 :1) to give Example 317 (2.1 g, 27percent).TLC: DCM:EA:MeOH=1:1:0.1 Rf(compound S7-9) = 0.9Rf(Example 317) = 0.3

Reference： [1]Patent: WO2018/213281,2018,A1 .Location in patent: Paragraph 0347

84
[ 73455-13-7 ]
[ 63126-47-6 ]
6-((5-chloro-2-((S)-2-(methoxymethyl)pyrrolidine-1-carbonyl)pyridin-4-yl)amino)-4-(((R)-1-cyclopropylethyl)amino)-1-methylquinolin-2(1H)-one [ No CAS ]

Reference： [1]Patent: WO2018/215798,2018,A1

85
[ 73455-13-7 ]
[ 63126-47-6 ]
(S)-(4,5-dichloropyridin-2-yl)(2-(methoxymethyl)pyrrolidin-1-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; at 25℃; for 16h;	A mixture of HATU (155 mg, 0.41 mmol), 4,5-dichloropicolinic acid (39 mg, 0.20 mmol) and <strong>[63126-47-6](S)-2-(methoxymethyl)pyrrolidine</strong> (117 mg, 1.02 mmol) was stirred at 25C for 16h. The crude reaction mixture was directly purified by preparative HPLC (15 min gradient of 60:40 to 0:100 hhOMeOH (both modified with 0.1 % formic acid); flow rate 20 mLmin 1) affording the title compound (39 g, 66%) as a colourless oil that existed as a mixture of rotamers. Rotamer . 1 H NMR (500 MHz, Methanol-d4) d 8.71 (s, 1 H), 7.96 (s, 1 H), 4.44- 4.38 (m, 1 H), 3.82-3.75 (m, 1 H), 3.68-3.64 (m, 2 H), 3.40 (s, 3 H), 2.14-1.96 (m, 5 H). Rotamer B : 1 H NMR (500 MHz, Methanol-d4) d 8.69 (s, 1 H), 7.95 (s, 1 H), 4.85-4.78 (m, 1 H), 3.75-3.69 (m, 1 H), 3.63-3.58 (m, 2 H), 3.17 (s, 3 H), 2.14-1.96 (m, 4 H), 1.94-1.80 (m, 1 H). LCMS (Method T2) Rt = 1.39 min; m/z 289.1 [M+H]+.
39 mg	With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; at 25℃; for 16h;	A mixture of HATU (0.15 g, 0.41 mmol), 4,5-dichloropyridine-2-carboxylic acid (39 mg, 0.20 mmol) and (2S)-2-(methoxymethyl)pyrrolidine (1.32 mL, 1.02 mmol) was stirred at 25 00 for 16h. HPLC purification gave (4,5-dichloro-2-pyridyl)-[(2S)-2- (methoxymethyl)pyrrolidin-1-yl]methanone (39 mg) as a colourless oil. LCMS (Method T2) Rt= 1.39 mins, mlz 289.1 [M+H]. NMR showed two rotamers: RotamerA: 1H NMR (500 MHz, Methanol-d4) delta 8.71 (5, 1H), 7.96 (5, 1H), 4.44-4.38 (m, 1H), 3.82-3.75 (m, 1H), 3.68-3.64(m, 2H), 3.40 (5, 3H), 2.14-1.96 (m, 5H).

Reference： [1]Patent: WO2019/197842,2019,A1 .Location in patent: Paragraph 00360
[2]Patent: WO2018/215798,2018,A1 .Location in patent: Paragraph 00364

86
6-chloro-5-cyano-4-((1-methyl-2-oxo-4-((2-(pyrimidin-2-yl)propan-2-yl)amino)-1,2-dihydroquinolin-6-yl)amino)picolinic acid [ No CAS ]
[ 63126-47-6 ]
(S)-2-chloro-6-(2-(methoxymethyl)pyrrolidine-1-carbonyl)-4-((1-methyl-2-oxo-4-((2-(pyrimidin-2-yl)propan-2-yl)amino)-1,2-dihydroquinolin-6-yl)amino)nicotinonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1.5h;Microwave irradiation; Inert atmosphere;	General procedure: T3P (50 wtpercent in EtOAc, 44 mg, 0.069 mmol), DIPEA (26 uL, 0.15 mmol) and azetidine (4 uL, 0.055 mmol) were added sequentially to a solution of 6-chloro-5-cyano-4-((1-methyl-2- oxo-4-((2-(pyrimidin-2-yl)propan-2-yl)amino)-1,2-dihydroquinolin-6-yl)amino)picolinic acid (Example 9f, 24 mg, 0.050 mmol) in DMF (0.26 mL). The reaction mixture was stirred at rt for 16 h. Water (10 mL) was added and the aqueous mixture was extracted with EtOAc (3 x 10 mL). The organic extracts were combined, dried (Na2SO4) and concentrated in vacuo. Purification by HPLC (ACE 5 C18-PFP 250 x 21.2 mm column; 15 mm gradient of 60:40 to 0:100 H20:MeOH (both modified with 0.1 percent formic acid); flow rate 20 mLmin1 Agilent 6120 MS-Prep LC) afforded the title compound (6 mg, 21percent) as a yellow solid. 1H NMR (600 MHz, Methanol-d4) O 8.79 (d, J= 4.9 Hz, 2 H), 8.15 (d, J= 1.9 Hz, 1 H), 7.62 (d, J= 8.9 Hz, 1 H), 7.59 (dd, J = 8.9, 1.9 Hz, 1 H), 7.36 (t, J = 4.9 Hz, 1 H), 7.26 (5, 1 H), 5.07 (5, 1 H), 4.69 (t, J = 7.8 Hz, 2 H), 4.14 (t, J= 7.8 Hz, 2 H), 3.60 (s, 3 H), 2.36 (app. quin., J= 7.8 Hz, 2 H), 1.85 (s, 6 H); LCMS (Method T4) Rt = 2.80 mins, mlz 529.1819 [M+H] expected 529.1862 for C27H26ClN8O2.

Reference： [1]Patent: WO2018/215798,2018,A1 .Location in patent: Paragraph 00228

87
6-amino-4-fluoronicotinonitrile [ No CAS ]
[ 63126-47-6 ]
C₁₂H₁₆N₄O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃;	General procedure: A mixture of 6-amino-4-fluoronicotinonitrile 7 (4.11 g, 30 mmol), 2-methoxyethanamine (4.5 g, 60 mmol), and DIPEA (1.16 g, 90 mmol) in DMF (120 mL) was stirred at 60°C until the reaction was completed by TLC. After quenched with water, the reaction solution was extracted with CH2Cl2 (3 ×100 mL), washed with sequentially with satd NaHCO3 (aq) and brine and then dried over anhydrous Na2SO4. Filtration, evaporation, and chromatography on silica gel afforded the product 8 (3.84 g, 67percent).

Reference： [1]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 1932 - 1941

88
2-[3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-1-yl]-3-(trifluoromethyl)benzoic acid [ No CAS ]
[ 63126-47-6 ]
5-(4-chlorophenyl)-2-({1-[2-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}-6-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%		A solution of 2-[3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5- dihydro- 1 H- 1 ,2,4-triazol- 1 -yl } methyl)- 1H- 1 ,2,4-triazol- 1 -yl] -3-(trifluoromethyl)benzoic acid (Example 54A, 46.2 mg, 80.1 muiotaetaomicron) in N,N-dimethylformamide (410 mu) was treated with HATU (45.7 mg, 120 muiotaetaomicron) and stirred 1 h at room temperature. (2S)-2-(methoxymethyl)pyrrolidine (13.8 mg, 120 muiotaetaomicron) was added followed by N,N-diisopropylethylamine (42 mu, 240 muiotaetaomicron). The resulting mixture was stirred overnight at room temperature. Purification by preparative HPLC (Method 4) afforded 44.5 mg (82 % of th.) of the title compound. LC-MS (Method 2): Rt = 1.96 min; MS (ESIpos): m/z = 674.2 [M+H]+ -NMR (400 MHz, DMSO-d6) delta [ppm]: 8.81-8.65 (m, 1H), 8.14-7.54 (m, 7H), 6.91 (d, 1H), 5.22-4.90 (m, 2H), 4.38- 4.19 (br m, 1H), 4.08-3.76 (m, 3H), 3.24-2.82 (m, 7H), 1.89-1.39 (m, 4H).

Reference： [1]Patent: WO2019/81307,2019,A1 .Location in patent: Page/Page column 310-311

89
2-[3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-1-yl]pyridine-3-carboxylic acid [ No CAS ]
[ 63126-47-6 ]
5-(4-chlorophenyl)-2-[1-(3-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%		A solution of 2-[3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5- dihydro- 1 H- 1 ,2,4-triazol- 1 -yl } methyl)- IH- 1 ,2,4-triazol- 1 -yl]pyridine-3-carboxylic acid (Example 33A, 80.0 mg, 157 muiotaetaomicron) in N,N-dimethylformamide (1.0 ml) was treated with HATU (89.5 mg, 235 muiotaetaomicron) and stirred 30 min at room temperature. (2S)-2-(methoxymethyl)pyrrolidine (27.1 mg, 235 muiotaetaomicron) was then added followed by and N,N-diisopropylethylamine (82 mu, 470 muiotaetaomicron). The resulting mixture was stirred 5 h at room temperature. Purification by preparative HPLC (Method 4) afforded 69.9 mg (73 % of th.) of the title compound. LC-MS (Method 2): Rt = 1.78 min; MS (ESIpos): m/z = 607.2 [M+H]+ -NMR (400 MHz, DMSO-d6) delta [ppm] : 9.25 (s, IH), 8.60 (dd, IH), 8.08-7.94 (m, IH), 7.83-7.53 (m, 5H), 6.94 (d, IH), 5.20-4.96 (m, 2H), 4.40-4.24 (m, IH), 4.20-3.44 (m, 4H), 3.28-3.21 (m, 3H, overlap wit HDO peak), 3.08-2.88 (m, 3H), 2.03-1.46 (m, 4H).

Reference： [1]Patent: WO2019/81307,2019,A1 .Location in patent: Page/Page column 363-364

90
[ 392-56-3 ]
[ 63126-47-6 ]
C₁₂H₁₂F₅NO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%		In a 50 mL two-necked reaction vessel, add 0.21 mL (1.69 mmol) of (S) -2- (methoxymethyl) pyrrolidine and 5 mL of THF under a nitrogen atmosphere.The reaction solution was cooled to -70 C.After cooling, add 1.16 mL of n-butyllithium / n-hexane solution (n-BuLi content 1.86 mmol) dropwise,The mixture was stirred for 20 minutes.Prepare a mixed solution of hexafluorobenzene 0.78 mL (6.76 mmol) and THF 7 mL in a separate reaction vessel,This mixed solution was added dropwise to the reaction solution cooled to -70 C. and stirred for 4 hours.After stirring, add water and extract with ethyl acetate.The organic layer was washed with water and saturated brine.Then, dry with sodium sulfate,By concentrating with an evaporator (S) -1264 mg (0.939 mmol,(S) -2- (methoxymethyl) pyrrolidine yield 56 mol%) was obtained.

Reference： [1]Patent: JP2019/142780,2019,A .Location in patent: Paragraph 0062; 0063; 0064; 0065; 0066

91
[ 50-00-0 ]
ethyl 1-[5-({4-[4-methoxy-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}carbamoyl)pyrazin-2-yl]piperidine-4-carboxylate [ No CAS ]
[ 63126-47-6 ]
C₃₁H₃₇F₃N₆O₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid; In water; at 90℃; for 1h;	General procedure: Ethyl 1-[5-({4-[4-methoxy-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}carbamoyl)pyrazin-2-yl]piperidine-4-carboxylate (41, 200 mg),acetic acid (4.0 mL), a 36% aqueous formaldehyde solution (145 muL),and 3,3-dimethylpiperidine (215 mg) were mixed and the mixture wasstirred at 90 C for 1 h. The reaction mixture was cooled to roomtemperature and concentrated under reduced pressure, and the residuewas diluted with ethyl acetate. The mixture was washed with an aqueoussodium hydrogen carbonate solution and a saturated aqueous sodiumchloride solution, and dried over anhydrous sodium sulfate. Theinsoluble materials were separated by filtration and the filtrate wasconcentrated under reduced pressure. The residue was purified by basicsilica gel column chromatography (hexanes-ethyl acetate).

Reference： [1]Bioorganic and medicinal chemistry,2020

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Isomers

Technical Information

• 1,4-Addition of an Amine to a Conjugated Enone • 1,4-Addition of an Amine to a Conjugated Enone • Acetal Formation • Amides Can Be Converted into Aldehydes • Amine Synthesis from Nitriles • Amine Synthesis from Nitriles • Amines Convert Acyl Chlorides into Amides • Amines Convert Esters into Amides • Azide Reduction by LiAlH4 • Azide Reduction by LiAlH4 • Basicity of Amines • Buchwald-Hartwig C-N Bond and C-O Bond Formation Reactions • Chan-Lam Coupling Reaction • Chichibabin Reaction • Diazotization Reaction • DIBAL Attack Nitriles to Give Ketones • Enamine Formation • Esters Are Reduced by LiAlH4 to Give Alcohols • Esters Hydrolyze to Carboxylic Acids and Alcohols • Ether Synthesis by Oxymercuration-Demercuration • Ethers Synthesis from Alcohols with Strong Acids • Formation of an Amide from an Amine and a Carboxylic Acid • Formation of an Amide from an Amine and a Carboxylic Acid • Grignard Reagents Transform Esters into Alcohols • Heat of Combustion • Hemiaminal Formation from Amines and Aldehydes or Ketones • Hemiaminal Formation from Amines and Aldehydes or Ketones • Hofmann Elimination • Hofmann Rearrangement • Hydride Reductions • Hydrolysis of Imines to Aldehydes and Ketones • Imine Formation from Amines and Aldehydes or Ketones • Leuckart-Wallach Reaction • Mannich Reaction • Methylation of Ammonia • Methylation of Ammonia • Nitrosation of Amines • Nomenclature of Ethers • Peptide Bond Formation with DCC • Petasis Reaction • Preparation of Amines • Preparation of Ethers • Preparation of LDA • Primary Ether Cleavage with Strong Nucleophilic Acids • Reactions of Amines • Reactions of Ethers • Reduction of an Amide to an Amine • Reduction of an Amide to an Amine • Reductive Amination • Reductive Amination • Ring Opening of Azacyclopropanes • Ring Opening of Azacyclopropanes • Ring Opening of Oxacyclobutanes • Ring Opening of Oxacyclopropane • Specialized Acylation Reagents-Vilsmeier Reagent • Strecker Synthesis • Synthesis of 2-Amino Nitriles • Synthesis of Alcohols from Tertiary Ethers • The Nucleophilic Opening of Oxacyclopropanes • Ugi Reaction

Historical Records

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Code	Phrase
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P220	Keep/Store away from clothing/combustible materials.
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P378
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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.
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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.
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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
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H226	Flammable liquid and vapour
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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
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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. 63126-47-6 ] {[proInfo.proName]}

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[ 63126-47-6 ] Synthesis Path-Downstream 1~91

Technical Information

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Ethers

Amines

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[ 63126-47-6 ]

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[ 63126-47-6 ]